TOXICOLOGICAL PROFILE FOR
CHLORFENVINPHOS

Prepared by:

Research Triangle Institute
Under Contract No. 205-93-0606

Prepared for:

US. DEPARTMENT OF HEALTH AND HUMAN SERVICES
Public Health Service
Agency for Toxic Substances and Disease Registry

September 1997

CHLORFENVINPHOS

DISCLAIMER

The use of company or product. namc(s) is for identiﬁcation only and does not imply endorsement: by the
Agency for Toxic Substances and Disease Registry.

CAT. no? .
PUBLIC HEALTH

CHLORFENVINPHOS iii

UPDATE STATEMENT , / ,
V

Toxicological proﬁles are revised and republished as necessary, but no less than once every three years.
For information regarding the update status of previously released proﬁles, contact ATSDR at:

Agency for Toxic Substances and Disease Registry (A! 1/ /0
Division of Toxicology/Toxicology Information Branch 3,, 5,. _ r”
1600 Clifton Road NE, E-29 / '1 770 6
Atlanta, Georgia 30333 I j g? 7
,,

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FOREWORD

This toxicological proﬁle is prepared in accordance with guidelines* developed by the Agency for
Toxic Substances and Disease Registry (ATSDR) and the Environmental Protection Agency (EPA). The
original guidelines were published in the Federal Register on April 17, 1987. Each proﬁle will be revised
and republished as necessary.

The ATSDR toxicological proﬁle succinctly characterizes the toxicologic and adverse health effects
information for the hazardous substance described therein. Each peer-reviewed proﬁle identiﬁes and
reviews the key literature that describes a hazardous substance's toxicologic properties. Other pertinent
literature is also presented, but is described in less detail than the key studies. The proﬁle is not intended
to be an exhaustive document; however, more comprehensive sources of specialty information are
referenced.

The focus of the proﬁles is on health and toxicologic information; therefore, each toxicological
proﬁle begins with a public health statement that describes, in nontechnical language, a substance's
relevant toxicological properties. Following the public health statement is information concerning levels of
signiﬁcant human exposure and, where known, signiﬁcant health effects. The adequacy of information to
determine a substance's health effects is described in a health effects summary. Data needs that are of
signiﬁcance to protection of public health are identiﬁed by ATSDR and EPA.

Each proﬁle includes the following:

(A) The examination, summary, and interpretation of available toxicologic information and
epidemiologic evaluations on a hazardous substance to ascertain the levels of signiﬁcant human
exposure for the substance and the associated acute, subacute, and chronic health effects;

(B) A determination of whether adequate information on the health effects of each substance is
available or in the process of development to determine levels of exposure that present a
signiﬁcant risk to human health of acute, subacute, and chronic health effects; and

(C) Where appropriate, identiﬁcation of toxicologic testing needed to identify the types or levels of
exposure that may present signiﬁcant risk of adverse health effects in humans.

The principal audiences for the toxicological proﬁles are health professionals at the Federal, State,
and local levels; interested private sector organizations and groups; and members of the public.

This proﬁle reﬂects ATSDR’s assessment of all relevant toxicologic testing and information that has
been peer-reviewed. Staff of the Centers for Disease Control and Prevention and other Federal scientists
have also reviewed the proﬁle. In addition, this proﬁle has been peer-reviewed by a nongovernmental
panel and was made available for public review. Final responsibility for the contents and views expressed
in this toxicological proﬁle resides with ATSDR.

W

David Satcher, M.D., Ph.D.
Administrator
Agency for Toxic Substances and
Disease Registry

vi

*I'l'El I

The toxicological proﬁles are developed in response to the Superfund Amendments and
Reauthorization Act (SARA) of 1986 (Public Law 99—499) which amended the Comprehensive
Environmental Response, Compensation, and Liability Act of 1980 (CERCLA or Superfund). This public
law directed ATSDR to prepare toxicological proﬁles for hazardous substances most commonly found at
facilities on the CERCLA National Priorities List and that pose the most signiﬁcant potential threat to
human health, as determined by ATSDR and the EPA. The availability of the revised priority list of 275
hazardous substances was announced in the Federal Register on April 29, 1996 (61 FR 18744). For prior
versions of the list of substances, see Federal Register notices dated April 17, 1987 (52 FR 12866);
October 20, 1988 (53 FR 41280); October 26, 1989 (54 FR 43619); October 17,1990 (55 FR 42067);
October 17, 1991 (56 FR 52166); October 28, 1992 (57 FR 48801); and February 28, 1994 (59 FR 9486).
Section 104(i)(3) of CERCLA, as amended, directs the Administrator of ATSDR to prepare a
toxicological proﬁle for each substance on the list.

CHLORFENVINPHOS vii

CONTRIBUTORS

CHEMICAL MANAGER(S)/AUTHORS(S):

Alfred S. Dorsey, Jr., D.V.M.
ATSDR, Division of Toxicology, Atlanta, GA

Steven S. Kueberuwa, M.S.
Research Triangle Institute, Research Triangle Park, NC

THE PROFILE HAS UNDERGONE THE FOLLOWING ATSDR INTERNAL REVIEWS:

1. Green Border Review. Green Border review assures consistency with ATSDR policy.

2. Health Effects Review. The Health Effects Review Committee examines the health effects
chapter of each proﬁle for consistency and accuracy in interpreting health effects and classifying
end points.

3. Minimal Risk Level Review. The Minimal Risk Level Workgroup considers issues relevant to

substance-speciﬁc minimal risk levels (MRLs), reviews the health effects database of each
proﬁle, and makes recommendations for derivation of MRLs.

 

CHLORFENVINPHOS ix

PEER REVIEW

A peer review panel was assembled for chlorfenvinphos. The panel consisted of the following members:

1. Dr. Frederick Oehme, Professor, Kansas State University, Manhattan, KS;

2. Dr. Casey Robinson, Professor of Pharmacology and Toxicology, University of Oklahoma,
Oklahoma City, OK; and

3. Dr. Syed Naqvi, Professor of Biology, Southern University Department of Biological Sciences,
Baton Rouge, LA.

These experts collectively have knowledge of chlorfenvinphos' physical and chemical properties, toxico-
kinetics, key health end points, mechanisms of action, human and animal exposure, and quantiﬁcation of
risk to humans. All reviewers were selected in conformity with the conditions for peer review speciﬁed
in Section 104(i)(13) of the Comprehensive Environmental Response, Compensation, and Liability Act,
as amended.

Scientists from the Agency for Toxic Substances and Disease Registry (ATSDR) have reviewed the peer
reviewers' comments and determined which comments will be included in the proﬁle. A listing of the
peer reviewers' comments not incorporated in the proﬁle, with a brief explanation of the rationale for
their exclusion, exists as part of the administrative record for this compound. A list of databases
reviewed and a list of unpublished documents cited are also included in the administrative record.

The citation of the peer review panel should not be understood to imply its approval of the proﬁle's ﬁnal
content. The responsibility for the content of this proﬁle lies with the ATSDR.

 

 

CHLORFENVINPHOS xi

CONTENTS
FOREWORD ....................................................................... v
CONTRIBUTORS .................................................................. vii
PEER REVIEW ..................................................................... ix
LIST OF FIGURES ................................................................. xv
LIST OF TABLES ................................................................. xvii
1. PUBLIC HEALTH STATEMENT .................................................... l
1.1 WHAT IS CHLORFENVINPHOS? .............................................. 1
1.2 WHAT HAPPENS TO CHLORFENVINPHOS WHEN IT ENTERS THE
ENVIRONMENT? ........................................................... 2
1.3 HOW MIGHT I BE EXPOSED TO CHLORFENVINPHOS? ......................... 2
1.4 HOW CAN CHLORFENVINPHOS ENTER AND LEAVE MY BODY? ................ 3
1.5 HOW CAN CHLORFENVINPHOS AFFECT MY HEALTH? ........................ 3
1.6 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN
EXPOSED TO CHLORFENVINPHOS? .......................................... 4
1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO
PROTECT HUMAN HEALTH? ................................................ 5
1.8 WHERE CAN I GET MORE INFORMATION? ................................... 6
2. HEALTH EFFECTS ............................................................... 7
2.1 INTRODUCTION ........................................................... 7
2.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE .................. 7
2.2.1 Inhalation Exposure .................................................... 9
2.2.2 Oral Exposure ....................................................... 16
2.2.3 Dermal Exposure ..................................................... 47
2.3 TOXICOKINETICS ......................................................... 49
2.3.1 Absorption .......................................................... 50
2.3.2 Distribution ......................................................... 51
2.3.3 Metabolism .......................................................... 54
2.3.4 Elimination and Excretion .............................................. 59
2.3.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models . . 60
2.4 MECHANISMS OF ACTION ................................................. 63
2.4.1 Pharmacokinetic Mechanisms ........................................... 63
2.4.2 Mechanisms of Toxicity ................................................ 66
2.4.3 Animal-to—Human Extrapolations ........................................ 68
2.5 RELEVANCE TO PUBLIC HEALTH .......................................... 69
2.6 BIOMARKERS OF EXPOSURE AND EFFECT .................................. 89
2.6.1 Biomarkers Used to Identify or Quantify Exposure to Chlorfenvinphos .......... 90
2.6.2 Biomarkers Used to Characterize Effects Caused by Chlorfenvinphos ........... 92
2.7 INTERACTIONS WITH OTHER CHEMICALS .................................. 93

2.8 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE ....................... 94

CHLORFENVINPHOS xii

2.9 METHODS FOR REDUCING TOXIC EFFECTS ................................. 96
2.9.1 Reducing Peak Absorption Following Exposure ............................. 96

2.9.2 Reducing Body Burden ................................................ 97

2.9.3 Interfering with the Mechanism of Action for Toxic Effects ................... 97

2.10 ADEQUACY OF THE DATABASE ............................................ 98
2.10.1 Existing Information on Health Effects of Chlorfenvinphos . . .................. 98

2.10.2 Identiﬁcation of Data Needs ........................................... 101

2.10.3 Ongoing Studies ..................................................... 114

3. CHEMICAL AND PHYSICAL INFORMATION ...................................... 115
3.1 CHEMICAL IDENTITY .................................................... 115
3.2 PHYSICAL AND CHEMICAL PROPERTIES ................................... 115

4. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL ............................ 119
4.1 PRODUCTION ........................................................... 119
4.2 IMPORT/EXPORT ........................................................ 119

4.3 USE ..................................................................... 120
4.4 DISPOSAL ............................................................... 123

5. POTENTIAL FOR HUMAN EXPOSURE ........................................... 125
5.1 OVERVIEW .............................................................. 125

5.2 RELEASES TO THE ENVIRONMENT ........................................ 126
5.2.1 Air ............................................................... 128

5.2.2 Water ............................................................. 128

5.2.3 Soil ............................................................... 129

5.3 ENVIRONMENTAL FATE .................................................. 129
5.3.1 Transport and Partitioning ............................................. 129

5.3.2 Transformation and Degradation ........................................ 133

5.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT ............... 141
5.4.1 Air ............................................................... 141

5.4.2 Water ............................................................. 141

5.4.3 Sediment and Soil ................................................... 142

5.4.4 Other Environmental Media ............................................ 142

5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE .................. 144

5.6 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES ...................... 145

5.7 ADEQUACY OF THE DATABASE ........................................... 146
5.7.1 Identiﬁcation of Data Needs ........................................... 146

5.7.2 Ongoing Studies ..................................................... 150

6. ANALYTICAL METHODS ....................................................... 151
6.1 BIOLOGICAL SAMPLES ................................................... 151
6.2 ENVIRONMENTAL SAMPLES .............................................. 153

6.3 ADEQUACY OF THE DATABASE ........................................... 157
6.3.1 Identiﬁcation of Data Needs ........................................... 159

6.3.2 Ongoing Studies ..................................................... 161

7. REGULATIONS AND ADVISORIES ............................................... 163

8. REFERENCES ................................................................. 165

CHLORFENVINPHOS xiii

9. GLOSSARY ................................................................... 181
APPENDICES

A. MINIMAL RISK LEVEL WORKSHEETS .......................................... A-l
B. USER'S GUIDE ................................................................ B-l

C. ACRONYMS, ABBREVIATIONS, AND SYMBOLS .................................. C-l

 

CHLORFENVINPHOS xv'

2-1

2-2

2-3

2-5

5-1

5-3

5-4

LIST OF FIGURES

Levels of Signiﬁcant Exposure to Chlorfenvinphos - Inhalation .......................... ll
Levels of Signiﬁcant Exposure to Chlorfenvinphos - Oral .............................. 28
Proposed Mammalian Metabolic Pathway for Chlorfenvinphos .......................... 46
Conceptual Representation of the Physiologically-based Pharmacokinetic (PBPK)

Model for a Hypothetical Chemical Substance ....................................... 62
Existing Information on Health Effects of Chlorfenvinphos ............................ 100
Frequency of NPL Sites With Chlorfenvinphos Contamination ......................... 127
Hydrolysis Pathways for Chlorfenvinphos in Water . . . ._ .............................. 135
Environmental Degradation Pathways for Chlorfenvinphos in Soil ...................... 137

Environmental Transformation Pathways for Chlorfenvinphos in Plants .................. 140

 

 

CHLORFENVINPHOS xvii

2-1

2-3

2—4

3-2

4-1

4—2

6-1

6-2

6-3

6-4

7-1

LIST OF TABLES
Levels of Signiﬁcant Exposure to Chlorfenvinphos - Inhalation .......................... 10
Levels of Signiﬁcant Exposure to Chlorfenvinphos - Oral .............................. 18
Genotoxicity of Chlorfenvinphos In Vivo ........................................... 87
Genotoxicity of Chlorfenvinphos In Vitro ........................................... 88
Chemical Identity of Chlorfenvinphos ............................................. 116
Physical and Chemical Properties of Chlorfenvinphos ................................ 117
Previously Registered Uses of Chlorfenvinphos ..................................... 121
Chlorfenvinphos Product Registrations and Dates of Cancellation in the United States ....... 124
Analytical Methods for Determining Chlorfenvinphos in Biological Samples .............. 152
Analytical Methods for Determining Chlorfenvinphos in Environmental Samples .......... 154

Analytical Methods for Determining Environmental Degradation Products
of Chlorfenvinphos ............................................................ 15 8

Analytical Methods for Determining Biomarkers for Chlorfenvinphos ................... 160

Regulations and Guidelines Applicable to Chlorfenvinphos ............................ 164

 

CHLORFENVINPHOS

1. PUBLIC HEALTH STATEMENT

This public health statement tells you about chlorfenvinphos and the effects of exposure.

The Environmental Protection Agency (EPA) identiﬁes the most serious hazardous waste sites in
the nation. These sites make up the National Priorities List (NPL) and are the sites targeted for
long-term federal clean-up activities. Chlorfenvinphos has been found in at least 1 of the

1,428 current or former NPL sites. However, it’s unknown how many NPL sites have been
evaluated for this substance. As more sites are evaluated, the sites with chlorfenvinphos may
increase. This is important because exposure to this substance may harm you and because these

sites may be sources of exposure.

When a substance is released from a large area, such as an industrial plant, or from a container,
such as a drum or bottle, it enters the environment. This release does not always lead to
exposure. You are exposed to a substance only when you come in contact with it by breathing,

eating, or drinking the substance or by skin contact.

If you are exposed to chlorfenvinphos, many factors determine whether you'll be harmed. These
factors include the dose (how much), the duration (how long), and how you come in contact with
it. You must also consider the other chemicals you‘re exposed to and your age, sex, diet, family

traits, lifestyle, and state of health.

1.1 WHAT IS CHLORFENVINPHOS?

Chlorfenvinphos is the common name of an organophosphorus insecticide used to control insect
pests on livestock. It was also used to control household pests such as ﬂies, ﬂeas, and mites.
This chemical is synthetic and does not occur naturally in the environment. Chlorfenvinphos was
sold under common trade names including Birlane®, Dermaton®, Sapercon®, Steladone®, and

Supona®.

CHLORFENVINPHOS 2

1. PUBLIC HEALTH STATEMENT

The pure chemical (100% chlorfenvinphos) is a colorless liquid with a mild odor. Commercial
preparations commonly used in insecticides sold in stores were usually 90% chlorfenvinphos.
Most of chlorfenvinphos was used in liquid form. The substance easily mixes with acetone,

ethanol, and propylene glycol. It is slowly broken down by water and is corrosive to metal.

1.2 WHAT HAPPENS TO CHLORFENVINPHOS WHEN IT ENTERS THE
ENVIRONMENT?

Chlorfenvinphos enters the environment from runoff after rainfall and leaching from hazardous
waste sites. After it has leached, it may be present in the soil and underground water (wells). It
may be present in surface water (rivers and ponds) aﬁer it has run off the land. From soil, it may
also be washed into surface waters by rain. It may also move from soil to the air by evaporation
or by being absorbed by plants. No information is available now to show that it can be found in

ﬁsh or other freshwater animals, or in seafood, or in plants that are eaten by people.
1.3 HOW MIGHT I BE EXPOSED TO CHLORFENVINPHOS?

Most cases of unintentional chlorfenvinphos poisoning have resulted from short exposures to very
high concentrations of this substance. Usually this occurred when people unintentionally
swallowed it. Workers involved in pesticide application, or dairy farming, cattle or sheep holding,
or poultry production, may have inhaled, swallowed, or contaminated their skin with a large
amount of the substance if they did not properly protect themselves when using it. The most
common way for people to be exposed to chlorfenvinphos is by eating imported agricultural
products contaminated with it and by using pharmaceutical products that contain lanolin. Lanolin
is a natural grease from sheep’s wool wax that is used as a base for many medications, cosmetic
skin lotions, and creams that are rubbed on the skin to keep the skin from drying.

Chlorfenvinphos used to control ﬂies in animal buildings and holding pens can contaminate
sheep’s wool. If you live in areas surrounding hazardous waste disposal sites or treatment
facilities for chlorfenvinphos, you could be exposed to it by contact with soils, runoff water,
surface water, or groundwater contaminated by spills or leaks on the site or facility. People who

work in the disposal of chlorfenvinphos or its wastes are more likely to be exposed. You are

CHLORFENVINPHOS 3

1. PUBLIC HEALTH STATEMENT

most likely to be exposed to Chlorfenvinphos if you live near chemical plants where it was
manufactured, or near dairy or poultry farms, or cattle or sheep holding areas where it was used;

or if you live near hazardous waste sites that contain it.

1.4 HOW CAN CHLORFENVINPHOS ENTER AND LEAVE MY BODY?

If you breathe air containing Chlorfenvinphos, you may absorb it into your body through your
lungs. If you eat food or drink water containing this substance, it may be absorbed from your
stomach and intestines. Chlorfenvinphos may also enter your body through your skin. Once in
the body, it is rapidly broken down and eliminated from the body, mostly when you urinate. It

does not build up in your tissues.

1.5 HOW CAN CHLORFENVINPHOS AFFECT MY HEALTH?

To protect the public from the harmful effects of toxic chemicals and to ﬁnd ways to treat people
who have been harmed, scientists use many tests. One way to see if a chemical will hurt people is
to learn how the chemical is absorbed, used, and released by the body; for some chemicals, animal
testing may be necessary. Animal testing may also be used to identify health effects such as
cancer or birth defects. Without laboratory animals, scientists would lose a basic method to get
information needed to make wise decisions to protect public health. Scientists have the
responsibility to treat research animals with care and compassion. Laws today protect the welfare

of research animals and scientists must comply with strict animal care guidelines.

Chlorfenvinphos affects the nervous system. In animals and people, high doses of the substance
produce effects on the nervous system similar to those produced by high doses of muscarine and
pure nicotine. Some mild symptoms of exposure are headache, dizziness, weakness, feelings of
anxiety, confusion, runny nose, constriction of the pupils of the eye, and inability to see clearly.
More severe symptoms may include nausea and vomiting, abdominal cramps, slow pulse,
diarrhea, pinpoint pupils, difﬁculty in breathing, and passing out (fainting). These signs and

symptoms may start to develop within 30—60 minutes and reach their maximum effect after

CHLORFENVINPHOS 4

1. PUBLIC HEALTH STATEMENT

6—8 hours. Very high exposure to chlorfenvinphos has killed people who swallowed it by
accident or who swallowed large amounts of the substance to commit suicide. We do not know if
people who swallow small quantities of chlorfenvinphos over long periods of time will have
permanent damage to their immune systems. In almost all cases, complete recovery occurred
when exposure stopped. There is no evidence that long-term exposure to small amounts of the
chlorfenvinphos causes any other harmﬁil health effects in people. The substance has not been
shown to cause birth defects or to prevent conception in people. The International Agency for
Research on Cancer, the Environmental Protection Agency, and the National Toxicology Program
have not yet studied chlorfenvinphos for cancer in people and animals. In animal studies, high

doses of chlorfenvinphos produced effects on the nervous system similar to those seen in people.

1.6 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN
EXPOSED TO CHLORFENVINPHOS?

Most of the signs and symptoms resulting from chlorfenvinphos poisoning are due to the
inhibition of an enzyme called “acetylcholinesterase” in the nervous system. This enzyme is also
found in your red blood cells and a similar enzyme (pseudocholinesterase) is found in blood
plasma. The most common test for exposure to many pesticides (including chlorfenvinphos) that
contain the element phosphorus is to determine the level of cholinesterase activity in the red blood
cells or plasma. This test requires only a small amount of blood and can be done in your doctor's
oﬂice. It takes weeks for this enzyme to completely recover to normal levels following exposure;
therefore, a valid test may be conducted a number of days following the suspected exposure. This
test indicates only exposure to a chemical substance of this type. It does not speciﬁcally show
exposure to chlorfenvinphos. Other chemicals or disease conditions may also alter the activity of
this enzyme. There is a wide range of normal cholinesterase activity among individual people in
the general population. If your normal or baseline value has not been established through a
previous test, you might have to repeat the test several times to determine if your enzyme activity

is recovering.

Speciﬁc tests are available to identify chlorfenvinphos or its break-down products in your blood,

body tissue, and urine. These tests are not usually available through your doctor's office and

CHLORFENVINPHOS

1. PUBLIC HEALTH STATEMENT

require special equipment and sample handling. If you need the speciﬁc test, your doctor can
collect the sample and send it to a special laboratory for analysis. Chlorfenvinphos is rapidly
broken down to other chemicals and removed from the body (in urine), so this test must be done
in the ﬁrst few days after exposure to make sure that you have really breathed, swallowed, or got

Chlorfenvinphos on your skin.

1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO
PROTECT HUMAN HEALTH?

The federal government develops regulations and recommendations to protect public health.
Regulations m be enforced by law. Federal agencies that develop regulations for toxic
substances include the Environmental Protection Agency (EPA), the Occupational Safety and
Health Administration (OSHA), and the Food and Drug Administration (FDA).

 

Recommendations provide valuable guidelines to protect public health but cannot be enforced by
law. Federal organizations that develop recommendations for toxic substances include the
Agency for Toxic Substances and Disease Registry (ATSDR) and the National Institute for
Occupational Safety and Health (NIOSH).

Regulations and recommendations can be expressed in not-to-exceed levels in air, water, soil, or
food that are usually based on levels that affect animals, then they are adjusted to help protect
people. Sometimes these not-to-exceed levels diﬁ‘er among federal organizations because of
different exposure times (an 8-hour workday or a 24-hour day), the use of different animal

studies, or other reasons.

Recommendations and regmlations are also periodically updated as more information becomes
available. For the most current information, check with the federal agency or organization that

provides it.

The federal government has set standards or guidelines to protect people from the possible
harmful health effects of Chlorfenvinphos. These include regulated concentration limits for

agricultural products, public right-to-know requirements about production and use of

CHLORFENVINPHOS

1. PUBLIC HEALTH STATEMENT

chlorfenvinphos, and regulated quantities requiring emergency response procedures if an

accidental release occurred.
1.8 WHERE CAN I GET MORE INFORMATION?

If you have any more questions or concerns, please contact your community or state health or
environmental quality department or:

Agency for Toxic Substances and Disease Registry

Division of Toxicology

1600 Cliﬁon Road NE, Mailstop E-29
Atlanta, GA 30333

* Information line and technical assistance

Phone: (404) 639-6000
Fax: (404) 639-6315 or 6324

ATSDR can also tell you the location of occupational and environmental health clinics. These

clinics specialize in recognizing, evaluating, and treating illnesses resulting from exposure to

hazardous substances.

* To order toxicological proﬁles. contact:

National Technical Information Service
5285 Port Royal Road

Springﬁeld, VA 22161

Phone: (800) 553-6847 or (703) 487-4650

CHLORFENVINPHOS 7

2. HEALTH EFFECTS

2.1 INTRODUCTION

The primary purpose of this chapter is to provide public health ofﬁcials, physicians, toxicologists, and other
interested individuals and groups with an overall perspective of the toxicology of chlorfenvinphos. It contains
descriptions and evaluations of toxicological studies and epidemiological investigations and provides

conclusions, where possible, on the relevance of toxicity and toxicokinetic data to public health.

A glossary and list of acronyms, abbreviations, and symbols can be found at the end of this proﬁle.

2.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE

To help public health professionals and others address the needs of persons living or working near hazardous
waste sites, the information in this section is organized ﬁrst by route of exposurcLinhalation, oral, and
dermal; and then by health effect—death, systemic, immunological, neurological, reproductive,
developmental, genotoxic, and carcinogenic effects. These data are discussed in terms of three exposure

periods—acute (14 days or less), intermediate (15—364 days), and chronic (365 days or more).

Levels of signiﬁcant exposure for each route and duration are presented in tables and illustrated in ﬁgures.
The points in the ﬁgures showing no—observed—adverse-eﬂ‘ect levels (NOAELs) or lowest-observed-adverse-
effect levels (LOAELs) reﬂect the actual doses (levels of exposure) used in the studies. LOAELS have been
classiﬁed into "less serious" or "serious" effects. "Serious" effects are those that evoke failure in a biological
system and can lead to morbidity or, mortality (e.g., acute respiratory distress or death). "Less serious" effects
are those that are not expected to cause signiﬁcant dysfunction or death, or those whose signiﬁcance to the
organism is not entirely clear. ATSDR acknowledges that a considerable amount of judgment may be required
in establishing whether an end point should be classiﬁed as a NOAEL, "less serious" LOAEL, or "serious"
LOAEL, and that in some cases, there will be insufﬁcient data to decide whether the effect is indicative of
signiﬁcant dysfunction. However, the Agency has established guidelines and policies that are used to classify
these end points. ATSDR believes that there is sufficient merit in this approach to warrant an attempt at
distinguishing between "less serious" and "serious" effects. The distinction between "less serious" effects and
"serious" effects is considered to be important because it helps the users of the proﬁles to identify levels of

exposure at which major health effects start to appear. LOAELs or NOAELs should also help in determining

CHLORFENVINPHOS 8

2. HEALTH EFFECTS

whether or not the effects vary with dose and/or duration, and place into perspective the possible signiﬁcance

of these effects to human health.

The signiﬁcance of the exposure levels shown in the Levels of Signiﬁcant Exposure (LSE) tables and ﬁgures
may differ depending on the user's perspective. Public health officials and others concerned with appropriate
actions to take at hazardous waste sites may want information on levels of exposure associated with more
subtle effects in humans or animals (LOAEL) or exposure levels below which no adverse effects (NOAELs)
have been observed. Estimates of levels posing minimal risk to humans (Minimal Risk Levels or MRLs) may

be of interest to health professionals and citizens alike.

Estimates of exposure levels posing minimal risk to humans (Minimal Risk Levels or MRLs) have been made
for chlorfenvinphos. An MRL is deﬁned as an estimate of daily human exposure to a substance that is likely
to be without an appreciable risk of adverse effects (noncarcinogenic) over a speciﬁed duration of exposure.
MRLs are derived when reliable and sufficient data exist to identify the target organ(s) of effect or the most
sensitive health eﬂ‘ect(s) for a speciﬁc duration within a given route of exposure. MRLs are based on
noncancerous health effects only and do not consider carcinogenic effects. MRLs can be derived for acute,
intermediate, and chronic duration exposures for inhalation and oral routes. Appropriate methodology does

not exist to develop MRLs for dermal exposure.

Although methods have been established to derive these levels (Barnes and Dourson 1988; EPA 1990),
uncertainties are associated with these techniques. Furthermore, ATSDR acknowledges additional
uncertainties inherent in the application of the procedures to derive less than lifetime MRLs. As an example,
acute inhalation MRLs may not be protective for health effects that are delayed in development or are acquired
following repeated acute insults, such as hypersensitivity reactions, asthma, or chronic bronchitis. As these
kinds of health effects data become available and methods to assess levels of signiﬁcant human exposure

improve, these MRLs will be revised.

A User's Guide has been provided at the end of this proﬁle (see Appendix B). This guide should aid in the
interpretation of the tables and ﬁgures for Levels of Signiﬁcant Exposure and the MRLs.

CHLORFENVINPHOS 9

2. HEALTH EFFECTS

2.2.1 Inhalation Exposure

2.2.1.1 Death

There are no reports of deaths in humans exposed by acute-, intermediate-, or chronic-duration inhalation to

chlorfenvinphos.

No studies were located regarding lethality in animals after intermediate- or chronic-duration inhalation
exposure to chlorfenvinphos. A study investigated whether the difference in the route of absorption or the
mode of lethality is responsible for the higher lethality of the micron-sized (>1 um) aerosols in male rats. The
study reported 0, 60, and 100% mortality in rats at the 83, 144, and 236 mg/m3 ambient air concentrations,
respectively. The deaths occurred 3 and 4 hours after initiation of the exposure to micron-sized
chlorfenvinphos aerosols. There was 0, 80, and 100% mortality in rats at the 254, 471, and 1,019 mg/m3
ambient air concentrations, respectively. The LC50 value calculated from the mortality of the rats was
markedly increased by cannulation (from 133 mg/m3 for non-cannulated to 489 mg/m3 for cannulated rats) for
the micron-sized aerosol ambient air concentrations. However, there was essentially no difference in the LC50
values (509 mg/m3 for non-carmulated and 475 mg/m3 for cannulated rats) calculated from the mortality of the
rats that were administered the more inhalable submicron-sized aerosols ambient air concentrations. These
data indicate that the micron-sized aerosols were about 4 times more potent in producing lethality than the
submicron-sized aerosols. This is also an indication that swallowed chlorfenvinphos contributed to the
lethality; this was more evident for the less inhalable micron-sized aerosol ambient air concentrations. Elapsed
time from the start of exposure to death was not changed by the cannulation in both the micron-sized and the
submicron—sized aerosols. The authors surmised that death from acute exposure to chlorfenvinphos aerosols
probably derives from inhibition of acetylcholinesterase(AChE) activity (Takahashi et al. 1994). In another
study with rats, the acute lethality of chlorfenvinphos was unaffected in male rats in snout-only or whole body

exposures (Tsuda et al. 1986). The LC50 for death in rats is shown in Table 2-1 and plotted in Figure 2-1.

2.2.1.2 Systemic Effects

No studies were located regarding the gastrointestinal, hematological, musculoskeletal, hepatic, renal,
endocrine, dermal, ocular, or body weight effects in humans or animals following acute-, intermediate-, or

chronic-duration inhalation exposure to chlorfenvinphos. Existing human data on the metabolic effects of the

Table 2-1. Levels of Signiﬁcant Exposure to Chlorfenvinphos - Inhalation

 

 

 

_ Exposure! LOAEL
Key to Speciesl duration] NOAEL Less serious Serious
ﬁgure (strain) frequency System (mg/m3) (mg/m3) (mglm3) Reference
ACUTE EXPOSURE
Death
1 Rat once 133 M (LCso) Takahashiet al.
(Fischer- 344) ‘994
Systemic
2 Rat 4 hr Resp 390 M (apnea) Takahashietal.
(Fischer— 344) 1994
Cardio 390 M (progressive increase in
blood pressure.
bradycardia)
Neurological
3 Rat 4 hr 83 M (salivation. urination. Takahashietal.
(Fischer— 344) exophthalmos. twitches, 1994

and tremors)

 

8'The number corresponds to entries in Figure 2-1.

Cardio = cardiovascular; hr = hour; LCso = lethal concentration, 50% kill; LOAEL = lowest-observed—adverse-effect level; M = male; NOAEL = no-observed- adverse-effect level; Resp =
respiratory

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Figure 2-1. Levels of SigniﬁcantExposure to Chlorfenvinphos - Inhalation

 

Acute (514 days)
Systemic
K
(D
s \
é‘ a? 3’
.{b i" Q
(mg/m3) (as 5 $3 3
0 Q9 (5” 5,
10000 - Q
1000 ~
21 2r
0 0
1r
I .
10 - 3!
° 0
10 -
Key
rat - L050 (animals) The number neia to
O LOAEL for serious effects ' l m" 9°“
1 _ (amma s) mam,“ to

0.1

 

 

 

 

 

 

0 LOAEL for less serious effects (animals) mm in Table 24-

 

 

$103$d3 HJJVSH '3

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ll

CHLORFENVINPHOS 12

2. HEALTH EFFECTS

substance are limited to chronic-duration exposure. Existing animal data on the respiratory and

cardiovascular effects are limited to acute-duration exposure.

The highest NOAEL value and all LOAEL values for adverse systemic effects in each reliable study for each

species and duration category are shown in Table 2-1 and plotted in Figure 2-1.

Respiratory Effects. No studies were located regarding respiratory effects in humans aﬁer exposure to

chlorfenvinphos for any duration category.

Acute-duration exposure of rats to inhalation aerosol chlorfenvinphos ambient air concentrations produced
cardiorespiratory changes in the treated rats at high ambient air concentrations. Male Fischer 344 rats exposed
to the micron-sized (>1 mm) or submicron—sized (<1 um) chlorfenvinphos aerosols for 4 hours suffered
cardiorespiratory effects. Rats exposed to the lethal concentration of 1,220 mg/m3 of the submicron-sized
aerosols showed a progressive increase in blood pressure followed by an apnea during which the blood
pressure was maximally increased. Rats exposed to 390 mg/m3 of the micron-sized aerosols also exhibited
cardiorespiratory changes similar to changes caused by the submicron—sized aerosols (data were not shown in
the report). No signiﬁcant qualitative difference was observed in cardiorespiratory changes between the
micron-sized and the submicron-sized aerosols, suggesting that the mode of lethality is not different between
the two types of aerosols. A LOAEL of 390 mg/m3 for apnea was established in this study (Takahashi et al.
1994). In a previous study (Takahashi et a1. 1991), Sprague-Dawley rats exhibited similar signs at an

intravenous dose of 16 mg/kg of chlorfenvinphos.

Cardiovascular Effects. No studies were located regarding cardiovascular effects in humans after

exposure to chlorfenvinphos for any duration category.

Acute exposure of rats to inhalation aerosol chlorfenvinphos ambient air concentrations produced
cardiorespiratory changes in the treated rats at high ambient air concentrations. Adult male Fischer 344 rats
exposed to the micron-sized (>1 pm) or submicron-sized (<1 um) chlorfenvinphos aerosols for 4 hours
suffered cardiorespiratory effects. Rats exposed to the lethal concentration of 1,220 mg/m3 of the submicron-
sized aerosols showed a progressive increase in blood pressure followed by apnea during which the blood
pressure was maximally increased. Bradycardia was observed in the electrocardiograph (ECG) at the pressor
period, which was characterized by a prolonged TP time without a change in PQ, QRS, and ST time. Rats

exposed to 390 mg/m3 of the micron-sized aerosols also exhibited cardiorespiratory changes similar to those

CHLORFENVINPHOS 13

2. HEALTH EFFECTS

caused by the submicron-sized aerosols (data were not shown in the report). No signiﬁcant qualitative
difference was observed in cardiorespiratory changes between the micron-sized and the submicron-sized
aerosols, suggesting that the mode of lethality is not different between the two types of aerosols. A LOAEL of
390 mg/m3 for progressive increased blood pressure and bradycardia was established in this study (Takahashi
et al. 1994).

Metabolic Effects. The information on the metabolic effects of chronic-duration inhalation exposure to
chlorfenvinphos provides only inconclusive evidence. Examinations of 31 manufacturing workers who
directly handled the chlorfenvinphos (and other similar compounds) for 19—53 years revealed signiﬁcantly
lowered NBT (nitroblue tetrazolium).dye reduction in both stimulated and non-stimulated cells, as well as a
signiﬁcant decrease of the spontaneous E rosette formation (not inﬂuenced by exposure time) in the blood
(early E rosettes, 52%; late E rosettes, 57%) as compared to controls (early E rosettes, 57%; late E rosettes,
63%). No correlation was found between the spontaneous E rosette formation and acetylcholinesterase
activity. The authors of this study concluded that depressed NBT-dye reduction and diminished spontaneous
E rosette formation may be regarded as a probable mode of the effect of organophosphoric chemicals on
metabolic and membrane damage to human cells. About half of the subjects in the study were smokers
(Wysocki et al. 1987). However, the data from this study are not reliable for evaluating the inhalation toxicity
of chlorfenvinphos because the workers were also concurrently exposed to greater concentrations of other

known toxic substances.

No studies were located regarding metabolic effects in animals after exposure to chlorfenvinphos for any

duration category.

2.2.1.3 Immunological and Lymphoreticular Effects

No studies were located regarding the immunological and lymphoreticular effects in humans following acute-
or intermediate-duration inhalation exposure to chlorfenvinphos. However, chronic-duration inhalation
exposure to organophosphoric pesticides caused a depression of immune responses and, consequently,
produced damage to humoral mechanisms in humans. Examination of 31 manufacturing workers who directly
handled the organophosphoric pesticide chlorfenvinphos (and other compounds) for 19—53 years revealed
signiﬁcantly lowered NBT-dye reduction in both stimulated and non—stimulated cells, and a decreased
percentage of phagocytic cells (P<0.001, 0.05, and 0.002, respectively) in pesticide workers occupationally

exposed to an estimated average ambient chlorfenvinphos concentration of 0.21 mg/nf’. These analyses

CHLORFENVINPHOS 14

2. HEALTH EFFECTS

parameters of the NBT test showed a positive linear correlation with the degree of acetylcholinesterase activity
reduction. The exposure time had no effect on NET reduction test parameters, but there was a negative linear
correlation with the phagocytic index of the NBT test (r = -0.4879, P<0.01). A signiﬁcant decrease of the
spontaneous E rosette formation (not inﬂuenced by exposure time) was found in the blood of the exposed
workers (early E rosettes, 52%; late E rosettes, 57%), as compared to controls (early E rosettes, 57%; late E
rosettes, 63%). No correlation was found between the spontaneous E rosette formation and
acetylcholinesterase activity. No signiﬁcant differences were found in number of white blood cells, mainly
neutrophils, in the two examined subgroups, but the absolute lymphocyte count in the peripheral blood of the
exposed subjects was lower when compared to controls (1,941.9 versus 2,380 cells/mm3,.P<0.05). The
authors of this study concluded that depressed NBT-dye reduction and diminished spontaneous E rosette
formation may be regarded as a probable mode of action of organophosphoric chemicals on metabolic and
membrane damage to human cells. Acetylcholinesterase activity, which showed a time-independent positive
linear relationship to lowered NBT-dye reduction in the subjects, was above 2 pmol in 17 of the subjects (with
an average age of 38.5 years). Eighteen (58.1%) of the subjects examined showed symptoms of chronic
bronchitis; seven (23.3%) subjects in the control group also had signs indicating previous (anamestic) chronic
bronchitis. It is generally understood that chronic bronchitis stems from changes in humoral rather than
cellular immune response. About half of the subjects were smokers. The maximal estimated airborne
concentrations of substances in the workplace were: 0.654 mg/m3 (formothion), 0.483 mg/m3 (sumithion),
trace (DDVP), 0.21 mg/m3 (chlorfenvinphos), and 1.09 mg/m3 (malathion) (Wysocki et al. 1987). The data
ﬁom this study are not reliable for evaluating the inhalation toxicity of chlorfenvinphos because the workers

were also concurrently exposed to greater concentrations of other known immunotoxic substances.

No studies were located regarding immunological and lymphoreticular effects in animals after acute-,

intermediate—, or chronic-duration inhalation exposure to chlorfenvinphos.

2.2.1.4 Neurological Effects

No studies were located regarding neurological effects in humans after acute- or intermediate-duration
inhalation exposure to chlorfenvinphos. The single study that reported neurological effects in humans ﬁom
inhalation exposure to chlorfenvinphos involved occupational exposure. A group of nine gardeners (pesticide
mixers) who worked with the organophosphates (dimethoate, formothion, isofenphos and occasionally
chlorfenvinphos) for an unspeciﬁed duration complained of headaches. The gardeners had a mean difference

(before and aﬁer exposure) of 0.56 nmol/mL for acetylcholinesterase and 2.67 nmol/mL for butyryl-

CHLORFENVINPHOS 15

2. HEALTH EFFECTS

cholinesterase. Since the symptoms could also result from exposure to the other organophosphates
(dimethoate, formothion, isofenphos) to which the workers were also exposed, the role of chlorfenvinphos
exposure in this incident is not certain. In addition, no data were given on air concentrations of the

organophosphate pesticides (Kolmodin-Hedman and Eriksson 1987).

No studies were located regarding neurological effects in animals aﬁer intermediate- or chronic-duration
inhalation exposure to chlorfenvinphos. Acute exposure of rats to aerosols of chlorfenvinphos produced
neurological signs indicative of cholinergic response stemming from inhibition of acetylcholinesterase
activity. Surviving adult male Fischer 344 rats (27 of 60) exposed to the micron-sized (>1 mm) or submicron-
sized (<1 pm) chlorfenvinphos aerosols for 4 hours (83, 130, 144, 236, 254, 322, 471, 623, 1,019, or

1,065 mg/m3) exhibited cholinergic signs: salivation, urination, exophthahnos, twitches, and tremors, at

283 mg/m3. The inhalation experiments were conducted using a nose-only inhalation chamber. (To examine
the toxicological signiﬁcance of swallowed chlorfenvinphos, a drain cannula was placed in the esophagus
under pentobarbital sodium anesthesia.) Toxic signs were not assessed in detail during the exposure because
the rats were in the animal holder. There were no differences in toxic signs between the micron-sized and the

submicron-sized aerosols (Takahashi et a1. 1994).

All LOAEL values for neurological eﬁ‘ects in each reliable study for each species and duration category are

shown in Table 2-1 and plotted in Figure 2-1.

No studies were located regarding the following health effects in humans or animals after acute-,

intermediate-, or chronic-duration inhalation exposure to chlorfenvinphos:

2.2.1.5 Reproductive Effects

2.2.1.6 Developmental Effects

2.2.1.7 Genotoxic Effects

Other genotoxicity studies for chlorfenvinphos are described in Section 2.5.

CHLORFENVINPHOS 16

2. HEALTH EFFECTS

2.2.1.8 Cancer

No studies were located regarding carcinogenic effects in humans or animals following inhalation exposure to

chlorfenvinphos.

2.2.2 Oral Exposure

2.2.2.1 Death

There are no reports of deaths in humans exposed by intermediate- or chronic-duration ingestion of
chlorfenvinphos. A 16-month—old child who accidentally drank an unspeciﬁed amount of chlorfenvinphos,
used for ﬂea treatment in the home, died despite treatment in a hospital (Felthous 1978).

Chlorfenvinphos is extremely toxic to rodents and dogs by the oral route in acute doses. The oral LD50 values
for rats, rabbits, and dogs have been estimated to be 9.7, 300, 50.5 mg/kg, respectively (Ambrose et a1. 1970).
An acute oral LD50 of 23 mg/kg was calculated from the mortality data of an unspeciﬁed number of male
Wistar rats that were given varying doses of chlorfenvinphos in olive oil (Hutson and Logan 1986). Similarly,
the acute oral LD50 of chlorfenvinphos in male rats as a single dose in olive oil was estimated to be

15.4 mg/kg. Animals that died from the effects of chlorfenvinphos did so within 12 hours of dosing; no
further deaths were noted up to 72 hours after dosing. The chlorfenvinphos LD50 value for rats pretreated with
dieldrin (0.2 mg/kg) was estimated to be 157 mg/kg; thus, dieldrin pretreatment induced a 10-fold protective
effect against the acute toxicity of the organophosphate (Hutson and Wright 1980). Aﬁer prolonged

(105 minutes) exhibition of cholinergic signs, death occurred at the 20 mg/kg close when Sprague-Dawley rats
were orally administered single doses of 1.25, 5, or 20 mg/kg chlorfenvinphos (Takahashi et a1. 1991). In
another study with Wistar rats, the acute oral LD50 was signiﬁcantly decreased in rats fed a protein-deﬁcient
(4.5%) diet during the 60 days of administration. The 60-day rat LD50 value was reduced from a control value
of 23.0 mg/kg to 7.4 mg/kg in males and 25.5 mg/kg to 10.2 mg/kg in females (Puzynska 1984). Pretreatment
of male Fischer 344 rats with 15 mg/kg chlorfenvinphos followed by a further 15 mg/kg dose signiﬁcantly
reduced the male oral LD50 for chlorfenvinphos from a positive control value of 34.3 mg/kg to 105.6 mg/kg;
about 3.08-fold (P<0.05). Deaths occurred between 2 hours and 1 day after oral administration of
chlorfenvinphos (Ikeda et al. 1992).

CHLORFENVINPHOS 17

2. HEALTH EFFECTS

Chlorfenvinphos appears to be less toxic to mice than to rats. In a lethality study with BDFl mice of both
sexes, the oral LD50 and maximum tolerated dose (MTD) for chlorfenvinphos (suspended in methylcellulose)
were estimated to be 148 mg/kg and 109 mg/kg, respectively. The mice were evaluated 5 days after
intragastric administration of the chlorfenvinphos doses (Kowalczyk-Bronisz et al. 1992). A mouse acute oral
LD50 of 100—200 mg/kg for chlorfenvinphos was cited from an earlier study in which male CFI mice were
used (Hutson and Logan 1986).

A rabbit acute oral LD50 of >500—1,000 mg/kg for chlorfenvinphos was cited from an earlier study in which
male New Zealand White rabbits were used (Hutson and Logan 1986).

A dog acute oral LD50 of >5,000 mg/kg for chlorfenvinphos was cited from an earlier study in which female
Beagle dogs were used (Hutson and Logan 1986).

In prolonged exposures, no signiﬁcant effect on mortality and survival was reported for rats and dogs given
chlorfenvinphos in the diet at doses as high as 90 mg/kg/day for 12 weeks or 24 mg/kg/day for 104 weeks
(Ambrose et a1. 1970).

The LD50 values and doses associated with death in each species and duration category are shown in Table 2-2

and plotted in Figure 2—2.

2.2.2.2 Systemic Effects

No studies were located regarding the hematological, cardiovascular, gastrointestinal, musculoskeletal,
hepatic, renal, endocrine, dermal, ocular, body weight, or other systemic effects in humans following acute-,
intermediate-, or chronic-duration oral exposure to chlorfenvinphos. Existing human data on the respiratory
and neurological effects are limited to acute-duration exposures. No studies were located regarding ocular

effects in animals following acute-, intermediate-, or chronic-duration oral exposure to chlorfenvinphos.

The highest NOAEL value and all LOAEL values for adverse systemic effects in each reliable study for each

species and duration category are shown in Table 2-2 and plotted in Figure 2-2.

Respiratory Effects. No human studies were located that reported direct effects on the respiratory

system following oral exposure to chlorfenvinphos. Respiratory effects in humans following accidental

Table 2-2. Levels of Signiﬁcant Exposure to Chlorfenvinphos - Oral

 

 

 

Exposure! LOAEL
. Duration]
Key ‘0 Species] Frequency NOAEL Less Serlous Serlous
"9"” (Strain) (SchIﬂc Route) System (mg/kglday) (mg/kglday) (mg/kglday) Reference

ACUTE EXPOSURE
Death

1 Rat once 9.7 M (LDso) Ambrose etal.
(VWstar) (so) 1970

2 Rat once 23 M (L050) Hutson and Logan
(Wistar) (GO) 1986

3 Rat once 15.4 M (LDso) Hutson and Wright
(Carworth (so) 1980
Farm E)

4 Rat once 34.3 M (L050) Ikeda et al. 1992
(Fischer- 344) (GO)

5 Rat once 20 (100% mortality) Takahashi et al.
(Sprague- (NS) 1991
Dawley)

6 Mouse once 148 (L050) Kowalczyk-
(BDF1) (GO) Bronisz et al. 1992

109 (MTD)

7 Dog once 50.5 (LDso) Ambrose et al.
(Mongrel) (GO) 1970

8 Rabbit once 300 M (LDso) Ambrose etal.
(NS) (Go) 1970

8103593 Hl'IVBH '3

SOHdNIANBdUO‘IHO

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Table 2-2. Levels of Signiﬁcant Exposure to Chlorfenvinphos - Oral (continued)
Exposure] LOAEL
Key to' S i 3! Duration!
pec e Frequency NOAEL Less Serious Serious
“9“” ‘Sm'm (Speciﬁc Route) 5’5“” (mglkglday) (mg/kglday) (mg/kglday) “mm“

 

Systemic
9 Rat 10d
(Wistar) ad Iibitum
(F)
10 Rat once

(Fischer- 344) (GO)

11 Rat once
(\Mstar) (GO)
12 Rat once
(Wistar) (GO)

Bd Wt 2.4 F

Metabolic

Hepatic

Endocr

Hepatic

2.4 F (30% increased
gastrointestinal
absorption of glucose;
32% decreased
gastrointestinal
absorption of Na')

15M (30% increased P-450
activity; 40% increased
aminopyrine-N—demethyla
se activity; 27%
increased aniline
hydroxylase activity)

6.15 M (>300% elevation of
plasma corticosteroids)

30M (51% increase in serum
sorbitol dehydrogenase;
37% to 109% increase in
liver aromatic
aminotransferase
activity)

30 F (105% increase in serum
sorbitol dehydrogenase;
32% decrease in serum
glucose-S-phosphate
isomerase)

Barna and Simon
1973

lkeda et al. 1991

Osicka-Koprowska
et al. 1984

Puzynska 1984

8103533 HJJVBH 'Z

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6i

 

 

 

Table 2-2. Levels of Signiﬁcant Exposure to Chlorfenvinphos - Oral (continued)
Exposure! LOAEL
. Duration!
1‘” ‘0 SsPtWrs’ Frequency NOAEL Less Serious Serious
gum ( m n) (Speciﬁc Route) System (mglkglday) (mg/kglday) (mg/kglday) Reference
Neurological
13 Rat 10 d 2.4 b F (52% inhibition of plasma Bama and Simon
(Wistar) ad Iibitum cholinesterase activity; 1973
(F) 30% inhibition of
erythrocyte activity)
14 Rat once 13M (20% decrease in the Brzezinski 1978
(Wistar) (GO) noradrenaline level)
15 Rat once 30 M (salivation, fasciculation, Ikeda et ai. 1992
(Fischer- 344) (Go) lacrimation. tremors,
irregular respiration, and
prostration)
16 Rat once 6.2 M (10-30% decrease in Osicka-Koprowska
(Wistar) (so) brain and blood et al. 1984
cholinesterase activity)
17 Rat once 1 M 2M (38% decrease in brain Osumi et al. 1975
(Wistar) (so) cholinesterase activity)

5103:];43 Hl‘lVBH '3

SOHdNIANBdUO‘lHO

Table 2-2. Levels of Signiﬁcant Exposure to Chlorfenvinphos - Oral

Exposurel

Duration]

Frequency
(Speciﬁc Route)

Key tO' Species!

figure (Strain) NOAEL

System (mg/kglday)

18 Rat once
(Wistar) (GO)

19 Rat once 1 .25
(Sprague- (NS)
Dawley)

LOAEL

Less Serlous
(mg/kglday)

30M (87% inhibition of serum

30F

acetylcholinesterase
activity; 58% inhibition of
brain acetylcholin-
esterase activity; 20%
increase in brain
aromatic amino-
transferase activity)
(93% inhibition of serum
acetylcholinesterase
activity; 39% inhibition of
brain
acetylcholinesterase
activity; 30% to 42%
increase in brain
aromatic amino-
transferase activity; 32%
elevation of brain
glucosephosphate
isomerase)

(continued)

Serious

i (mglkglday) RO'ONI'IC.

Puzynska 1984

5 M (>90% reduction of Takahashi at al.
erythrocyte cholinesterase 1991
activity; fasciculations,
twitches, convulsions.
chromodacryorrhea,
exophthalmos, gasping,
Iacrimation. prostration,
salivation, Straub tail reflex.
urination)

$103533 Hl‘WBI-l 'Z

SOHleANBdUO'IHO ‘ ‘

13

Table 2-2. Levels of Signiﬁcant Exposure to Chlorfenvinphos - Oral (continued)

 

 

Exmm’ LOAEL
. Duration]
:21": 2:331 Frequency NOAEL Less Serious 59'1“”
(Specific Route) System (mg/kglday) (mg/kglday) (mg/kelday) ”hm“
INTERMEDIATE EXPOSURE
Systemic
20 Rat 12 wk Resp 90 M Ambrose et al.
(Wistar) ad libilum 1970
(F) Cardio 90 M
Gastro 90 M
Hepatic 90 M
Renal 0.9 M 2.7 M (signiﬁcant reduction of
relative kidney weight)
1 F 3 F (signiﬁcant reduction of
relative kidney weight)
Endocr 90 M
Dermal 90 M
21 Rat 30 d Bd Wt 0.8 F Barna and Simon
(Wistar) ad libitum 1973
(F) Metabolic 0.8 F (12% increased
gastrointestinal
absorption of glucose;
23% decreased
gastrointestinal .
absorption of Na’)
22 Dog 12 wk Resp 10 M Ambrose et al.
(Mongrel) ad Iibitum 1970
(F) Cardio 10 M
Gastro 10 M
Musclskel 10 M
Hepatic 10 M
Renal 10 M
Endocr 10 M
Bd Wt 10 M
Other 10 M

$103533 Hl'lVBH '3

SOHleANBdUO'IHO

Key tO' Speciesl
figure (Strain)

Table 2-2. Levels of Signiﬁcant Exposure to Chlorfenvinphos - Oral

Exposure!
Duration!

FMW'WY NOAEL

(Specific Route) System

LOAEL

(continued)

 

Less Serious Serious

Reference

 

lmmunologicalILymphoreticular

23 Mouse 90d
(057w 6N) 1 x/d
(GO)
1.5
24 Rabbit 90d
(NS) 1 x/d
(GO)
Neurological
25 Rat 12 wk 2.7
(WIstar) ad Iibitum
F
( ) 3
26 Rat 3-6 mo
(Sprague- (F)
Dawley)
27 Rat 1yr
(Sprague— (F)
Dawley)

1.5c

3

10

9M

10F

10.5

10.5

(190% increase of spleen
endogenous colonies;
162% increase of spleen
exogenous colonies;
50% reduction in thymus
weight)

(15% decrease in

plaque-forming cells;

25% reduction in EA

rosettes-forming cells)

(16% elevation of serum
hemagglutinin; 66%
elevation of hemolysin
activity; increased
antibody production)

(signiﬁcant depression of
plasma and erythrocyte
cholinesterase activity)
(significant depression of
plasma and erythrocyte
cholinesterase activity)

(38% inhibition of whole
blood
acetylcholinesterase)

(abnormal response to
muscle stimuli)

Kowalczyk-Bronis
z et al. 1992

Roszkowski 1978

Ambrose et al.
1970

Maxwell and
LeQuesne 1982

Maxwell and
LeQuesne 1982

8103333 Hl‘lVBH '8

SOHleANBdUO'IHO

 

 

 

Table 2-2. Levels of Signiﬁcant Exposure to Chlorfenvinphos - Oral (continued)
Exposure]
K t I _ Duration! LOAEL
ﬂey ° 5:32:99 Frequency NOAEL Less Serlous 39'5“”
9"" ( ") (59%“ RN“) 5’3“” (mg/kalday) (mg/kglday) (mglkglday) “mm“
28 Rat 3 mo 10.5 (abnormal response to Maxwell and
(Sprague- (F) muscle stimuli) LeQuesne 1982
Dawley)
Reproductive
29 Rat 3 gen 3 F (50% decrease in fertility in Ambrose et al.
(VVIStar) ad Iibitum F/2 generation) 1970
(F)
Developmental
30 Rat 12 wk 2.7 9M (signiﬁcant depression of Ambrose et al.
(Wistar) ad Iibitum growth) 1970
(F) 3 0 F (significant depression of
growth)
31 Rat 3 gen 10 (66% decrease in pup Ambrose et al.
(Wistar) ad Iibitum viability; 46% decrease in 1970

(F)

lactation index)

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Table 2-2. Levels of Signiﬁcant Exposure to Chlorfenvinphos - Oral (continued)

 

 

Ex urel
Key to. s (.3, mm“, LOAEL
991: Frequency
“9“" (Strain) (Specific Route) System (mglgslgla-y) (3:972:33 (afglﬁydsay) Reference
CHRONIC EXPOSURE
Systemic
32 Rat 104 wk Resp 21 M Ambrose et al.
(Wista r) ad Iibitum 1 970
(F) Cardio 21 M
Gastro 21 M
Hemato 21 M
Musclskel 21 M
Hepatic 2.1 7M (signiﬁcant increase in
relative liver weight)
Renal 21 M
Endocr 21 M
Dermal 21 M
Bd Wt 2.4 8 F (signiﬁcant decrease in
body weight gain)
33 Dog 104 wk Cardio 10 M Ambrose at al.
(Beagle) ad Iibitum 1970
(F) 50 F
Hemato 10 M
50 F
Hepatic 10 M
50 F
Renal 10 M
50 F
Endocr 10 M
50 F
Bd Wt 10 M
50 F

51335:!3 Hl'lVEH 'Z

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Table 2-2. Levels of Signiﬁcant Exposure to Chlorfenvinphos - Oral (continued)

 

 

Exposurel
Ke t . S ies/ Duration! LOAEL
V ° 9“ Frequency NOAEL Loss Serious Serious
“9"" (Strain) (Speclﬂc Route) 5’3“” (mg/kg/day) (mg/kglday) (mg/kglday) “hm“
Neurological
34 Rat 104 wk 0.7 d M (45% inhibition of plasma Ambrose et al.
(wistar) ad Iibitum cholinesterase activity; 1970
(F) 33% inhibition of
erythrocyte
cholinesterase activity)
0-3 F (48% inhibition of plasma
cholinesterase activity;
20% inhibition of
erythrocyte
cholinesterase activity)
35 Dog 104 wk 2 10M (36% inhibition of Ambrose et al.
(Beagle) ad Iibitum erythrocyte 1970
(p) cholinesterase)
1° F (36% inhibition of

erythrocyte
cholinesterase)

$103533 HJJVBH '3

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Table 2-2. Levels of Signiﬁcant Exposure to Chlorfenvinphos - Oral (continued)

 

 

 

Exposure! L L
K . Duration! OAE
ﬂey to 83c?“ Frequency NOAEL Less Serious Serious
9"" ( 'a ") (ch'ﬂc “0““) sym'" (mo/kelday) (mg/kglday) (mglkglday) “mm“
Reproductive
36 Rat 104 wk 21 M Ambrose et al.
(Wistar) ad Iibitum 1970
(F)

 

aThe number corresponds to entries in Figure 2-2.

bUsed to derive an acute oral minimal risk level (MRL) of 0.002 mglkg/day. Dose divided by an uncertainty factor of 1000 (10 for use of a LOAEL, 10 for extrapolation from animals
to humans, and 10 for human variability).

cUsed to derive an intermediate oral MRL of 0.002 mglkg/day. Dose divided by an uncertainty factor of 1000 (10 for use of a LOAEL, 10 for extrapolation from animals to humans.
and 10 for human variability).

dUsed to derive a chronic oral MRL of 0.0007 mglkg/day. Dose divided by an uncertainty factor of 1000 (10 for use of a LOAEL, 10 for extrapolation from animals to humans.
and 10 for human variability).

Bd Wt = body weight; d = day(s); EA = erythrocyte acetylcholinesterase; Endocr = endocrine; F = female; (GO) = gavage, oil; gen = generation; Hemato = hematological;
Ld = lactation day(s); LDso = lethal dose, 50% kill; LOAEL = lowest-observed-adverse-effect level; M = male; mo = month(s); NOAEL = no—observed-adverse-effect level;
NS = not specified; x = time(s); yr = year(s)

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Figure 2-2. Levels of Signiﬁcant Exposure to Chlorfenvinphos - Oral

 

SOHdNIANadHO'IHO

 

 

 

 

 

 

 

 

Acute (514 days)
Systemic
«3' «P
0 a? \s é’
s $5 s a? 5’
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0.01 - m mouse . . - n for effects other I
. r eff m al
h rabblt LOAEL forseious. ects(a m s) w than cancer :
d dog 0 LOAEL for less serious effects (animals) .
. The number next to U
0 NOAEL (animals) each point corresponds
0.001 - toentriesinTable 2-2.
0.0001 -

83

(mg/kg/day)

1000

100

10

0.1

0.01

0.001

0.0001

 

Figure 2-2. Levels of Significant Exposure to Chlorfenvinphos - Oral (cont.)

Intermediate (15-364 days)

 

 

 

 

sttemic
S
If? I? 0* $3? 5
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to entries in Tabie 2-2.

 

 

 

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Figure 2-2. Levels of Signiﬁcant Exposure to Chlorfenvinphos - Oral (cont.)
Chronic (2365 days)
Systemic
(t ,g 5 g k \
9 a? 4:? as a? 5 4? .9
5' (U -S 3 0 . g, \ 0 3 5‘
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h rabbit _ _ \‘Jthan cancer r
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CHLORFENVINPHOS 31

2. HEALTH EFFECTS

ingestion of a mange-mite medication containing organic phosphate or intentional ingestion of the preparation
Enolofos®, which contains 50% chlorfenvinphos, in suicide attempts reported in two clinical reports stemmed

from central cholinergic disturbances (Cupp et a1. 1975; Pach et a1. 1987).

In animal studies, no effects on the respiratory system were noted in rats and dogs orally administered
chlorfenvinphos at doses as high as 100 mg/kg/day (rats) or 50 mg/kg/day (dogs) for 12 weeks; or in rats at
doses as high as 24 mg/kg/day for 104 weeks (Ambrose et al. 1970).

Cardiovascular Effects. Evidence from animal studies indicates that chlorfenvinphos is not directly
toxic to the cardiovascular system but may modulate the function of the cardiovascular system via its effect on
the central nervous system. Relative heart-to-body weight ratios of weanling albino (Wistar) rats were not
signiﬁcantly altered when administered daily chlorfenvinphos doses of 0.27, 0.9, 2.7, 9, or 90 mg/kg/day
(males): 0.3, 1, 3, 10, or 100 mg/kg/day (females) in the diet for 12 weeks. Similarly, no effects on relative
heart-to—body weight ratios were reported for Wistar rats given chlorfenvinphos at doses of 0.7, 2.1, 7, or

21 mg/kg/day (males) or 0.8, 2.4, 8, or 24 mg/kg/day (females) in the diet for 104 weeks in another part of the
same study (Ambrose et al. 1970). However, cardiovascular function was not assessed in these studies. No
gross or microscopic histopathology in heart tissues or changes in relative heart weights were evident in
mongrel dogs administered daily chlorfenvinphos doses of 0.01, 0.1, l, or 10 mg/kg/day (males) or 0.05, 0.5,
5, or 50 mg/kg/day (females) for 12 weeks (Ambrose et al. 1970). However, cardiovascular function was not
assessed in this study. Similarly, no effects on heart-to-body weight ratios were reported for Beagle dogs
given chlorfenvinphos at doses of 0.3, 2, or 10 mg/kg/day (males), or 1.5, 10, 50 mg/kg/day (females) in the
diet for 104 weeks in another part of the same study (Ambrose et a1. 1970).

A study concluded that the alteration of brain and liver activities of the aromatic amino acid transferases may
be due to the inhibitory effect of chlorfenvinphos on noradrenaline (norepinephrine) activity (Puzynska 1984).
In other studies, chlorfenvinphos was shown to independently inhibit noradrenaline (norepinephrine) activity
in vivo in rats rapidly (3 hours) at doses as low as 4 mg/kg (Brzezinski 1978; Osumi et a1. 1975). On this basis,
it has been postulated that chlorfenvinphos may also act via central noradrenergic mechanisms, disturbing the
dynamic equilibrium between the rate of formation and utilization of noradrenaline (norepinephrine). It was
postulated that this action via central noradrenergic mechanisms by chlorfenvinphos may be responsible for the

changes in blood pressure observed in other studies after chlorfenvinphos intoxication (Brzezinski 1978).

CHLORFENVINPHOS 32

2. HEALTH EFFECTS

Gastrointestinal Effects. No gross or microscopic histopathology was evident in the gastrointestinal
tract of rats and dogs given oral doses of up to 100 mg/kg/day (female rats) or 50 mg/kg/day (female Beagle
dogs) chlorfenvinphos for 12 weeks (Ambrose et al. 1970). Similarly, no gross or microscopic
histopathology was evident in the stomach, or small and large intestine of weanling albino (Wistar) rats of
both sexes chronically (104 weeks) given daily dietary chlorfenvinphos doses of 0.7, 2.1, 7, or 21 mg/kg/day
(males) or 0.8, 2.4, 8, or 24 mg/kg/day (females) (Ambrose-ct al. 1970).

Hematological Effects. Information on the hematological effects from oral exposure to
chlorfenvinphos is limited. Investigations conducted to evaluate the serological effects of chlorfenvinphos
on 4 groups of rabbits of both sexes at a doses of 10 mg/kg for 90 days found signiﬁcant increases of
hemolysin and hemagglutinin serum titer, as compared to controls. Hemagglutinin and hemagglutinin IgG
titer were increased by 16 and 18%, respectively, while hemolysin and hemolysin IgG titer were elevated by
66 and 102%, respectively (Roszkowski 1978). In a 104-week oral study in Beagle dogs, no effects were
reported on monitored hematological parameters (hemoglobin, hematocrit, total/differential leucocyte
counts) at doses of 10 mg/kg/day for male dogs and 50 mg/kg/day for female dogs (Ambrose et al. 1970).
Similarly, no effects were seen on monitored hematological parameters (hemoglobin, hematocrit,
total/differential leucocyte counts) in rats orally administered chlorfenvinphos (21 mg/kg/day, males;

24 mg/kg/day, females) for 104 weeks (Ambrose et al. 1970).

Musculoskeletal. In animal studies, no gross or microscopic histopathology changes in the
musculoskeletal system were observed in dogs orally administered chlorfenvinphos at doses as high as

50 mg/kg/day (females) for 12 weeks, or in rats at doses as high as 24 mg/kg/day (females) for 104 weeks
(Ambrose et a]. 1970).

Hepatic EffeCts. The limited information on the hepatic effects of chlorfenvinphos indicates that the
substance is not signiﬁcantly hepatotoxic by the oral route in acute- or intermediate-duration exposure. No
changes in liver weight (relative to body weight) were reported in Fischer 344 rats given a single oral
chlorfenvinphos dose of 15 mg/kg. However, P-450 activity was increased by 30%. Aminopyrine-
N—demethylase and aniline hydroxylase activities were also increased by 40 and 27%, respectively (Ikeda et
al. 1991). Mature Wistar rats of both sexes were kept on diets containing 4.5% of casein (low-protein diet),
26% of casein (optimal-protein diet), or standard (Murigran) diet and 30 mg/kg/day of chlorfenvinphos for
30 days to evaluate the effects of oral chlorfenvinphos exposure on serum activity of sorbitol dehydrogenase

(SDH), and on brain and liver activities of the aromatic amino acids transferases L-phenylalanine

CHLORFENVINPHOS 33

2. HEALTH EFFECTS

aminotransferase (Phen AT), L—tyrosine aminotransferase (Tyr AT), and L-tryptophan aminotransferase
(Try AT). Both male and female rats exhibited disturbances in the activities of these enzymes.
Chlorfenvinphos signiﬁcantly decreased the activities of Phen AT (females = 41%, P<0.01), Tyr AT
(females = 30, P<0.01), and Try AT (males = 20%, females = 42%, P<0.01) in the brain of the rats.
Concomitantly, chlorfenvinphos signiﬁcantly increased the activities of Phen AT (males = 37%, females =
54%, P<0.01), Tyr AT (males = 75, female = 150%, P<0.001)), and Try AT (males = 109%, females =
62%, P<0.001) in the liver of the rats, and developed a rise in the activity of sorbitol dehydrogenase (SDH)
in serum (4.5% protein diet, males = NS, females = 94%; standard diet, males = 51%, females = 105%).
There was also a 32% decrease in serum glucose-6-phosphate isomerase in females. In general, these
changes were more pronounced in female rats fed standard Murigran diet. However, no changes in protein

levels were reported in the study (Puzynska 1984).

In other animal studies, no gross or microscopic histopathology in liver tissues was evident in weanling
albino (Wistar) rats administered daily chlorfenvinphos doses of 0.27, 0.9, 2.7, 9, or 90 mg/kg/day (males)
or 0.3, l, 3, 10, or 100 mg/kg/day (females) in the diet for 12 weeks (Ambrose et a1. 1970). In a chronic
study (104 weeks) in which this strain of rats (both sexes) was given daily dietary chlorfenvinphos doses of
0.7, 2.1, 7, or 21 mg/kg/day (males) or 0.8, 2.4, 8, or 24 mg/kg/day (females), increased relative liver
weights were observed in males at the 7 mg/kg/day dose level. No gross or microscopic histopathology in
the liver tissues examined or changes in relative liver weights were reported at any dose level (Ambrose et

al. 1970). Hepatic function was not assessed in this study.

No gross or microscopic liver histopathology or changes in relative liver weights were evident in mongrel
dogs administered daily chlorfenvinphos doses of 0.01, 0.1, 1, or 10 mg/kg/day (males) or 0.05, 0.5, 5, or
50 mg/kg/day (females) for 12 weeks (Ambrose et a1. 1970). Similarly, no gross or microscopic liver
histopathology or signiﬁcant changes in relative kidney weights were evident in Beagle dogs (2/sex) fed
daily dietary chlorfenvinphos doses of 0.3, 2, or 10 mg/kg/day (males), or 1.5, 10, or 50 mg/kg/day
(females) for 104 weeks. No adverse effects on liver function as indicated by alterations in serum
bromosulfalein (BSP), serum glutamic oxaloacetic transaminase (SGOT), and serum alkaline phosphatase

(SAP) or in blood urea nitrogen (BUN) levels were reported for the test animals (Ambrose et a1. 1970).

Renal Effects. The relative kidney weight ratios of weanling albino (Wistar) rats administered daily
chlorfenvinphos doses of 0.27, 0.9, 2.7, 9, or 90 mg/kg/day (males), or 0.3, 1, 3, 10, or 100 mg/kg/day
(females) in the diet for 12 weeks were signiﬁcantly and irreversibly decreased at the 2.7 mg/kg/day (males)

CHLORFENVINPHOS 34

2. HEALTH EFFECTS

and 3 mg/kg/day (females) dose levels (Ambrose et al. 1970). However, no quantitative data on the
reduction of relative kidney weight were provided in this study. No gross or microscopic histopathology in
the kidney and urinary bladder tissues examined or changes in relative kidney weights were evident in
Wistar rats of both sexes given daily dietary chlorfenvinphos doses of 0.7, 2.1, 7, or 21 mg/kg/day (males)
or 0.8, 2.4, 8, or 24 mg/kg/day (females) in a chronic study (104 weeks) (Ambrose et al. 1970). Renal

function was not assessed in either study.

No gross or microscopic histopathology in kidney tissues or changes in relative kidney weights were evident
in mongrel dogs administered daily chlorfenvinphos doses of 0.01, 0.1, 1, or 10 mg/kg/day (males) or 0.05,
0.5, 5, or 50 mg/kg/day (females) for 12 weeks (Ambrose et al. 1970). Similarly, no gross or microscopic
renal histopathology or signiﬁcant changes in relative kidney weights were evident in Beagle dogs fed daily
dietary chlorfenvinphos doses of 0.3, 2, or 10 mg/kg/day (males), or 1.5, 10, or 50 mg/kg/day (females) for

104 weeks (Ambrose et al. 1970). However, renal function was not assessed in these studies.

Endocrine Effects. A signiﬁcant increase (>300%) in plasma corticosterone was observed at 1 and
3 hours and in plasma aldosterone from 1 to 6 hours after treatment of male Wistar rats with a single
chlorfenvinphos dose of 6. 1 5 mg/kg (50% LDSO) by stomach tube. Maximal increase in plasma
corticosteroid levels occurred within 1 hour, while the brain cholinesterase activity was only slightly
inhibited at that time. The authors surmised that changes in plasma corticosteroids are not related to the
decrease of cholinesterase activity in the brain (Osicka—Koprowska et a1. 1984). The toxicological

signiﬁcance of these ﬁndings is unknown.

No gross or microscopic histopathology was evident in endocrine organs (pancreas, thyroid, adrenal,
pituitary) of weanling albino (Wistar) rats or Beagle dogs given oral doses of up to 100 mg/kg/day (female
rats) or 50 mg/kg/day (female Beagle dogs) chlorfenvinphos for 12 weeks (Ambrose et al. 1970). Similarly,
no gross or microscopic histopathology was evident in endocrine organs (pancreas, thyroid, adrenal,
pituitary) of weanling albino (Wistar) rats of both sexes chronically (104 weeks) given daily dietary
chlorfenvinphos doses of 0.7, 2.1, 7, or 21 mg/kg/day (males) or 0.8, 2.4, 8, or 24 mg/kg/day (females)
(Ambrose et al. 1970).

Dermal Effects. No adverse changes were observed in the skin of weanling albino (Wistar) rats of both
sexes given oral doses of up to 100 mg/kg/day (female rats) chlorfenvinphos for 12 weeks (Ambrose et al.

1970). Similarly, no adverse changes were observed in the skin of weanling albino (Wistar) rats of both

CHLORFENVINPHOS 35

2. HEALTH EFFECTS

sexes chronically (104 weeks) given daily dietary chlorfenvinphos doses of 0.7, 2.1, 7, or 21 mg/kg/day
(males) or 0.8, 2.4, 8, or 24 mg/kg/day (females) (Ambrose et al. 1970).

Body Weight Effects. A signiﬁcant but slightly reversible depression on growth was observed at

9 mg/kg/day (males) or 10 mg/kg/day (females) in weanling albino (Wistar) rats. The rats were
administered daily chlorfenvinphos doses of 0.27, 0.9, 2.7, 9, or 90 mg/kg/day (males) or 0.3, 1, 3, 10, or
100 mg/kg/day (females) in the diet for 12 weeks (Ambrose et al. 1970). In an accompanying chronic study
(104 weeks) in which this strain of rats (both sexes) was given daily dietary chlorfenvinphos doses of 0.7,
2.1, 7, or 21 mg/kg/day (males) or 0.8, 2.4, 8, or 24 mg/kg/day (females), no consistent difference in body
weight gains in males was evident at any dose level tested, as compared to undosed controls. However,
chlorfenvinphos exposure caused a signiﬁcant decrease in body weight gain in females in the 8 and

24 mg/kg/day dose groups from the 26th week until near the end of the study. The decreased body weight
gain became statistically insigniﬁcant at the end of the study (Ambrose et al. 1970). In another rat study,
body weight gains in adult female albino (Wistar) rats were unaffected following orally administered
Birlane® (chlorfenvinphos) at a dose of 0 or 2.4 mg/kg/day in the diet for 10 days or 0 or 0.8 mg/kg/day in
the diet for 30 days (Bama and Simon 1973).

Likewise, no signiﬁcant effect on body weight was observed in mongrel dogs following dietary
chlorfenvinphos doses of 0.01, 0.1, 1, or 10 mg/kg/day (males), or 0.05, 0.5, 5, or 50 mg/kg/day (females)
for 12 weeks (Ambrose et al. 1970). In a chronic study (104 weeks) in which Beagle dogs were given daily
dietary chlorfenvinphos doses of 0.3, 2, or 10 mg/kg/day (males), or 1.5, 10, or 50 mg/kg/day (females), no
signiﬁcant changes in body weight were evident at any dose level tested, as compared to undosed controls

(Ambrose et al. 1970).

Metabolic EffeCts. In animal studies, pairs of Carworth Farm E strain male rats orally administered a
single [‘4C]chlorfenvinphos dose of 2.5 or 13.3 mg/kg in olive oil (with or without prior monooxygenase

induction with dieldrin) exhibited minimal changes in the metabolic proﬁles (Hutson and Wright 1980).

Other Systemic Effects. No signiﬁcant effect on food consumption was observed in weanling albino
(Wistar) rats administered daily chlorfenvinphos doses of 0.27, 0.9, 2.7, 9, or 90 mg/kg/day (males) or 0.3,
1, 3, 10, or 100 mg/kg/day (females) in the diet for 12 weeks (Ambrose et al. 1970). In a chronic study
(104 weeks) in which weanling albino (Wistar) rats of both sexes were given daily dietary chlorfenvinphos

doses of 0.7, 2.1, 7, or 21 mg/kg/day (males) or 0.8, 2.4, 8, or 24 mg/kg/day (females), no consistent

CHLORFENVINPHOS 36

2. HEALTH EFFECTS

difference in food consumption was evident at any dose level tested, as compared to undosed controls
(Ambrose et al. 1970). In dog studies, no signiﬁcant effect on food consumption was observed in mongrel
dogs given dietary chlorfenvinphos doses of 0.01, 0.1, 1, or 10 mg/kg/day (males) or 0.05, 0.5, 5, or

50 mg/kg/day (females) for 12 weeks (Ambrose et al. 1970). Similarly, no signiﬁcant changes in food
consumption were evident at any dose level tested in a chronic study (104 weeks) in which Beagle dogs
were given daily dietary chlorfenvinphos doses of 0.3, 2, or 10 mg/kg/day (males) or 1.5, 10, or

50 mg/kg/day (females) (Ambrose et a1. 1970).

2.2.2.3 Immunological and Lymphoreticular Effects

No studies were located regarding the immunological and lymphoreticular effects in humans following

acute-, intermediate-, or chronic-duration oral exposure to chlorfenvinphos.

The limited information on the immunological and lymphoreticular effects of chlorfenvinphos indicates that
the substance is moderately immunotrophic to the rodent immune system in oral exposures. The gastro-
intestinal absorption of glucose was increased by 30% over control values in adult female albino (Wistar)
rats orally administered Birlane® (chlorfenvinphos) at a dose of 0 or 2.4 mg/kg/day in the diet for 10 days.
Similarly, gastrointestinal absorption of glucose was increased by 12% over control values following orally
administered Birlane® (chlorfenvinphos) at a dose of 0 or 0.8 mg/kg/day in the diet of Wistar rats for

30 days. The changes in glucose and Na+ absorption were not considered statistically signiﬁcant (P>0.05)
by the investigators (Bama and Simon 1973). It has been observed in other studies that an increased
metabolic activity of neutrophils and monocytes during phagocytosis is accompanied by higher
consumption of glucose and oxygen. Hydrogen peroxide is then derived from the pentose cycle, NAD—, and
NADP-oxidase action (Kolanoski 1977 as cited in Wysocki et al. 197 7). The relationship between

increased gastrointestinal absorption of glucose and increased glucose utilization is not clear.

In an intermediate-duration dietary study with albino (Wistar) rats, there was a signiﬁcant and irreversible
reduction in relative spleen weight of female rats given 23 mg/kg/day chlorfenvinphos for 12 weeks.
However, no gross or microscopic histopathology was evident in the spleen and bone marrow tissues of the
rats upon examination (Ambrose et al. 1970). In dogs, relative spleen weights were unaffected following
dietary doses of 10 mg/kg/day (males) or 50 mg/kg/day (females) to mongrel dogs for 12 weeks. In

addition, no gross or microscopic histopathology was evident in the spleen and bone marrow tissues of the

CHLORFENVINPHOS 37

2. HEALTH EFFECTS

dogs upon examination (Ambrose et al. 1970). No quantitative data on the reduction of relative spleen

weights were provided in these studies.

A study was undertaken to evaluate selected serological and cytoimmunological reactions in rabbits
subjected to a long-term poisoning with subtoxic oral doses (10 mg/kg in a soya oil solution with a small
amount of food) of chlorfenvinphos for 90 days (shortened chronic poisoning). Both control group (soya
oil) and treatment group rabbits were immunized with sheep red blood cells 6 days prior to ending the
experiment. Chlorfenvinphos treatment signiﬁcantly elevated serum hemagglutinin level (16%) and
hemolysin activity (66%, P<0.05) and increased the number of nucleated lymphoid cells producing
hemolytic antibody to sheep erythrocytes as compared to controls (treated 906, P<0.05 and controls 618).
Spleen cytomorphology changes, manifested mainly as transformation of primary follicles into secondary
ones with well developed germinal centers, were also observed (Roszkowski 1978). After 90 days of oral
intoxication of C57BL/6 mice and (C57BL/6 x DBA/2)F1 (BDFl/Iiw) hybrid mice (6—8-weeks—old) with
chlorfenvinphos (suspended in 1% methylcellulose solution), a dose-related decrease in number of
hemolysin-producing cells was observed. Plaque-forming cells (PFC) were 58% at the 6 mg/kg dose group
and 85% at the 3 mg/kg dose level, as compared to control values. Chlorfenvinphos treatment also caused
reduction in E rosettes-forming cell numbers by 30% at the 6 mg/kg dose level, 25% at the 3 mg/kg dose
level, and 45% at the 6 mg/kg dose level. Spleen colonies were stimulated as evidenced by the increase of
endogenous spleen colonies; and exogenous spleen colonies (CFU-S) increased 190% at the 1.5 mg/kg dose
level, 137% at the 6 mg/kg dose level, 162% at 1.5 mg/kg dose level, and 70% at the 6 mg/kg dose level,
respectively. When the IgM PFC number was tested 3 weeks later, after the exposure to chlorfenvinphos in
the small dose (1.5 mg/kg), an increase (about 40%) in plaque number was observed. There was a 50%
reduction in thymus weight at the 1.5 mg/kg dose level, as compared to controls, as well as signiﬁcant
involution of the thymus. IgM levels returned to normal values, indicating the reversible nature of the
immunotrophic effect of chlorfenvinphos (Kowalczyk-Bronisz et a1. 1992). The LOAEL of 1.5 mg/kg/day,
based on adverse immunologic/lymphoreticular effects in this study, was used to derive an intermediate oral

MRL of 0.002 mg/kg/day for chlorfenvinphos.

In a chronic-duration (104 weeks) dietary study in which weanling albino (Wistar) rats of both sexes were
given daily dietary chlorfenvinphos doses of 0.7, 2.1, 7, or 21 mg/kg/day (males) or 0.8, 2.4, 8, or

24 mg/kg/day (females), no histopathological changes in the spleen or bone marrow were evident at any
dose level tested, as compared to undosed controls. In addition, no changes in absolute or relative spleen

weights were reported (Ambrose et a1. 1970). Likewise, no histopathological changes in the spleen or bone

CHLORFENVINPHOS 38

2. HEALTH EFFECTS

marrow were evident in Beagle dogs given daily dietary chlorfenvinphos doses of 0.3, 2, or 10 mg/kg/day
(males) or 1.5, 10, or 50 mg/kg/day (females) for 104 weeks. In addition, no changes in absolute or relative

spleen weights were reported (Ambrose et al. 1970).

The highest NOAEL values and all reliable LOAEL values for immunological and lymphoreticular effects

in each species and duration category are presented in Table 2-2 and plotted in Figure 2-2.
2.2.2.4 Neurological Effects

No studies were located regarding neurological effects in humans following intermediate- or chronic-
duration oral exposure to chlorfenvinphos. In humans, chlorfenvinphos inhibits cholinesterase activity in
the central and peripheral nervous system when ingested in acute-duration exposures (Cupp et al. 1975;
Pach et al. 1987). A 16-year-old white male mistakenly took a full swallow of a mange-mite medication
(identiﬁed as Der'rnaton® which contains 25% organophosphate, like chlorfenvinphos, as an active
ingredient) prescribed by a veterinarian for his dog. Approximately 90 minutes later, he was hospitalized
with symptoms of abdominal cramps, nausea, vomiting, generalized weakness, cold dry skin, constricted
pupils, ﬁne generalized muscular twitching, and apprehension. On physical examination, his blood pressure
was 152/102, pulse was 96 and irregular, respiration was 24, and rectal temperature was 94.2 °F. While in
the emergency room, gastric lavage of 4 L was done and 1 mg of atropine given intravenously. On transfer
to the intensive care unit, respiration had increased in rate and depth, skin was warm and slightly
diaphoretic, muscle twitching had increased, and he complained of double vision. Emesis persisted. The
patient developed hypothermia which lasted for 2 hours. Four and one-half hours after admission, the
patient was listless and apathetic, but oriented. Blood analysis showed plasma and erythrocyte
cholinesterase levels of 0.3 and 1.1 umol/minute, respectively. Twenty—four hours later, plasma and
erythrocyte cholinesterase levels were 0.8 and 12.7 pmol/minute, respectively. He was given 1 g of
pralidoxime intravenously over a 15-minute period, repeated in 1 hour. Forty-eight hours after admission,
signs of improvement were evident. The patient was discharged 5 days after admission without residual
effects (Cupp et al. 1975). Another clinical report described anticholinesterase symptoms (unconsciousness,
absence of tendon reﬂexes, 80% reduction of erythrocyte acetylcholinesterase activity, 100% reduction in
plasma pseudocholinesterase activity, respiratory failure, bronchial tree hypersecretion) in a 29-year-old
male patient hospitalized 3 hours after a suicide attempt during which he drank about 50 mL of the

preparation ‘Enolofos®, which contains 50% chlorfenvinphos (Pach et al. 1987).

CHLORFENVINPHOS 39

2. HEALTH EFFECTS

The existing information on neurological effects in animals following acute-, intermediate-, and chronic-
duration oral exposures to chlorfenvinphos indicates that the substance causes disruptions in the central and
peripheral nervous system in rats manifested as cholinesterase inhibition (Bama and Simon 1973; Osicka—
Koprowska et al. 1984; Takahashi et al. 1991) and interference with noradrenaline (norepinephrine) activity
in central adrenergic mechanisms (Brzezinski 1978; Osumi et al. 1975). Inhibition of acetylcholinesterase
activity results in accumulation of acetylcholine at muscarinic and nicotinic receptors leading to peripheral
and central nervous system effects. These effects usually appear within a few minutes to a few hours after
exposure depending on the extent of exposure. When chlorfenvinphos was evaluated for acute lethality in
animals, death occurred within 12 hours in tested rats, rabbits, and dogs and was usually preceded by the
characteristic signs of cholinergic response—salivation, lacrimation, muscle fasciculation, diarrhea, emesis,

tremors, irregular respiration, and prostration (Ambrose et al. 1970, Ikeda et al. 1992).

In acute-duration studies, brain cholinesterase activity was strongly inhibited in male Fischer 344 rats

(8 weeks old) that were orally treated with 30 mg/kg chlorfenvinphos or pretreated with 15 mg/kg for

24 hours before treatment with 30 mg/kg chlorfenvinphos. This was accompanied by clinical
anticholinesterase symptoms which included salivation, fasciculation, lacrimation, tremors, irregular
respiration, and prostration which resulted in deaths 1—24 hours after administration of the chlorfenvinphos
doses. Although chlorfenvinphos pretreatment did not change the nature of these symptoms, it aggravated
the inhibition of brain cholinesterase activity (Ikeda et al. 1992). Plasma and erythrocyte cholinesterase
activities were inhibited by 52 and 30%, respectively, at the only tested Birlane® (chlorfenvinphos) dietary
dose of 2.4 mg/kg/day administered to adult female albino (Wistar) rats for 10 days (Bama and Simon
1973). The LOAEL of 2.4 mg/kg/day from the 10—day dosing protocol of this study, based on adverse

neurological effects in rats was used to derive an acute oral MRL of 0.002 mg/kg/day for chlorfenvinphos.

Brain and erythrocyte acetylcholinesterase, and plasma pseudocholinesterase activities were reduced by
290% and 50%, respectively, following acute oral treatment of male Sprague-Dawley rats with
chlorfenvinphos. Rats administered chlorfenvinphos orally attained maximum inhibition of cholinesterase
activity in less than two hours. The rats also exhibited cholinergic signs that included fasciculations,
twitches, convulsions, chromodacryorrhea, exophthalmos, gasping, lacrimation, prostration, salivation,
Straub tail reﬂex, and urination. The clinical signs lasted for 8 hours. No effects were observed at the
1.25 mg/kg dose level (Takahashi et al. 1994). Cholinesterase activity in the brain of male Wistar rats was
unaffected 3 hours after oral administration of 1 mg/kg of chlorfenvinphos. However, at doses of 2 and

4 mg/kg, oral chlorfenvinphos produced marked decreases in the brain cholinesterase activity to 38 and 18%

CHLORFENVINPHOS 4o

2. HEALTH EFFECTS

of control (P<0.001), respectively. The maximum inhibition occurred 3 hours aﬁer administration, after which
the cholinesterase activity elevated gradually. Activity in the brain decreased steadily with time and, at

72 hours, still remained 67% of control. Erythrocyte acetylcholinesterase activity also decreased after 4 mg/kg
of chlorfenvinphos; the lowest level (20%, P<0.001) was attained 3 hours after treatment (Osumi et a1. 1975).

Acute oral exposure to chlorfenvinphos was also associated with reversible sleep disturbance in male Wistar
rats. Single oral chlorfenvinphos doses up to 1 mg/kg did not affect the awake-sleep cycle in the rats, but
spontaneous electroencephalogram (EEG) showed a prominent arousal pattern and appearance of slow wave
sleep and parasleep was markedly depressed in doses over 2 mg/kg. The duration of arousal pattern was
proportional to the doses but, nonetheless, the awake-sleep cycle returned to control values on the second day;
a rebound increase in parasleep occurred on the third day at doses over 4 mg/kg. Atropine at a dose of

2 mg/kg (administered to one rat 2 hours after chlorfenvinphos administration) was antidotal to the
chlorfenvinphos-induced disturbance of EEG arousal pattern, depressing the EEG arousal pattern without
affecting cholinesterase activity in the brain. As a positive control, physostigmine, a reversible cholinesterase
inhibitor, in doses of 0.05 and 0.1 mg/kg, produced an increase in wakefulness during the ﬁrst hour.
Thereafter, the arousal pattern was reduced, and slow wave sleep and parasleep patterns increased, as
compared with the control, 3~5 hours aﬁer the administration of chlorfenvinphos. According to these
investigators, appearance of EEG arousal pattern after treatment with chlorfenvinphos is indicative of central
cholinergic activation. A LOAEL of 2 mg/kg with a NOAEL of 1 mg/kg for 38% decrease in brain
cholinesterase activity and reversible sleep disturbances was determined in this study (Osumi et al. 1975).
This study was not used to calculate an acute oral MRL because it was deemed less appropriate because of the

gavage (oral) route of administration. An oral feeding study is preferred for this purpose by ATSDR.

In intermediate-duration studies, plasma and erythrocyte cholinesterase activities were inhibited by 36 and 3%,
respectively, at a chlorfenvinphos dose of 0.8 mg/kg/day following dietary administration of 0 or

0.8 mg/kg/day Birlane® (chlorfenvinphos) to adult female albino (Wistar) rats for 30 days (Bama and Simon
1973). However, the change in erythrocyte acetylcholinesterase activity was not considered signiﬁcant and
therefore, this study was not used to derive an intermediate MRL. Similarly, the change in plasma
pseudocholinesterase was not used to derive an intermediate MRL because while the inhibition of plasma
pseudocholinesterase may have some physiological signiﬁcance, alteration in the levels of this enzyme is
generally regarded more as a biomarker of exposure to organophosphate compounds than as an adverse

neurological effect. In other intermediate rat studies, mature rats of both sexes kept on diets containing 4.5% ‘

CHLORFENVINPHOS 41

2. HEALTH EFFECTS

of casein (low-protein diet), 26% of casein (optimal—protein diet), or standard (Murigran) diet for 30 days
exhibited depressed cholinesterase activities following oral exposure to chlorfenvinphos. These alterations
consisted of signiﬁcant inhibition in pseudocholinesterase activity in the serum (4.5% protein diet: males =
97%, females = 96%; standard diet: males = 87%, females = 93%) and brain (4.5% protein diet: males = 83%,
females = 87%; standard diet: males = 58%, females = 39%), with more pronounced effects in the brain of
female rats fed low-protein diets (87%). The activity of this enzyme returned to normal values 14 days after
dosing (Puzynska 1984). Blood and plasma cholinesterase activity was depressed at 29 mg/kg/day (males) or
210 mg/kg/day (females), with a NOAEL of 2.7 mg/kg/day (males) or 3 mg/kg/day (females) following
dietary administration of chlorfenvinphos doses of 0.27, 0.9, 2.7, 9, or 90 mg/kg/day (males), or 0.3, 1, 3, 10,
or 100 mg/kg/day (females) in the diet to weanling albino (Wistar) rats for 12 weeks. No gross or microscopic
histopathology was evident in the brain tissues examined (Ambrose et a1. 1970). Similarly, plasma
cholinesterase activity was consistently depressed, while erythrocyte cholinesterase activity was sporadically
depressed in all dose groups in mongrel dogs administered daily chlorfenvinphos doses of 0.01, 0.1, 1, or

10 mg/kg/day (males) or 0.05, 0.5, 5, or 50 mg/kg/day (females) in the diet for 12 weeks. No gross or
microscopic histopathology was evident in the brain and spinal cord tissues examined (Ambrose et a1. 1970).
Due to incomplete reporting of this study, it was not clear if there was a NOAEL for the inhibition of
erythrocyte cholinesterase activity. No quantitative data on the depression of plasma or erythrocyte

cholinesterase activity were provided in this study.

In another intermediate-duration study, whole blood cholinesterase activity in Sprague-Dawley rats was
markedly inhibited at 3 and 6 months of exposure following exposure to 10.5 mg/kg/day chlorfenvinphos

(0.9 and 0.6x10'6 mol/minute; control, 2.4 and l.9x10‘S mol/minute, respectively, P<0.001). After 3 and

6 months of exposure to chlorfenvinphos, plasma cholinesterase activity was also markedly inhibited (0.4 and
0.4x10" mol/minute; control, 1.9 and l.6x10*S mol/minute, respectively; P<0.001). After 3—6 months, all

36 Sprague-Dawley rats in this study had repetitive and increasingly diminishing muscle ﬁber depolarization
when given double stimuli. The greatest reduction in peak depolarization occurred with an interval of

4 muscle action potential amplitude (ms) and a large but slightly smaller reduction at 7 ms. These phases
probably coincide with refractoriness of some muscle ﬁbers due either to repetitive activity (at 4 ms) or reﬂex
activity (at 7 ms). Double and repetitive stimulation at rates even as low as 0.5 Hz reduced or abolished the
prolonged negative potential and repetitive activity. These abnormalities became more marked with time, even
on constant dosing. Spike potentials were recorded between the direct response and reﬂex responses with
latency similar to the repetitive activity potential. These electrophysiological abnormalities may be attributable

to acetylcholinesterase inhibition at neuromuscular junctions (Maxwell and LeQuesne 1982).

CHLORFENVINPHOS 42

2. HEALTH EFFECTS

In chronic-duration studies, chlorfenvinphos signiﬁcantly inhibited both plasma and erythrocyte cholinesterase
activities in a dose-dependent manner in weanling albino (Wistar) rats fed daily chlorfenvinphos doses of 0.7,
2.1, 7, or 21 mg/kg/day (males) or 0.8, 2.4, 8, or 24 mg/kg/day (females) mg/kg/day in the diet for 104 weeks.
Plasma and erythrocyte cholinesterase activities were inhibited by 48% in females and 45% in males in the
ﬁrst week of treatment and by 20% in females and 33% in males in the fourth week of treatment, respectively,
at the lowest dose tested (0.7 mg/kg/day for males and 0.8 mg/kg/day for females). No gross or microscopic
histopathology was evident in the brain tissue examined (Ambrose et al. 1970). The LOAEL of

0.7 mg/kg/day, based on adverse neurological effects in rats in this study, was used to derive a chronic oral
MRL of 0.0007 mg/kg/day for chlorfenvinphos.

Similarly, chlorfenvinphos signiﬁcantly inhibited both plasma and erythrocyte cholinesterase activities in
Beagle dogs fed daily chlorfenvinphos doses of 0.3, 2, or 10 mg/kg/day (males), or 1.5, 10, or 50 mg/kg/day
(females) in the diet (moist) for 104 weeks. Plasma cholinesterase activities were signiﬁcantly inhibited at all
dietary levels through week 39 of the study; 49% inhibition at ambient air concentrations of 0.3 mg/kg/day
(males) and 1.5 mg/kg/day (females) groups. During the ﬁrst 12 weeks, erythrocyte cholinesterase activity
was signiﬁcantly and consistently inhibited (36%) only in the 10 mg/kg/day (males) and 50 mg/kg/day
(females) dose groups. No gross or microscopic histopathology was evident in the brain and spinal cord

tissues examined (Ambrose et al. 1970).

Besides its cholinergic action, chlorfenvinphos may also act via central noradrenergic mechanisms in rats by
accelerating the noradrenaline (norepinephrine) turnover in the brain in vivo. Three hours after oral
administration of 4 mg/kg of chlorfenvinphos, the brain noradrenaline (norepinephrine) level of male Wistar
rats was reversibly decreased by 16% (Osumi et al. 1975). In another study with male Wistar rats, 13 mg/kg of
oral chlorfenvinphos decreased cerebral noradrenaline (norepinephrine) level by 20% as compared to the
control rats. Other rats that received oral chlorfenvinphos 30 minutes after pretreatment with disulﬁram
injection (400 mg/kg intraperitoneally) as positive controls exhibited a 50% decrease of cerebral

noradrenaline (norepinephrine); the level was observed in time intervals of 1—3 hours, peaking at 89%
decrease after 6 hours. Based on these observations, it was suggested that chlorfenvinphos accelerates the rate
of noradrenaline (norepinephrine) disappearance from the rat brain in vivo. Thus, besides being a cholinergic
agent, chlorfenvinphos may also act via central noradrenergic mechanisms, disturbing the dynamic equilibrium
between the rate of formation and utilization of noradrenaline (norepinephrine). It was postulated that this
action via central noradrenergic mechanisms by chlorfenvinphos may be responsible for the changes in blood

pressure observed in other studies after chlorfenvinphos intoxication (Brzezinski 1978).

CHLORFENVINPHOS 43

2. HEALTH EFFECTS

Sprague-Dawley rats fed chlorfenvinphos doses of 10.5 mg/kg/day for 1 year had repetitive and increasingly
diminishing muscle ﬁber depolarization when given double stimuli. The greatest reduction in peak
depolarization occurred with an interval of 4 muscle action potential amplitude (ms) and a large but slightly
smaller reduction at 7 ms. These phases probably coincide with refractoriness of some muscle ﬁbers due
either to repetitive activity (at 4 ms) or reﬂex activity (at 7 ms). These electrophysiological abnormalities may

be attributable to acetylcholinesterase inhibition at neuromuscular junctions (Maxwell and LeQuesne 1982).

The highest NOAEL values and all reliable LOAEL values for neurological effects in each species and
duration category are presented in Table 2—2 and plotted in Figure 2-2.

2.2.2.5 Reproductive Effects

No studies were located regarding reproductive effects in humans following acute-, intermediate-, or chronic-

duration oral exposure to chlorfenvinphos.

No studies were located regarding reproductive effects in animals following acute-duration oral exposure to
chlorfenvinphos. The limited information on the reproductive toxicity of chlorfenvinphos indicates that
chlorfenvinphos may interfere with the reproductive competence of rats, In a 3-generation reproductive study,
chlorfenvinphos induced adverse reproductive effects (decreased fertility and maternal body weight gain) at a
LOAEL of 2.7 mg/kg/day in albino (Wistar) rats given chlorfenvinphos at a doses of 2.7, 9, or 27 mg/kg/day
(males) or 3, 10, or 30 mg/kg/day (females) in the diet for 1 1 weeks. The chlorfenvinphos dosed rats were
mated for 20 days to produce an F/ 1a generation and remated, 10 days aﬁer weaning of the F/ 1a pups, to
produce an F/ 1b generation. Each generation was fed the chlorfenvinphos doses for 11 weeks before mating.
The study reported decreased maternal body weights of 3, 5, and 1 1%, respectively, for F/0 parental generation
animals fed 0, 3, or 10 mg/kg/day; 9, 2, and 19%, respectively, for F/1 parental generation animals fed 0, 3, or
10 mg/kg/day; and 14 and 10%, respectively, for F/2 parental generation animals fed 0 or 3 mg/kg/day
chlorfenvinphos. The changes in maternal body weight gain were not considered signiﬁcant. However,
fertility (pregnancy/mating x 100) was decreased by 49% in the F/1b parents at the 10 mg/kg/day dose level.
In the F/2b parents, fertility was decreased by 50% at the 3 mg/kg/day dose level and by 84% in the

10 mg/kg/day dose level. No gross or microscopic histopathology was evident in male and female gonads

examined. No adverse effects on gestation were noted at any exposure levels (Ambrose et a1. 1970).

CHLORFENVINPHOS 44

2. HEALTH EFFECTS

In intermediate-duration studies, chlorfenvinphos had no effect on relative testes weight at any of the doses
tested in weanling albino (Wistar) rats administered daily chlorfenvinphos doses of 90 mg/kg/day (males) or

100 mg/kg/day (females) in diet for 12 weeks. No gross or microscopic histopathology was evident in any of
the gonads (Ambrose et a1. 1970).

In chronic-duration studies, no gross or microscopic gonad histopathology in either sex or changes in the
relative weights of the testes in males were reported in albino (Wistar) rats administered daily

chlorfenvinphos doses of 21 mg/kg/day (males) or 24 mg/kg/day (females) in the diet for 104 weeks (Ambrose
et a1. 1970). Similarly, no gross or microscopic gonad histopathology in either sex or changes in the relative
weights of the testes in males were reported in mongrel dogs administered daily chlorfenvinphos doses of 0.01,
0.1, 1, or 10 mg/kg/day (males) or 0.05, 0.5, 5, or 50 mg/kg/day (females) in the diet for 12 weeks (Ambrose et

al. 1970). Reproductive function was not evaluated in these studies.

The highest NOAEL values and all reliable LOAEL values for reproductive effects in each species and
duration category are presented in Table 2—2 and plotted in Figure 2—2.

2.2.2.6 Developmental Effects

No studies were located regarding developmental effects in humans following acute-, intermediate-, or

chronic-duration oral exposure to chlorfenvinphos.

No studies were located regarding developmental effects in animals following acute-duration oral exposures in
animals. Oral chlorfenvinphos interfered with development in intermediate- and chronic-duration exposures as
well as multigenerational studies in animals. Weanling albino (Wistar) rats administered daily dietary doses of
chlorfenvinphos (0.27, 0.9, 2.7, 9, or 90 mg/kg/day for males; 0.3, 1, 3, 10, or 100 mg/kg/day for females) for
12 weeks exhibited slightly reversible but significant depression of grth at doses of 9 mg/kg/day (males) or
10 mg/kg/day (females). No quantitative data on the depression of grth were provided in the study
(Ambrose et al.1970). In a chronic feeding study (104 weeks) in which weanling albino (Wistar) rats were
given chlorfenvinphos in the diet at doses of 0.7, 2.1, 7, or 21 mg/kg/day (males) or 0.8, 2.4, 8, or

24 mg/kg/day (females) for 104 weeks, chlorfenvinphos signiﬁcantly decreased body weight gain of females at
the 8 and 24 mg/kg/day ambient air concentrations from the 26th week till towards the end of the study. The
decrease in body weight gain was not statistically signiﬁcant at the end of the study. An increased relative

liver weight was observed in males at the 7 mg/kg/day dose level, but no other signs of hepatopathology were

CHLORFENVINPHOS 45

2. HEALTH EFFECTS

reported. No consistent differences in body weight gains in males, survival of the test animals, food
consumption, or mortality were evident at any dose level tested, as compared to undosed controls. No gross or
microscopic histopathology was evident in any of the tissues (heart, lungs, liver, kidney, urinary bladder,
spleen, stomach, small and large intestine, skeletal muscle, skin, bone marrow, pancreas, thyroid, adrenal,
pituitary) examined to indicate teratogenicity. No changes in organ-to-body weight were observed in the heart
and kidney (Ambrose et al. 1970). Dietary exposure to chlorfenvinphos exposure caused decreases in viability
and lactational indices in a 3-generation reproductive study with albino (Wistar) rats. In this study, the rats
were given chlorfenvinphos in the diet at doses of 2.7, 9, or 27 mg/kg/day (males) or 3, 10, or 30 mg/kg/day
(females) for 11 weeks. The chlorfenvinphos-dosed rats were mated for 20 days to produce an F/ 1a generation
and remated 10 days after weaning of the F/ 1a pups to produce an F/lb generation. Each generation was fed
the chlorfenvinphos doses for 11 weeks before mating. The pup Viability index (pups surviving 5 days/pups
born alive x 100) decreased by 66% for F/ 1b pups at a maternal dose of 10 mg/kg/day. No offspring in the

27 mg/kg/day (males) or 30 mg/kg/day (females) dose group survived beyond the F1 generation. The lactation
index was also decreased by 46% in the F/ lb offsprings at the 10 mg/kg/day dose level. No gross or
microscopic histopathology was evident in any of the tissues examined. There were no gross signs of

teratogenicity (Ambrose et al. 1970).

The highest NOAEL values and all reliable LOAEL values for developmental effects in each species and
duration category are presented in Table 2-2 and plotted in Figure 2-2.

2.2.2.7 Genotoxic Effects

No studies were located regarding genotoxic effects in animals after oral exposure to chlorfenvinphos. Other

genotoxicity studies are discussed in Section 2.5.

2.2.2.8 Cancer

No studies were located regarding carcinogenic effects in humans or animals following oral exposure to

chlorfenvinphos.

CHLORFENVINPHOS 46

2. HEALTH EFFECTS

Figure 2-3. Proposed Mammalian Metabolic Pathway for Chlorfenvinphos

   

 

r = 14C-Iabeled]
OH
0 ' o
02H50 ~ 4 CH CHO\ /, 02H50\ //
/P\ / H 3 , \ /H / \ /H
Cszo O'C‘=C\CI CH30H20 0- =C< CI HO 0-0:me
C| Liver microsomes, CI [oxidalive de-ethylation] CI
NADPH,02
O
/
0| Cl CHac: Cl
Chlorolenvinphos H . l | H
[Zh'cm‘im71'|(2'.'4"hdi|°"‘1'°'°h emiacea Acetylaldehyde 2-Chloro-1-(2',4‘-dich|orophenyl)
p eny)vnny d'e‘ yp osp ale] vinylethylhydrogen phosphate
(rat, dog)
o=c*—CH201 o=C'—CHa
Cl Cl
__.——.
Diethylphosphoric acid glultathione-S translerase
CI CI
2,4-Dichlorophenacylchloride 2,4-Dichloroacetophenone
Reductase/NADH C'H(QH)CH20H Reduclase/
liver microsomes NADH
Cl
C'H(OH)CH2CI C‘H(OH)CH3
//'v "V
CI CI M
‘ 2,4-Dichloro-
phenyl ethanediol
Cl
2-Chloro-1-(2',4'-dichlord Glucuronyl 1-(2',4‘-Difhlorophenyl)
phenyl) ethanol UDPGA l"an5:|'ase ethanol
Glucuronyl
O CH CH CH OG lransferase
C'H(0H)cf ( ) 2 UDPGA
OG 60— CH— CH3
Cl
Cl . . -
2 4-Dichloromandelic 1-(2 '4 -D|chlorophenyl)
'- - elhanedioI-2-glucuronide
acud glucuronlde (rat, dog) 1-(2‘,4--Dicchlorophenyl)
ethanol glucuronide
(rat, dog)
C'H(OH)COZH COOH CONHCHZCOOH
CI Cl CI
—T’ ﬂ
CI 002 CI Cl
2,4—Dichloromandelic acid 2,4—Dichloro- 2,4-Dichloro

(rat, dog) benzoic acid benzoyl glycine

CHLORFENVINPHOS 47

2. HEALTH EFFECTS

2.2.3 Dermal Exposure
2.2.3.1 Death

No studies were located regarding death in humans after acute-, intermediate-, or chronic-duration dermal

exposure to chlorfenvinphos.

The dermal LD,o values in rabbits for undiluted chlorfenvinphos and emulsiﬁable concentrate have been

estimated to be 400 and 1,087 mg/kg, respectively (Ambrose et a1. 1970).
2.2.3.2 Systemic Effects

No studies were located regarding respiratory, cardiovascular, gastrointestinal, hematological, hepatic,
musculoskeletal, hepatic, renal, endocrine, dermal, ocular, body weight, metabolic, or other systemic effects in

humans or animals following acute-, intermediate-, or chronic-duration dermal exposure to chlorfenvinphos.
2.2.3.3 Immunological and Lymphoreticular Effects

No studies were located regarding immunological and lymphoreticular effects in humans or animals after

acute-, intermediate-, or chronic-duration dermal exposure to chlorfenvinphos.
2.2.3.4 Neurological Effects

No studies were located regarding neurological effects in humans after intermediate-, or chronic-duration
dermal exposure to chlorfenvinphos. Dermally-applied chlorfenvinphos formulations signiﬁcantly inhibited
plasma cholinesterase activity in healthy human male volunteers without prior occupational exposure to the
substance. Three different chlorfenvinphos formulations were used in this study: 80% weight per volume
(w/v) emulsiﬁable concentrate (EC), mainly chlorfenvinphos and emulsiﬁers; 24% w/v EC, mainly isometric
trimethyl benzenes with 41/2% w/v emulsiﬁers; 25% w/w wettable powder (WP), mainly colloidal silica,
ﬁorisil, triphenylphosphate, sodium triphosphates, empicol LZ and tamal. The formulations were
administered separately in single applications to the forearm skin of 9 adult human males for periods up to

4 hours in doses of 4—10 mg chlorfenvinphos/kg body weight. The 80% EC and 25% EC formulations had no

effect on cholinesterase activity levels in the volunteers. Only plasma and erythrocyte cholinesterase activities

CHLORFENVINPHOS 48

2. HEALTH EFFECTS

of volunteers who received a single application of the 24% emulsiﬁable concentrate (5 and 10 mg
chlorfenvinphos/kg body weight equivalent to a dermal dose of 5 mg/cmz) were inhibited. Plasma and

erythrocyte cholinesterase were inhibited by 53-76% and 9%, respectively (Hunter 1969).

No studies were located regarding neurological effects in animals aﬁer intennediate— or chronic-duration
dermal exposure to chlorfenvinphos. Acute-duration dermal exposure of laboratory animals to
chlorfenvinphos resulted in the depression of plasma cholinesterase without clinical symptoms. Two dogs of
unspeciﬁed sex treated with a daily dose of 0.3% chlorfenvinphos applied topically to the spinal area from
head to tail for 7 days (3 consecutive days, 1 day skipped, then 4 consecutive days) suffered 28% depression in
plasma cholinesterase activity by day 8. No clinical signs resulting ﬁom cholinesterase depression were

observed in any of the dogs (V estweber and Kruckenberg 1972).

2.2.3.5 Reproductive Effects

No studies were located regarding reproductive effects in humans or animals after acute-, intermediate-, or

chronic-duration dermal exposure to chlorfenvinphos.

2.2.3.6 Developmental Effects

No studies were located regarding developmental effects in humans aﬁer acute-, intermediate-, or chronic-

duration dermal exposure to chlorfenvinphos.

2.2.3.7 Genotoxic Effects

No studies were located regarding genotoxic effects of chlorfenvinphos in humans or animals following

dermal exposure.

Other genotoxicity studies for chlorfenvinphos are described in Section 2.5.

2.2.3.8 Cancer

No studies were located regarding carcinogenic effects in humans or animals after dermal exposure to

chlorfenvinphos.

CHLORFENVINPHOS 49

2. HEALTH EFFECTS

2.3 TOXICOKINETICS

The absorption of chlorfenvinphos after inhalation exposure in humans or animals is unknown due to lack of
data. Ingested chlorfenvinphos is rapidly absorbed in humans. In animals, oral chlorfenvinphos is also well
absorbed to an extent of 267.1—72.5% of the administered dose. Although no information on the dermal
absorption of chlorfenvinphos in animals is available, dermally applied chlorfenvinphos formulations were
rapidly and extensively absorbed in humans; the rate and extent of absorption was dependent on solvents used

in the preparation.

In humans, absorbed chlorfenvinphos is widely distributed and has been detected in compartments that include
serum, cervical mucus, follicular and sperm ﬂuids, and milk at levels of up to 0.42 ug/kg for environmental
exposures and 15 ng/mL in an acute poisoning case. The distribution of absorbed chlorfenvinphos in animals

is unknown because of lack of data.

In humans, absorbed chlorfenvinphos is extensively metabolized via oxidative dealkylation by liver
microsomal fractions. Based on human and animal data, the mechanism for oxidative dealkylation of
chlorfenvinphos proceeds initially via monooxygenation of the alpha-carbon atom of the alkoxy group to
produce an unstable hemiacetal which breaks down by oxidative 0- and N—alkylation mechanisms to
acetaldehyde and 2-chloro-1-(2,4-dichlorophenyl) vinylethylhydrogen phosphate. Acetophenone produced in
the succeeding step is reduced to the alcohol and conjugated by glutathione transferases. Data from animal
studies suggest that electrophilic metabolic intermediates or epoxides may be produced in the metabolism of

chlorfenvinphos.

The elimination or excretion of chlorfenvinphos in humans and animals after inhalation or dermal exposures is
unknown due to lack of data. In humans, ingested chlorfenvinphos is rapidly removed from the blood and
passed into the tissues. Chlorfenvinphos has been detected in human sperm ﬂuid and milk samples. In
animals, ingested chlorfenvinphos is rapidly eliminated via the urine (70-90%), feces (about 16%), and

expired air (0.5%).

CHLORFENVINPHOS 50

2. HEALTH EFFECTS

2.3.1 Absorption

2.3.1.1 Inhalation Exposure

No studies were located regarding absorption of chlorfenvinphos after inhalation exposure in humans or

animals.

2.3.1.2 Oral Exposure

A 29-year-old male was hospitalized with severe respiratory distress and bronchial tree hypersecretion. The
patient had ingested about 50 mL of the preparation Enolofos®, which contains 50% chlorfenvinphos, in a
suicide attempt. The concentration of chlorfenvinphos in the serum was 300 ng/mL upon admission. This is
the only known human chlorfenvinphos poisoning case in which hemoperfusion intervention was employed.
The mean clearance of chlorfenvinphos during hemoperfusion was low (68 mL/min) and only 0.42 mg of the
poison was recovered. The poison level in the serum was low (15 ng/mL) immediately before the procedure,
and gradually rose in successive blood samples indicating that chlorfenvinphos passes fairly easily from the
tissues into blood. This may be related to secondary resorption from the digestive tract. The highest value of
clearance was observed in the fourth hour of hemoperﬁJsion, in contrast to the observations during
hemoperfusion performed for other drug poisoning, when the value of the clearance was lowest in the last
hour. The serum chlorfenvinphos levels decreased temporarily within a few hours even prior to the beginning
of hemoperfusion, either due to rapid inactivation or to rapid passage into the tissues where the

organophosphates accumulate (Pach et a]. 1987).

In animal studies, a total of 67. 1—72.5% of the administered radioactivity was recovered from the urine of
pairs of Carworth Farm E strain male rats administered [”C]chlorfenvinphos orally at doses of 2.5 or
13.3 mg/kg in olive oil (with or without prior monooxygenase induction with dieldrin). This is suggestive of

gastrointestinal absorption of 267.1—72.5% (Hutson and Wright 1980).
2.3.1.3 Dermal Exposure
A study conducted to assess the potential dermal absorption of chlorfenvinphos for humans (since the most

likely route of entry is through the skin in occupational exposures) applied the substance to the forearm skin of

nine healthy human male volunteers who had no prior occupational exposure to the substance. Three different

CHLORFENVINPHOS 51

2. HEALTH EFFECTS

chlorfenvinphos formulations were used in this study: 80% w/v EC, mainly chlorfenvinphos and emulsiﬁers;
24% w/v EC, mainly isometric trimethyl benzenes with 4.5% w/v emulsiﬁers; 25% weight per weight (w/w)
wettable powder, mainly colloidal silica, ﬂorisil, triphenylphosphate, sodium triphosphates, empicol L2 and
tamal. The formulations were administered separately in single applications to the forearm skin of nine adult
human males for periods up to 4 hours in doses of 4—10 mg chlorfenvinphos/kg body weight. The 80% EC
formulation was applied at doses of 4, 5, 10, or 10 mg/kg body weight for periods of 4, 3.7, 3.8, or 4 hours on
approximate skin areas of 36, 38, 320, or 336 cm2, respectively. The 24% EC formulation was applied at
doses of 5, 5, 10, 10, or 10 mg/kg body weight for periods of 4, 3.8, 4.1, 4, or 4 hours on approximate skin
areas of 272, 420, 800, 600, or 880 cm2, respectively. The 25% WP formulation was applied at doses of 5 or
5 mg/kg body weight for periods of 4.2 or 3.8 hours on approximate skin areas of 80 or 70 cmz, respectively.
The extent and ease of absorption or permeability factor of the applied doses depended on the formulation,
relating to solvents in the preparation. The dermal absorption of the 80% EC formulation was 1.43, 1.81, 0.06,
or 0.32 mg/cmZ/hour, corresponding to applied doses of 4, 5, 10, or 10 mg/kg body weight for periods of 4, 3.7,
3.8, or 4 hours on approximate skin areas of 36, 38, 320, or 336 cm2, respectively. The dermal absorption of
the 24% EC formulation was 0.18, 0.12, 0.14, 0.20, or 0.08 mg/cmZ/hour corresponding to applied doses of 5,
5, 10, 10, or 10 mg/kg body weight for periods of 4, 3.8, 4.1, 4, or 4 hours on approximate skin areas of 272,
420, 800, 600, or 880 cm2, respectively. The dermal absorption of the 25% wettable powder formulation was
0.35 mg/cmZ/hour corresponding to applied doses of 5 mg/kg body weight for periods of 4.2 hours on
approximate skin areas of 80 cm2. Concentrations of intact chlorfenvinphos of 14.4, 12.0, or 0.5 pg/L were
found 24 hours post-exposure in the blood of volunteers for whom chlorfenvinphos absorption rates of 0.20,
0.14, or 0.08 mg/cmZ/hour, respectively, had been estimated. Concentrations of intact chlorfenvinphos of 22,
3.8, <2.8, 2.9, 2.6, 0.2, or <0.7 rig/L were found 8 hours later in the blood of volunteers for whom
chlorfenvinphos absorption rates of 1.81, 1.43, 0.32, 0.18, 0.12, and 0.06 mg/cmZ/hour, respectively, had been
estimated (Hunter 1969).

No studies were located regarding absorption of chlorfenvinphos after dermal exposure in animals.

2.3.2 Distribution

2.3.2.1 Inhalation Exposure

As an organophosphorus compound, chlorfenvinphos is not expected to accumulate in the body tissues

because of its expected short half-life. However, chlorfenvinphos was found in some of the 41 specimens of

CHLORFENVINPHOS 52

2. HEALTH EFFECTS

cervical mucus, follicular and sperm ﬂuids, and human milk that were examined in Germany. Chlorfen-
vinphos levels of 13.66, 1.69, 2.02, and 1.89 ug/kg were detected in 4 of the 11 samples of cervical mucus.
Chlorfenvinphos levels of 0.42 ug/kg were detected in l of the 10 sperm ﬂuid samples and l of the 10 human
milk samples, respectively. The detection of Chlorfenvinphos in the cervical mucus, which showed the highest
levels, was unexpected because it was believed to be the most unlikely site for accumulation in the body. It
was suggested that a connection exists between the activities of the cervical glands of the endocervix and the
appearance of some pesticides in the cervical mucus which might show a new way for accumulation.
Accordingly, the data indicate that organophosphorus environmental pollutants, like Chlorfenvinphos, can
appear in the human reproductive organs, exposing even germ-cells and, thus, present a risk of interference
with the process of reproduction (Wagner et a1. 1990). Since the data were generated from environmental

exposure, the combined route of exposure may include inhalation.

No studies were located regarding the distribution of Chlorfenvinphos after inhalation exposure in animals.

2.3.2.2 Oral Exposure

Although Chlorfenvinphos is a hydrophilic substance, it has hitherto not been widely found in human tissues
because it is not expected to persist in these tissues. As an organophosphorus compound, Chlorfenvinphos is
not expected to accumulate in the body tissues because of its expected short half-life. However,
Chlorfenvinphos was found in some of the 41 specimens of cervical mucus, follicular and sperm ﬂuids, and
human milk that were examined. Chlorfenvinphos levels of 13.66, 1.69, 2.02, and 1.89 ug/kg were detected in
4 of the 11 samples of cervical mucus. Chlorfenvinphos levels of 0.42 ug/kg were detected in l of the

10 sperm ﬂuid samples and 1 of the 10 human milk samples, respectively. The detection of Chlorfenvinphos in
the cervical mucus, which showed the highest levels, was unexpected because it is the most unlikely
compartment for accumulation in the body. It was suggested that a connection exists between the gland’s
activities and the appearance of some pesticides in the cervical mucus, which might show a new way for
accumulation. Accordingly, these data indicate that new environmental pollutants, like Chlorfenvinphos, can
appear in the human organs, exposing even germ-cells and, thus, present a risk of adverse effects on
reproduction (Wagner et al. 1990). Since the data were generated from environmental exposure, the combined

route of exposure possibly include oral.

A 29-year-old male was hospitalized with severe respiratory distress and bronchial tree hypersecretion. The

patient had ingested about 50 mL of the preparation Enolofos®, which contains 50% Chlorfenvinphos, in a

CHLORFENVINPHOS 53

2. HEALTH EFFECTS

suicide attempt. The concentration of chlorfenvinphos in the serum was 300 ng/mL upon admission. This is
the only human chlorfenvinphos poisoning case in which hemoperfusion intervention was employed. The
mean clearance of chlorfenvinphos during hemoperfusion was low (68 mL/minute) and only 0.42 mg of the
poison was recovered. The poison level in the serum was low (15 ng/mL) immediately before the procedure,
and gradually rose in successive blood sampling indicating that chlorfenvinphos passes fairly easily from the
tissues into blood. This may be related to secondary resorption from the digestive tract. The highest value of
clearance was observed in the fourth hour of hemoperfusion, in contrast to the observations during
hemoperfusion performed for other drug poisoning, when the value of the clearance was lowest in the last
hour. The serum chlorfenvinphos levels decreased temporarily within a few hours even prior to the beginning
of hemoperfusion, either due to rapid inactivation or to rapid passage into the tissues where the

organophosphates accumulate (Pach et a1. 1987).

No studies were located regarding the distribution of chlorfenvinphos in animals after oral exposure.

2.3.2.3 Dermal Exposure

No studies were located regarding the distribution of chlorfenvinphos after dermal exposure in humans or

animals.

Although chlorfenvinphos is a hydrophilic substance, it has hitherto not been widely found in human tissues
because it is not expected to persist in these tissues. As an organophosphorus compound, chlorfenvinphos is
not expected to accumulate in the body tissues because of its expected short half—life. However,
chlorfenvinphos was found in some of the 41 specimens of cervical mucus, follicular and sperm ﬂuids, and
human milk that were examined. Chlorfenvinphos levels of 13.66, 1.69, 2.02, and 1.89 ug/kg were detected in
4 of the 11 samples of cervical mucus. Chlorfenvinphos levels of 0.42 ug/kg were detected in l of the

10 sperm ﬂuid samples and 1 of the 10 human milk samples, respectively. The detection of chlorfenvinphos in
the cervical mucus, which showed the highest levels, was unexpected because it is the most unlikely
compartment for an accumulation in the body. It was suggested that a connection exists between the gland
activities and the appearance of some pesticides in the cervical mucus, which might show a new way for
accumulation. Accordingly, this data indicate that new environmental pollutants, like chlorfenvinphos, can
appear in the human organs, contacting even germ-cells and, thus, present risk of adverse effects on
reproduction (Wagner et al. 1990). Since the data were generated from environmental exposure, the combined

route of exposure possibly includes dermal.

CHLORFENVINPHOS 54

2. HEALTH EFFECTS

2.3.3 Metabolism

An adapted scheme for the mammalian metabolic pathway of chlorfenvinphos (Akintonwa 1984; Akintonwa
1985; Akintonwa and Itam 1988; Hunter et a1. 1972; Hutson and Millbum 1991; Hutson and Wright 1980) is

presented in Figure 2-3.
2.3.3.1 Inhalation Exposure

No studies were located regarding the metabolism of chlorfenvinphos after inhalation exposure in humans or

animals.
2.3.3.2 Oral Exposure

In humans, the rates of chlorfenvinphos de-ethylation by liver microsomal fractions are 0.36 nmol/minute per
mg protein (range 0.11—0.82) without induction and 1.03 nmol/minute per nmol of cytochrome P-450 (range

0.42—1.78) with induction (Hutson and Logan 1986).

In animal studies, pairs of Carworth Farm E strain male rats administered [”C]chlorfenvinphos orally at doses
of 2.5 or 13.3 mg/kg in olive oil (with or without prior monooxygenase induction with dieldrin) exhibited
minimal changes in the metabolic proﬁles. Urine samples were collected at 12 and 32 hours and analyzed by
chromatography for metabolites of chlorfenvinphos using authentic standards: de—ethylchlorfenvinphos or
2-chloro-1-(2’,4’-dichlorophenyl) vinylethylhydrogen phosphate, 1-(2',4'-dichlorophenyl) ethanol,
1-(2',4'-dichlorophenyl) ethanediol, 2,4-dichloromandelic acid, and 2,4-dichlorobenzoyl glycine. The
metabolites 2—chloro-1-(2,4-dichlorophenyl) vinylethylhydrogen phosphate, l-(2,4-dichlorophenyl) ethanol,
1-(2,4-dichlorophenyl) ethanediol, 2,4-dichloromandelic acid, and 2,4—dichlorobenzoyl glycine were identiﬁed
in the urine by this method. Increased monooxygenase induction (dieldrin pretreatment) favored the
production of the glucuronide of 1-(2,4-dichlorophenyl) ethanol and decreased yield of 2,4-dichloromandelic
acid and 2,4-dichlorobenzoyl glycine at a low dose level. At the high dose level, an increased yield of
l-(2,4-dichlorophenyl) ethanol, an increase in the relative yield of 2,4-dichloromandelic acid and 2,4-dichloro-
benzoyl glycine, and a doubling in the relative yield of de-ethylchlorfenvinphos occurred with a concomitant
reduction in the relative yields of the glucuronides. The authors suggested that the relatively low amount of
radioactivity eliminated within 0—32 hours via the urine of high-dose rats was probably due to limited

absorption/metabolism. The results support the conclusion that the effect of enzyme induction on the

CHLORFENVINPHOS 55

2. HEALTH EFFECTS

metabolism of substrates of that enzyme are dose-dependent with respect to enzyme saturation. Therefore,
alterations in metabolism are not necessarily a consequence of enzyme induction alone (Hutson and Wright
1980). The tissue distribution of organophosphoric ester metabolizing enzymes in the livers of mammalian
species has been suggested to be an important factor in accounting for species speciﬁcity of the toxicity of
some phosphate triester anticholinesterase agents, including chlorfenvinphos. These enzymes were
identiﬁed as microsomal monooxygenases, esterases, and glutathione—s-transferases. The acute oral LD50
values of chlorfenvinphos for the rat, mouse, rabbit, and dog which have been estimated as 10, 100, 500,
and 12,000 mg/kg, respectively, correlated fairly well with the relative rates of chlorfenvinphos
O-dealkylation and relative in vivo chlorfenvinphos-induced decreases in the rates of hexobarbital
metabolism in these species. The relative rates of dealkylation in the rat, mouse, rabbit, and dog have been
estimated as 1, 8, 24, and 80, respectively. The relative rates of chlorfenvinphos-induced decreases in
hexobarbital metabolism in the rat, mouse, rabbit, and dog have been estimated as 4, 17, 5, and 1,

respectively (Hansen 1983).

An investigator in an earlier study had suggested that the enzyme system responsible for this reaction was
found to be microsomal and required molecular oxygen and NADPI—I2 for activity. The activity of this
enzyme system in isolated washed rat, mouse, and dog liver microsomes had rates of product formation of
0.02, 0.65, and 2.00 nmol (per mg of microsomal protein per minute), respectively. The activity of this
enzyme system in isolated washed rabbit liver microsomes had a rate of product formation similar to the
other species used in this study. The maximum speciﬁc activity of liver microsomes with respect to the
dealkylation of chlorfenvinphos achieved in dieldrin-pretreated and phenobarbital-pretreated mice was

3.6 nmol at 1.6 mg/kg daily for 62 weeks and 6.0 nmol at 12 mg/kg daily for 40 weeks, respectively. The
maximum speciﬁc activity of liver microsomes with respect to the dealkylation of chlorfenvinphos achieved
in dieldrin-pretreated and phenobarbital-pretreated dogs was 4.1 nmol (per mg of microsomal protein per
minute) at 2.0 mg/kg daily for 4 weeks and 9.2 nmol (per mg of microsomal protein per minute) at 20 mg/kg
daily for 4 weeks, respectively. The activity of the enzyme system oxygen: NADPH2 oxidoreductase (with
chlorfenvinphos as substrate) in isolated washed monkey liver microsomes had a rate of product formation
of 1.00 nmol (per mg of microsomal protein per minute). The maximum speciﬁc activity of liver
microsomes with respect to the dealkylation of chlorfenvinphos achieved in dieldrin-pretreated monkeys
given oral chlorfenvinphos doses of 0.03 mg/kg/day for 6.15 years was 1.8 nmol (per mg of microsomal
protein per minute). The mechanism of this reaction has been proposed to be mediated by oxidative
dealkylation of chlorfenvinphos to the relatively nontoxic metabolite, 2-chloro-1-(2,4-dichlorophenyl) vinyl
ethylhydrogen phosphate and acetaldehyde. The enzyme system was readily inducible, especially in the rat,

CHLORFENVINPHOS 56

2. HEALTH EFFECTS

by the administration of phenobarbital or dieldrin. The maximum speciﬁc activity of liver microsomes with
respect to the dealkylation of chlorfenvinphos achieved in dieldrin-pretreated and phenobarbital-pretreated
rats was 12.4 nmol at 8 mg/kg/day for 4 weeks and 5.7 nmol at 14 mg/kg/day for 4 weeks, respectively. A
600-fold increase in speciﬁc activity was observed in the liver of dieldrin-pretreated rats. In rats pretreated
with dieldrin at 200 ppm in the diet for 12 days, the acute LDSO for chlorfenvinphos was increased by a
factor of 6—8 (Donninger 1971).

A quantitative study of the species distribution of phosphate esterases and glutathione S—alkyl transferase
found that these enzymes are signiﬁcantly less in quantity in the pig than in all the other species studied,
suggesting a signiﬁcantly varied distribution among some mammalian species. The author of the study
concluded that the distribution of these enzymes is an important factor in accounting for the species
speciﬁcity of at least some anticholinesterase agents and that the glutathione-dependent alkyl transferase is
predominantly a methyl transferase. The contribution of these two enzyme systems to the detoxiﬁcation of
any particular phosphate triester is dependent on the structure and solubility of the molecule (Donninger
1971).

These ﬁndings were conﬁrmed by three other reports. In the report by Hutson and Millbum (1991), the oral
LD50 values for rat, mouse, rabbit, and dog are 10—30 mg/kg, 150, 500, and >5,000 mg/kg, respectively. The
oral LD50 in the rabbit has been reported to be as high as >12,000 mg/kg in some studies. The difference in
toxicity in rats and dogs was found to be due to differences in several pharrnacokinetic and
pharmacodynamic factors. These factors include differences in the rates of absorption and metabolism,
bioavailability in blood, and rates of uptake by the brain, as well as the sensitivity of brain cholinesterase to
the phosphorylating action of the compound. In studies using rats and dogs, the most important reaction in
detoxiﬁcation is the conversion of chlorfenvinphos to de-ethylchlorfenvinphos by oxidative de-ethylation.
The reaction is catalyzed by a hepatic microsomal monooxygenase, probably cytochrome P-450. The
relative rates of de-ethylation in liver slices were 1, 8, 24, and 88 for the rat, mouse, rabbit, and dog,
respectively. Thus, an excellent inverse correlation between oral LD50 and rate of de-ethylation was
established. Also evidence for the signiﬁcance of the reaction in viva was provided from experiments in
which rats were protected 7-fold from the action of chlorfenvinphos by pre-treatment with dieldrin in the
diet for 12 days. This treatment induces cytochrome P-450 microsomal monooxygenase and, thus,
chlorfenvinphos de-ethylation. However, the author cautioned that species differences in toxicity response

are often multi-factorial, and metabolism can be a minor component (Hutson and Millbum 1991).

CHLORFENVINPHOS 57

2. HEALTH EFFECTS

In the second report, Ikeda et al. (1991) found the metabolism of chlorfenvinphos in kidney subcellular
fractions and in the serum of Fischer 344 rats (orally pretreated with chlorfenvinphos followed by oral
treatment with a similar chlorfenvinphos dose or 50 mg/kg phenobarbital in 24 hours), with or without the
NADPH-generating system, to be negligible. Metabolism of chlorfenvinphos in the liver subcellular fraction
without the NADPH-generating system was also practically negligible. However, when the NADPH—
generating system was added to the liver subcellular fraction, chlorfenvinphos metabolism increased
signiﬁcantly (203% in the 9,000 g fraction and 178% in the microsomes) in the chlorfenvinphos-pretreated
animals and in the phenobarbital-pretreated animals (565%). Additionally, chlorfenvinphos pretreatment
increased cytochrome P-450 content (3 0%) in the hepatic microsomal fraction; phenobarbital pretreatment
caused a 180% increase. Hepatic microsomal cytochrome b5 content and cytochrome P-450 reductase activity
were also increased by chlorfenvinphos and phenobarbital pretreatment (121 and 130%, respectively, for
chlorfenvinphos, and 126 and 139%, respectively, for phenobarbital). Both chlorfenvinphos and phenobarbital
pretreatment signiﬁcantly increased protein content (P<0.001) in the microsomal fraction. Chlorfenvinphos
treatment did not increase liver weight (relative to body weight). Increases were also noted in cytochrome
P—450-linked activities such as aminopyrine N-demethylase (40%) and aniline hydroxylase (27%) content in
the hepatic microsomal fraction and hexobarbital sleeping time and zoxazolamine paralysis time. Both
chlorfenvinphos and phenobarbital are potent inducers of cytochrome P—450, which is involved in the
metabolic detoxication of chlorfenvinphos. Thus, the authors concluded that the increase in hepatic
chlorfenvinphos metabolism may be due to the induction of the hepatic cytochrome P-450 system caused by
the single oral short-term treatment with chlorfenvinphos. Also this induction may be one of the reasons for
the decrease in plasma chlorfenvinphos concentration which may be responsible for the reduction in toxicity of

subsequent exposure to chlorfenvinphos (Ikeda et al. 1991).

The third report was a theoretical analysis that predicted the mammalian biotransformation products based on
the recognition of the structure of chlorfenvinphos, understanding of Types 1 and II metabolism of foreign
compounds, and mechanistic biochemistry (Akintonwa 1984). This analysis also acknowledged that
cytochrome P-450 monooxygenase (an inducible enzyme) is the relevant enzyme which mediates the
biotransformation of chlorfenvinphos via oxidative dealkylation of to the relatively nontoxic metabolite,
2-chloro-1-(2,4-dichlorophenyl) vinyl ethylhydrogen phosphate or de-ethylchlorfenvinphos. Thirteen
metabolites of chlorfenvinphos were predicted for mammals from theoretical biotransformation as justiﬁed by
the known structure of chlorfenvinphos and understanding of biochemical reactions of monooxygenation,
reduction, hydrolysis, glucuronidation, glutathione-S—transferase conjugation, and amino acid conjugation.

The 13 metabolites predicted are: 2-chloro-l-(2’,4’-dichlorophenyl) vinyldiethyl phosphate; acetaldehyde;

CHLORFENVINPHOS 58

2. HEALTH EFFECTS

2-chloro-1-(2’,4’-dichlorophenyl) vinylethylhydrogen phosphate; 2,4-dichlorophenacylchloride; 2-chloro—
l-(2’,4’-dichlorophenyl) ethanol; 2,4—dichloromandelic acid; 2,4-dichloromandelic acid ester glucuronide;
2,4—dichloroacetophenone; 1-(2',4’-dichlorophenyl) ethanol; 1-(2’,4’-dichlorophenyl) ethanediol;
1-(2’,4’-dichlorophenyl) ethanediol-Z-glucuronide; 1-hydroxy-1-(2’,4’-dichlorophenyl) acetyl glycine; and
1-(2’,4’-dichlorophenyl) ethanediol. 2—Chloro-1-(2’,4’-dichlorophenyl) vinylethylhydrogen phosphate,
2,4—dichloromandelic acid, 1-(2’,4’-dichlorophenyl) ethanediol-Z-glucuronide, and l-(2’,4’-dichlorophenyl)
ethanediol are predicted speciﬁcally for the dog and rat. l-Hydroxy-1-(2’,4’-dichlorophenyl) acetyl glycine
(the glycine conjugate of 2,4—dichloromandelic acid) was not conﬁrmed in the rat while 2,4-dichlorohippuric
acid was present in the dog, but not in the rat. While the theoretical or predictive approach to metabolite
identiﬁcation elucidates all the possible mechanistic pathways in the derivation of each metabolite and
identiﬁes all toxic or hazardous intermediates, only actual experimentation, which begins with theoretical
prediction, can provide species differences in the proportion of metabolites and the toxicity of these
metabolites. Thus, the theoretical approach to chlorfenvinphos metabolism in mammals effectively reveals
that the monooxygenation of the vinyl group would produce an unstable epoxide (2-hydroxyl groups attached
to a carbon) to yield 2,4-dichlorophenyl glyoxylate and 2,4-dichlorobenzoic acid through decarboxylation and
oxygenation. The author of this study postulated that the 2,4-dichlorobenzoyl glycine (2,4-dichlorohippuric
acid) was produced in the rat by this mechanism. The production of electrophilic metabolic intermediates or
epoxides in the metabolism of chlorfenvinphos, which could react with nucleophilic cellular components
(DNA, RNA, and proteins) leading to carcinogenesis, was considered unlikely by this theoretical approach
(Akintonwa 1984).

2,4-Dichlorophenacyl chloride, an intermediary metabolite of chlorfenvinphos and dimethylvinphos, is
excreted from mammals mainly as 1-(2,4-dichlorophenyl)ethyl glucuronide (Hutson et a1. 1977). The authors
assumed that this arose via the reductive dechlorination of the phenacyl halide to the acetophenone, which was
then reduced to the alcohol and conjugated. A further investigation of the proposed reductive dechlorination
step (using subcellular fractions of rat liver) led the authors to conclude that it is likely that the mechanism of
reaction is a nucleophilic attack by sulphur (of the second GSH) on sulphur (of the chlorfenvinphos/GSH
conjugate), with the expulsion of the phenacyl anion as the leaving group. The enzyme may be regarded as

one of the glutathione transferases (Hutson et a1. 1977).

An assay developed for determining monooxygenase activity in human fetal livers, as a measure of the rate of
decrease in substrate (Supona®, chlorfenvinphos) concentration, was found reliable for incubations at 37 °C

for periods up to 10 minutes. Incubations in excess of 10 minutes were unreliable due to an unexpected

CHLORFENVINPHOS 59

2. HEALTH EFFECTS

increase in E246nm readings. The investigators concluded that hydrolysis, rather than monooxygenation, of
chlorfenvinphos, was probably responsible for the observed increase in readings. Using 5- and 10-minute
incubations, speciﬁc activity values for monooxygenase in whole liver homogenates of 13- and 16-week—old
human fetuses were determined to be 6.47zt0.84 and 5.26i0.46 pg/mg, respectively; no monooxygenase
activity could be detected in whole liver homogenates of 24-week-old fetuses. The authors concluded that,
similar to in vivo observations, the mechanism for oxidative dealkylation of chlorfenvinphos proceeds initially
via monooxygenation of the alpha-carbon atom of the alkoxy group to produce an unstable hemiacetal which
breaks down by oxidative 0— and N-alkylation mechanisms to acetaldehyde and 2-chloro-l-(2,4-dichloro—
phenyl) vinylethylhydrogen phosphate (Akintonwa and Itam 1988).

2.3.3.3 Dermal Exposure

No studies were located regarding metabolism of chlorfenvinphos after dermal exposure in humans or

animals.
2.3.4 Elimination and Excretion
2.3.4.1 Inhalation Exposure

No studies were located regarding excretion of chlorfenvinphos after inhalation exposure in humans or

animals.
2.3.4.2 Oral Exposure

A male patient, aged 29, was admitted to the hospital 3 hours after a suicide attempt during which he drank
about 50 mL of the preparation Enolofos® which contains 50% chlorfenvinphos. The concentration of
chlorfenvinphos in the serum was 300 ng/mL upon admission. In this, the only human chlorfenvinphos
poisoning in which hemoperfusion intervention was employed, the mean clearance of chlorfenvinphos during
hemoperfusion was low, 68 mL/minute; and only 0.42 mg of the poison was recovered. The level of the
poison in the serum was low (15 ng/mL) immediately before the procedure and gradually rose in successive
blood sampling. At all times in successive blood samples during the procedure, there was an increase of
chlorfenvinphos level in the serum, indicating that chlorfenvinphos passes fairly easily from the tissues into

blood. This may be related to secondary resorption from the digestive tract. The highest value of clearance

CHLORFENVINPHOS 60

2. HEALTH EFFECTS

was observed in the fourth hour of hemoperfusion, in contrast to the observations during hemoperfusion
performed for other drug poisoning, when the value of the clearance was lowest in the last hour. The serum
chlorfenvinphos levels decreased temporarily within a few hours even prior to the beginning of
hemoperfusion, either due to rapid inactivation or to rapid passage into the tissues where the

organophosphates accumulate (Pach et al. 1987).

In animal studies, pairs of Carworth Farm E strain male rats administered [”C]chlorfenvinphos orally at doses
of 2.5 or 13.3 mg/kg in olive oil (with or without prior monooxygenase induction with dieldrin) eliminated
about 50% of the administered radioactivity in the urine in the ﬁrst 12 hours, 9—13% in the next 12 hours,
3.5—6% in the subsequent 16 hours, and 4.2—5% in the ﬁnal 42 hours of monitoring. A total of 67. 1—72.5% of
the administered radioactivity was recovered from the urine. Only 15.2—16.9% of the administered
radioactivity was eliminated in the urine in the ﬁrst 12 hours, 2.5—8.2% in the next 12 hours, 6.1—6.6% in the
subsequent 18 hours, and 07—14% in the ﬁnal 42 hours of monitoring. Only 26.2—31.7% of the total dose
was recovered in the urine in the high-dose animals. Dieldrin pretreatment resulted in a more rapid elimination
as well as a greater percentage elimination of the administered [”C]chlorfenvinphos doses (Hutson and Wright
1980). All of the Birlane® (chlorfenvinphos) dose of 0.8 mg/kg/day administered in the diet for 30 days to

2 groups of adult female albino (Wistar) rats was removed from the body (excreted or metabolized) in 4 days.
The dose was excreted mostly in the urine (70—90%) and feces (about 16%) with minor amounts (0.5%) in

expired air (Bama and Simon 1973).

2.3.4.3 Dermal Exposure

No studies were located regarding excretion of chlorfenvinphos after dermal exposure in humans or animals.

2.3.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models

Physiologically based pharmacokinetic (PBPK) models use mathematical descriptions of the uptake and
disposition of chemical substances to quantitatively describe the relationships among critical biological
processes (Krishnan et al. 1994). PBPK models are also called biologically based tissue dosimetry models.
PBPK models are increasingly used in risk assessments, primarily to predict the concentration of potentially
toxic moieties of a chemical that will be delivered to any given target tissue following various combinations of

route, dose level, and test species (Clewell and Andersen 1985). Physiologically based pharmacodynamic

CHLORFENVINPHOS 61

2. HEALTH EFFECTS

(PBPD) models use mathematical descriptions of the dose-response function to quantitatively describe the

relationship between target tissue dose and toxic end points.

PBPK/PD models reﬁne our understanding of complex quantitative dose behaviors by helping to delineate and
characterize the relationships between: (1) the extemal/exposure concentration and target tissue dose of the
toxic moiety, and (2) the target tissue dose and observed responses (Andersen et a1. 1987; Andersen and
Krishnan 1994). These models are biologically and mechanistically based and can be used to extrapolate the
pharmacokinetic behavior of chemical substances from high to low dose, from route to route, between species,
and between subpopulations within a species. The biological basis of PBPK models results in more

meaningful extrapolations than those generated with the more conventional use of uncertainty factors.

The PBPK model for a chemical substance is developed in four interconnected steps: (1) model
representation, (2) model parametrization, (3) model simulation, and (4) model validation (Krishnan and
Andersen 1994). In the early 19905, validated PBPK models were developed for a number of toxicologically
important chemical substances, both volatile and nonvolatile (Krishnan and Andersen 1994; Leung 1993).
PBPK models for a particular substance require estimates of the chemical substance-speciﬁc physicochemical
parameters, and species-speciﬁc physiological and biological parameters. The numerical estimates of these
model parameters are incorporated within a set of differential and algebraic equations that describe the
pharmacokinetic processes. Solving these differential and algebraic equations provides the predictions of

tissue dose. Computers then provide process simulations based on these solutions.

The structure and mathematical expressions used in PBPK models signiﬁcantly simplify the true complexities
of biological systems. If the uptake and disposition of the chemical substance(s) is adequately described,
however, this simpliﬁcation is desirable because data are oﬁen unavailable for many biological processes. A
simpliﬁed scheme reduces the magnitude of cumulative uncertainty. The adequacy of the model is, therefore,

of great importance, and model validation is essential to the use of PBPK models in risk assessment.

PBPK models improve the pharmacokinetic extrapolations used in risk assessments that identify the maximal
(i.e., the safe) levels for human exposure to chemical substances (Andersen and Krishnan 1994). PBPK
models provide a scientiﬁcally-sound means to predict the target tissue dose of chemicals in humans who are
exposed to environmental levels (for example, levels that might occur at hazardous waste sites) based on the
results of studies where doses were higher or were administered in different species. Figure 2-4 shows a

conceptualized representation of a PBPK model.

CHLORFENVINPHOS

62

2. HEALTH EFFECTS

Figure 2-4. Conceptual Representation of a Physiologically Based
Pharmacokinetic (PBPK) Model for a Hypothetical Chemical Substance

Inhaled chemical — — — 1 — — —>Exhaled chemical

|
I
l l

 

lngesﬁon
Lungs I

 

 

 

/

 

 

 

A

Liver

 

 

 

 

Vmax 1 Km GI

 

 

 

chzm<

Tract

 

 

Fat

 

 

 

 

 

1%

r>—ImHI>

Slowly
perfused ‘
tissues

 

 

 

 

A

UOOPW

Richly
perfused
tissues

 

 

 

 

A

UOOF‘W

Kidney ‘

 

 

 

Urine

 

 

 

‘l

 

 

 

 

 

Skin ‘

 

 

Source: adapted from Krishnan et al. 1994

A

I

L - - Chemicals in air
contacting skin

Note: This is a conceptual representation of a physiologically based pharmacokinetic (PBPK) model for a
hypothetical chemical substance. The chemical substance is shown to be absorbed via the skin, by
inhalation, or by ingestion, metabolized in the liver, and excreted in the urine or by exhalation.

CHLORFENVINPHOS '63

2. HEALTH EFFECTS

If PBPK models for chlorfenvinphos exist, the overall results and individual models are discussed in this
section in terms of their use in risk assessment, tissue dosimetry, and dose, route, and species extrapolations.

A physiologically based pharmacokinetic (PBPK) analysis used data from a study with 8-week old Fischer 344
rats as a model to study the mechanism of protection by initial chlorfenvinphos exposure against the toxicity of
a subsequent exposure. The analysis concluded that, contrary to expectation, the body burden of
chlorfenvinphos decreased after the initial exposure upon subsequent challenge exposure. The model
predicted that decreased body burden of oral chlorfenvinphos dose might be due to the decrease in the plasma
concentration after a challenge with chlorfenvinphos. In the rat study on which the model is based, the acute
oral toxicity of chlorfenvinphos was reduced by the oral pretreatment of rats with chlorfenvinphos after a
subsequent challenge dose. This was accompanied by reduction in brain cholinesterase, liver, and plasma
concentrations of chlorfenvinphos (by one-third and 4—10 times, respectively). Unbound fractions of
chlorfenvinphos in blood and liver were estimated by the in vitro experiments and pretreatment did not change
the unbound fraction of chlorfenvinphos. The authors stated that, according to the PBPK model, the decrease
in body burdens of the oral chlorfenvinphos dose may be caused mainly by an increase in intrinsic clearance of
chlorfenvinphos by the liver and a decrease in the partition coefﬁcient of chlorfenvinphos between the
emergent blood and he liver. The increase in the intrinsic clearance was suggested to be related to the
metabolic induction of P-450 observed in vitro. Additionally, pretreatment decreased the absorption rate
constant of the oral chlorfenvinphos dose. Essentially, this is responsible for the protection afforded against

toxicity of subsequent exposure to chlorfenvinphos (Ikeda et al. 1992).

2.4 MECHANISMS OF ACTION

2.4.1 Pharmacokinetic Mechanisms

The level of activity of cholinesterases in the livers of mammalian species and the distribution of these
enzymes have been suggested to be important factors in accounting for species speciﬁcity of some phosphate
triester anticholinesterase agents, including chlorfenvinphos. These factors may account for the great variation
in the toxicity of chlorfenvinphos among different animal species. The acute oral LDso values of
chlorfenvinphos for the rat, mouse, rabbit, and dog are 10, 100, 500, and 1,200 mg/kg, respectively. The
relative conversion rates of chlorfenvinphos (by 0-dealkylation) to the diester by liver slices from the rat,
mouse, rabbit, and dog were 1, 8, 24, and 80 hours, respectively; these values correlate well with the published
acute oral LD50 values for the species. The enzyme system responsible for this reaction was found to be

microsomal and required molecular oxygen and NADPH2 for activity. The activity of this enzyme system in

CHLORFENVINPHOS 64

2. HEALTH EFFECTS

isolated rat, mouse, and dog liver (washed) microsomes had rates of product formation of 0.02, 0.65, and
2.00 nmol (per mg of microsomal protein per minute), respectively. The activity of this enzyme system in
isolated washed rabbit liver microsomes had a rate of product formation similar to that of other species used in

this study.

The maximum speciﬁc activity of liver microsomes with respect to the dealkylation of chlorfenvinphos
achieved in dieldrin-pretreated and phenobarbital-pretreated mice was 3.6 nmol at 1.6 mg/kg/day for 62 weeks
and 6.0 nmol at 12 mg/kg/day for 40 weeks, respectively. The maximum speciﬁc activity of liver microsomes
with respect to the dealkylation of chlorfenvinphos achieved in dieldrin— and phenobarbital-pretreated dogs
was 4.1 nmol (per mg of microsomal protein per minute) at 2.0 mg/kg/day for 4 weeks and 9.2 nmol (per mg
of microsomal protein per minute) at 20 mg/kg/day for 4 weeks, respectively. The activity of the enzyme
system oxygen: NADPH2 oxidoreductase (with chlorfenvinphos as substrate) in isolated washed monkey liver
microsomes had a rate of product formation of 1.00 nmol (per mg of microsomal protein per minute). The
maximum speciﬁc activity of liver microsomes with respect to the dealkylation of chlorfenvinphos achieved in
dieldrin-pretreated monkeys given oral chlorfenvinphos doses of 0.03 mg/kg/day for 6.15 years was 1.8 nmol
(per mg of microsomal protein per minute). It has been proposed that the mechanism of this reaction is
mediated by oxidative dealkylation of chlorfenvinphos to the relatively nontoxic metabolite, 2—chloro—
1-(2,4-dichlorophenyl) vinyl ethylhydrogen phosphate and acetaldehyde. The enzyme system was readily
inducible, especially in the rat, by the administration of phenobarbital or dieldrin.

The maximum speciﬁc activity of liver microsomes with respect to the dealkylation of chlorfenvinphos
achieved in dieldrin— and phenobarbital-pretreated rats was 12.4 nmol at 8 mg/kg/day for 4 weeks and 5.7 nmol
at 14 mg/kg/day for 4 weeks, respectively. A 600-fold increase in speciﬁc activity was observed in the liver of
dieldrin-pretreated rats; in rats pretreated with dieldrin at 200 ppm in the diet for 12 days, the acute LDS,o for
chlorfenvinphos was increased by a factor of 6—8. A quantitative study of the species distribution of phosphate
esterases and glutathione S—alkyl transferase found that these enzymes are signiﬁcantly less in the pig than all
the other species studied, suggesting a signiﬁcantly varied distribution among some mammalian species. The
author of the study concluded that the distribution of these enzymes is an important factor in accounting for the
species speciﬁcity of at least some anticholinesterase agents and that the glutathione-dependent alkyl
transferase is predominantly a methyl transferase; the contribution of these two enzyme systems to the
detoxiﬁcation of any particular phosphate triester is dependent on the structure and solubility of the molecule

(Donninger 1971).

CHLORFENVINPHOS 65

2. HEALTH EFFECTS

These ﬁndings were conﬁrmed by two other reports. In one, the oral LD50 values for rat, mouse, rabbit, and
dog were 10—30, 150, 500, and >5,000 mg/kg, respectively; it can be >12,000 mg/kg in the rabbit. The
difference in toxicity in rats and dogs was found to be due to rates of absorption and metabolism,
bioavailability in blood, and rates of uptake by the brain and sensitivity of brain cholinesterase to the
phosphorylating action of the compound. In studies using rats and dogs, the most important reaction in
detoxiﬁcation is the conversion of chlorfenvinphos to de-ethylchlorfenvinphos by oxidative de-ethylation.
The reaction is catalyzed by a hepatic microsomal monooxygenase, probably cytochrome P-450. The
relative rates of de-ethylation in liver slices were 1, 8, 24, and 88 for the rat, mouse, rabbit, and dog,
respectively. Thus, an excellent inverse correlation between oral LD50 and rate of de-ethylation was
established. Also evidence for the signiﬁcance of the reaction in vivo was provided from experiments in
which rats were protected 7-fold from the action of chlorfenvinphos by pre-treatment with dieldrin in the
diet for 12 days. This treatment induces cytochrome P-450 microsomal monooxygenase and, thus,
chlorfenvinphos de-ethylation. The de-ethylation was induced about 40-fold (measured in vitro) relative to
cytochrome P-450 concentration. However, the author cautioned that species differences in toxicity
response are often multi-factorial, and metabolism can be a minor component (Hutson and Millbum 1991).
In the second report, the metabolism of chlorfenvinphos in kidney subcellular fraction and in the serum of
Fischer 344 rats (orally pretreated with chlorfenvinphos followed by an oral treatment with a similar
chlorfenvinphos dose or 50 mg/kg phenobarbital in 24 hours), with or without the NADPH-generating
system, was found to be negligible. Metabolism of chlorfenvinphos in the liver subcellular fraction without
the NADPH-generating system was also practically negligible. However, when the NADPH-generating
system was added to the liver subcellular fraction, chlorfenvinphos metabolism increased signiﬁcantly
(203% in the 9,000 g fraction and 178% in the microsomes) in the chlorfenvinphos-pretreated animals and
in the phenobarbital-pretreated animals (565%). Additionally, chlorfenvinphos pretreatment increased
cytochrome P-450 content (3 0%) in the hepatic microsomal fraction; phenobarbital pretreatment caused a
180% increase. Hepatic microsomal cytochrome b5 content and cytochrome P-450 reductase activity were
also increased by chlorfenvinphos and phenobarbital pretreatment (121 and 130%, respectively, for
chlorfenvinphos and 126 and 139%, respectively, for phenobarbital). Both chlorfenvinphos and
phenobarbital pretreatment signiﬁcantly increased protein content (P<0.001) in the microsomal fraction.
Chlorfenvinphos treatment did not increase liver weight (relative to body weight). Increases were also
noted in cytochrome P-450-1inked activities such as aminopyrine N-demethylase (40%) and aniline
hydroxylase (27%) content in the hepatic microsomal fraction and hexobarbital sleeping time and
zoxazolamine paralysis time. Both chlorfenvinphos and phenobarbital are potent inducers of cytochrome

P-450, which is involved in the metabolic detoxication of chlorfenvinphos. Thus, the authors concluded

CHLORFENVINPHOS 66

2. HEALTH EFFECTS

that the increase in hepatic chlorfenvinphos metabolism may be due to the induction of the hepatic
cytochrome P-450 system caused by the single oral short-term treatment. Also this induction may be one of
the reasons for the decrease in plasma chlorfenvinphos concentration, which may be responsible for the

reduction in toxicity of subsequent exposure to chlorfenvinphos (Ikeda et al. 1991).

Some of the major sites and enzyme systems involved in the detoxication of direct-acting neurotoxic
organophosphates, like chlorfenvinphos, are NADPH—P-450, GSH transferase, FAD-monooxygenase and
esterases; the most important of these is monooxygenase. The major activation step for microsomal
monooxygenases is of critical importance for the toxicity of organophosphate compounds like
chlorfenvinphos. According to this study, the relative rates of chlorfenvinphos 0-dealkylation in rats, mice,
rabbits, and dogs are 1, 8, 24, and 88, respectively. These rates correlated well with the oral LD50 values for
these species, which were given as 10, 100, 500, and 12,000 mg/kg for rats, mice, rabbits, and dogs,
respectively. According to the author, the potential for oxidative 0-dealkylation in the P-450 pathway
varies widely with species, with activity toward chlorfenvinphos correlating well with species selectivity.
The author concluded that the biotransformation of delayed neurotoxicants will certainly inﬂuence relative
potencies, but the distinction between a delayed neurotoxicant and the neurotoxicity of organophosphate
compounds, which is mainly limited to acute effects, depends more heavily on pharmacodynamic than
pharmacokinetic considerations. Thus, the pharmacokinetics of delayed neurotoxicants differ from the

pharmacokinetics of neurotoxic organophosphates, like chlorfenvinphos (Hansen 1983).

2.4.2 Mechanisms of Toxicity

Most chlorfenvinphos toxicity results from the inhibition of cholinesterase activity in the central and
peripheral nervous system when administered by the oral (Cupp et a1. 1975; Pach et a1. 1987) or inhalation
route in acute-duration exposures in humans (Kolmodin-Hedman and Eriksson 1987), and when
administered by the oral (Bama and Simon 1973; Osicka—Koprowska et a1. 1984; Takahashi et a1. 1991) or
dermal route in acute-duration exposures in animals. Inhibition of cholinesterase activity results in
accumulation of acetylcholine at muscarinic and nicotinic receptors leading to peripheral and central
nervous system effects. These effects usually appear within a few minutes to a few hours after exposure
depending on the extent of exposure. The enzyme is responsible for terminating the action of the
neurotransmitter acetylcholine in the synapse of the pre- and post-synaptic nerve endings or in the
neuromuscular junctions. On arrival of a nerve impulse at the synaptic gutter between the pre- and post-

synaptic nerve endings or effector muscle ﬁber endplates, there is a release of acetylcholine from the pre-

CHLORFENVINPHOS 67

2. HEALTH EFFECTS

synaptic terminals. At the post-synaptic nerve ending, acetylcholine acts as a chemical mediator to
perpetuate the action potential. However, the action of acetylcholine does not persist long as it is

hydrolyzed by the enzyme, acetylcholinesterase, and rapidly removed.

As an anticholinesterase organophosphate, chlorfenvinphos inhibits the activity of the acetylcholinesterase
enzyme by reacting with the esteratic sites of the enzyme to form a stable phosphorylated complex which is
incapable of destroying acetylcholine at the synaptic gutter between the pre- and post-synaptic nerve
endings in the central and peripheral nervous system or neuromuscular junctions of skeletal muscles,
resulting in the accumulation of acetylcholine at these sites. This leads to continuous or excessive
stimulation of cholinergic ﬁbers in the post-ganglionic parasympathetic nerve endings, neuromuscular
junctions of the skeletal muscles, resulting in hyperpolarization of nerve or muscle ﬁbers and receptor
desensitization until hydrolysis of the phosphorylated cholinesterase occurs. In some cases, a dealkylation
and stabilization of the phosphorylated enzyme (“aging”) occurs such that hydrolysis can no longer take
place and the enzyme is irreversibly inhibited. In such cases, return of acetylcholinesterase activity parallels

the time required to resynthesize this enzyme.

In the parasympathetic system, stimulation of postganglionic ﬁbers on the effector organs is mimicked by
muscarine, and the receptors for the transmitters are called muscarinic receptors. They are found primarily
in smooth muscle, the heart, and the exocrine glands. Stimulation of these receptors 'by inhibition of
acetylcholinesterase activity produces signs and symptoms of cholinergic poisoning that include
bronchoconstriction and increased bronchial secretions, increased salivation and lacrimation, exophthalmos,
increased sweating, increased gastrointestinal tone and peristalsis, nausea, vomiting, abdominal cramps,
diarrhea, hypotension and bradycardia that can lead to heart block, involuntary urination caused by

contraction of the smooth muscle of the bladder, and constriction of the pupils or miosis.

At the autonomic ganglia and neuromuscular junctions, stimulation of transmission is mimicked by the
action of nicotine, and the receptors are called nicotinic receptors. Inhibition of acetylcholinesterase activity
leads to abnormal continuous or excessive stimulation of the receptor muscle ﬁbers, causing weakness of
the muscles, involuntary twitching, fasciculations, cramps, and eventual paralysis of the muscles. Paralysis
of the respiratory muscles leads to respiratory failure and death. The central nervous system effects are due
to accumulation of acetylcholine at various cortical, subcortical, and spinal levels (primarily in the cerebral
cortex, hippocampus, and extrapyramidal motor system). Accumulation of acetylcholine in the central

nervous system causes tension, anxiety, restlessness, insomnia, headache, emotional instability, neurosis,

CHLORFENVINPHOS 68

2. HEALTH EFFECTS

excessive dreaming and nightmares, apathy, drowsiness, confusion, slurred Speech, tremor, ataxia,
convulsions, depression of respiratory and circulatory centers, and coma. The most likely cause of death in
fatal organophosphate poisoning is paralysis associated with respiratory failure (Cupp et al. 1975; Klaassen et

al. 1986; Shankar; Takahashi et al. 1991; Williams and Burson 1985).

The results of pretreatment of New Zealand white rabbits with 0.007 mg/kg oxotremorine, a direct agonist of
muscarinic receptors, followed by treatment with 0.5 mg/kg chlorfenvinphos by hypothalamic inﬁision
suggests that the chlorfenvinphos is neither an agonist nor antagonist of the muscarinic receptors in the rabbit
hypothalamus. No overt changes in behavior or changes in hippocampal EEG were observed in the rabbits

following infusion with 0.5 mg/kg chlorfenvinphos (Gralewicz et al. 1995).

Organophosphate-induced hypotension (reported for chlorfenvinphos only in rats receiving intravenous doses)
(Takahashi et al. 1991) has been suggested to be due to factors other than inhibition of cholinesterase activity
(Kojima et al. 1992). A study concluded that the alteration of brain and liver activities of the aromatic amino
acid transferases may be due to the inhibitory effect of chlorfenvinphos on noradrenaline (norepinephrine)
activity (Puzynska 1984). In other studies, chlorfenvinphos was shown to independently inhibit noradrenaline
(norepinephrine) activity in vivo in rats rapidly (3 hours) at doses as low as 4 mg/kg (Brzezinski 1978; Osumi
et al. 1975). On this basis, it has been postulated that chlorfenvinphos may also act via central noradrenergic
mechanisms, disturbing the dynamic equilibrium between the rate of formation and utilization of noradrenaline
(norepinephrine). This action via central noradrenergic mechanisms by chlorfenvinphos may be responsible
for the changes in blood pressure observed in other studies after chlorfenvinphos intoxication (Brzezinski

1978).

It has also been suggested that the cholinergic action of organophosphates like chlorfenvinphos may interfere
with the pathways controlling the secretory activity of the anterior pituitary lobe and the adrenal cortex whose
hormones inﬂuence the activities of many enzymes, including aromatic amino acid transferases (Puzynska
1984). Interference with the secretory activity of the adrenal cortex may lead to a disruption in the normal

activities of one or more components of the renal blood pressure regulatory systems (Klaassen et al. 1986).

2.4.3 Animal-to-Human Extrapolations

In one study, the rates of chlorfenvinphos de-ethylation by human liver microsomal fractions are

0.36 nmol/minute per mg protein (range 0.1 1—0.82) without induction and 1.03 nmol/minute per nmol of

CHLORFENVINPHOS 69

2. HEALTH EFFECTS

cytochrome P-450 (range 0.42—1.78) with induction. The rates of chlorfenvinphos de-ethylation by liver
microsomal fractions are 0.62 nmol/minute/mg protein (range 0.36—0.93) and 1.30 nmol/minute/nmol
cytochrome P-450 (range 0.81—1.74) for uninduced rabbits. The rabbit is considered relatively resistant to the
acute toxic action of chlorfenvinphos, with an LD50 of 500—1 ,000 mg/kg (provided in another study). These
results demonstrate that human hepatic cytochrome P-450 is almost as active as that of rabbits. However, the
authors stressed that these results refer to the total cytochrome P-450 complement of the cells and take no
account of the several forms known to exist which differ from species to species, or of the environmental
factors, and the other factors involved in the acute toxicity of chlorfenvinphos in humans. Based on the
findings in this study, it appears that humans may de-ethylate chlorfenvinphos more like rabbits or mice than

like rats (Hutson and Logan 1986).
2.5 RELEVANCE TO PUBLIC HEALTH
Overview

Chlorfenvinphos is an insecticide that was broadly used in the United States in both agriculture and control of
pests in residential dwellings, gardens, and on household pets from 1963 until 1991, when all products

containing chlorfenvinphos as an active ingredient were canceled (REFS 1995).

The absorption of chlorfenvinphos after inhalation exposure in humans or animals is unknown due to lack of
data. Ingested and derrnally contacted chlorfenvinphos is rapidly absorbed in humans and animals; the rate of
absorption is dependent on the solvent in which the substance is dissolved. In humans, absorbed
chlorfenvinphos is widely distributed and has been detected in compartments that include serum, cervical
mucus, follicular and sperm ﬂuids, and milk. It is extensively metabolized via oxidative dealkylation by liver
microsomal fractions. Data from animal studies suggest that electrophilic metabolic intermediates or epoxides
may be produced in the metabolism of chlorfenvinphos. There is no information on the elimination or
excretion of chlorfenvinphos in humans and animals after inhalation or dermal exposures; however, ingested
chlorfenvinphos is rapidly eliminated via the urine and feces, and expired air in animals. In humans, ingested
chlorfenvinphos is rapidly removed from the blood and passed into the tissues; chlorfenvinphos has been

detected in human sperm ﬂuid and milk samples.

As an anticholinesterase organophosphate, the principal toxic effect of chlorfenvinphos is the inhibition of

cholinesterase activity in the central and peripheral nervous system when administered by the oral or

CHLORFENVINPHOS 70

2. HEALTH EFFECTS

inhalation route in acute-duration exposures in humans and the inhibition of cholinesterase activity in the
central and peripheral nervous system when administered by the oral, or dermal route in acute-duration
exposures. Inhibition of cholinesterase activity results in the accumulation of acetylcholine at acetylcholine
receptors leading to cholinergic responses in the peripheral (muscarinic and nicotinic) and central nervous
system and neuromuscular junctions. Severe inhibition of acetylcholinesterase activity oﬁen leads to
cholinergic symptoms in humans and laboratory animals, which include excessive glandular secretions
(salivation, lacrimation, rhinorrhea, miosis), exophthalmos, bronchoconstriction, vasodilation, hypotension,
diarrhea, nausea, vomiting, urinary incontinence, and bradycardia. Tachycardia, mydriasis, fasciculations,
cramping, twitching, muscle weakness, and muscle paralysis are associated with nicotinic receptor
stimulation. Central nervous system toxicity may be mediated by either muscarinic or nicotinic receptors and
includes respiratory depression, anxiety, insomnia, headache, apathy, drowsiness, dizziness, loss of
concentration, confusion, tremors, convulsions, and coma. In non-fatal exposures, the effects are transient and
recovery is rapid and complete following cessation of exposure. In sufficiently high doses, chlorfenvinphos
exposure has resulted in death of humans, rats, and mice. These effects usually occur within a few minutes to
a few hours after dosing, depending on the extent of exposure. In addition, chlorfenvinphos may interfere with

the activity of noradrenaline (norepinephrine) in central adrenergic mechanisms in animals.

The greatest potential for signiﬁcant exposure to this compound is found in occupational settings (i.e.,
manufacture and application of chlorfenvinphos). Currently, the most common exposure scenario for the
general population comes from home use of imported foods and lanolin-containing pharmaceutical products.
Workers involved in disposal of chlorfenvinphos—contaminated wastes are at a higher risk of exposure.
Populations potentially at higher risk of exposure are: people living in the vicinity of plants where
chlorfenvinphos was manufactured; people living near dairy farms, cattle or sheep holding areas, or poultry
producing-facilities where chlorfenvinphos was used; and populations living near hazardous waste sites
containing chlorfenvinphos. No association has been reported between chlorfenvinphos toxicity and low-level

environmental contamination.

CHLORFENVlNPHOS 71

2. HEALTH EFFECTS

Minimal Risk Levels for Chlorfenvinphos

Inhalation MRLs.

Inhalation MRLs for acute-, intermediate, or chronic-duration exposure to Chlorfenvinphos have not been
calculated because adequate data for developing these MRLs are not available. The available human reports

involve mixed exposures. The available animal studies reported serious effects.

A human study reported immunological effects at a LOAEL of 0.21 mg/m3 following prolonged occupational
exposure to Chlorfenvinphos by the inhalation route. However, the subjects of this study were also
concurrently exposed to greater concentrations of other potentially immunotoxic substances such as
formothion, sumithion, and malathion (Wysocki et al. 1987). In another human study, a group of nine
gardeners (pesticide mixers) exposed to unknown concentrations of a mixture of pesticides (Chlorfenvinphos,
dimethoate, formothion, isofenphos), complained of headaches and had a mean difference (before and after
exposure) of 0.56 nmol/mL for acetylcholinesterase and 2.67 nmol/mL for butyrylcholinesterase
(Kolmodin-Hedman and Eriksson 1987). However, since these symptoms could also result from exposure to
the other organophosphate pesticides in the mixture, the etiology for these symptoms is uncertain. Therefore

the study was not useful for developing inhalation MRLs.

The available inhalation animal studies reported only serious effects (mortality, apnea, salivation, urination,
exophthalmos, twitches, and tremors) (Takahashi et al. 1994; Tsuda et al. 1986) following exposure to
Chlorfenvinphos. Therefore, the data from these studies are not appropriate for use in the calculation of

MRLs.

Oral MRLs.

- An MRL of 0.002 mg/kg/day has been developed for acute—duration oral exposure (14 days or less) to

Chlorfenvinphos.

This MRL for Chlorfenvinphos is based on a LOAEL of 2.4 mg/kg/day for neurological effects (3 8%
erythrocyte cholinesterase inhibition) in female rats (Bama and Simon 1973). In the study, two groups of
adult female albino (Wistar) rats weighing 208 g were orally administered Birlane® (Chlorfenvinphos) at dose

of 0 or 2.4 mg/kg/day in the diet for 10 days. The study was designed to investigate the effects of oral

CHLORFENVINPHOS 72

2. HEALTH EFFECTS

chlorfenvinphos on body weight increase, the gastrointestinal absorption of glucose, Na*, and Ca2+, and the
effects of oral chlorfenvinphos on plasma and erythrocyte cholinesterase activity levels. Plasma
cholinesterase activity was inhibited by 52%, and erythrocyte cholinesterase activity level was inhibited by
30% at a dose of 2.4 mg/kg/day (the only dose tested). Gastrointestinal absorption of glucose was increased
by 30% over control values while Na+ absorption was decreased by 32% below control values.
Gastrointestinal absorption of Ca2+ and body weight increases were unaffected by chlorfenvinphos exposure.
These changes in the gastrointestinal absorption of glucose, but Na+ were not considered statistically

signiﬁcant (P>0.05) by the investigators.

The central nervous system is the principal target of chlorfenvinphos toxicosis. Chlorfenvinphos, an
anticholinesterase organophosphate, inhibits cholinesterase activity in the central and peripheral nervous
system in humans and animals (Cupp et a1. 1975; Gralewicz et al. 1990; Hunter 1969; Maxwell and LeQuesne
1982; Osumi et al. 1975; Osicka-Koprowska et a1. 1984; Pach et al. 1987; Takahashi et a1. 1991; Vestweber
and Kruckenberg 1972). Chlorfenvinphos also inhibits noradrenaline (norepinephrine) activity in the central
nervous system in animals (Brzezinski 1978; Osumi et al. 1975). Human subjects exposed to large acute doses
of chlorfenvinphos exhibited severe cholinergic signs. These cholinergic signs were relieved by the
administration of atropine and/or pralidoxime, indicating cholinesterase inhibition etiology (Cupp et a1. 1975;
Pach et a1. 1987). In rats, low to moderate doses (2.4—30 mg/kg) of oral chlorfenvinphos signiﬁcantly
inhibited cholinesterase activities in a number of tissues: the brain, erythrocyte, and plasma (Bama and Simon
1973; Osicka-Koprowska et a1. 1984; Puzynska 1984). An acute-duration oral study also found alterations in
noradrenaline (norepinephrine) level in rat brain following exposure to chlorfenvinphos. A chlorfenvinphos
dose of 13 mg/kg decreased noradrenaline (norepinephrine) levels in rat brains by 20%, as compared to control
rats. According to the investigators, chlorfenvinphos accelerated the rate of NA disappearance from the brain

(Brzezinski 1978).

Therefore, it is appropriate to base the acute oral MRL for chlorfenvinphos on cholinesterase inhibition.

It should be noted that a study by Osumi et a1. (1975) which determined a NOAEL of 1 mg/kg/day and a
LOAEL of 2 mg/kg/day for 38% inhibition of brain cholinesterase in rats was not used to calculate an acute
oral MRL because it was deemed less appropriate due to the gavage (oral) route of administration of the test

substance. An oral feeding study is preferred by ATSDR.

CHLORFENVINPHOS 73

2. HEALTH EFFECTS

- An MRL of 0.002 mg/kg/day has been developed for intermediate-duration oral exposure
(15—3 64 days) to chlorfenvinphos.

The MRL is based on a LOAEL of 1.5 mg/kg/day for adverse immunological/lymphoreticular effects in
mice (Kowalczyk-Bronisz et a1. 1992). In this study male and female inbred C57BL/6 mice and (C57BL/6
x DBA/2)F1 (BDFl/Iiw) hybrid mice (6—8 weeks old) were orally dosed with chlorfenvinphos (suspended
in 1% methylcellulose solution) and evaluated for 5 days for the effect of chlorfenvinphos exposure on the
mouse immune system. The mice were exposed to oral chlorfenvinphos doses of 0, 1.5, 3, or 6 mg/kg (0,
1/ 100, 1/50, or 1/25 LDSO) daily for 3 months; the control group was given 1% methylcellulose. Then
exposed and control mice were immunized by intraperitoneal injections of 0.2 mL 10% sheep red blood
cells. The IgM-PFC (plaque-forming or antibody-producing cells) number in spleen cell suspension was
tested on day 4 after immunization and the procedure repeated 3 weeks after the exposure to chlorfen-
vinphos had been ceased. Exposed and control groups were subjected to immunological tests and
hematological examinations. Lymphatic organs were histologically examined. A dose-related decrease in
the number of hemolysin-producing cells was observed: plaque-forming cells (PFC) were 58% at the

6 mg/kg dose group and 85% at the 3 mg/kg dose level as compared to control values. Chlorfenvinphos
treatment also caused reduction in the number of E rosette-forming cells by 30% at the 6 mg/kg dose level
and by 25% at the 3 mg/kg dose level. Increases in Interlukin-l (Il-l) activity and delayed-type
hypersensitivity (DTH) reaction were observed 24 hours after challenge. Spleen colonies were stimulated,
as evidenced by the increase of endogenous spleen colonies and exogenous spleen colonies (CFU-S).
CFU-S increased 190% at the 1.48 mg/kg dose level; 137% at the 6 mg/kg dose level; 162% at 1.5 mg/kg
dose level; and 70% at the 6 mg/kg dose level. When the IgM PFC number was tested 3 weeks later, after
the exposure to chlorfenvinphos in the small dose (1.5 mg/kg), an increase (about 40%) in number of
plaques was observed. There was a 50% reduction in thymus weight at the 1.5 mg/kg dose level, compared

to controls; significant involution of the thymus was also noted.

In other studies, adverse immunologic/lymphoreticular effects have been associated with exposure to oral
chlorfenvinphos. In an intermediate-duration dietary study with albino (Wistar) rats, there was a significant
and irreversible reduction in relative spleen weight of female rats given 23 mg/kg/day chlorfenvinphos for
12 weeks (Ambrose et al. 1970). A study was undertaken to evaluate selected serological and
cytoimmunological reactions in rabbits subjected to a long-term poisoning with subtoxic oral doses

(10 mg/kg in a soya oil solution with a small amount of food) of chlorfenvinphos for 90 days.

Chlorfenvinphos treatment signiﬁcantly elevated serum hemagglutinin levels (16%) and hemolysin activity

CHLORFENVlNPHOS 74

2. HEALTH EFFECTS

(66%, P<0.05), and also increased the number of nucleated lymphoid cells producing hemolytic antibody to
sheep erythrocytes, compared to controls (treated 906, P<0.05 and controls 618). Spleen cytomorphology
changes, manifested mainly as transformation of primary follicles into secondary ones with well developed

germinal centers, were also observed (Roszkowski 1978).

Therefore, it is appropriate to base the intermediate oral MRL for chlorfenvinphos on immunological eﬁ‘ects.

- An MRL of 0.0007 mg/kg/day has been derived for chronic-duration oral exposure (365 days or more)

to chlorfenvinphos.

This MRL for chlorfenvinphos was developed from a LOAEL of 0.7 mg/kg/day for adverse neurological
effects in rats (Ambrose et a1. 1970). In this study, four matched groups of weanling albino (Wistar) rats were
culled to a narrow starting weight range and fed daily GC-4072 (technical chlorfenvinphos) doses of 0, 0.7,
2.1, 7, or 21 mg/kg/day (males) or 0, 0.8, 2.4, or 8, or 24 mg/kg/day (females) in the diet for 104 weeks. An
additional group of non-littermate rats were administered 21 mg/kg/day (males) or 24 mg/kg/day (females)
chlorfenvinphos for 104 weeks. Plasma and erythrocyte cholinesterase (ChE) activity levels were obtained
from 4 rats of each sex per dose group at 1, 4, 8, and 12 weeks. At 13 weeks, 4 rats/sex/dose group were
sacriﬁced for histopathologic examination. The rats in the 21 mg/kg/day (males) and 24 mg/kg/day (females)
were sacriﬁced on the 95th week, and all other dose group animals were sacriﬁced on the end of the study
(104 weeks). At each autopsy, relative organ weights were determined for heart and kidneys. All animals
sacriﬁced in moribund condition, as well as those sacriﬁced at week 13, 95, and 104 weeks were examined
grossly and microscopically, and organs (heart, lungs, liver, kidney, urinary bladder, spleen, stomach, small
and large intestine, skeletal muscle, skin, bone marrow, pancreas, thyroid, adrenal, pituitary) from these
animals were histopathologically examined. Chlorfenvinphos signiﬁcantly decreased body weight gain of
females at the 8 and 24 mg/kg/day dose groups from the 26th week until near the end of the study, although the
decreased body weight gain became statistically insigniﬁcant at the end of the study. Increased relative liver
weights were observed in males at the 7 mg/kg/day dose level, but no other signs of hepatopathology were
reported. Compared to undosed controls, no consistent differences in body weight gains in males, survival of
the test animals, food consumption, or mortality were evident at any dose level tested. No gross or
microscopic histopathology was evident in any of the organs (heart, lungs, liver, kidney, urinary bladder,
spleen, stomach, small and large intestine, skeletal muscle, skin, bone marrow, pancreas, thyroid, adrenal,
pituitary) and tissues examined. No changes in organ-to-body weight were observed in the heart, kidney,

spleen and testes.

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2. HEALTH EFFECTS

Although the neurological effects of prolonged human exposure to low oral doses of chlorfenvinphos are not
known due to a lack of studies, clinical reports of accidental and intentional acute exposure to relatively high
doses of chlorfenvinphos-containing organic phosphate products indicate that neurological effects, mediated
by cholinesterase inhibition (Cupp et al. 1975; Pach et al. 1987), may be the most sensitive toxicological
consequences of human exposure to chlorfenvinphos. Similarly, chlorfenvinphos signiﬁcantly inhibited both
plasma and erythrocyte cholinesterase activities in Beagle dogs fed daily chlorfenvinphos doses of 0.3, 2, or
10 mg/kg/day (males), or 1.5, 10, or 50 mg/kg/day (females) in the diet (moist) for 104 weeks. Plasma
cholinesterase activities were signiﬁcantly inhibited at all dietary levels through week 39 of the study; 49%
inhibition was noted at the 0.3 mg/kg/day (males) and 1.5 mg/kg/day (females) dose levels. Erythrocyte
cholinesterase activity was signiﬁcantly and consistently inhibited (36%) during the ﬁrst 12 weeks only in the

10 mg/kg/day (males) and 50 mg/kg/day (females) dose levels (Ambrose et al. 1970).

Death. Data are not available to estimate the lethal dose of chlorfenvinphos by any route or for any
duration of exposure in humans. However, one study reported the death of a 16-year-old victim following
unintentional ingestion of an unspeciﬁed amount of chlorfenvinphos (Felthous 1978). In animal studies, the
acute inhalation LC50 for rat is estimated as 130 mg/m3 (Tsuda et al. 1986). The acute oral LD50 for technical
chlorfenvinphos for both sexes of rat is variously estimated as 15.4 mg/kg (Hutson and Wright 1980);

22.8 mg/kg (Hutson and Logan 1986); 34.3 mg/kg (Ikeda et al. 1992); and 9.7 mg/kg/day (Ambrose et al.
1970). The acute oral LD50 values for male and female rats have been given as 23 mg/kg and 25.5 mg/kg,
respectively (Puzynska 1984). Chlorfenvinphos appears to be less acutely toxic to mice than to other
experimental animals, with estimated LD50 values of 148 mg/kg (male) and 109 mg/kg (female) (Kowalczyk-
Bronisz et al. 1992). The LD,O for rabbits has been estimated to be 300 mg/kg (Ambrose et al. 1970) and
500—1,000 mg/kg (Hutson and Logan 1986); the estimated LD,o for dogs is 50.5 mg/kg/day (Ambrose et al.
1970).

The dermal LD50 values for undiluted chlorfenvinphos and emulsiﬁable concentrate for rabbits have been
estimated as 400 and 1,087 g/kg, respectively (Ambrose et al. 1970). No reports of human deaths resulting
from dermal exposure to chlorfenvinphos were located, but evidence from non-lethal human data and animal
studies (Hunter 1969; Vestweber and Kruckenberg 1972) indicates that human lethality by this route of

exposure is unlikely.

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2. HEALTH EFFECTS

Systemic Effects.

Respiratory Eﬂects. No studies were located regarding respiratory effects in humans following acute-,
intermediate- or chronic-duration inhalation, oral, or dermal exposure to chlorfenvinphos. Respiratory effects
were noted in two clinical reports of human ingestion: accidental ingestion of a mange-mite medication
containing organic phosphate; and intentional ingestion in a suicide attempt of the preparation Enolofos®,
which contains 50% chlorfenvinphos. In both cases, effects stemmed from central cholinergic disturbances
(Cupp et al. 1975; Pach et al. 1987). Animal data indicate that acute-duration inhalation exposure to high
doses of chlorfenvinphos (16—390 mg/m3) may be accompanied by transient apnea (Takahashi et al. 1991,
1994). No effects on the respiratory system were noted in rats and dogs orally administered chlorfenvinphos at
doses as high as 100 mg/kg/day (rats) or 50 mg/kg/day (dogs) for 12 weeks; or in rats at doses as high as

24 mg/kg/day for 104 weeks (Ambrose et al. 1970). Due to inadequate data, it is unknown whether human

exposure to environmental concentrations of chlorfenvinphos could result in adverse respiratory effects.

Cardiovascular Eﬂects. No studies were located regarding cardiovascular effects in humans following acute-,
intermediate-, or chronic-duration inhalation, oral, or dermal exposure to chlorfenvinphos. Animal data
indicate that acute-duration inhalation exposure to high doses of chlorfenvinphos (16—390 mg/m3) may be
preceded by an initial hypotension followed by steadily increasing hypertension and abnormal cardiac
conductivity (Takahashi et al. 1991, 1994). Evidence from animal studies also indicates that oral
chlorfenvinphos is not directly toxic to the cardiovascular system, but may modulate the function of the
cardiovascular system via its effect on the central nervous system (Ambrose et al. 1970; Klaassen et al. 1986;
Puzynska 1984). Although this route of exposure may not be relevant to human exposure to chlorfenvinphos,
Sprague-Dawley rats also exhibited similar signs at a dose of 16 mg/kg following intravenous administration
of the chlorfenvinphos (Takahashi et al. 1991). Due to inadequate data, it is unknown whether human

exposure to environmental concentrations of chlorfenvinphos could result in adverse cardiovascular effects.

Gastrointestinal Effects. No studies were located regarding gastrointestinal effects in humans following
acute-, intermediate-, or chronic-duration oral exposure to chlorfenvinphos. Acute- and intermediate-duration
oral exposures to chlorfenvinphos increased gastrointestinal absorption of glucose, while decreasing the gastro-
intestinal absorption of Na+; however, Ca2+ absorption was unaffected in adult Wistar rats. These changes in
glucose and Na+ absorption were not considered statistically signiﬁcant (P>0.05) by the investigators (Bama
and Simon 1973). Weanling albino (Wistar) rats of both sexes chronically administered daily dietary
chlorfenvinphos doses of 21 mg/kg/day (males) or 24 mg/kg/day (females) exhibited no gross or microscopic

CHLORFENVlNPHOS 77

2. HEALTH EFFECTS

histopathology in the stomach or small and large intestine at autopsy (Ambrose et a1. 1970). Based on the
available information, human exposure to chlorfenvinphos at hazardous waste sites is not likely to result in any

signiﬁcant adverse gastrointestinal effects.

Hematological Effects. The hematological effects from inhalation exposure to chlorfenvinphos are not
known due to lack of data in humans and laboratory animals. Similarly, the hematological effects of oral
chlorfenvinphos exposure are not certain because of limited and inconclusive data in animals.

Uncorroborated investigations conducted on 4 groups of male and female rabbits (13 each) at a dose of

10 mg/kg for 90 days to evaluate the serological effects of chlorfenvinphos reported signiﬁcant increases of
hemolysin and hemagglutinin serum titers as compared to controls. Hemagglutinin and hemagglutinin IgG
titers were increased by 16 and 18%, respectively, while hemolysin and hemolysin IgG titers were elevated by
66 and 102%, respectively (Roszkowski 1978). However, no effects were observed on monitored
hematological parameters in rats and Beagle dogs given oral chlorfenvinphos (up to 24 mg/kg/day for rats and
50 mg/kg/day for dogs) for 104 weeks (Ambrose et al. 1970). Due to the lack of data on the hematological
effects of chlorfenvinphos in humans and scarcity of data in animals, the hematological effects of human

exposure to chlorfenvinphos are uncertain,

Musculoskeletal Effects. No studies were found regarding musculoskeletal effects in humans or animals
following inhalation or dermal exposure to chlorfenvinphos. In animal oral studies, no effects on the
musculoskeletal system were noted in dogs orally administered chlorfenvinphos at doses as high as

50 mg/kg/day (females) for 12 weeks; or in rats at doses as high as 24 mg/kg/day (females) for 104 weeks
(Ambrose et a1. 1970). Therefore, adverse musculoskeletal effects in humans from exposure to

chlorfenvinphos at hazardous waste sites are not likely.

Hepatic Effects. Based on the currently available data, chlorfenvinphos exposure at environmental levels is
not likely to present risk of liver injury to humans. No hepatic effects were reported in humans from exposure
to chlorfenvinphos by any route. Although chlorfenvinphos proved to be porphyrinogenic in tissue culture
without induction and markedly porphyrinogenic with induction (Koeman et al. 1980), no such evidence was
found in the currently available in vivo studies. The limited information on the hepatic effects of
chlorfenvinphos indicates that the substance is not signiﬁcantly hepatotoxic by the oral route in acute-,
intermediate-, or chronic—duration exposures. While no changes in liver weight (relative to body weight) were
reported in Fischer 344 rats given a single oral chlorfenvinphos dose of 15 mg/kg, P-450 activity was

increased by 30%. Aminopyrine-N—demethylase and aniline hydroxylase activities were also increased by

CHLORFENVINPHOS 78

2. HEALTH EFFECTS

40 and 27%, respectively (Ikeda et al. 1991). Although intermediate oral administration of doses of
chlorfenvinphos induced alterations in serum sorbitol dehydrogenase and brain and liver levels of aromatic
amino acids transferases L-phenylalanine aminotransferase, L-tyrosine aminotransferase, and L—tryptophan
aminotransferase in mature Wistar rats (Puzynska 1984), no gross or microscopic histopathology in liver
tissues was evident in weanling albino (Wistar) rats administered daily dietary chlorfenvinphos doses of

90 mg/kg/day (males) or 100 mg/kg/day (females) or in mongrel dogs given daily dietary doses of

10 mg/kg/day (males) or 50 mg/kg/day (females) for 12 weeks. However, relative liver weights were
signiﬁcantly and irreversibly decreased in the rats at a dose of 2.7 mg/kg/day (males) or 3 mg/kg/day (females)
(Ambrose et al. 1970). In chronic (104 weeks) feeding studies, increased relative liver weights were observed
in males at a dose of 7 mg/kg/day following dietary administration of chlorfenvinphos to both sexes. No liver
histopathological or adverse liver function effects were reported in Beagle dogs fed daily dietary
chlorfenvinphos doses of 10 mg/kg/day (males) or 50 mg/kg/day (females) for 104 weeks (Ambrose et al.
1970).

Renal Effects. No studies were located regarding renal effects in humans or animals following acute-,
intermediate-, or chronic-duration oral exposure to chlorfenvinphos. In one study, no gross or microscopic
histopathology in kidney tissues was evident in weanling albino (Wistar) rats administered daily dietary
chlorfenvinphos doses of 90 mg/kg/day (males) or 100 mg/kg/day (females), or in mongrel dogs given daily
dietary doses of 10 mg/kg/day (males) or 50 mg/kg/day (females) for 12 weeks. However, relative kidney
weights were signiﬁcantly and irreversibly decreased in the rats at a dose of 2.7 mg/kg/day (males) or

3 mg/kg/day (females) (Ambrose et al. 1970). In chronic (104 weeks) feeding studies, no gross or
microscopic histopathology in the kidney and urinary bladder tissues examined or changes in relative kidney
weights were evident in this strain of rats following daily doses of 21 mg/kg/day (males) or 24 mg/kg/day
(females) (Ambrose et al. 1970). No kidney histopathological or adverse kidney function effects were
reported in Beagle dogs fed daily dietary chlorfenvinphos doses of 10 mg/kg/day (males) or 50 mg/kg/day
(females) for 104 weeks (Ambrose et al. 1970). Renal function was not assessed in these studies. Due to the
lack of adequate data on the renal effects on chlorfenvinphos in humans and animals, the renal effects of

human exposure to chlorfenvinphos are not known.

Endocrine Effects. There are no reports of endocrine effects in humans exposed by acute-, intermediate-, or
chronic-duration ingestion of chlorfenvinphos. No studies were located regarding endocrine effects in animals
after intermediate- or chronic-duration oral exposure to this insecticide. Although a signiﬁcant increase

(>300%) of plasma corticosterone was observed at 1 and 3 hours, and of plasma aldosterone from 1 to 6 hours

CHLORFENVINPHOS 79

2. HEALTH EFFECTS

aﬁer treatment of male Wistar rats with a single chlorfenvinphos dose of 6.15 mg/kg (50% LDSO) by stomach
tube (Osicka-Koprowska et a1. 1984), the toxicological signiﬁcance of these ﬁndings and relevance to human

health are unknown.

Dermal Effects. No studies were found regarding dermal effects in humans or animals following inhalation or
dermal exposure to chlorfenvinphos. In animal oral studies, no adverse changes were seen in the skin of
weanling albino (Wistar) rats of both sexes given oral doses of up to 100 mg/kg/day (female rats)
chlorfenvinphos for 12 weeks (Ambrose et a1. 1970). Similarly, no adverse changes were seen in the skin of
weanling albino (Wistar) rats of both sexes chronically (104 weeks) given daily dietary chlorfenvinphos doses
of 0.7, 2.1, 7, or 21 mg/kg/day (males) or 0.8, 2.4, 8, or 24 mg/kg/day (females) (Ambrose et a1. 1970).
Therefore, adverse dermal effects in humans from exposure to chlorfenvinphos at hazardous waste sites are

not likely.

Ocular Eﬂects. No studies were located regarding ocular effects in humans or animals following acute-,
interrnediate—, or chronic—duration inhalation, oral, or dermal exposure to chlorfenvinphos. Consequently, it is
not known whether human exposure to environmental concentrations of chlorfenvinphos could result in

adverse ocular effects.

Body Weight Effects. No studies were located regarding body weight effects in humans following acute-,
intermediate-, or chronic-duration inhalation, oral, or dermal exposure to chlorfenvinphos. In animal studies,
acute-duration exposure of adult rats to oral Birlane® (chlorfenvinphos) at a dose of 2.4 mg/kg/day in the diet
for 10 days did not affect body weight increases. Body weight increases were also unaffected following oral
doses of 0.8 mg/kg/day in the diet for 30 days (Bama and Simon 1973). Similarly, no body weight changes
were seen in mongrel dogs exposed to dietary chlorfenvinphos at a dose of 10 mg/kg/day (males) or

50 mg/kg/day (females) for 12 weeks (Ambrose et al. 1970). However, oral exposure of weanling rats for the
same duration was associated with a signiﬁcant but slightly reversible depression on growth, observed at a
dose of 9 mg/kg/day (males) or 10 mg/kg/day (females). In an accompanying chronic-duration oral study
(104 weeks), chlorfenvinphos also signiﬁcantly and reversibly decreased body weight gain of female
weanlings at dose levels of 28 mg/kg/day. Beagle dogs given daily dietary chlorfenvinphos doses of

10 mg/kg/day (males) or 50 mg/kg/day (females) for the same duration (104 weeks) exhibited no signiﬁcant
changes in body weight (Ambrose et a1. 1970). Based on the available information, human exposure to
environmental concentrations of chlorfenvinphos is not likely to result in any signiﬁcant adverse body weight

effects.

CHLORFENVINPHOS 80

2. HEALTH EFFECTS

Metabolic Effects. Occupational exposure to airborne chlorfenvinphos signiﬁcantly lowered NBT-dye
reduction in‘both stimulated and non-stimulated cells, and caused a signiﬁcant decrease of the spontaneous E
rosette formation (not inﬂuenced by exposure time) in the blood (early E rosettes, 52%; late E rosettes, 57%).
The authors of this study concluded that this may be regarded as a probable mechanism by which
organophosphoric chemicals interfere with metabolism and cause membrane damage in human cells. About
half of the subjects in the study were smokers (Wysocki et a1. 1987). In animal studies, Carworth Farm E
strain male rats orally administered a single [”C]chlorfenvinphos dose of 2.5 or 13.3 mg/kg in olive oil (with
or without prior monooxygenase induction with dieldrin) exhibited minimal changes in the metabolic proﬁles
(Hutson and Wright 1980). However, the gastrointestinal absorption of glucose was increased by 30% over
control values, while Na+ absorption was decreased by 32% below control values in adult female albino
(Wistar) orally administered Birlane‘ID (chlorfenvinphos) at a dose of 2.4 mg/kg/day in the diet for 10 days,
although, Ca2+ absorption was unaffected. Similarly, oral chlorfenvinphos increased glucose absorption 12%
while decreasing Na+ absorption by 23% at a dose of 0.8 mg/kg/day in the diet to this strain of rats for 30 days.
Gastrointestinal absorption of Ca2+ was, likewise, unaffected by chlorfenvinphos exposure in this intermediate
exposure to oral chlorfenvinphos. The changes in glucose and Na+ absorption were not considered statistically
signiﬁcant (P>0.05) by the investigators (Bama and Simon 1973). The LOAEL of 2.4 mg/kg/day from the
10-day dosing protocol of this study, based on adverse neurological effects in rats was used to derive an acute

oral MRL of 0.002 mg/kg/day for chlorfenvinphos.

Evidence from rat studies indicates that the alteration of brain and liver activities of the aromatic amino acid
transferases by chlorfenvinphos may be due to the inhibitory effect of the substance on noradrenaline
(norepinephrine) activity, since noradrenaline (norepinephrine) has been shown to affect amino acid

transferase (L—tyrosine aminotransferase) activity in another study (Puzynska 1984).

Based on the available information, human exposure to environmental concentrations of chlorfenvinphos is

not likely to result in any signiﬁcant adverse metabolic effects.

Other Systemic Effects. No studies were located regarding other systemic effects in humans following acute-,
intermediate-, or chronic-duration inhalation, oral, or dermal systemic effects ﬁom exposure to
chlorfenvinphos. In animal studies, no signiﬁcant effect on food consumption was evident in weanling albino
(Wistar) rats administered daily dietary chlorfenvinphos doses of 90 mg/kg/day (males) or 100 mg/kg/day
(females) or in mongrel dogs given daily dietary doses of 10 mg/kg/day (males) or 50 mg/kg/day (females) for

12 weeks. Similarly, in chronic (104 weeks) feeding studies, no signiﬁcant effect on food consumption was

CHLORFENVINPHOS 81

2. HEALTH EFFECTS

evident in rats and Beagle dogs following daily doses of 21 mg/kg/day (males) or 24 mg/kg/day (females) and
10 mg/kg/day (males) or 50 mg/kg/day (females), respectively (Ambrose et al. 1970). Based on the available
information, human exposure to environmental concentrations of chlorfenvinphos is not likely to result in any

signiﬁcant adverse effects on food consumption effects.

Immunological and Lymphoreticular Effects. Only one study was located that reported
immunological effects in humans. In this report, occupational exposure to inhaled chlorfenvinphos for an
average of 15 years was associated with damage to humoral mechanisms in humans. The subjects exhibited
signiﬁcant decrease of the spontaneous E rosette formation and lowered absolute lymphocyte count in the
peripheral blood. However, the subjects were also concurrently exposed to greater concentrations of other
potentially immunotoxic substances such as formothion, sumithion, and malathion (Wysocki et al. 1987). In
animal studies, the gastrointestinal absorption of glucose was increased by 30% over control values in adult
female albino (Wistar) rats orally administered Birlane® (chlorfenvinphos) at a dose of 0 or 2.4 mg/kg/day in
the diet for 10 days. Similarly, gastrointestinal absorption of glucose was increased by 12% over control
values following orally administered Birlane® (chlorfenvinphos) at a dose of 0 or 0.8 mg/kg/day in the diet to
this strain of rats for 30 days. However, the changes in glucose and Na+ absorption were not considered
statistically signiﬁcant (P>0.05) by the investigators (Bama and Simon 1973). It has been observed in other
studies that an increased metabolic activity of neutrophils and monocytes during phagocytosis is accompanied
by higher consumption of glucose and oxygen. Hydrogen peroxide is then derived from the pentose cycle,
NAD-, and NADP-oxidase action (Kolanoski 1977 as cited in Wysocki et al. 1977). However, the
relationship between increased gastrointestinal absorption of glucose and increased glucose utilization is not
clear. In other animal studies, rabbits orally exposed to chlorfenvinphos for 90 days also exhibited
significantly elevated serum hemagglutinin level (16%) and hemolysin activity (66%, P<0.05) as well as
increased numbers of nucleated lymphoid cells producing hemolytic antibodies to sheep erythrocytes. Spleen
cytomorphology changes, manifested mainly as transformation of primary follicles into secondary ones with
well developed germinal centers, were also observed (Roszkowski 1978). Intermediate-duration dietary
exposure of rats resulted in a signiﬁcant and irreversible reduction in relative spleen weight of female rats
given 23 mg/kg/day chlorfenvinphos for 12 weeks. However, no gross or microscopic histopathology was
evident in the spleen and bone marrow tissues of the rats upon examination (Ambrose et al. 1970). No
histopathological changes in the spleen or bone marrow or changes in absolute or relative spleen weights were
noted in rats or Beagle dogs of both sexes given dietary chlorfenvinphos doses of 21 mg/kg/day (males) or

24 mg/kg/day (females), or 10 mg/kg/day (males) or 50 mg/kg/day (females), respectively, for 104 week
(Ambrose et al. 1970). C57BL/6 mice and (C57BL/6 x DBA/2)Fl (BDFl/Iiw) hybrid mice (6—8 weeks old)

CHLORFENVINPHOS 82

2. HEALTH EFFECTS

orally exposed to chlorfenvinphos for 90 days exhibited a reversible reduction in the number of E rosette-
forming cells as well as a dose-related decrease in the number of hemolysin—producing cells, reduction in the
number of plaque-forming cells, increases in Interlukin-l activity and DTH reaction, stimulation of spleen
colonies, and disturbance in humoral immune factors (immunoglobulins) at a LOAEL of 1.5 mg/kg
(Kowalczyk—Bronisz et al. 1992). The LOAEL of 1.5 mg/kg/day, based on adverse immunolymphoreticular
effects in this study, was used to derive an intermediate oral MRL of 0.002 mg/kg/day for chlorfenvinphos.
While the existing human inhalation study and the animal oral studies provide some indication that
chlorfenvinphos exposure is associated With immunological changes, these changes were not consistent with
depressive effect on immune reactions. Thus, the changes reported in these studies may simply be
immunological mobilizations of the organisms to xenobiotics as opposed to damage to the major
histocompatibility complex. Consequently, it is not certain that human inhalation or oral exposure to

chlorfenvinphos can result in immune dysfunction.

Neurological Effects. No studies were located regarding neurological effects in humans aﬁer acute— or
intermediate-duration inhalation exposure to chlorfenvinphos, or after intermediate- or chronic-duration
dermal exposure. Chlorfenvinphos inhibits cholinesterase activity in the central and peripheral nervous system
of humans and animals (Ambrose et al. 1970; Barna and Simon 1973; Cupp et al. 1975; Gralewicz et al.
1989a, 1989b, 1990; Hunter 1969; Maxwell and LeQuesne 1982; Osicka—Koprowska et al. 1984; Pach et al.
1987; Takahashi et al. 1991; Vestweber and Kruckenberg 1972). It also interferes with noradrenaline
(norepinephrine) activity in central adrenergic mechanisms in animals (Brzezinski 1978; Osumi et al. 1975).
Inhibition of acetylcholinesterase activity results in accumulation of acetylcholine at muscarinic and nicotinic
receptors leading to peripheral and central nervous system effects. These effects usually appear within a few
minutes to a few hours after exposure, depending on the extent of exposure. In a human case report, a
16-year-old white male who mistakenly ingested a formulation (identiﬁed as Dermaton®) was hospitalized

90 minutes afterward with symptoms of abdominal cramps, nausea, vomiting, generalized weakness, cold dry
skin, hypothermia, listlessness, constricted pupils, hypertension, respiratory distress, ﬁne generalized muscular
twitching, and apprehension. Plasma and erythrocyte activity levels were signiﬁcantly inhibited. All vital

signs returned to normal after gastric lavage and treatment with atropine and pralidoxime (Cupp et al. 1975).

The available information indicates that chlorfenvinphos has similar neurological effects in animals. The
information indicates that the substance causes disruptions in the central and peripheral nervous system in rats
and dogs following acute-, intermediate-, or chronic-duration exposures via the oral route at doses as low as

0.8 mg/kg/day (Ambrose et al. 1970; Bama and Simon 1973; Maxwell and LeQuesne 1982; Osumi et al.

CHLORFENVINPHOS 83

2. HEALTH EFFECTS

1975; Puzynska 1984; Takahashi et al. 1994). These disruptions are mediated by the inhibition of
cholinesterase activity in the peripheral and central nervous tissue and are manifested as abnormal muscle
reﬂex, muscle fasciculations, Straub tail reﬂex, twitches, convulsions, chromodacryorrhea, exophthalmos,
gasping, lacrimation, prostration, salivation, sleep disturbances, diarrhea, emesis, and urination (Ambrose et al.
1970; Maxwell and LeQuesne 1982; Osumi et a1. 1975; Puzynska 1984; Takahashi et a1. 1991).
Cholinesterase activity in the brain of male Wistar rats was unaffected 3 hours after oral administration of

1 mg/kg of chlorfenvinphos. However, at doses of 22 mg/kg, oral chlorfenvinphos produced a marked
decrease in the brain cholinesterase activity to 18—3 8% of the control (P<0.001) value. The maximum
inhibition occurred 3 hours after the administration, after which the cholinesterase activity increased
gradually. Erythrocyte cholinesterase activity also decreased after 4 mg/kg of chlorfenvinphos; the lowest
level (20%, P<0.001) was attained 3 hours aﬁer treatment (Osumi et al. 1975). This study was not used to
calculate an acute oral MRL because it was deemed less appropriate due to the gavage (oral) route of
administration. An oral feeding study is preferred for this purpose by the ATSDR MRL Workgroup. In a
chronic-duration study, chlorfenvinphos signiﬁcantly inhibited both plasma and erythrocyte cholinesterase
activities in a dose-dependent manner in weanling albino (Wistar) rats fed daily chlorfenvinphos doses of 0.7,
2.1, 7, or 21 mg/kg/day (males) or 0.8, 2.4, 8, or 24 mg/kg/day (females) mg/kg/day in the diet for 104 weeks.
Plasma and erythrocyte cholinesterase activities were inhibited by 48% in females and 45% in males in the
ﬁrst week of treatment and by 20% in females and 33% in males in the fourth week of treatment, respectively,
at the lowest dose tested (0.7 mg/kg/day for males and 0.8 mg/kg/day for females). No gross or microscopic
histopathology was evident in the brain tissue examined (Ambrose et al. 1970). The LOAEL of

0.7 mg/kg/day, based on adverse neurological effects in rats in this study, was used to derive a chronic oral
MRL of 0.0007 mg/kg/day for chlorfenvinphos. In another study, all 36 Sprague-Dawley rats exposed to
chlorfenvinphos doses of 10.5 mg/kg/day in the diet for 3—6 months exhibited repetitive muscle activity when
given two electrical stimuli simultaneously. This is indicative of hyper stimulation due to depletion or
inactivation of neuromuscular junction cholinesterase. The abnormality became more marked with time, even
on constant dosing (Maxwell and LeQuesne 1982). The indications from this study may be useful in
explaining electrophysiological abnormalities described in some workers chronically exposed to some

organophosphorus compounds.

Besides its cholinergic action, there is limited evidence that chlorfenvinphos acts via central noradrenergic
mechanisms in rats by accelerating the noradrenaline (norepinephrine) turnover in the brain in vivo by the

release of noradrenaline (norepinephrine) from brain tissue stores (Brzezinski 1978).

CHLORFENVINPHOS 84

2. HEALTH EFFECTS

On the basis of the existing evidence, human exposure to chlorfenvinphos is likely to result in neurological

effects stemming from interference with both the central cholinergic and adrenergic mechanisms.

Reproductive Effects. No studies were located regarding reproductive effects in humans following
acute-, intermediate-, or chronic-duration inhalation, oral, or dermal exposure to chlorfenvinphos. Reports
from single-generation, intennediatc- or chronic-duration rat and dog studies are largely negative for
reproductive effects (Ambrose et al. 1970). However, these studies did not evaluate reproductive function. A
3-generation reproductive study in albino (Wistar) rats reported signiﬁcant (50%) reduction in fertility in the
F/2 generation at a LOAEL of 3 mg/kg/day (Ambrose et al. 1970). Although human data are lacking, the
indications provided by the animal data suggest that adverse reproductive effects may result from prolonged

human exposure to chlorfenvinphos at levels found at hazardous wastes sites.

Developmental Effects. No studies were located regarding developmental effects in humans following
acute-, intermediate-, or chronic-duration inhalation exposure to chlorfenvinphos; or regarding acute-duration
exposure of animals to chlorfenvinphos. A statistical model for hazard identiﬁcation concluded that
chlorfenvinphos is likely to interfere with development in rabbits and hamsters but not in rats. The model was
essentially a database of 175 probable, suspected, unknown, and probably negative teratogenic or embryotoxic
drugs and chemical compounds. For each of the compounds, including chlorfenvinphos, the results of any
developmental toxicity testing in up to 14 animal species and any reports of mutagenicity or carcinogenicity
were recorded. The compounds were categorized with respect to their human developmental toxicant effect:
-1 .0 testing negative, 0.0 not tested (unknown), 0.5 tested with equivocal results (suspicious), and 1.0 testing
positive. Although the model did not evaluate the adverse reproductive effects potential of chlorfenvinphos in
primates, mice, and dogs, it correctly classiﬁed the study compounds 63—91% of the time. The model had a
sensitivity of 62~75%, and a positive predictive value of 75—100%. However, the model had a negative
predictive value of 64-91 %, indicating the model is not optimal for hazard identiﬁcation (Jelovsek et al. 1989).
In acute exposures, chlorfenvinphos inhibited respiratory efﬁciency of juvenile rats in a dose-dependent
manner at a LOAEL of 29 mg/kg/day. At 300 mg/kg/day, chlorfenvinphos completely arrested respiration in
these rats (Skonieczna et al. 1981). In a 3-generation rat study, chlorfenvinphos induced signiﬁcant but
slightly reversible body weight gains in female rats at a LOAEL of 28 mg/kg/day as well as increased pup
mortality and reduced lactational index at a LOAEL of 2.7 mg/kg/day. However, no teratogenic effects were
reported in offspring rats (Ambrose et al. 1970). In single-generation intermediate- and chronic-duration
studies with juvenile rats in which the rats were given dietary chlorfenvinphos doses of 90 mg/kg/day (males)
or 100 mg/kg/day (females) for 12 weeks, or 21 mg/kg/day (males) or 24 mg/kg/day (females) in the diet for

CHLORFENVINPHOS 85

2. HEALTH EFFECTS

104 weeks, no signiﬁcant effects on development were reported (Ambrose et a1. 1970). Although human data
are lacking, the indications provided by the animal data suggest that adverse developmental effects may result

from prolonged human exposure to chlorfenvinphos at levels found at hazardous wastes sites.

Genotoxic Effects. No studies were located regarding genotoxic effects of chlorfenvinphos in humans or
animals following any route of exposure. Chlorfenvinphos was negative for mutagenicity in both base-pair
change-type strains microorganisms (WP2 hcr of Escherichia coli; TA1535, TA1537, TA1538, TA98 of
Salmonella typhimurium). In a mutagenicity study, the dose-response curve at doses of 0, 50, 500, and

5,000 ug/plate, for the mutagenic activity of chlorfenvinphos for the S. typhimurium strain TA100 was
reduced by the S9 mix (metabolic activation). At present, no mutagenic pesticide whose activity decreases in
the presence of the S9 mix is carcinogenic except captan (F-28) (Moriya et a1. 1983). The mutagenic potency
of chlorfenvinphos for strain TA100 has been reported as 0.038 revertants/nmol, indicative of a positive
response (Dean 1972; Moriya et a1. 1983; Vishwanath and Kaiser 1986). A mixture of 15 pesticides
(containing 0.3% chlorfenvinphos) tested negative for mutagenicity in the Salmonella microsome assay, with
or without metabolic activation with PCB-induced rat liver S9, at concentrations up to 500 ug/plate in the
Salmonella-microsome assay. The mixture also failed to induce SCEs in human lymphocytes in vitro as well
as in vivo mutagenicity in the micronucleus bone marrow assay in male Wistar rats at concentrations
proportional to the ratio determined in foods ranging from 0.1 to 20 pg/mL (Dolara et al. 1993). In other large-
scale screening programs which revealed microbial mutagenic activity in four new compounds (all
fungicides), chlorfenvinphos (without metabolic activation) exhibited no mutation induction capacity in a rec-
assay procedure (prescreening of DNA-damaging chemicals) utilizing strains of Bacillus subtilis, H17 Rec+
and M45 Rec-. Also, no mutation potential was evident in a reversion-assay (determination of mutation
speciﬁcities) in which two tryptophan—requiring strains (auxotrophic) of E. coli (B/r try WP2 and WP2 try hcr)
and four strains of S. typhimurium (TA1535, TA1536, TA1537, TA153 8) were used. The E. coli auxotrophic
strains and Salmonella TA1535 are reversible by base-pair change-type mutagens and the three Salmonella
strains (TA1536, TA1537, and TA1538) are reversible by frameshift mutagens (Shirasu 1973; Shirasu et al.
1976)

There are no unequivocal data to indicate that chlorfenvinphos reacts directly with DNA in vivo or in vitro to
produce mutations in either germ or somatic cells. In a study to determine the ability of vinyl phosphate
esters, like chlorfenvinphos, to form methylated bases in DNA of calf thymus failed to detect 6-methyl
guanine, a known mutagen. In both the reaction with dsDNA and ssDNA, 7-methyl guanine was the main

methylation product. However, all methyl derivatives of adenine constituted about 40% and 50% of all

CHLORFENVINPHOS 86

2. HEALTH EFFECTS

methylation products in the case of dsDNA and ssDNA, respectively. 3-Methylcytosine was the only methyl
derivative of a pyrimidine identiﬁed (Wiaderkiewicz et a1. 1986). In another study, tetrachlorvinphos
(Gardona®) was evaluated for its potential to induce chromosomal aberrations and SCEs in vitro in a primary
culture of Swiss mice spleen cells at concentrations of 0.25, 0.50, 1.0, or 2.0 ug/mL. After 4 hours of
treatment, tetrachlorvinphos induced a high percentage of metaphases with chromosomal aberrations in the
mouse spleen cells in a dose-dependent manner. According to the authors, the results indicate that tetra-
chlorvinphos in the tested concentrations is mutagenic in mouse spleen cell cultures (Amer and Aly 1992). In
this study, a structural analog of chlorfenvinphos (tetrachlorvinphos) was used; therefore, the data are difﬁcult
to relate to chlorfenvinphos without extensive structure-activity relationship analysis. Data from these studies

are shown on Tables 2—3 and 2-4.

Cancer There are no epidemiological or laboratory animal data to evaluate the carcinogenicity of
chlorfenvinphos in humans by any route of exposure. However, a study to determine the ability of vinyl
phosphate esters, like chlorfenvinphos, to form methylated bases in DNA of calf thymus failed to detect
6-methyl guanine, a known mutagen. In both the reaction with dsDNA and ssDNA, 7-methyl guanine was the
main methylation product. However, all methyl derivatives of adenine constituted about 40% and 50% of all
methylation products in the case of dsDNA and ssDNA, respectively. 3-Methylcytosine was the only methyl
derivative of pyrimidine identiﬁed (Wiaderkiewicz et al. 1986). It is noteworthy that the production of
electrophilic metabolic intermediates or epoxides in the metabolism of chlorfenvinphos, which could react
with nucleophilic cellular components (DNA, RNA, and proteins) leading to carcinogenesis, was considered

unlikely by a theoretical analysis (Akintonwa 1985).

In a mutagenicity study, the dose-response curve, at doses of 0, 50, 500, and 5,000 ug/plate, for the mutagenic
activity of chlorfenvinphos for the S. typhimurium strain TA100 was reduced by the S9 mix (metabolic
activation). At present, no mutagenic pesticide whose activity decreases in the presence of the S9 mix is
carcinogenic except captan (F —28) (Moriya et al. 1983). A theoretical analysis that predicted the mammalian
biotransfonnation products based on the recognition of the structure of chlorfenvinphos, understanding of
Types 1 and II metabolism of foreign compounds, and mechanistic biochemistry, also acknowledged that
cytochrome P-450 monooxygenase (an inducible enzyme) is the relevant enzyme which mediates the
biotransfonnation of chlorfenvinphos. The author of this study postulated that the 2,4-dichlorobenzoyl glycine
(2,4—dichlorohippuric acid) was produced in the rat by this mechanism. The production of electrophilic

metabolic intermediates or epoxides in the metabolism of chlorfenvinphos, which could react

87

CHLORFENVINPHOS

2. HEALTH EFFECTS

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CHLORFENVINPHOS 89

2. HEALTH EFFECTS

with nucleophilic cellular components (DNA, RNA, and proteins) leading to carcinogenesis, was considered

unlikely by this theoretical approach (Akintonwa 1984).

In contrast, tetrachlorvinphos (Gardona®), a structural analog to chlorfenvinphos, was evaluated for potential
to induce chromosomal aberrations and SCEs in vitro in a primary culture of Swiss mice spleen cells at
concentrations of 0.25, 0.50, 1.0, or 2.0 pg/mL. After 4 hours of treatment, tetrachlorvinphos induced a high
percentage of metaphases with chromosomal aberrations in the mouse spleen cells in a dose-dependent
manner. The corresponding number of metaphases for tetrachlorvinphos doses of 0.25, 0.50, 1.0, and

2.0 ug/m were 150, 590, 590, 600, and 600. According to the authors, the results of this evaluation indicate
that tetrachlorvinphos (in the tested concentrations) ismutagenic in mouse spleen cell cultures (Amer and Aly
1992). However, in both of these studies, structural analogs of chlorfenvinphos (methylbromophenvinphos
and tetrachlorvinphos, respectively) were used; therefore, the data are difﬁcult to relate to chlorfenvinphos

without extensive structure-activity relationship analysis.

Although neither human epidemiological evidence or evidence from rodent cancer bioassays is available, the
current theoretical evidence indicates that human exposure to chlorfenvinphos is not likely to present cancer

risk.

2.6 BIOMARKERS OF EXPOSURE AND EFFECT

Biomarkers are broadly deﬁned as indicators signaling events in biologic systems or samples. They have been

classiﬁed as markers of exposure, markers of effect, and markers of susceptibility (NAS/NRC 1989).

Due to a nascent understanding of the use and interpretation of biomarkers, implementation of biomarkers as
tools of exposure in the general population is very limited. A biomarker of exposure is a xenobiotic substance
or its metabolite(s), or the product of an interaction between a xenobiotic agent and some target molecule(s) or
cell(s) that is measured within a compartment of an organism (NRC 1989). The preferred biomarkers of
exposure are generally the substance itself or substance-speciﬁc metabolites in readily obtainable body ﬂuid(s)
or excreta. However, several factors can confound the use and interpretation of biomarkers of exposure. The
body burden of a substance may be the result of exposures from more than one source. The substance being
measured may be a metabolite of another xenobiotic substance (e.g., high urinary levels of phenol can result
from exposure to several different aromatic compounds). Depending on the properties of the substance (e.g.,

biologic half-life) and environmental conditions (e.g., duration and route of exposure), the substance and all of

CHLORFENVINPHOS 90

2. HEALTH EFFECTS

its metabolites may have left the body by the time samples can be taken. It may be difficult to identify
individuals exposed to hazardous substances that are commonly found in body tissues and ﬂuids (e.g., essential
mineral nutrients such as copper, zinc, and selenium). Biomarkers of exposure to chlorfenvinphos are

discussed in Section 2.6.1.

Biomarkers of effect are deﬁned as any measurable biochemical, physiologic, or other alteration within an
organism that, depending on magnitude, can be recognized as an established or potential health impairment or
disease (NAS/NRC 1989). This deﬁnition encompasses biochemical or cellular signals of tissue dysfunction
(e.g., increased liver enzyme activity or pathologic changes in female genital epithelial cells), as well as
physiologic signs of dysfunction such as increased blood pressure or decreased lung capacity. Note that these
markers are not often substance speciﬁc. They also may not be directly adverse, but can indicate potential
health impairment (e.g., DNA adducts). Biomarkers of effects caused by chlorfenvinphos are discussed in
Section 2.6.2.

A biomarker of susceptibility is an indicator of an inherent or acquired limitation of an organism’s ability to
respond to the challenge of exposure to a speciﬁc xenobiotic substance. It can be an intrinsic genetic or other
characteristic or a preexisting disease that results in an increase in absorbed dose, a decrease in the
biologically effective dose, or a target tissue response. If biomarkers of susceptibility exist, they are discussed

in Section 2.8, Populations That Are Unusually Susceptible.

2.6.1 Biomarkers Used to Identify or Quantify Exposure to Chlorfenvinphos

Chlorfenvinphos is rapidly absorbed from the gastrointestinal tract and widely distributed throughout the body
in humans (Pach et al. 1987; Wagner et al. 1990). Traces of unchanged chlorfenvinphos have been detected in
animal urine following exposure (Hunter 1972; Szczepaniak and Sienkiewitcz 1980). Chlorfenvinphos
undergoes biotransfomration to a variety of polar metabolites, including 2-chloro-l-(2,4-dichlorophenyl) vinyl-
ethylhydrogen phosphate; l-(2,4-dichlorophenyl) ethanol; 1-(2,4-dichlorophenyl) ethanediol; 2,4—dichloro-
mandelic acid; and 2,4—dichlorobenzoyl glycine (Hutson and Wright 1980), which have been detected in
animals. Analysis of urine samples for the presence of these metabolites represents a potentially preferable
means of assessing exposure since this method 15 non-invasive. However, as an organophosphate,
chlorfenvinphos lS rapidly metabolized and excreted from the body; therefore, urinary metabolite analysis 15

useful only 1n the evaluation of recent exposures.

CHLORFENVINF’HOS 91

2. HEALTH EFFECTS

The major action resulting from human exposure to chlorfenvinphos is the inhibition of cholinesterase activity
(see Section 2.4). Two pools of cholinesterases are present in human blood: acetylcholinesterase in
erythrocytes and pseudocholinesterase in plasma. Acetylcholinesterase, present in human erythrocytes, is
identical to the enzyme present in neuromuscular tissue (the target of chlorfenvinphos action), while plasma
pseudocholinesterase has no known physiological function. Inhibition of both forms of cholinesterase
activities has been associated with exposure to chlorfenvinphos in humans and animals (Cupp et a1. 1975;
Gralewicz et al. 1989a, 1989b, 1990; Hunter 1969; Maxwell and LeQuesne 1982; Osicka—Koprowska et al.
1984; Pach et al. 1987; Takahashi et a1. 1991; Vestweber and Kruckenberg 1972). Inhibition of erythrocyte,
plasma, or whole blood cholinesterase activities may be used as a marker of exposure to chlorfenvinphos.
However, inhibition of cholinesterase activity is a common action of anticholinesterase compounds, which
include organophosphates, like chlorfenvinphos, and carbamate compounds. In addition, a wide variation in
normal cholinesterase values exists in the general population, and there are no studies which report a
quantitative association between cholinesterase activity levels and exposure to chlorfenvinphos in humans.
Thus, the inhibition of cholinesterase activity is not a specific biomarker of effect for chlorfenvinphos
exposure; it is indicative only of effect and is not useful for dosimetric analysis. It should be noted that
changes in plasma cholinesterase (pseudOcholinesterase) activity are considered a more sensitive biomarker of
exposure for organophosphate exposure than changes in erythrocyte cholinesterase activity (Endo et a1. 1988;
Hayes et a1. 1980). It has been suggested that in the absence of baseline values for cholinesterase activity,
sequential post-exposure cholinesterase analyses be used to conﬁrm a diagnosis of organophosphate (like

chlorfenvinphos) poisoning (Coye et al. 1987).

This method of using the inhibition of cholinesterase activity as an indicator for exposure to organophosphate
exposure lacks even greater specificity when used to assess exposure to compounds like chlorfenvinphos
which are weak cholinesterase inhibitors. As a vinyl phosphate, chlorfenvinphos is metabolized to desethyl
chlorfenvinphos which could be detected in urine as a speciﬁc biomarker of exposure to chlorfenvinphos or
other vinyl phosphates. The method of detection involves conversion of urinary desethyl chlorfenvinphos to
the more easily measurable methyl desethyl chlorfenvinphos with diazomethane. The analyses of 24-hour
samples of urine from 14 male volunteers were made at 14-day intervals on four occasions (days 10, 24, 38,
and 52) during exposure, and on one occasion, 15—16 days aﬁer cessation of exposure, using this novel
detection method. The average daily excretion of beta-methyl desethyl chlorfenvinphos during exposure was
120 ug, which was 4.7% of the dose. In post-exposure urine, the concentrations of beta-methyl desethyl
chlorfenvinphos were 0 in most cases, and no greater than 5—10 ug/day in the remainder. The excretion rate of

alpha-methyl desethyl chlorfenvinphos was 15 3:5 ug/day during exposure, but fell to O or <5 ug/day post-

CHLORFENVINPHOS 92

2. HEALTH EFFECTS

exposure. Thus, the higher level of excretion of desethyl chlorfenvinphos in the urine found in an acute
dosing experiment was not maintained when the dose was diminished four-fold and administered daily.
However, since desethyl chlorfenvinphos accounts for only about 5% of the dose at this low exposure level, its
concentration in urine would lack sensitivity when used as an index of exposure to chlorfenvinphos (Hunter et
al. 1972). Although this method of assessing chlorfenvinphos exposure may not be useful in low exposure
conditions, the method could be used to evaluate exposure to high doses of chlorfenvinphos such as occurs in
human acute poisoning cases. It has been suggested that the concentration of chlorfenvinphos (or its unique
metabolites) in the blood may be a better index of exposure than inhibition of cholinesterase activity (Hunter

1968,1969)
2.6.2 Biomarkers Used to Characterize Effects Caused by Chlorfenvinphos

Inhibition of erythrocyte, plasma, or whole blood cholinesterase activities in humans and animals that results
from chlorfenvinphos exposure (Barna and Simon 1973; Brzezinski 1978; Cupp et al. 1975; Pach et a1. 1987;
Kolmodin—Hedman and Eriksson 1987; Osicka—Koprowska et a1. 1984; Osumi et al. 1975; Takahashi et al.
1991) may be used as a marker of effect for chlorfenvinphos exposure. However, inhibition of cholinesterase
activity is a common action of anticholinesterase compounds, which include organophosphates, like
chlorfenvinphos, and carbamate compounds. In addition, a wide variation in normal cholinesterase values
exists in the general population, and there are no studies which report a quantitative association between
cholinesterase activity levels and exposure to chlorfenvinphos in humans. Thus, inhibition of cholinesterase
activity is not a specific biomarker of effect for chlorfenvinphos exposure; it is indicative only of effect and not

useful for chlorfenvinphos-speciﬁc dosimetric analysis.

It should be noted that plasma cholinesterase (pseudocholinesterase) activity is considered a more sensitive
biomarker of effect for organophosphate exposure than erythrocyte cholinesterase activity (Endo et a1. 1988;
Hayes et a1. 1980). It has been suggested that in the absence of baseline values for cholinesterase activity,
sequential post-exposure cholinesterase analyses be used to conﬁrm a diagnosis of organophosphate poisoning
(Coye et al. 1987).

In combination with analysis of reductions in the level of cholinesterase activity, the manifestations of severe
organophosphate (chlorfenvinphos) poisoning, clinically characterized by a collection of cholinergic signs and
symptoms, which may include dizziness, fatigue, tachycardia or bradycardia, miosis, diarrhea, and vomiting

(Chambers and Levi 1992; Cupp et al. 1975; Klaassen et a1. 1986; Takahashi et a1. 1991; Williams and Burson

CHLORFENVINPHOS 93

2. HEALTH EFFECTS

1985), are useful biomarkers of effect for identifying poisoned victims of organophosphates
(chlorfenvinphos). Also, these manifestations are not speciﬁc to chlorfenvinphos but to anticholinesterase
compounds (such as organophosphates and carbamate compounds) in general. A positive response to atropine

treatment is considered a conﬁrmation of organophosphate poisoning.

For more information on biomarkers for renal and hepatic effects of chemicals see AT SDR/CDC
Subcommittee Report on Biological Indicators of Organ Damage (1990) and for information on biomarkers

for neurological effects see OTA (1990).

2.7 INTERACTIONS WITH OTHER CHEMICALS

The toxicity of chlorfenvinphos may be affected by other substances. Some chemicals may increase the
toxicity of chlorfenvinphos in an additive manner. Chemical substances such as other anticholinesterase
organophosphates, carbamates, or some pyrethroid insecticides that cause neurotoxicity are expected to act in

an additive manner with chlorfenvinphos with respect to its potential to induce cholinergic toxicity.

As a direct-acting cholinesterase activity inhibitor (P=O type in contradistinction from P=S types), other
chemicals may interfere with the toxicity of chlorfenvinphos indirectly by accelerating its metabolism to less
toxic metabolites through their actions on drug-metabolizing enzymes, speciﬁcally, glutathione-S—transferase
and P-450 or mixed function monooxygenases (Akintonwa 1984, 1985; Akintonwa and Itam 1988; Donninger
1971; Hansen 1983; Hutson and Logan 1986; Hutson and Millbum 1991; Hutson and Wright 1980). The
duration and intensity of action of chlorfenvinphos is largely determined by the speed at which it is
metabolized via oxidative 0-dealkylation in the body by liver microsomal cytochrome P-450 or mixed
function monooxygenases (MFO). More than 200 drugs, insecticides, carcinogens, and other chemicals are
known to induce the activity of liver microsomal drug—metabolizing enzymes. The characteristic biological
actions of these chemicals are highly varied. Although there is no relationship between their actions or
structures and their ability to induce enzymes, most of the inducers are lipid-soluble at physiological pH.
These inducers of the MFO system include the following classes of drugs: hypnotic and sedatives
(barbiturates, ethanol, tetrahydrofuran, metyrapone); anesthetic gases (methoxyﬂurane, halothane); central
nervous system stimulants (amphetamine); anticonvulsants (diphenylhydantoin); tranquilizers (meprobamate);
antipsychotics (triflupromazine); hypoglycemic agents (carbutamide); anti-inﬂammatory agents
(phenylbutazone); muscle relaxants (orphenadrine); analgesics (aspirin, morphine); antihistaminics

(diphenhydramine); alkaloids (nicotine); polychlorinated aromatic hydrocarbons; insecticides (chlordane,

CHLORFENVINPHOS 94

2. HEALTH EFFECTS

DDT, BHC, aldrin, dieldrin, heptachlorepoxide); pyrethrins; steroid hormones (testosterone, progesterone,
cortisone); and polycyclic aromatic hydrocarbons (3-methylcholanthrene, 3,4-benzpyrene, (x-naphthoﬂavone)
(Akintonwa 1984; Hansen 1983; Hutson and Logan 1986; Hutson and Millbum 1991; Hutson and Wright
1980; Ikeda et a1. 1991; Klaassen et al. 1986; Williams and Burson 1985). Thus, exposure to any of these
enzyme inducers prior to, or concurrent with, exposure to chlorfenvinphos may result in accelerated
biotransformation of chlorfenvinphos to its less toxic metabolites. Conversely, since chlorfenvinphos is active
per se, concurrent exposure to chlorfenvinphos and MFO enzyme-inhibiting substances (e.g., carbon
monoxide; ethylisocyanide; SKF 525A, halogenated alkanes, such as CCL; alkenes, such as vinyl chloride;
and allylic and acetylenic derivatives) would increase the mammalian half-life and, thus, the toxicity of
chlorfenvinphos (Akintonwa 1984; Akintonwa and Itam 1988; Donninger 1971; Hansen 1983; Hutson and
Logan 1986; Hutson and Millbum 1991; Hutson and Wright 1980; Williams and Burson 1985).

Chlorfenvinphos exposure may interfere with the short-acting muscle relaxant succinylcholine used
concurrently with anesthetics. The action of succinylcholine is terminated by means of its hydrolysis by
plasma cholinesterase (Klaassen et al. 1986). Since plasma cholinesterase activity is strongly inhibited by
chlorfenvinphos in humans (Cupp et al. 1975; Kolmodin-Hedman and Eriksson 1987; Pach et al. 1987;
Takahashi et al. 1991; Vestweber and Kruckenberg 1972) and animals (Gralewicz et al. 1989a, 1989b, 1990;
Kolmodin-Hedman and Eriksson 1987; Maxwell and LeQuesne 1982; Osicka-Koprowska et al. 1984; Pach et
al. 1987; Takahashi et al. 1991; Vestweber and Kruckenberg 1972), it is expected that concurrent exposure to
chlorfenvinphos may result in the prolongation of the action of succinylcholine leading to prolonged muscular

paralysis.

2.8 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE

A susceptible population will exhibit a different or enhanced response to chlorfenvinphos than will most
persons exposed to the same level of chlorfenvinphos in the environment. Reasons may include genetic
makeup, age, health and nutritional status, and exposure to other toxic substances (e.g., cigarette smoke).
These parameters may result in reduced detoxiﬁcation or excretion of chlorfenvinphos, or compromised
function of target organs aﬂ‘ected by chlorfenvinphos. Populations who are at greater risk due to their
unusually high exposure to chlorfenvinphos are discussed in Section 5.6, Populations With Potentially High

Exposure.

CHLORFENVINPHOS 95

2. HEALTH EFFECTS

The magnitude of chlorfenvinphos toxicity, like the toxicity of any xenobiotic, is affected by the rate of its
metabolic biotransformation to less toxic substances (Klaassen et al. 1986). Therefore, low xenobiotic
metabolizing activity would result in greater toxicity. The newborn of several animal species, including
humans, have an almost complete lack of ability to metabolize xenobiotics and may be more sensitive to
chlorfenvinphos toxicity. Studies on experimental animals showed that starvation depressed P-450 activity
due to actual loss of the enzyme protein (Boyd and Carsky 1969; Puzynska 1984). Thus, it is expected that
dietary deﬁciency in protein would increase chlorfenvinphos toxicity by diminishing its metabolism in the
liver. Hereditary factors may also contribute to population sensitivity to chlorfenvinphos. Atypical plasma
cholinesterase with low activity is present in a small percentage of the human population. This is the result of
an hereditary factor with 0.04% occurrence in the population. Since plasma cholinesterase activity is strongly
inhibited by chlorfenvinphos (Cupp et al. 1975; Gralewicz et al. 1989a, 1989b, 1990; Kolmodin—Hedman and
Eriksson 1987; Maxwell and LeQuesne 1982; Osicka—Koprowska et a1. 1984; Pach et al. 1987; Takahashi et
al. 1991; Vestweber and Kruckenberg 1972), it is expected that individuals who have atypical ChE (or low
plasma cholinesterase activity) will be unusually sensitive to the muscle relaxant succinylcholine (Klaassen et
al. 1986) and may suffer prolonged muscle paralysis if administered succinylcholine while exposed to
chlorfenvinphos. Congenital low plasma cholinesterase activity may also increase subpopulation sensitivity to
chlorfenvinphos exposure. This is because, after exposure, plasma cholinesterase acts as a depot for
chlorfenvinphos due to its strong afﬁnity for the substance (Davies and Holub 1980; Edson and Noakes 1960;
Klemmer et al. 1978; Williams et al. 1959), thus decreasing the availability of the chlorfenvinphos dose to
neuromuscular tissue, the target of chlorfenvinphos toxicity in the population with normal plasma
cholinesterase levels. In individuals with congenital low plasma cholinesterase activity, less chlorfenvinphos
is bound in the blood and more unbound chlorfenvinphos is in circulation to reach neuromuscular tissue, the

target of chlorfenvinphos toxicity.

Individuals who have abnormally low tissue cholinesterase due to prior exposure to cholinesterase activity
inhibitors are also exceptionally susceptible to the cholinesterase activity-inhibiting toxicity of
chlorfenvinphos. These individuals may include those who are occupationally exposed to anticholinesterases,
such as other cholinesterase activity inhibiting organophosphate or carbamate pesticides. In this regard,
patients on medication that inhibit cholinesterase activity may also be unusually susceptible to the

cholinesterase activity inhibiting toxicity of chlorfenvinphos.

CHLORFENVINPHOS 96

2. HEALTH EFFECTS

2.9 METHODS FOR REDUCING TOXIC EFFECTS

This section will describe clinical practice and research concerning methods for reducing toxic effects of
exposure to chlorfenvinphos. However, because some of the treatments discussed may be experimental and
unproven, this section should not be used as a guide for treatment of exposures to chlorfenvinphos. When
speciﬁc exposures have occurred, poison control centers and medical toxicologists should be consulted for
medical advice. The following text provides speciﬁc information about treatment following exposures to

chlorfenvinphos.
2.9.1 Reducing Peak Absorption Following Exposure

Organophosphate insecticides like chlorfenvinphos are rapidly absorbed after inhalation, ingestion, or dermal
contact (Hutson and Wright 1980; Ikeda et al. 1991; Wagner et al. 1990). In oral exposures, emesis is not
indicated because of the danger of aspiration of stomach contents by an obtunded patient. Gastric lavage, with
a solution of 5% sodium bicarbonate or 2% potassium permanganate, may be indicated within the ﬁrst

60 minutes after ingestion to get rid of unabsorbed chlorfenvinphos in the stomach (Cupp et al. 1975; Pach et
al. 1987; Shankar 1967, 1978). Activated charcoal can also be used, but cathartics are not necessary due to the
diarrhea induced by muscarinic activity. However, if diarrhea is not present in the patient, cathartics, mixed

with activated charcoal, can be used.

Decontamination is the ﬁrst step in reducing dermal or conjunctiva] absorption. This decontamination should
begin immediately after the exposure is recognized. Contaminated clothing should be removed, and skin, hair,
and nails should be washed with soap and plenty of water. Health care workers and emergency responders
should be protected from secondary contamination, and clothes and other contaminated material should be
treated as contaminated waste. Eyes should be irrigated with copious amounts of room-temperature water or
saline, if available, for at least 15 minutes. If irritation, lacrimation, or especially pain, swelling, and
photophobia persist aﬂer 15 minutes of irrigation, expert ophthalmologic care should be sought (Ellenhom and
Barceloux 1988).

If exposure is via inhalation, the exposed individual should be moved to fresh air and efforts should be
directed toward the maintenance of an open airway, airway suctioning, endotracheal intubation. Artiﬁcial

ventilation with supplemental oxygen may be helpful (Ellenhom and Barceloux 1988).

CHLORFENVINPHOS 97

2. HEALTH EFFECTS

2.9.2 Reducing Body Burden

Chlorfenvinphos is rapidly metabolized, with an estimated mammalian biological half-life of 12—15.13 hours
(Akintonwa 1984; Akintonwa and Itam 1988; Donninger 1971; Hutson and Millbum 1991; Hutson and
Wright 1980). Consequently, efforts at reducing body burdens of poisoned persons may not be critical to the
outcome. Although hemoperfusion has been successfully used in one case of chlorfenvinphos poisoning
(Pach et al. 1987), dialysis and hemoperfusion are not recommended in organophosphate poisonings because
of the extensive tissue distribution of the absorbed doses (Mucke et al. 1970; Poklis et al. 1980). The use of
P-450—inducing substances such as some antipsychotics (triﬂupromazine) and analgesics (aspirin, morphine)
would tend to accelerate the metabolism of chlorfenvinphos, thereby decreasing its toxicity (Akintonwa 1984;
Akintonwa and Itam 1988; Donninger 1971; Hutson and Millbum 1991; Hutson and Wright 1980; Klaassen et
al. 1986; Williams and Burson 1985).

2.9.3 Interfering with the Mechanism of Action for Toxic Effects

As an anticholinesterase organophosphate, the principal toxic effects of chlorfenvinphos in humans and
laboratory animals derive from inhibition of cholineSterase activity (Cupp et al. 1975; Gralewicz et al. 1989a,
1989b, 1990; Hunter 1969; Kolmodin-Hedman and Eriksson 1987; Maxwell and LeQuesne 1982; Osicka—
Koprowska et al. 1984; Pach et al. 1987; Takahashi et a1. 1991; Vestweber and Kruckenberg 1972). Severe
inhibition of the activities of these enzymes results in accumulation of acetylcholine at its sites of action, and
excessive or interminable stimulation of both sympathetic and parasympathetic cholinergic receptors leading

to muscarinic and nicotinic effects (Klaassen et al. 1986; Williams and Burson 1985).

Timely treatment of chlorfenvinphos poisoning cases with atropine and cholinesterase regeneration with
pralidoxime and other oximes, signiﬁcantly reduces the cholinergic effects (Cupp et al. 1975; Pach et al.
1987).

Pralidoxime acts by hydrolyzing phosphorylated acetylcholinesterase and is effective in counteracting the
paralytic effects (muscular weakness and fasciculations) of anticholinesterase agents, such as
chlorfenvinphos, if it is administered prior to the “aging” (See Mechanisms of Toxicity) of the phosphorylated
enzyme (Williams and Burson 1985). Pralidoxime is most effective if started within the first 24 hours,
preferably within 6—8 hours of exposure, prior to the irreversible phosphorylation of the enzyme (Shankar
1967, 1978; Schenker 1992).

CHLORFENVINPHOS 98

2. HEALTH EFFECTS

Atropine is an anti-muscarinic agent which, in large doses, alleviates bronchoconstriction and reduces
secretion in the oral cavity and the airway. Atropine also counters some of the central nervous system effects
(Cupp et a1. 1975; Pach et a1. 1987). It is recommended that atropine be given immediately by intravenous
injection at a dose of 2 mg and every 10—20 minutes thereafter at an intramuscular dose of 0.67 mg until
evidence of "atropinization" or muscarinic blockade, such as ﬂushing, dry mouth, dilated pupils, and
tachycardia is seen (Shankar 1978). Atropine therapy is required for less than 24 hours because of the shorter
duration of effect (Schenker et al. 1992). The most clinically important indication for continued atropine
treatment is persistent wheezing (pulmonary rales) or bronchorrhea (Woo 1990). Pralidoxime acts to
regenerate inhibited cholinesterase enzyme activity at all affected sites (Shankar 1967, 1978; Schenker 1992;
Taitelman 1992).

2.10 ADEQUACY OF THE DATABASE

Section 104(I)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with the
Administrator of EPA and agencies and programs of the Public Health Service) to assess whether adequate
information on the health effects of chlorfenvinphos is available. Where adequate information is not
available, ATSDR, in conjunction with the National Toxicology Program (NTP), is required to assure the
initiation of a program of research designed to determine the health effects (and techniques for developing

methods to determine such health effects) of chlorfenvinphos.

The following categories of possible data needs have been identiﬁed by a joint team of scientists from
ATSDR, NTP, and EPA. They are deﬁned as substance-speciﬁc informational needs that if met would reduce
the uncertainties of human health assessment. This deﬁnition should not be interpreted to mean that all data
needs discussed in this section must be ﬁlled. In the future, the identiﬁed data needs will be evaluated and

prioritized, and a substance-speciﬁc research agenda will be proposed.

2.10.1 Existing Information on Health Effects of Chlorfenvinphos

The existing data on health effects of inhalation, oral, and dermal exposure of humans and animals to
Chlorfenvinphos are summarized in Figure 2-5. The purpose of this ﬁgure is to illustrate the existing
information concerning the health effects of chlorfenvinphos. Each dot in the ﬁgure indicates that one or more
studies provide information associated with that particular effect. The dot does not necessarily imply anything

about the quality of the study or studies, or should missing information in this ﬁgure be interpreted as a "data

CHLORFENVINPHOS 99

Figure 2-5. Existing Information on Health Effects of Chlorfenvinphos

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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CHLORFENVINPHOS 100

2. HEALTH EFFECTS

need." A data need, as deﬁned in ATSDR's Decision Guide for Identz'ﬁ/ing Substance-Specific Data Needs
Related to Toxicological Proﬁles (ATSDR 1989), is substance-speciﬁc information necessary to conduct
comprehensive public health assessments. Generally, ATSDR deﬁnes a data gap more broadly as any

substance—speciﬁc information missing from the scientiﬁc literature.

The available information indicates that chlorfenvinphos is a toxic substance to most species of experimental
animals, deriving its toxicity principally from the inhibition of cholinesterase activity. All three reports
concerning the health effects of chlorfenvinphos in humans described individuals or group of individuals
exposed either occupationally or in the home by accident. The route in the occupational exposure reports is
believed to be dermal, although an occupational exposure was reported as inhalation. The route for the
accidental exposure case was oral. Thus, Figure 2-5 reﬂects that information exists for oral and inhalation
exposures in humans. However, all of the human reports on inhalation exposures are limited because of
probable concurrent or sequential exposures to other substances of similar qualitative toxicity present in the
environment (workplace or home), such as other organophosphate pesticides present as components of
organophosphate—containing household products. In all cases, the doses at which these effects occurred in the
human studies are not known and the purity of the material to which these subjects were exposed is
questionable because of the accidental nature of the exposures, thus rendering evaluation of substance-
relatedness to these reported toxicities uncertain. The availablehuman data, therefore, fail to ﬁilly characterize
the human health effects from acute-, intermediate-, or chronic-duration inhalation exposures to

chlorfenvinphos.

Information regarding the health effects of chlorfenvinphos following ingestion in laboratory animals is also
limited due to a paucity of deﬁnitive studies. Only limited information is available on the health effects
resulting from dermal exposures. In all health effects categories, acute-, intermediate-, and chronic-duration
exposure data for inhalation exposure are limited for both humans and laboratory animals. Consequently, it
was not possible to develop acute-, intermediate-, or chronic-duration inhalation MRLS for chlorfenvinphos.
Furthermore, no information on the carcinogenic effects of chlorfenvinphos exposure is available for humans

or laboratory animals by any route of exposure.

An acute oral MRL of 0.002 mg/kg/day has been derived for chlorfenvinphos from a LOAEL of
2.4 mg/kg/day, based on adverse neurological effects in rats (Barna and Simon 1973). An intermediate oral
MRL of 0.002 mg/kg/day for chlorfenvinphos has been developed from a LOAEL of 2 mg/kg/day, based on

adverse immunolymphoreticular effects in mice (Kowalczyk-Bronisz et al. 1992). A chronic oral MRL of

CHLORFENVINPHOS 101

2. HEALTH EFFECTS

0.0007 mg/kg/day for chlorfenvinphos has been developed from a LOAEL of 0.7 mg/kg/day, based on adverse
neurological effects in rats (Ambrose et a1. 1970).

2.10.2 Identification of Data Needs

Acute-Duration Exposure. No data are available on the acute-duration effects of human inhalation
exposure to chlorfenvinphos. The available animal inhalation studies reported only serious effects (mortality,
apnea, salivation, urination, exophthahnos, twitches, and tremors) (Takahashi et a1. 1994; Tsuda et a1. 1986)
following exposure to chlorfenvinphos. Therefore, the data from these studies are not appropriate for use in

the derivation of an acute-duration inhalation MRL.

The information available on acute oral human exposures consists primarily of studies that reported
interference with central cholinergic and adrenergic mechanisms (disturbances in cholinesterase and
noradrenaline (norepinephrine) levels) and secondary effects resulting from these disturbances manifested as
neurological symptoms and death in some cases. The adverse effects reported in humans included death
(Felthous 1978) and neurological effects (Cupp et a1. 1975; Kolmodin-Hedman and Eriksson 1987; Pach et al.
1987). In animals effects noted from acute oral exposure to chlorfenvinphos included death in rats (Ambrose
et a1. 1970; Hutson and Logan 1986; Hutson and Wright 1980; Ikeda et al. 1991, 1992; Puzynska 1984;
Takahashi et a1. 1991), mice (Hutson and Logan 1986; Kowalczyk—Bronisz et a1. 1992; Wysocka—Paruszewska
et a1. 1980), dogs (Hutson and Logan 1986; Ambrose et a1. 1970), and rabbits (Ambrose et a1. 1970; Hutson
and Logan 1986); systemic effects in rats, i.e., hepatic (Ikeda et a1. 1991; Puzynska 1984), endocrine
(Osicka—Koprowska et al. 1984), and metabolic (Bama and Simon 1973); and neurological effects in rats
(Bama and Simon 1973; Brzezinski 1978; Ikeda et a1. 1992; Osicka—Koprowska et al. 1984; Osumi et a1. 1975;
Puzynska 1984; Takahashi et al. 1991). Thus, the acute effects of oral chlorfenvinphos are relatively well-

characterized, stemming principally from the inhibition of cholinesterase activity.

No effects were noted in humans dermally exposed to chlorfenvinphos for acute durations (Hunter 1968). In
animals, death (Ambrose et a1. 1970) and neurological effects (V estweber and Kruckenberg 1972) have

resulted from dermal exposure to chlorfenvinphos.

Additional studies via the inhalation and dermal routes of exposure would be helpful for establishing a dose-
response relationship and for identifying thresholds for adverse effects for these routes of exposure to

chlorfenvinphos. This information is necessary for determining levels of signiﬁcant exposure to

CHLORFENVINPHOS 102

2. HEALTH EFFECTS

chlorfenvinphos. This information is necessary for determining levels of signiﬁcant exposure to
chlorfenvinphos that are associated with adverse health effects for the protection of potentially exposed

populations living near hazardous waste sites that contain chlorfenvinphos.

Intermediate-Duration Exposure. No information is available on the effects of human intermediate-
duration exposure, by any route (inhalation, oral, dermal). No animal studies were available on intennediate-

duration inhalation or dermal exposure to chlorfenvinphos.

Available information on the adverse effects resulting from intermediate-duration oral exposure of animals to
chlorfenvinphos include death in rats and dogs (Ambrose et al. 1970); systemic effects in rats, i.e., renal
(Ambrose et al. 1970) and metabolic (Barna and Simon 1973); immunological/lymphoreticular effects in rats
(Ambrose et al. 1970: Kowalczyk-Bronisz et al. 1992; Roszkowski 1978); neurological effects in rats
(Ambrose et al. 1970; Bama and Simon 1973; Maxwell and LeQuesne 1982) and dogs (Ambrose et al. 1970);
reproductive effects in rats (Ambrose et al. 1970); developmental effects in rats (Ambrose et al. 1970).
Additional available studies found no effects on mortality in rats and dogs (Ambrose et al. 1970); no
signiﬁcant systemic effects, i.e., respiratory, cardiovascular, gastrointestinal, musculoskeletal, hepatic, renal,
endocrine, and body weight in dogs or respiratory, cardiovascular, gastrointestinal, hepatic, renal, endocrine,
dermal effects in rats (Ambrose et al. 1970) endocrine system effects in mice (Kowalczyk-Bronisz et al. 1992),
or body weight changes in rabbits (Roszkowski 1978) and rats (Bama and Simon 1973; Maxwell and
LeQuesne 1982); no immunological/lymphoreticular effects in rats and dogs (Ambrose et al. 1970); and no
reproductive effects in rats (Ambrose et a1. 1970). Data from these studies sufﬁciently demonstrate that
chlorfenvinphos interferes with the immunological/ lymphoreticular system. An intermediate oral MRL of
0.002 mg/kg/day for chlorfenvinphos has been developed from a LOAEL of 2 mg/kg/day, based on adverse

immunolymphoreticular effects in mice (Kowalczyk-Bronisz et al. 1992).

Due to the lack of adequate human or animal data for effects from intermediate-duration inhalation exposure to
chlorfenvinphos, no intennediate-duration inhalation MRL was derived for chlorfenvinphos. Additional
studies via the inhalation and dermal routes of exposure would be helpful for establishing a dose-response
relationships and for identifying thresholds for adverse effects for chlorfenvinphos exposure. This

information is necessary for determining levels of signiﬁcant exposure to chlorfenvinphos that are associated
with adverse health effects for the protection of potentially exposed populations living near hazardous waste

sites that contain chlorfenvinphos.

CHLORFENVINPHOS 103

2. HEALTH EFFECTS

Chronic-Duration Exposure and Cancer. No controlled epidemiological studies regarding the
systemic toxicities of chlorfenvinphos resulting from chronic-duration inhalation exposure are available.
However, two retrospective epidemiological studies regarding the systemic toxicities of chlorfenvinphos
resulting from chronic-duration inhalation exposures are available. Although the existing human studies
reported immunological (Wysocki et a1. 1987) and neurological effects (Kolmodin-Hedman and Eriksson
1987), the subjects in the Wysocki et a1. (1987) report were also concurrently exposed to greater
concentrations of other potentially immunotoxic substances such as formothion, sumithion, and malathion
while the subjects in the Kolmodin-Hedman and Eriksson (1987) study were exposed to unknown
concentrations of a mixture of potentially neurotoxic pesticides which included dimethoate, fonnothion, and
isofenphos. Therefore, data from these studies were not useful for developing a chronic inhalation MRL for

chlorfenvinphos.

There is no information on the effects of chronic human oral exposure to chlorfenvinphos. In animals the
existing information on adverse effects from chronic oral exposure to chlorfenvinphos is limited to systemic
effects, i.e., hepatic and body weight effects in rats (Ambrose et a1. 1970); and neurological eﬁ'ects in rats and
dogs (Ambrose et a1. 1970). Additional available studies found no effects on mortality in rats and dogs
(Ambrose et a1. 1970); no signiﬁcant systemic effects, i.e., cardiovascular, hematological, hepatic, renal,
endocrine, or body weight in dogs, or respiratory, cardiovascular, gastrointestinal, hematological,
musculoskeletal, renal, endocrine, or dermal effects in rats (Ambrose et al. 1970); no immunological/
lymphoreticular effects in rats and dogs (Ambrose et al. 1970); and no reproductive effects in rats (Ambrose et
a1. 1970). Data from these studies sufﬁciently demonstrate that chlorfenvinphos is an anticholinesterase
organophosphate. A chronic oral MRL of 0.0007 mg/kg/day for chlorfenvinphos has been developed from a
LOAEL of 0.7 mg/kg/day, based on adverse neurological effects in rats (Ambrose et a1. 1970).

No information on the effects of chronic-duration dermal exposure to chlorfenvinphos is currently available.

No epidemiological studies or chronic rodent cancer bioassays are available for assessing the carcinogenic
potential of chlorfenvinphos. However, a study to determine the ability of vinyl phosphate esters (like
chlorfenvinphos) to form methylated bases in DNA of calf thymus failed to detect 6-methyl guanine, a known
mutagen. In both the reaction with dsDNA and ssDNA, 7-methyl guanine was the main methylation product.
However, all methyl derivatives of adenine constituted about 40% and 50% of all methylation products in the
case of dsDNA and ssDNA, respectively. 3-Methylcytosine was the only methyl derivative of pyrimidine

identiﬁed. An analog of chlorfenvinphos, methylbromophenvinphos, was used in this study (Wiaderkiewicz et

CHLORFENVINPHOS 104

2. HEALTH EFFECTS

identiﬁed. An analog of chlorfenvinphos, methylbromophenvinphos, was used in this study (Wiaderkiewicz et
al. 1986); therefore, the data are difﬁcult to relate to chlorfenvinphos without extensive structure-activity
relationship analysis. In a mutagenicity study, the dose—response curve, at doses of 0, 50, 500, 5,000 ug/plate
for the mutagenic activity of chlorfenvinphos for the S. typhimurium strain TA100 was reduced by the S9 mix
(metabolic activation). At present, no mutagenic pesticide for which activity decreases in the presence of the

S9 mix is carcinogenic except captan (F-28) (Moriya et al. 1983).

Additional studies via the inhalation and dermal routes of exposure would be helpful for establishing a dose—
response relationships and for identifying thresholds for adverse effects for prolonged exposure to
chlorfenvinphos. This information is necessary for determining levels of signiﬁcant exposure to
chlorfenvinphos that are associated with adverse health effects for the protection of potentially exposed
populations living near hazardous waste sites that contain chlorfenvinphos. Inhalation, oral, and dermal
bioassays would be helpful to determine whether populations with long-term inhalation, oral, or dermal
exposure (especially those living near hazardous waste sites or establishments where wastes containing

chlorfenvinphos are released into the air or water) are at risk of developing cancers.

Genotoxicity. No studies were located regarding genotoxic effects of chlorfenvinphos in humans
following inhalation, oral, or dermal exposure. Chlorfenvinphos was negative for mutagenicity in both base-
pair change-type strains microorganisms (WP2 hcr of E. coli; TA1535, TA1537, TA1538, TA98 of S.
typhimurium). In a mutagenicity study, the dose-response curve, at doses of 0, 50, 500, and 5,000 gag/plate, for
the mutagenic activity of chlorfenvinphos for the S. typhimurium strain TA100 was reduced by the S9 mix
(metabolic activation). At present, no mutagenic pesticide whose activity decreases in the presence of the

S9 mix is carcinogenic except captan (F-28) (Moriya et al. 1983). The mutagenic potency of chlorfenvinphos
for strain TA100 has been reported as 0.038 revertants/nmol, indicative of a positive response (Dean 1972;
Moriya et al. 1983; Vishwanath and Kaiser 1986). A mixture of 15 pesticides (containing 0.3%
chlorfenvinphos) tested negative for mutagenicity in the Salmonella microsome assay, with or without
metabolic activation with PCB-induced rat liver S9, at concentrations up to 500 ug/plate in the Salmonella-
microsome assay. The mixture also failed to induce SCEs in human lymphocytes in vitro as well as in vivo
mutagenicity in the micronucleus bone marrow assay in male Wistar rats at concentrations proportional to the
ratio determined in foods (range = 0.1—20 ug/mL) (Dolara et al. 1993). In other large-scale screening
programs, which revealed microbial mutagenic activity in four new compounds (all fungicides),
chlorfenvinphos (without metabolic activation) exhibited no mutation induction capacity in a rec-assay

procedure (prescreening of DNA-damaging chemicals) utilizing strains of B. subtilis, H17 Rec+ and

CHLORFENVINPHOS 105

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M45 Rec-. Also, no mutation potential was evident in a reversion-assay (determination of mutation
speciﬁcities) in which two tryptophane-requiring strains (auxotrophic) of E. coli (B/r try WP2 and WP2 try
hcr) and four strains of S. typhimurium (TA1535, TA1536, TA1537, TA1538) were used. The E. coli
auxotrophic strains and Salmonella TA1535 are reversible by base-pair change-type mutagens and the three
Salmonella strains (TA1536, TA1537, and TA153 8) are reversible by frameshift mutagens (Shirasu 1973;
Shirasu et al. 1976).

There are no unequivocal data to indicate that chlorfenvinphos reacts directly with DNA in vivo or in vitro to
produce mutations in either germ or somatic cells. In a study to determine the ability of vinyl phosphate esters
(like chlorfenvinphos) to form methylated bases in DNA of calf thymus, DNA failed to detect 6-methyl
guanine, a known mutagen. In the reaction both with dsDNA and ssDNA, 7-metliyl guanine was the main
methylation product. However, all methyl derivatives of adenine constituted about 40% and 50% of all
methylation products in the case of dsDNA and ssDNA, respectively. 3-Methylcytosine was the only methyl
derivative of pyrimidine identiﬁed (Wiaderkiewicz et a1. 1986). In another study, tetrachlorvinphos
(Gardona®) was evaluated for potential to induce chromosomal aberrations and SCEs in vitro in a primary
culture of Swiss mice spleen cells at concentrations of 0.25, 0.50, 1.0, or 2.0 ug/mL. Tetrachlorvinphos
induced a high percentage of metaphases with chromosomal aberrations in the mouse spleen cells after 4 hours
of treatment in a dose-dependent manner. According to the authors, the results indicate that tetrachlorvinphos
in the tested concentrations are mutagenic in mouse spleen cell cultures (Amer and Aly 1992). In both of these
studies, structural analogs of chlorfenvinphos (methylbromophenvinphos and tetrachlorvinphos, respectively)
were used; therefore, the data are difficult to relate to chlorfenvinphos without extensive structure-activity
relationship analysis. These limited data suggest that chlorfenvinphos might not be genotoxic. Thus, the
existing information on the mutagenic potential of chlorfenvinphos is equivocal. Additional genotoxicity
assays in microorganisms and mammalian cells (in vivo and in vitro) will be helpful in determining if the
substance is clastogenic or can cause mutation in somatic or germ cells. This information is necessary to
determine whether potentially exposed populations, especially those living near hazardous waste sites, are at

risk of developing genetic diseases.

Reproductive Toxicity. No studies were located regarding reproductive effects in humans following
acute-, intermediate-, or chronic-duration inhalation, oral, or dermal exposure to chlorfenvinphos. Animal
studies regarding reproductive effects after acute-, intermediate-, or chronic- inhalation or dermal exposure to
chlorfenvinphos, or acute-duration oral exposure to chlorfenvinphos are also lacking. A 3-generation

reproductive study in albino (Wistar) rats orally exposed to chlorfenvinphos reported signiﬁcant (14%)

CHLORFENVINPHOS 106

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reduction in fertility and decrease in maternal body weight gains at a LOAEL of 2.7 mg/kg/day (Ambrose et
al. 1970). Single-generation studies, in which rats and dogs were exposed to chlorfenvinphos for
intermediate- or chronic-durations found no histopathology or changes in relative weights of the testes and
ovaries of the tested animals (Ambrose et a1. 1970). However, these studies did not evaluate reproductive
function. Consequently, additional reproductive toxicity studies in animals exposed to chlorfenvinphos via
inhalation, oral, or dermal route would be helpful in evaluating the potential for chlorfenvinphos to cause
adverse reproductive effects in humans. This information is necessary to determine whether potentially
exposed populations, especially those living near hazardous waste sites, are at risk of developing

reproductive diseases.

Developmental Toxicity. No studies were located regarding developmental effects in humans
following acute-, intermediate-, or chronic-duration inhalation, oral, or dermal exposure to chlorfenvinphos.
Animal studies regarding developmental effects after acute—, intermediate- or chronic-duration inhalation
and dermal exposure to chlorfenvinphos are also lacking. The limited information on the developmental
toxicity of oral chlorfenvinphos exposure indicates that the substance may interfere with the normal
development of rats by inhibiting cellular respiration (Skonieczna et al. 1981) and interfering with maternal
body weight gains, and reducing lactational index and offspring survivability in the developing rodents
(Ambrose et al. 1970). A statistical model for hazard identiﬁcation developed for use in predicting the
developmental toxicity of 175 chemicals, including chlorfenvinphos, produced equivocal results concerning
the developmental toxicity of chlorfenvinphos to the rat, rabbit, and hamster. The model was essentially a
database of 175 probable, suspected, unknown, and probably negative teratogenic or embryotoxic drugs and
chemical compounds. For each of the compounds, including chlorfenvinphos, the results of any
developmental toxicity testing in up to 14 animal species and any reports of mutagenicity or carcinogenicity
were recorded. The compounds were categorized with respect to their human developmental toxicant
effect: - l .0 testing negative, 0.0 not tested (unknown), 0.5 tested with equivocal results (suspicious), and

1.0 testing positive. However, the model had a sensitivity of 62—75%, a positive predictive value of
75~100%, and a negative predictive value of 64—91%, indicating that it is not optimal for hazard
identiﬁcation (Jelovsek et al. 1989). Additional information on the developmental effects in animals
exposed to chlorfenvinphos via the inhalation, oral, or dermal route would be helpful in evaluating the
potential for chlorfenvinphos to cause developmental toxicity in humans. This information is necessary to
determine whether offspring of potentially exposed populations, especially those living near hazardous

waste sites, are at risk of developmental adverse effects.

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lmmunotoxicity. No studies were located regarding immunological and lymphoreticular effects in
humans following acute- or intermediate-duration inhalation exposure to chlorfenvinphos, or regarding
immunological and lymphoreticular effects in humans following acute-, intermediate-, or chronic—duration
oral exposure to chlorfenvinphos. No studies were available regarding immunological and lymphoreticular
effects in animals following acute-, intermediate-, or chronic-duration inhalation or dermal exposure to

chlorfenvinphos.

Only one study was located that reported immunological effects in humans. In this report, occupational
exposure to inhaled chlorfenvinphos for an average of 15 years was associated with damage to humoral
mechanisms in humans. This study is not suitable for assessing the immunological and lymphoreticular
effects of human exposure to chlorfenvinphos because the subjects of this study were also concurrently
exposed to greater concentrations of other potentially immunotoxic substances such as formothion,
sumithion, and malathion (Wysocki et a1. 1987). In animal studies, intermediate-duration dietary exposure
of rats resulted in a signiﬁcant and irreversible reduction in relative spleen weight of female rats given

23 mg/kg/day chlorfenvinphos for 12 weeks. However, no gross or microscopic histopathology was evident
in the spleen and bone marrow tissues of the rats upon examination (Ambrose et a1. 1970). A chronic study
in dogs and rats did not note any histopathological changes in the spleen or bone marrow or changes in
absolute or relative spleen weights in Wistar rats or Beagle dogs of both sexes given dietary chlorfenvinphos
doses of 21 mg/kg/day (males) or 24 mg/kg/day (females), or 10 mg/kg/day (males) or 50 mg/kg/day
(females), respectively, for 104 week (Ambrose et al. 1970). In other animal studies, C57BL/6 mice and
(C57BL/6 x DBA/2)F1 (BDF 1/Iiw) hybrid mice (6—8 weeks old) orally exposed to chlorfenvinphos for

90 days exhibited a reversible reduction in the number of E rosettes-forming cells as well as a dose-related
decrease in number of hemolysin producing cells; reduction in the number of plaque-forming cells;
increases in Interlukin-l activity and DTH reaction; stimulation of spleen colonies; and disturbance in

humoral immune factors (immunoglobulins) at a LOAEL of 1.5 mg/kg (Kowalczyk-Bronisz et al. 1992).

Rabbits orally exposed to chlorfenvinphos for 90 days also exhibited significantly elevated serum
hemagglutinin level (16%) and hemolysin activity (66%, P<0.05) as well as increased number of nucleated
lymphoid cells producing hemolytic antibody to sheep erythrocytes. Spleen cytomorphology changes,
manifested mainly as transformation of primary follicles into secondary ones with well developed germinal
centers, were also observed (Roszkowski 1978). While the existing human inhalation study and the animal
oral- studies provide some indication that chlorfenvinphos exposure is associated with immunological

changes, these changes were not consistent with depressive effect on immune reactions. Thus, the changes

CHLORFENVINPHOS 108

2. HEALTH EFFECTS

reported in these studies may simply be immunological mobilizations of the organisms to xenobiotics in
contradistinction from immune system damage. Consequently, additional TIER 11 animal immunotoxicity
testing (cell-mediated immunity, cell surface marker proﬁle immunopathology, humoral immunity, cytolytic
macrophage function, and bone marrow tests) via the inhalation, oral, or dermal route for chlorfenvinphos
would be helpful to more fully assess the potential of chlorfenvinphos to cause immunotoxicity in humans.
This information is necessary to determine whether potentially exposed populations, especially those living

near hazardous waste sites, are at risk of developing immunological diseases.

Neurotoxicity. No studies were located regarding neurological effects in humans after acute- or
intermediate-duration inhalation exposure to chlorfenvinphos; or following acute-, intermediate-, or chronic-
duration oral exposure; or after intermediate- or chronic-duration dermal exposure. In humans,
chlorfenvinphos inhibits cholinesterase activity in the central and peripheral nervous system when
administered by the oral (Cupp et al. 1975; Pach et al. 1987) or inhalation route in acute-duration exposures
(Kolmodin-Hedman and Eriksson 1987). Inhibition of cholinesterase activity results in accumulation of
acetylcholine at muscarinic and nicotinic receptors leading to peripheral and central nervous system effects.
These effects usually appear within a few minutes to a few hours after exposure depending on the extent of
exposure. In a human case report, a 16-year-old white male who mistakenly ingested a formulation
(identiﬁed as Dermaton®) was hospitalized 90 minutes afterward with symptoms of abdominal cramps,
nausea, vomiting, generalized weakness, cold dry skin, hypothermia, listlessness, constricted pupils,
hypertension, respiratory distress, ﬁne generalized muscular twitching, and apprehension. Plasma and
erythrocyte activity levels were signiﬁcantly inhibited. All vital signs returned to normal after gastric lavage

and treatment with atropine and pralidoxime (Cupp et al. 1975).

No studies were located regarding neurological effects in animals after acute- or intermediate-duration
inhalation or dermal exposure to chlorfenvinphos. The available information indicates that chlorfenvinphos
has similar neurological effects in animals. In animals, chlorfenvinphos inhibits cholinesterase activity in
the blood and neuromuscular tissue by the oral route in acute—duration exposures in rats at doses as low as

2 mg/kg (Bama and Simon 1973; Osicka—Koprowska et al. 1984; Osumi et al. 1975; Puzynska 1984;
Takahashi et a1. 1991); in rats following intermediate-duration exposures via the oral route at doses as low
as 9 mg/kg/day (Ambrose et al. 1970; Maxwell and LeQuesne 1982); and in dogs following chronic-
duration exposure via the oral route at doses as low as 0.7 mg/kg/day (Ambrose et al. 1970). These
disruptions in cholinesterase activity resulted in cholinergic responses manifested as abnormal muscle

reﬂex, muscle fasciculations, Straub tail reﬂex, twitches, convulsions, chromodacryorrhea, exophthalmos,

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gasping, lacrimation, prostration, salivation, sleep disturbances, diarrhea, emesis, and urination (Ambrose et
a1. 1970; Maxwell and LeQuesne 1982; Osumi et a1. 1975; Puzynska 1984; Takahashi et al. 1991). In one
of these studies, all 36 Sprague-Dawley rats exposed to chlorfenvinphos doses of 10.5 mg/kg/day in the diet
for 3—6 months exhibited repetitive muscle activity when given two simultaneous stimuli. This abnormality
became more pronounced with time, even on constant dosing (Maxwell and LeQuesne 1982). The ﬁndings
from this study may be useful in explaining electrophysiological abnormalities described in some workers

chronically exposed to some organophosphorus compounds.

Intraperitoneal administration of daily doses of 100, 150, 200, or 300 mg/kg/day chlorfenvinphos to White
Leghorn hens for 10 days or until death resulted in cholinergic signs. Typical cholinergic signs, including
inability to stand, salivation, and retching (as well as some deaths) were observed immediately after the
administration of any dose level of chlorfenvinphos, with or without atropine coadministration. No signs of
delayed neurotoxicity or evidence of neurological lesions suggestive of demyelination or neural damage
were observed in the brain and sciatic nerve tissues examined (Ambrose 1970). Although all doses of
chlorfenvinphos elicited cholinergic responses (leg weakness, salivation, and retching) from hens given 100,
150, 200, or 300 mg/kg by intraperitoneal injection, no signs of delayed neurotoxicity was evident after

20 days of observation (Ambrose et al. 1970).

Besides its cholinergic action, chlorfenvinphos also acts via central noradrenergic mechanisms in rats by
accelerating the noradrenaline (norepinephrine) turnover in the brain in vivo by the release of noradrenaline

(norepinephrine) from brain tissue stores (Brzezinski 1978).

Although the available toxicity information in humans and animals is sufﬁcient to establish that short- and
long-term exposure to chlorfenvinphos results in adverse neurological effects, additional animal studies by
the inhalation, oral, and dermal routes will be helpful in the more accurate assessment of the exposure levels

at hazardous waste sites at which these effects are likely to occur.

Epidemiological and Human Dosimetry Studies. Although the available epidemiological studies
sufﬁciently identify inhibition of cholinesterase activity as the characteristic and most critical effect of
human exposure to chlorfenvinphos, these studies inadequately identify the dose at which this effect occurs
(Cupp et al. 1975; Kolmodin-Hedman and Eriksson 1987; Pach et al. 1987; Wysocki et al. 1987). Well-
conducted acute-, intermediate-, and chronic-duration (for effects other than inhibition of cholinesterase

activity) human dosimetry studies are not available. Therefore, well conducted retrospective

CHLORFENVINPHOS 110

2. HEALTH EFFECTS

epidemiological studies would be helpful in determining and quantifying the effects (including neurologic,
immunologic, and reproductive effects) of inhalation, oral, or dermal chlorfenvinphos exposure on human
health; such studies would also provide useful data regarding the carcinogenic potential of chlorfenvinphos in
humans, especially people living around hazardous waste sites or establishments where wastes containing
chlorfenvinphos are released into the air or water, and people who are occupationally exposed to

chlorfenvinphos for long periods of time.

Biomarkers of Exposure and Effect.

Exposure. The major action resulting from human exposure to chlorfenvinphos is the inhibition of
acetylcholinesterase activity (see Section 2.4). Two pools of cholinesterases are present in human blood:
acetylcholinesterase in erythrocytes and neuromuscular tissue and butyrylcholinesterase (pseudocholin—
esterase) in plasma. Acetylcholinesterase, present in human erythrocytes, is identical to the enzyme present in
neuromuscular tissue (the target of chlorfenvinphos action). While plasma cholinesterase (pseudocholine—
sterase or butyrylcholinesterase) has no known physiological function, it has been suggested that it scavenges
acetylcholine that gets into the plasma. Inhibition of the activity of both forms of cholinesterase has been
associated with exposure to chlorfenvinphos in humans and animals (Cupp et al. 1975; Gralewicz et al. 1989a,
1989b, 1990; Hunter 1969; Kolmodin-Hedman and Eriksson 1987; Maxwell and LeQuesne 1982; Osicka—
Koprowska et al. 1984; Pach et al. 1987; Takahashi et al. 1991; Vestweber and Kruckenberg 1972). Inhibition
of erythrocyte, plasma, or whole blood cholinesterase may be used as a marker of exposure to chlorfenvinphos.
However, inhibition of cholinesterase activity is a common action of anticholinesterase compounds, which
include organophosphates like chlorfenvinphos, and carbamate compounds. In addition, a wide variation in
normal cholinesterase values exists in the general population, and there are no studies which report a

quantitative association between cholinesterase activity levels and exposure to chlorfenvinphos in humans.

Chlorfenvinphos undergoes biotransformation to a variety of polar metabolites, including 2-chloro-
1-(2,4—dichlorophenyl) vinylethylhydrogen phosphate; l-(2,4—dichlorophenyl) ethanol; 1-(2,4-dichlorophenyl)
ethanediol; 2,4-dichloromandelic acid; and 2,4-dichlorobenzoyl glycine (Hutson and Wright 1980), which
have been detected in animals. Analysis of blood samples for the presence of these metabolites represents a
potential means of assessing exposure. Analysis of urine samples for metabolic products provides a non—
invasive method for detecting exposure. As an organophosphate, chlorfenvinphos is rapidly metabolized and
excreted from the body; therefore, urinary metabolite analysis is useful only in the evaluation of recent

exposures (Hutson and Wright 1980). There are no studies which report a quantitative association between

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2. HEALTH EFFECTS

metabolite levels and exposure to chlorfenvinphos in humans. Therefore, these biomarkers are only indicative
of exposure and are also not useful for dosimetric analysis. The inhibition of cholinesterase activity method as
a measure of organophosphate exposure lacks even greater speciﬁcity when used to assess exposure to
compounds which are weak inhibitors of cholinesterase activity, like chlorfenvinphos (Hunter et al. 1972). As
a vinyl phosphate, chlorfenvinphos is metabolized to desethyl chlorfenvinphos, which could be detected in
urine as a speciﬁc biomarker of exposure to chlorfenvinphos, or other vinyl phosphates (Akintonwa 1984,
1985; Akintonwa and Itam 1988; Donninger 1971; Hansen 1983; Hutson and Logan 1986; Hutson arid
Millbum 1991; Hutson and Wright 1980). The method of detection involves conversion of urinary desethyl
chlorfenvinphos to the more easily measurable methyl desethyl chlorfenvinphos with diazomethane. This
method is a more speciﬁc biomarker for chlorfenvinphos exposure and has been successfully used as such in a
case of 14 male volunteers exposed to chlorfenvinphos for 53 days. However, since desethyl chlorfenvinphos
accounts for only about 5% of the dose at this low exposure level, its concentration in urine would lack
sensitivity when used as an index of exposure to chlorfenvinphos (Hunter et al. 1972). Although this method
of assessing chlorfenvinphos exposure may not be useful in low exposure conditions, the method could be
used to evaluate exposure to high doses that occur in human acute poisoning cases. Further research in the

adaptation of this method for low-dose exposure would be useful.

Effect. Inhibition of the activities of erythrocyte, plasma, or whole blood cholinesterase in humans and
animals that results from chlorfenvinphos exposure (Cupp et al. 1975; Gralewicz et al. 1989a, 1989b, 1990;
Hunter 1969; Kolmodin-Hedman and Eriksson 1987; Maxwell and LeQuesne 1982; Osicka-Koprowska et al.
1984; Pach et al. 1987; Takahashi et al. 1991; Vestweber and Kruckenberg 1972) may be used as a marker of
effect for chlorfenvinphos exposure. However, the inhibition of cholinesterase activity is a common action of
anticholinesterase compounds, which include organophosphates like chlorfenvinphos, and carbamate
compounds. In addition, a wide variation in normal cholinesterase values exists in the general population, and
there are no studies which report a quantitative association between cholinesterase activity levels and exposure
to chlorfenvinphos in humans. Thus, the inhibition of cholinesterase activity is not a speciﬁc biomarker of
effect for chlorfenvinphos exposure; it is indicative only of effect and is not useful for chlorfenvinphos-speciﬁc
dosimetric analysis. In combination with analysis of reductions in the level of cholinesterase activity, the
manifestations of severe organophosphate (chlorfenvinphos) poisoning, clinically characterized by a collection
of cholinergic signs and symptoms (which may include dizziness, fatigue, tachycardia or bradycardia, miosis,
and vomiting) (Chambers and Levi 1992; Cupp et al. 1975; Klaassen et al. 1986; Pach et al. 1987; Takahashi
et al. 1991; Williams and Burson 1985), are useful biomarkers of effect for identifying victims of

organophosphates (chlorfenvinphos) poisoning. These manifestations, however, are also not speciﬁc to

CHLORFENVINPHOS 112

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chlorfenvinphos, but to anticholinesterase compounds, such as organophosphates and carbamate compounds,
in general. A study conducted in rats reported that 1—6 hours after administration, chlorfenvinphos (13 mg/kg)
decreased the noradrenaline (norepinephrine) level in rat brain by 20% as compared to controls (Brzezinski
1978). A similar study in Wistar rats found a 16% transient reduction in brain noradrenaline (norepinephrine)
3 hours after oral dosing with 4 mg/kg chlorfenvinphos (Osumi et al. 1975). Further research on the
adrenergic effects of chlorfenvinphos exposure might provide a more speciﬁc biomarker for chlorfenvinphos
when used in combination with inhibition of cholinesterase activity and clinical signs of interference with the

central cholinergic mechanism.

Absorption, Distribution, Metabolism, and Excretion. No studies were located regarding the
absorption of chlorfenvinphos after inhalation exposure; or regarding the distribution or metabolism of
chlorfenvinphos after inhalation or dermal exposure; or regarding excretion of chlorfenvinphos after
inhalation or dermal exposure in humans. In humans, dermally applied chlorfenvinphos was absorbed in a
concentration-dependent manner with rates of 0.06—1 .43 mg/cmz/hour. Concentrations of intact
chlorfenvinphos of <0.7—22 rig/L were found in the blood of volunteers 8 hours later (Hunter 1969). The rates
of chlorfenvinphos de—ethylation by liver microsomal fractions are 0.36 nmol/minute per mg protein (range
0.1 1—0.82) without induction and 1.03 nmol/minute per nmol of cytochrome P-450 (range 0.42—1.78) with
induction (Hutson and Logan 1986). Chlorfenvinphos levels of 13.66, 1.69, 2.02, and 1.89 rig/kg were
detected in 4 of the 11 samples of cervical mucus in environmentally exposed persons. Chlorfenvinphos
levels of 0.42 rig/kg were detected in 1 of the 10 sperm ﬂuid samples and 1 of the 10 human milk samples,
respectively (Wagner et al. 1990). A serum concentration of 300 ng/mL chlorfenvinphos was reported for a
29-year-old patient who had attempted suicide by ingesting about 50 mL of the preparation Enolofos®, which
contains 50% chlorfenvinphos. The authors of this report surmised that orally absorbed chlorfenvinphos is

widely and rapidly distributed (Pach et al. 1987).

No studies were located regarding the absorption of chlorfenvinphos after inhalation or dermal exposure; or
regarding the distribution or metabolism of chlorfenvinphos after inhalation, oral, or dermal exposure; or
regarding excretion of chlorfenvinphos aﬂer inhalation or dermal exposure in animals. The available animal
studies indicate that orally administered chlorfenvinphos is minimally absorbed and metabolized in rats
(Hutson and Wright 1980). The metabolism of oral doses of the substance is mediated by hepatic microsomal
monooxygenase (cytochrome P—450) via oxidative dealkylation (Donninger 1971; Hutson and Millbum 1991;
Ikeda et al. 1991). Thirteen metabolites of chlorfenvinphos have been identiﬁed in animal studies or predicted

from theoretical biotransformation as justiﬁed by the known structure of chlorfenvinphos and understanding of

CHLORFENVlNPHOS 113

2. HEALTH EFFECTS

biochemical reactions of monooxygenation, reduction, hydrolysis, glUcuronidation, glutathione-S-transferase
conjugation, and amino acid conjugation. The 13 metabolites identiﬁed or predicted are: 2-chloro-
1-(2’,4’-dichlorophenyl) vinyldiethyl phosphate; acetaldehyde; 2—chloro-1-(2’,4’-dichlorophenyl) vinylethyl-
hydrogen phosphate; 2,4-dichlorophenacylchloride; 2-chloro—1-(2’,4’-dichlorophenyl) ethanol; 2,4—dichloro-
mandelic acid; 2,4—dichloromandelic acid ester glucuronide; 2,4-dichloroacetophenone; 1-(2’,4’-dichloro—
phenyl) ethanol; 1-(2’,4’-dichlorophenyl) ethanediol; 1-(2’,4’-dichlorophenyl) ethanediol-Z-glucuronide;
l-hydroxy- l-(2’,4’—dichlorophenyl) acetyl glycine; and 1-(2’,4’-dichlorophenyl) ethanediol (Akintonwa 1984,
1985; Akintonwa and Itam 1988; Hunter et a1. 1972; Hutson and Millbum 1991; Hutson and Wright 1980).
Orally absorbed chlorfenvinphos is eliminated mainly in the urine in rats in 0-32 hours (Hutson and Wright
1980). Additional studies in animals, designed to measure the rate of inhalation, gastrointestinal, and dermal
absorption, distribution, and excretion of chlorfenvinphos would be useful in extrapolating the toxicokinetics

of chlorfenvinphos in humans, especially those living around hazardous waste sites.

Comparative Toxicokinetics. Chlorfenvinphos inhibits cholinesterase activity in the central and
peripheral nervous system, resulting in cholinergic symptoms as reported in several human poisoning
incidents (Cupp et al. 1975; Hunter 1969; Pach et al. 1987; Kolmodin—Hedman and Eriksson 1987). However,
the purity of the material to which these subjects were exposed is questionable, and the doses at which these
effects occurred are unknown because of the accidental nature of the exposures. Therefore, it is difficult to
determination whether the adverse eﬁects reported in these human studies are attributable to exposure to
technical chlorfenvinphos. Although information is available that indicates that dermally applied
chlorfenvinphos was absorbed in a concentration-dependent manner (with rates of 006—1 .43 mg/cmz/hour),
inhibiting cholinesterase in a dose-dependent in the human subjects (Hunter 1969), information on the

toxicokinetics of chlorfenvinphos in humans is limited to serum levels following ingestion (Pach et al. 1987).

Similarly, chlorfenvinphos inhibits cholinesterase activity in the central and peripheral nervous system in
animals (Gralewicz et al. 1989a, 1989b, 1990; Kolmodin-Hedman and Eriksson 1987; Maxwell and LeQuesne
1982; Osicka—Koprowska et al. 1984; Pach et al. 1987; Takahashi et al. 1991; Vestweber and Kruckenberg
1972).

The level of activity of cholinesterases in the livers of mammalian species and the distribution of these
enzymes have been suggested to be important factors in accounting for species specificity of some phosphate
triester anticholinesterase agents, including chlorfenvinphos. These factors may account for the great

variation in the conversion of chlorfenvinphos to less toxic metabolites and, consequently, the toxicity of

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chlorfenvinphos among different animal species. The relative rates of conversion of chlorfenvinphos (by
0-dealkylation) to the diester by liver slices ﬁom the rat, mouse, rabbit, and dog are 1, 8, 24, and 80 hours,
respectively; evidently correlating with the published acute oral LD50 values for the species. A quantitative
study of the species distribution of phosphate esterases and glutathione S-alkyl transferase found that these
enzymes are signiﬁcantly less in the pig than all the other species studied (Donninger 1971; Hansen 1983;
Ikeda et al. 1991). The ease of absorption, bioavailability in blood, and rates of uptake by the brain and
sensitivity of brain cholinesterase to the phosphorylating action of the compound may be additional factors in
species sensitivity to the toxicity of chlorfenvinphos as demonstrated in the dog and rabbit (Hutson and

Millbum 1991).

Additional comparative studies regarding the absorption, distribution, and excretion of chlorfenvinphos after
inhalation, oral, or dermal exposure in animals would be useful in species or route-route extrapolation. This
information could be used to determine an appropriate animal model for the evaluation of the toxicokinetics of

chlorfenvinphos.

Methods for Reducing Toxic Effects. Although dialysis and hemoperfusion are currently not
recommended in organophosphate poisonings because of the extensive tissue distribution of the absorbed
doses (Miicke et al. 1970; Poklis et al. 1980), hemoperfusion has been successfully used in one
chlorfenvinphos poisoning treatment (Pach et al. 1987). Further studies are necessary in view of the relatively
few clinical observations concerning the use of hemoperﬁision in the treatment of acute poisoning caused by

vinyl phosphate compounds like chlorfenvinphos.

2.10.3 Ongoing Studies

No information on ongoing studies in humans or laboratory animals for chlorfenvinphos was located.

CHLORFENVINPHOS 115

3. CHEMICAL AND PHYSICAL INFORMATION

3.1 CHEMICAL IDENTITY

Chlorfenvinphos is a synthetic organophosphorus insecticide that has been used as a soil or foliar insecticide.
It was also used to control insect pests on livestock and to control household pests. Information regarding the

chemical identity of Chlorfenvinphos is located in Table 3-1.

3.2 PHYSICAL AND CHEMICAL PROPERTIES

Chlorfenvinphos is a vinyl organophosphate insecticide. The technical material is an amber liquid with a mild
odor containing about 80—90% Chlorfenvinphos (trans and cis isomers with a typical ratio of 8.521). It is
sparingly soluble in water, but miscible with most organic solvents. It hydrolyzes slowly in water, but is
unstable in alkali (Worthing 1983). Information regarding the physical and chemical properties of
Chlorfenvinphos is located in Table 3-2.

CHLORFENVINPHOS

3. CHEMICAL AND PHYSICAL INFORMATION

116

Table 3-1. Chemical Identity of Chlorfenvinphos

 

Characteristic

Information

Reference

 

Chemical name

Synonym(s)

Registered trade name(s)

Chemical formula

Chemical structure

Identification numbers:
CAS Registry
NIOSH RTECS

EPA Hazardous Waste

OHM/TADS

DOT/UN/NA/IMCO

HSDB
NCI

2-chloro-1-(2,4-dichlorophenyl)

vinyl diethyl phosphate

Phosphoric acid 2-chloro-1-(2,4-
dichlorophenyl)etheny| diethyl ester;

0,0-diethyl O-[2-chloro-1 -

(2,4-dichlorophenyl)vinyl] phosphate;
2,4—dichIoro-(x-(chloromethylene)benzy|

alcohol diethyl phosphate

CVP; SD 7859; Compound 4072;
Birlane; Dermaton; Sapecron;

Steladone; Supona
C12H14C|304P

CH3CH20\O CHCI

CHSCHZO
c:

470—90—6
TB 8750000
No data
810041

UN 2783 Organophosphorus pesticide

1540
No data

Worthing 1983

Merck 1989

Merck 1989

Worthing 1983

Worthing 1983

Merck 1989
HSDB 1996

HSDB 1996
HSDB 1996
HSDB 1996

 

CAS = Chemical Abstracts Services; DOT/UN/NA/IMCO = Department of Transportation/United
Nations/North America/international Maritime Dangerous Goods Code; EPA = Environmental Protection
Agency; HSDB = Hazardous Substances Data Bank; NCI = National Cancer Institute; NIOSH = National
Institute for Occupational Safety and Health; OHM/T ADS = Oil and Hazardous Materials/Technical
Assistance Data System; RTECS = Registry of Toxic Effects of Chemical Substances

CHLORFENVINPHOS

117

3. CHEMICAL AND PHYSICAL lNFORMATlON

Table 3-2. Physical and Chemical Properties of Chlorfenvinphos

 

 

Property Information Reference
Molecular weight 359.56 Merck 1989
Color Amber liquid (Technical) Merck 1989
Colorless liquid Hartley 1987
Physical state Liquid Merck 1989
Melting point -19 to —23 °C (Technical) Worthing 1987
—16 to —22 °C Ouellette 1977

Boiling point at 0.01 mm
Boiling point at 0.5 mm

Density at 25 °C
Odor

Odor threshold:
Water
Air

Solubility:
Water at 23 °C

Organic solvent(s)

Partition coefficients:
Log Kow
Log K0c

Vapor pressure at 25 °C

Henry's law constant: at 25 °C

Autoignition temperature
Flashpoint
Flammability limits at 25 °C

Conversion factors (25 °C)

Explosive limits

120 °C (Technical)
167—170 °C (Technical)

1.5272 g/mL
Mild odor

No data
No data

145 ppm

Miscible with acetone, ethanol,
propylene glycol, dichloro-
methane, hexane, xylene

3.806
2.45

4x10‘6 mm Hg
7.5x10“5 mm Hg
1.7x10‘7 mm Hg

1 .53x10‘8 atm-ma/mol
2.76x10'9 atm-m3/mol

No data
No data
No data

1 ppm = 14.7 mg/m3
1 mg/m3 = 0.068 ppm

No data

Merck 1989
Merck 1989

Merck 1989
Merck 1989

Merck 1989

Merck 1989; Worthing 1983

Bowman and Sans 1983
Kenaga 1980

Worthing 1983
Merck 1989
Verschueren 1983

HSDB 1996
Domine et al. 1992

 

CHLORFENVlNPHOS 119

4. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL

4.1 PRODUCTION

Chlorfenvinphos was introduced into the United States in 1963 (Hayes 1982), by the Shell International
Chemical Company Ltd., Ciba AG (now Ciba-Geigy AG), and by Allied Chemical Corporation (Worthing
1983). The Burroughs Wellcome Company produced several chlorfenvinphos-containing formulated products
including Dermaton® dust, Dermaton® dip, Dermaton® II, and DerrnatoriD ﬂea and tick collars (EPA 1978a,
1978b, 1979, 1982a, 1982b, 1983). Information on current production of chlorfenvinphos is conﬂicting. One
source lists current base producers of the compound as American Cyanamid Company (under the trade names
Birlane® and Supona®) and Ciba Ltd. (under the trade names Sapecron® and Steladone®) (Farm Chemicals
Handbook 1993). However, no producers of chlorfenvinphos were identiﬁed in a recent Directory of

Chemical Producers for the United States of America (SRI 1993).

Chlorfenvinphos is produced by reaction of triethyl phosphite with 2,2,2',4'-tetrachloroacetophenone
(Worthing 1983). The technical grade material contains greater than 92% chlorfenvinphos as both the Z
(trans) and E (cis) isomers in a ratio (ZzE) of 8.5:1 (Spencer 1982; Worthing 1983).

No information on historic production volumes was found; however, there are currently no registered uses for

chlorfenvinphos in the United States (REFS 1995).

No information is available in the Toxics Release Inventory (TRI) database on total environmental releases of
chlorfenvinphos from production facilities because chlorfenvinphos is not included under SARA, Title III (40
CFR 372.65), and, therefore, is not one of the toxic chemicals that facilities are required to report to the Toxics

Release Inventory database (EPA 1995).

4.2 IMPORT/EXPORT

Chlorfenvinphos is not likely to be imported as there are currently no registered uses for this compound as a
pesticide in the United States (REFS 1995). No deﬁnitive information on recent or historic import volumes

was found.

CHLORFENVINPHOS 120

4. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL

Current production of chlorfenvinphos in the United States could not be veriﬁed (SR1 1993), but production
for domestic consumption is not permitted as all registered uses in the United States were canceled in 1991
(REFS 1995). Production of pesticides for export whose registered uses in the United States have been
cancelled is legal under US. law. The Federal Insecticide, Fungicide, and Rodenticide Act (F IFRA) generally
prohibits the EPA from releasing complete information on pesticide production, sales, and distribution. In a
recent report by the Foundation for the Advancement of Science and Education, the authors report that no
government agency maintains current records concerning what speciﬁc pesticides are exported (FASE 1996).

No deﬁnitive information on recent or historic export volumes was found.

4.3 USE

In the United States, chlorfenvinphos was registered for a variety of uses from 1963 until 1991 when all
products containing chlorfenvinphos as an active ingredient were canceled (REFS 1995). Chlorfenvinphos
was ﬁrst registered in 1963 under the trade name Derrnaton® as an insecticide/acaricide dip for veterinary use
in controlling ﬂeas and ticks on domestic pets and other animals. During the mid-19605 and early 1970s,
chlorfenvinphos was registered for additional uses as a residual ﬂy spray, surface spray, and larvicide. As part
of these registrations, chlorfenvinphos was used to control adult ﬂies in dairy barns, milk rooms, poultry
houses and yards, other animal buildings, feedlots, and animal holding pens; and to control larval ﬂies in
manure storage pits and piles, and in other refuse accumulation areas around dairies and feedlots (REFS
1995). Beginning in the early 19805, it was registered for additional uses under the trade name Dermaton®, in
a dust formulation for use in dog kennels and in dog collars for the control of ﬂeas and ticks (Farm Chemicals
Handbook 1984, 1993; Hayes 1982; REFS 1995).

Available formulations of chlorfenvinphos included a 0.5% dust, 10% pelletized granules, 21% emulsiﬁable
concentrate, 24.5% emulsiﬁable concentrate, 25% wettable powder(WP), and 40% seed dressing (with 2%
mercury compounds); however, some of these formulations were not registered for use in the United States
(Hayes 1982; REFS 1995; Spencer 1982). A summary of the registered uses of chlorfenvinphos in the United
States prior to the cancellation of its registration is given in Table 4-1 (REFS 1995).

Chlorfenvinphos was subject to re-registration by the Office of Pesticide Programs of EPA in the mid-19805.
At that time, the sole manufacturer, Shell International Chemical Company decided not to support

reregistration and allowed its registration of both the technical compound 4072 and of a variety of formulated

121

CHLORFENVlNPHOS

4. PRODUCTION, lMPORT/EXPORT, USE, AND DISPOSAL

 

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CHLORFENVINPHOS

4. PRODUCTION, IMPORT/EXPORT, USE. AND DISPOSAL

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CHLOHFENVINPHOS 123

4. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL

products to lapse and be canceled (EPA 1994). A summary of chlorfenvinphos product registrations and their

effective dates of cancellation are given in Table 4-2.

Outside the United States, Chlorfenvinphos is registered for use under the trade names Birlane", C8949, CGA
26351, Sapecron®, Steladone® and Supona® (Farm Chemicals Handbook 1993). Chlorfenvinphos (under the
trade name Birlane®) is used as a soil insecticide for controlling root maggots, root worms, and cutworrns
(Farm Chemicals Handbook 1984; Spencer 1982; Worthng 1983). As a foliar insecticide, it controls
Colorado beetles, Leptinotarsa decemlineata on potatoes, and scale insects on citrus, where it also exhibits
ovicidal activity against mite eggs. It also controls stem borers on maize, rice, and sugarcane, and whiteﬂies
(Benusia sp.) on cotton (Farm Chemicals Handbook 1984; Worthing 1983). Birlane" 24 controls root ﬂies,
phorid and sciarid ﬂy larvae, fruit ﬂies on maize and sweet corn, and wheat bulb ﬂies in winter wheat.
Birlane® 10% granules are used to control root ﬂies and Birlane" Liquid Seed Treatment is used to control
wheat bulb ﬂies in winter wheat. Supona® is used to control ticks, ﬂies, lice and mites on cattle; blowﬂies, lice
ked, and itchmites on sheep; and ﬂeas and ticks on dogs. Steladone® and Sapecron® are used as cattle dips or
sprays to control ectoparasites on cattle (Farm Chemicals Handbook 1984; REFS 1995; Spencer 1982).
Chlorfenvinphos is also used in public health applications for control of mosquito larvae (The Agrochemicals
Handbook 1 991 ).

No quantitative information on the volume of Chlorfenvinphos use in the United States or on historic trends in
use was found. It is known, however, that Chlorfenvinphos was ﬁrst introduced for use in the United States on
October 3, 1963, and that the last EPA approved label date for a Chlorfenvinphos-containing product was
September 1986. Use is likely to have declined from 1986 until January 22, 1991, when all uses of the
chemical were canceled in the United States (REFS 1995).

4.4 DISPOSAL

Chlorfenvinphos is considered to be an extremely hazardous substance (EPA 1988). The recommended
disposal method for Chlorfenvinphos consists of hydrolysis and subsequent transport to a landﬁll (IRPTC
1985). Chlorfenvinphos and Chlorfenvinphos-containing wastes should be treated by alkali and then mixed
with a portion of soil which is rich in organic matter before burial (at least to a depth of 0.5 meters) in a pit or
in clay soil. For disposal of large quantities of Chlorfenvinphos, incineration at high temperatures in a unit
equipped with an efﬂuent gas scrubbing device is recommended (IRPTC 1985). See Chapter 7 for further

information on regulations and advisories.

Table 4-2. Chlorfenvinphos Product Registrations and Dates of Cancellation in the United States

 

 

Percent Initial registration Effective cancellation
chlorfenvinfos ID number Product name date date

21.10 218-608 Arcadian Residual Fly Spray 09-29-66 02-21-86 '

21 .10 59—144 Residual Surface Spray and Larvicide 03-25-66 02-21-86

21.10 59-173 Coopona Poultry Premise Larvicide 03-07-73 02-21-86

24.50 59-136 Dermaton® Dip 10-03-63 07 -01-87

92.00 201 -209 Shell Technical Compound 4072, Insecticide for 12-13-66 10—10-89
Manufacturing Purposes Only

92.00 31629-1 Technical Compound 4072 Insecticide (for 06-07—74 10-10-89
Manufacturing Purposes Only)

00.50 59-189 Dermaton Dust 07-14-80 01-22-91

15.00 59-197 Dermaton Dog Collar 08-10-82 01-22-91

12.25 59-203 Dermaton II I 05-15-84 01-22-91

 

Source: EPA 1994

'lVSOdSICI (WV '38“ 'iHOchE/lHOdWI ‘NOIiOﬂGOHd '17

SOHdNIANEIdHOWHO

V31.

CHLORFENVINPHOS 125

5. POTENTIAL FOR HUMAN EXPOSURE

5.1 OVERVIEW

Chlorfenvinphos is currently released to the environment in the United States from runoff and leaching from
hazardous waste disposal sites. Soil is the environmental medium most likely to be contaminated with
chlorfenvinphos. The processes that may transport chlorfenvinphos from soil to other media include
volatilization to the air, leaching to groundwater, runoff to surface water, and absorption by plants.
Biodegradation appears to be the dominant process responsible for chlorfenvinphos loss from soil (Miles et al.
1979, 1983). Biodegradation, hydrolysis, and adsorption to organic matter are likely to be responsible for the
loss of chlorfenvinphos from water (Beynon et al. 1971, 1973', Rouchaud et al. 1988).

If released to air from soil or water via volatilization, chlorfenvinphos is expected to exist primarily in the
vapor phase, but can also be found associated with particulate matter (Eisenreich et al. 1981). In the vapor
phase, chlorfenvinphos can react with hydroxyl radicals (estimated half-life value of 7 hours) or with ozone
(estimated half-life value of 92 hours) (Atkinson and Carter 1984; Lyman et al. 1990; Meylan and Howard
1993).

If released to water, moderate adsorption to particulate matter will transport chlorfenvinphos from the water
column and partition it to suspended solids and sediment (Swann et a1 1983). The hydrolysis half-life value
for chlorfenvinphos in water is highly dependent on pH and temperature. At a pH of 6 and 8 and a
temperature of 20—30 °C, the half-life values were 170 and 80 days, respectively (Beynon et a1. 1971).

Chlorfenvinphos does not appear to partition extensively from water into aquatic organisms. Estimated whole-
body concentration factors for chlorfenvinphos were signiﬁcant, but relatively low, ranging from 37 to 460
(Mackay 1982; Veith et al. 1979; Veith et al. 1980 in Bysshe 1990). No experimentally measured
bioconcentration factor (BCF) values were located in the literature for any aquatic invertebrate or ﬁsh species.
Chlorfenvinphos is absorbed by plants primarily from the soil, but residues generally decline fairly rapidly in
the tissues through the course of the growing season (Beynon et a1. 1968; Suett 1971, 1975a).

The estimated half-life value of chlorfenvinphos in sandy soil ranges from 28 days (4 weeks) to 210 days
(30 weeks) (Beynon et al. 1973; Williams 1975a). The rate of degradation is inﬂuenced greatly by the soil

type, amount of organic matter in the soil, soil temperature, soil moisture content, and the history of

CHLORFENVINPHOS 126

5. POTENTIAL FOR HUMAN EXPOSURE

chlorfenvinphos use. Repeated application of chlorfenvinphos to agricultural soils enhanced microbial

degradation of the pesticide (Rouchaud et al. 1989a, 1991).

No information was found on concentrations of chlorfenvinphos in ambient air samples or in drinking water in
the United States. Chlorfenvinphos was detected in surface and groundwater samples (concentrations not
speciﬁed) at the one hazardous waste site where chlorfenvinphos was detected (HazDat 1996).
Chlorfenvinphos was also detected in soil samples (concentrations not specified) at the one hazardous waste
site where chlorfenvinphos was detected (HazDat 1996). It should be noted that the amount of

chlorfenvinphos found by chemical analysis is not necessarily the amount that is bioavailable.

Currently, both domestic and imported foods (fresh fruits and vegetables) and lanolin-containing
pharmaceutical products appear to be sources of some exposure for the general population. In the past,
occupational exposure to chlorfenvinphos may have occurred through dermal contact and inhalation of dusts
and sprays especially to workers applying the compound as a pesticide. Occupational exposure to

chlorfenvinphos was reported in California in workers who handled ﬂea control products (Ames et a1. 1989).

Workers involved in disposal of chlorfenvinphos or chlorfenvinphos-contaminated wastes are also at a higher
risk of exposure than the general population. People living in the vicinity of plants where chlorfenvinphos was
manufactured or formulated, or living near dairy farms, cattle or sheep holding areas, or poultry producing
facilities where chlorfenvinphos was used; and people living near hazardous waste sites containing

chlorfenvinphos also are potentially at higher risk of exposure.

Chlorfenvinphos has been identiﬁed in at least 1 of the 1,428 current or former EPA National Priorities List
(NPL) hazardous wastes sites (HazDat 1996). However, the number of sites evaluated for chlorfenvinphos is

not known. The frequency of these sites within the United States can be seen in Figure 5-1.

5.2 RELEASES TO THE ENVIRONMENT

Information on historic production of chlorfenvinphos (including producers, production sites, production
volumes and years of production) in the United States was not found. Releases of chlorfenvinphos are not
required to be reported under SARA Section 313; consequently there are no data for this chemical in the 1993
Toxics Release Inventory (EPA 1995).

Figure 5-1. Frequency of NFL Sites with Chlorfenvinphos Contamination

 

 

 

 

Derived from HazDat 1996

 

BHHSOdXE NVINnH 80:1 'WllNEJDd '9

SOHdNIANEHHO'IHO

LZL

CHLORFENVINPHOS 128

5. POTENTIAL FOR HUMAN EXPOSURE

There is one NPL hazardous waste site where chlorfenvinphos has been identiﬁed (HazDat 1996). Hazardous
waste disposal sites appear to be the major source for release of this compound into the environment since

there are currently no registered uses for it in the United States (REFS 1995).
5.2.1 Air

Chlorfenvinphos may have been released into the air in the past, during its production and processing.
Historically, chlorfenvinphos may have volatilized into the air during its use in sprays applied to dairy,
poultry, and cattle facilities to control ﬂies and ﬂy larvae, or from the skin of animals exposed to
chlorfenvinphos in cattle dips or sprays. Because of the relatively low volatility of the compound and lack of
registration for crop use in the United States (REFS 1995), releases to the air from registered uses would be

expected to be negligible.

Chlorfenvinphos was not detected in air samples collected at the one NPL hazardous waste site where it was
detected in some environmental media (HazDat 1996). No other information on releases of chlorfenvinphos to
air was located; however, there are no current registered uses of this compound in the United States (REFS
1995; SRI 1993).

5.2.2 Water

In the past, chlorfenvinphos may have been released to surface water during its production and processing.
Chlorfenvinphos also may have been released to water via runoff after its application to dairy, poultry, and
cattle facilities to control ﬂies and ﬂy larvae, or when residues from sheep or cattle dip tanks were discharged
onto soil (Inch et a1. 1972). Because chlorfenvinphos was never registered for use on crops in the United
States (REFS 1995), its releases to water from its registered uses would be expected to be minimal.
Adsorption to particulate matter will eventually transport chlorfenvinphos from water to suspended solids and

sediment.

Chlorfenvinphos has been detected in surface water and groundwater samples collected at the one NPL
hazardous waste site where it was detected (concentrations unspeciﬁed) in some environmental media
(HazDat 1996). No other information on releases of chlorfenvinphos to water was located; however, there are

no current registered uses of this compound in the United States (REFS 1995; SR1 1993).

. CHLORFENVINPHOS 129

5. POTENTIAL FOR HUMAN EXPOSURE

5.2.3 Soil

Chlorfenvinphos may have been released directly to soil during its production and processing and is likely to
have been released during its disposal as the recommended disposal practice for small quantities was burial in
a disposal pit or in clay soil (IRPTC 1985). The chemical may also have been released to soil and sediment
indirectly from runoff from treated manure storage areas, and areas around poultry or cattle holding areas, or
when residues from sheep or cattle dip tanks were discharged onto soil (Inch et al. 1972). Adsorption to
particulate matter will eventually transport Chlorfenvinphos from water to suspended solids and sediment.
Because chlorfenvinphos was not registered for crop use in the United States, its releases to soil from its

registered uses would be expected to be minimal.

Chlorfenvinphos has been detected in soil samples collected at the one NPL hazardous waste site where it was
detected in some environmental media (HazDat 1996). No other information on releases of Chlorfenvinphos to
soil or sediments was located; however, there are currently no registered uses of this chemical in the United

States (REFS 1995; SR1 1993).
5.3 ENVIRONMENTAL FATE
5.3.1 Transport and Partitioning

There is a paucity of experimental data regarding the transport and partitioning of Chlorfenvinphos in the air.
Given a vapor pressure ranging from 4.0xlO‘S mm Hg (Worthing 1983) to 7.5x106 mm Hg (Merck 1989),
Chlorfenvinphos should exist in the atmosphere in the vapor phase, but will also partition to available airborne
particulates (Eisenreich et a1. 1981). The solubility of 145 mg/L (Merck 1989) ensures that at least partial

removal of atmospheric Chlorfenvinphos will occur by wet deposition.

The transport of Chlorfenvinphos from water to air can occur due to volatilization. Henry‘s law constant
provides a qualitative indication of the importance of volatilization. Compounds with a Henry's law constant
(H) of <10'5 atm-m3/mol volatilize slowly from water (Thomas 1990). Chlorfenvinphos with an H value of
2.76x10'9 atm-m3/mol (Domine et al. 1992), therefore, will volatilize slowly from water. Since H <109 atm-
m3/mol, Chlorfenvinphos is less volatile than water and its concentration in water may increase as water
evaporates. Humidity in the air reduces the volatilization rate of water somewhat so the lower limit can be set

at 107; this means that Chlorfenvinphos could be considered essentially nonvolatile (Thomas 1990).

CHLORFENVINPHOS 130

5. POTENTIAL FOR HUMAN EXPOSURE

Adsorption to particulate matter will transport chlorfenvinphos from water and partition it to suspended solids
and sediment in water. The estimated organic carbon-adjusted soil sorption coefficient (Km) for
chlorfenvinphos is 280 (Kenaga 1980). This K0c value suggests that chlorfenvinphos in the water column
adsorbs moderately to suspended solids and sediments based on criteria established by Swann et al. (1983),
and this process may transport considerable amounts of chlorfenvinphos from water to particulate matter.
Partitioning of chlorfenvinphos from water to solid suspended matter was studied in a ﬁeld experiment.
Chlorfenvinphos was sprayed at a rate of 74 kg/ha on to the surface of a pond so the water contained an
average concentration of 6.1 ppm (Beynon et al. 1971). The concentration decreased to 2.0 ppm aﬁer 5 hours,
and to 0.12 ppm after 1 month. The sediment concentrations increased and persisted for at least 34 days after
treatment. Chlorfenvinphos disappears from water in two distinct phases, a rapid initial phase and a much
slower second phase. It is suggested that the ﬁrst phase represents the initial precipitation of the heavier
particles and uptake in plankton containing the adsorbed pesticide. Later, chlorfenvinphos is gradually
adsorbed to other suspended matter, which then precipitates much more slowly, or the second phase may

represent the slower removal of the residues by biotic processes.

Based on structure and activity relationships, certain regression equations have been developed to estimate the
bioconcentration factor (BCF) value for chlorfenvinphos from its water solubility and organic carbon partition
coefﬁcent (Koo) values. Using these regression equations, the BCF value for chlorfenvinphos in aquatic
organisms is estimated to be 37 (Kenaga 1980). A log octanol-water partition coefﬁcent (KW) value of

3.806 was reported by Bowman and Sans (1983). Using regression equations involving log KW, the following
BCF values were estimated; 306 (Mackay 1982), 343 (Veith et al. 1979), and 460 (Veith et al. 1980 in Bysshe
1990). No experimentally measured BCF values were located in the literature for any aquatic invertebrate or
ﬁsh species. However, bioconcentration of chlorfenvinphos in aquatic organisms, although relatively low,
ranging from 37 to 460, may have some environmental signiﬁcance. No information was found on the

biomagniﬁcation of chlorfenvinphos through aquatic or terrestrial food chains.

The transport processes that may move chlorfenvinphos from soil to other media are volatilization, leaching,
runoff, and absorption by plants. Based on the estimated Henry‘s law constant, volatilization is not expected to
be an important transport process for moving chlorfenvinphos from soil to other media. Like other pesticides,
chlorfenvinphos in soil partitions between soil-sorbed and soil-water phases (Racke 1992). This latter phase
may be responsible for the volatilization of chlorfenvinphos from soil; however, due to the low Henry's law
constant value, the rate of chlorfenvinphos volatilization from the soil-water phase to the atmosphere would be

low. In a laboratory study of volatilization from soil, chlorfenvinphos was incorporated into sterilized sand

CHLORFENVINPHOS 131

5. POTENTIAL FOR HUMAN EXPOSURE

and into a sterilized sandy loam at a concentration of 50 ppm. The media contained 25% moisture and were
maintained at 20 °C in an open beaker. Forty-ﬁve days after incorporation, more than 95% of the
chlorfenvinphos was still present in the beaker (Rouchaud et al. 1988). However, in a ﬁeld study conducted by
Williams (1975a), the author suggests that rapid loss (42% in 2 days) of surface-applied chlorfenvinphos
(granular) was probably due to volatilization and/or photodecomposition. Subsurface application of the
granular formulation at the same concentration showed only a 6% loss in 2 days post—application. In another
ﬁeld study, Suett (1977) reported that the combination of sunlight and warm wet soil for 48 hours immediately
after application of chlorfenvinphos marginally increased isomerization on both the coarse and ﬁne soil tilthes,

but did not enhance volatilization.

The reported K0c value of 280 (Kenaga 1980) suggests that the adsorption of chlorfenvinphos to soil is
moderately strong; therefore, the rates of leaching and runoff will be relatively minor processes in most soils.
Very little leaching of chlorfenvinphos and no leaching of its degradation products was observed in several
ﬁeld studies. The leaching characteristics of chlorfenvinphos were studied by applying it to sloping arable
land at 22 kg active ingredient/hectare (a.i./ha) and following its movement down a slope (Edwards et a1.
1971). Only 0.18% of the chlorfenvinphos applied was leached through the soil, but this was nine times more
than was observed with dieldrin in a similar experiment. Only very small amounts of chlorfenvinphos moved
down the slope and were present in runoff. In one of the experiments there was a pond located at the bottom
of the slope and residues could not be detected in the mud or water from this pond. Residues of the main soil
degradation products were not detected in the pond water at 23 or 36 weeks post—application. More
chlorfenvinphos leached vertically into drainage water than laterally over the soil surface. Chlorfenvinphos
residues in soil following broadcast applications on the surface showed that even after 150 days, only 1—1.5%
of the applied chlorfenvinphos leached to a depth of 7.5—1 5 cm despite 12 cm of rainfall that occurred during
the ﬁrst 60 days post-application (Williams 1975a). Furthermore, when the granular formulation was applied
at a depth of 7.5 cm, there was little movement of chlorfenvinphos below a depth of 10 cm. In a similar study
by Agnihotri et a1. (1981), when chlorfenvinphos granules were applied to the 0—15 cm soil layer, no leaching

of the compound occurred below the 15 cm depth over a period of 120 days.

Chlorfenvinphos is also transported from the soil of one area to soil of another area or from soil to surface
water (rivers, lakes, and streams) via runoff. Pesticides with a water solubility >10 mg/L move mainly in
solution phase in runoff water (Racke 1992). Chlorfenvinphos with a water solubility of 145 mg/L (Merck
1989) is expected to be found mainly in runoff water. This does not seem to be completely substantiated,

however, by results of several ﬁeld studies conducted in agricultural watersheds. In one ﬁeld study, only

CHLORFENVINPHOS 132

5. POTENTIAL FOR HUMAN EXPOSURE

03—06% of the applied chlorfenvinphos was found in runoff water after a rainfall event (Racke 1992). Braun
and Frank (1980) analyzed pesticide residues in surface water samples over a 3-year period (1975—77)
collected in 11 agricultural watersheds in Southern Ontario, Canada. Although chlorfenvinphos was known to
have been used as a soil pesticide in at least one of the watersheds, it was not detected in any surface water
samples (detection limit 1 pg/L [1 ppb]). In a more recent study, Frank et al. (1991) analyzed pesticide
residues in surface water samples over a 5-year period (1986—90) collected from the mouths of the 3 major
agricultural watersheds, the Grand, the Saugeen, and the Thames Rivers in Ontario, Canada. All three rivers
ﬂow into Lake Erie. Although it was known to have been used as a soil pesticide in the Thames River basin in
1988, no chlorfenvinphos residues were detected in any surface water samples during the study period
(detection limit <1 .0 ug/L [ppb]). Most recently, Wan et al. (1994) studied residues of several
organophosphate pesticides including chlorfenvinphos in farm ditch water, and sediments and farm soils in‘ the
lower Fraser Valley of British Columbia, Canada, from July through December 1991. The farm ditches
drained into three rivers: the Fraser, the Niicomekl, and the Sumas. During the study period, no sales of
chlorfenvinphos were reported. Chlorfenvinphos was used as a soil insecticide in 1990, but was not
recommended for this use in Canada in 1991. Although chlorfenvinphos was not detected in any of the farm
ditch water or sediment samples analyzed at the 7 sampling sites, it was detected in 7% of the soil samples.
Adsorption of chlorfenvinphos to particulate matter will transport the pesticide from the water column and
partition it to suspended solids and sediment. From these results, it seems clear that surface water runoff and
leaching of chlorfenvinphos into drainage water from treated agricultural ﬁelds is not likely to be a serious

problem.

Adsorption of chlorfenvinphos from water solutions of hydrogen, calcium, sodium, and potassium ions were
studied (Barba et al. 1991). In all cases, the saturating cations inﬂuenced the Freundlich—type adsorption, with
adsorption decreasing in the following sequence: H+> Ca2+> Na+> K for adsorption on two clays, kaolinite
and bentonite. The extent of adsorption of chlorfenvinphos was generally slower in kaolinite than in

bentonite.

When it was ﬁrst introduced, chlorfenvinphos was generally considered to be a non-systemic pesticide (i.e.,
when it is applied to soil it should not move into plants and when sprayed on plant foliage, it should not move
from the treated leaves into other untreated parts of the plant) (Rouchaud et al. 1989b). This view was based
on the fact that at plant maturity or at harvest, very low residues (<0.02 mg/kg [ 0.02 ppm]) were found in
turnips, carrots, cabbages, white radishes, and potatoes planted or sown in chlorfenvinphos-treated soil

(Beynon and Wright 1968; Beynon et al. 1968). In addition, no translocation of chlorfenvinphos from treated

CHLORFENVINPHOS 133

5. POTENTIAL FOR HUMAN EXPOSURE

leaves to other parts of plants was observed (Beynon et al. 1973). Earlier work with potato tubers under
recommended ﬁeld conditions also conﬁrmed this ﬁnding (Beynon et al. 1968). Rouchaud et al. (1989b),
however, found that in the foliage of the spring cauliﬂower, the concentration of chlorfenvinphos increased,
reaching a peak concentration 15 days after soil treatment, then progressively decreased until harvest. The
presence of chlorfenvinphos and two metabolites, trichloroacetophenone and 2,4-dichlorobenzoic acid, was
the result of their absorption by the plant from the soil and of their biodegradation by the plant. Two crops
were studied for their chlorfenvinphos uptake (Rouchaud et a1. 1991). The periods of time required for
chlorfenvinphos foliage concentrations to attain residues of 1 mg/kg (1 ppm) fresh weight were: cauliﬂower,
24—37 days; and Brussels sprouts, 41—45 days. Suett (1974, 1975a) also reported that carrots accumulated
high residue concentrations of chlorfenvinphos applied to the soil and continued to accumulate the pesticide
during the entire period of active plant growth. Thirty weeks after carrot seed was sown in soil treated with
chlorfenvinphos at a depth of 10 cm, the peel of the carrots contained 88% of the total chlorfenvinphos
residues found in the carrots. The upper 6 cm of carrot root always contained most of the chlorfenvinphos
residue irrespective of the application mode. Signiﬁcant residues of chlorfenvinphos were detected in
immature onion bulbs (64—76 days after seeding), with the level of chlorfenvinphos residue being much higher
in the roots and outer skin (Ritcey et al. 1991). The chlorfenvinphos concentrations in the bulbs dropped

below the detection limit (unspeciﬁed) by 96 days aﬁer seeding (2 months before harvesting).

In recent experiments, plant cuticle was investigated as the ﬁrst and rate-limiting barrier in foliar uptake of
chlorfenvinphos. Mobility studies of chlorfenvinphos across the cuticular membranes of bitter orange (Citrus
aurantium) leaves and green pepper (Capsicum annuum) fruits gave ﬁrst-order rate constants of

6.7 ($3.3)x108/second and 10.2 (13.4)x107/second, respectively (Bauer and Schonherr 1992). These
correspond to penetration half-lives of 120 days (2,874 hours) and 7.8 days (189 hours), respectively.

5.3.2 Transformation and Degradation

5.3.2.1 Air

One of the important reactions for most organic pollutants in the atmosphere is with hydroxyl radicals. No
rate constant for the reaction of hydroxyl radicals with chlorfenvinphos in air has been experimentally

determined. Using an estimation method, the estimated rate constant value for the vapor-phase reaction of
chlorfenvinphos with hydroxyl radicals is 5.3 1x10"1 cm3/radical-sec at 25 °C (Atkinson 1988; Meylan and

Howard 1993). Based on this value, and assuming an average annual atmospheric concentration of hydroxyl

CHLORFENVINPHOS 134

5. POTENTIAL FOR HUMAN EXPOSURE

radicals in the northem hemisphere of 4.8x105 radicals/cm3 (Lyman et a]. 1990), the estimated half-life value
(ﬁrst-order kinetics) of Chlorfenvinphos in the atmosphere due to this reaction is 7 hours. Thus,
Chlorfenvinphos is short-lived in the atmosphere. Chlorfenvinphos can also be degraded by ozonation in the
atmosphere. However, no rate constant for the reaction of ozone with Chlorfenvinphos in air has been
experimentally determined. An estimated value of the rate constant is 3x10 18cmS/molecule-sec at 25 °C
(Atkinson and Carter 1984; Meylan and Howard 1993). Based on this value and assuming an average
atmospheric ozone concentration of 9.6x10“ molecules/cm3 (Lyman et al. 1990), the estimated half-life value
(ﬁrst-order kinetics) of Chlorfenvinphos in the atmosphere due to this reaction is 92 hours (3.4 days).
Photolysis is probably the least signiﬁcant of the atmospheric degradation processes. Chlorfenvinphos is not
susceptible to direct photolysis in sunlight because its maximum absorption for ultraviolet light is 228 nm

(Schlett 1991), which is less than the 290 nm wavelength limit for sunlight absorption to occur.

5.3.2.2 Water

The processes that can result in the transformation and degradation of Chlorfenvinphos in water are hydrolysis,
photosensitized oxidation, and biodegradation. Hydrolysis pathways for Chlorfenvinphos in water are shown
in Figure 5-2. Chlorfenvinphos is most stable in water at ambient temperatures and neutral pH.
Chlorfenvinphos hydrolyzed slowly in water resulting in a half-life (ﬁrst-order kinetics) value of 170 days at
pH 6 and 80 days at pH 8 at 20—30 °C (Beynon et al. 1971). In laboratory studies, hydrolysis was observed
under conditions of high temperature and extreme pH (highly alkaline or highly acidic), resulting in a half-life
of >400 hours (>33 days) at pH 9.1, and >700 hours (58 days) at pH 1.1 at 38 °C (Agrochemicals Handbook
1991; Beynon et al. 1973; Hayes 1982). Hydrolysis probably does not contribute much to the initial
disappearance of Chlorfenvinphos from natural waters (Beynon et al. 1971). Based on hydrolysis studies
(Ruzicka et a1. 1967) conducted at 70 °C and correcting for temperature differences assuming an
environmental temperature of 20 °C, the aqueous hydrolysis half-life (ﬁrst-order kinetics) value of
Chlorfenvinphos is approximately 1—1.3 years (Harris 1990). Direct photolysis of Chlorfenvinphos is
negligible, since the compound does not signiﬁcantly absorb ultraviolet wavelength light >290 nm. No
information was found in the literature regarding the photosensitized reaction of Chlorfenvinphos in water with
ozone, hydroxyl radicals or singlet oxygen. Therefore, biodegradation appears to be the dominant degradation
process in natural waters. This is likely, as microbial degradation is the dominant degradation process in soils

(Miles et at. 1979, 1983; Rouchaud et a1. 1988).

Figure 5-2. Hydrolysis Pathways for Chlorfenvinphos in Water

Cl H
\ /
O C Cl

    
 

02450 \l H
/PO—C Cl
‘3sz0
Acidic, Chlorfenvinphos BZSiC‘
100'C 10ANaOH, 100° C
CI
Neutral
CICHZC(O) Cl C'CH20(°) :2 > 0'
Trichloroacetophenone Trichloroacetophenone
Stable
+ +
Cl
C2 H 50\E H O\
/P -OH C'*'C Cl
02 H5 0 II I
O OH

Diethyl phosphoric add 2,4-Dichlorophenylglycolic acid

+

CZHSO \H
/P—O Na+
C2H50

Diethyl phosphoric acid, sodium

EHnSOdXS NVWnH H05 ‘IVILNBLOd '9

SOHdNIANEdHO'lHO

98L

CHLORFENVINPHOS 136

5. POTENTIAL FOR HUMAN EXPOSURE

5.3.2.3 Sediment and Soil

Chlorfenvinphos in soil and sediment may undergo degradation and transformation by hydrolysis, and biotic
processes. Various screening studies have demonstrated that microbial degradation is the dominant
degradation process in soil (Miles et al. 1979, 1983; Rouchaud et al.1988, 1989a, 1989b). The hydrolysis of
chlorfenvinphos may occur in the soil/sediment-water phase, as opposed to the soil/sediment-sorbed phase. As
a result, the rate of hydrolysis is expected to be comparable to that in water. Based on the slow hydrolysis
rates observed in water (see Section 5.3.2.2), hydrolysis of chlorfenvinphos in soil is not expected to be
signiﬁcant. In the laboratory, chlorfenvinphos was incubated in sterilized and unsterilized soil for more than

2 months at 20 °C. The rate of disappearance of chlorfenvinphos from the sterilized soil was more than

15 times slower than that observed in unsterilized soil. The persistence of chlorfenvinphos was examined in
sterile and natural mineral (sandy loam/organic matter = 2.7%, pH = 7.2) and organic (muck, organic matter =
48%, pH = 6.5) soils at a range of temperatures (3—28 °C) for 24 weeks (Miles et a1. 1979, 1983). In general,
chlorfenvinphos is less stable in sandy loam than in muck, less stable at higher temperatures (the exception
was the stability of chlorfenvinphos in sterile sandy loam at all temperatures studied), and considerably less
stable in natural soils (half-lives s 11 weeks at 15 and 28 °C) compared to sterile soils (half-lives >24 weeks at
all temperatures), indicating the major role microbes play in degrading chlorfenvinphos in soil. A summary of

degradation pathways of chlorfenvinphos in soil is presented in Figure 5-3.

Chlorfenvinphos is degraded in soil to trichloroacetophenone, 2,4—dichloroacetophenone, a-(chloromethyl)-
2,4-dichlorobenzyl alcohol, and 1-(2',4'-dichlorophenyl)—ethan-1-ol (Rouchaud et al. 1988, 1991). Other
degradation products identiﬁed are 2,4—dichlorobenzoic acid, 2—hydroxy—4—chlorobenzoic acid, and
2,4-dihydroxybenzoic acid. None of the degradation products retain any pesticide characteristics.
Trichloroacetophenone is the main transformation product; when hydrolyzed, oxidized and decarboxylated, it
becomes 2,4—dichlorobenzoic acid. Reduction of trichloroacetophenone to oc-(chloromethyl)—2,4-dichloro-
benzyl alcohol is a slow process, and replacement of a chlorine atom by a hydrogen atom to become
2,4—dichloroacetophenone and l(-2',4'-dichlorophenyl)«ethan-l-ol is also slow. The degradation products
2-hydroxy—4-chlorobenzoic acid and 2,4—dihydroxybenzoic acid are produced from 2,4—dichlorobenzoic acid

by replacement of chlorine atoms by hydroxyl groups.

Biodegradation of chlorfenvinphos is inﬂuenced by several factors: soil type, presence of organic matter,

moisture content, soil temperature, and a history of chlorfenvinphos use. Chlorfenvinphos degrades fastest in

Figure 5-3. Environmental Degradation Pathways for Chlorfenvinphos in Soil

c\ /H
o 0 Cl
cszo\ ||

CH/HO

/Po Chlorlenvinphos
Cl Cl
CHCI
C2H5 ed M
/POC Cl CICHZCH Cl
——>
HO

Deselhyl chlorfenvinphos Trichloroacetophenone

   
 

0 CHCI
“0 \i ll
[’00 0' CICH2 OH
HO l
(HO)3P(O) ot-(Chloromelhyl)-2,4-dichlorobenzyl alcohol
Phosphoric acid
Cl
H
O\c CI HOCH 2ClH CI‘—CH2——
||
0
2,4-Dichlorobenzoic acid 1-(2.4-Dichlorophenyl)— 2,4-Dichlorophenyl

eihan-1,2-diol oxirane

2-Hydroxy-4—chlorobenzoic acid
HOCH2:|:HCl + CH —CH

2,4-Dihydroxybenzoic acid 2,4-Dichloroacetophenone 1-(2,4-Dichlorophenyl)-
ethan-1~ol

EHnSOdXE NVWOH H03 'lVLLNlLOd '9

SOHdNIANEHHO'IHO

LSL

CHLORFENVINPHOS 138

5. POTENTIAL FOR HUMAN EXPOSURE

sandy soils and slowest in peat, probably because of its degree of adsorption to organic matter (Beynon et al.
1973; Williams 1975a). Because the rate of degradation by hydrolysis is greater than expected, breakdown is
assumed to be mainly biotic. Initial half-life values of 4—30 weeks have been determined for sandy soils. In
peat, chlorfenvinphos persists longer. Chlorfenvinphos was found to be very slowly degraded in a peat soil
(47.8% organic matter), but was much less persistent on several sandy soils (16—22% organic matter)
(Williams 1975a). In the peat (soil water pH = 6.0), 70% of the applied chlorfenvinphos remained after

21 weeks and 30% remained after nearly 12 months. In sandy soil (soil water pH = 6.9—7.5) only 3—1 5% of
the applied chlorfenvinphos remained after a period of 15 weeks. The persistence in peat was attributed to
strong adsorption rendering the pesticide unavailable to microorganisms and to plant roots. In sandy soil,

rainfall was also correlated to increased loss of chlorfenvinphos.

Chlorfenvinphos was more stable and had increased persistence in soils that had been treated with organic
fertilizer such as pig slurry, cow manure, city refuse, or mushroom cultivation composts compared to
untreated control plots (Rouchaud et al. 1992a, 1992b). For example, the half-life of chlorfenvinphos at the
Gembloux site was 18, 36, 35, and 43 days for the control, city refuse compost, cow manure, and mushroom
compost plots, respectively. At another site (St. Katelijne-Waver), both a spring and summer application study
were conducted. In the spring study, the half-life of chlorfenvinphos was 9, 13, 14, and 21 days and in the
summer study, the half-life was 23, 42, 46, and 53 days for the control, city refuse compost, cow manure, and
mushroom compost plots respectively. The humic acid concentrations and the total soil organic matter content

were always higher in the organic fertilizer treated plots.

. Rates of chlorfenvinphos loss from soil also appear to be related to soil moisture conditions. In dry seasons,
although the initial rate of loss was high, the subsequent rate of degradation was slower than in wetter seasons
of higher soil moisture content (Williams 1975a). Under conditions of average summer rainfall and relatively
moist soils, the residues were less than 5% of applied dose, but when the soils were much drier than normal,

residues were higher at 15% of applied dose after the same period of time (Miles et al. 1984).

Degradation of chlorfenvinphos ceases in soil at low temperatures (below 6—7 °C) (Suett 1975b). A granular
formulation of chlorfenvinphos was broadcast at 2 kg active ingredient per hectare and incorporated to 10 cm
into sandy-loam soil in May and in September 1971. When applied in September, the chlorfenvinphos
persisted for a longer period than when applied in May. Degradation was slower during the winter while the
mean soil temperature remained below 6—7 °C. Rising soil temperature during the following spring rapidly

increased the rate of degradation. The late summer-early fall applications to control carrot ﬂies would leave

CHLORFENVINPHOS 139

5. POTENTIAL FOR HUMAN EXPOSURE

appreciable residues of chlorfenvinphos in the soil at the beginning of the next growing season which might
contribute to the terminal crop residues. Residues of chlorfenvinphos applied in May declined to less than
20% of the initially applied dose, and there was little loss subsequent to the December sampling. In the
September application, more than 60% of the chlorfenvinphos applied still remained when the loss rates
decreased in October. The relatively high concentration of chlorfenvinphos remaining then continued to
decline only slowly throughout the winter until March when the rate of loss of chlorfenvinphos residues

increased to rates similar to those of the previous September.

The catalytic degradation of chlorfenvinphos on H*, Ca2+, Na+, and K+ mono-ionic kaolinite and bentonite was
found to be inﬂuenced by the nature of the exchange cations and their degree of hydration in the order K+>
Na+> Ca2+> I-Il/Al3+ (Cémara et al. 1992). In both types of clays, the process of hydrolysis occurred in two
stages involving ﬁrst-order kinetics, giving different hydrolysis rates. The ﬁrst stage is characterized by a rapid

hydrolysis rate of short duration; the second phase is long with a slow but continuous hydrolysis rate.

An inverse relationship between the history of chlorfenvinphos use in the soil and foliage concentrations was
found that suggested enhanced biodegradation (Rouchaud et a1. 1991). The longer the history of
chlorfenvinphos use in a ﬁeld, the lower the chlorfenvinphos residues and residues of its metabolites that were
found; this suggests that speciﬁc soil microbial fauna adaptation was due to previous soil treatments. In soil
from cauliﬂower, Brussels sprouts, and Chinese cabbage ﬁelds, the half-life of chlorfenvinphos was found to
vary from 9 to 35 days; for chlorfenvinphos plus degradation products, the half-life ranged from 50 to 80 days
(Rouchaud et al. 1989a). The ﬁelds in which chlorfenvinphos exhibited the shorter half-lives were those with

the longer histories of chlorfenvinphos use in the soil, suggesting enhanced biodegradation was occurring.

Environmental transformation pathways for chlorfenvinphos in plants are summarized in Figure 5-4. A trans
to cis rearrangement of chlorfenvinphos sprayed on plant foliage has been observed (Beynon et al. 1973).
This conversion has been attributed to photochemical processes. The same conversion has not been observed
for chlorfenvinphos applied directly to soil. The initial half-life value of chlorfenvinphos on foliage is

2—3 days, and the rate of degradation decreases thereafter. Over 50% of the radioactivity from l4C-(vinyl)-
trans-chlorfenvinphos disappeared from foliage in 4—7 days. It is not known whether it is released as
chlorfenvinphos or as a degradation product. The major breakdown product of chlorfenvinphos on plant

foliage is a conjugate of the ethan-l-ol [8], probably with a sugar.

Figure 5-4. Environmental Transformation Pathways for Chlorfenvinphos in Plants

Cl H
O \ / Cl
l a c.
/
02H50
/ Chlorfenvinphos
Cl Cl
0 CHCI
cszod u
/POC Cl ClCHZCH Cl
————>
HO
Desethyl Chlorfenvinphos Trichloroacetophenone

   
 

CHCIC
Ho O>E° g
C' ClCH2 CH
(HO)3P(O) u-(ChloromethyI)-2,4-dichlorobenzyl alcohol
Phosphoric acid
CI
HO
\ﬁ (:1 HOCHchQCIv— CH 2—CHQCI
O
2,4-Dichlorobenzoic acid 1-(2.4-Dichlorophenyl)- 2,4-Dichlorophenyl

ethan-1 ,2-diol oxirane

2-Hydroxy-4-chlorobenzoic acid
1 HOCH2 2THCI + CH—CH

2,4-Dihydroxybenzoic acid 2,4-Dichloroacetophenone 1—(2,4-Dichlorophenyl)-
ethan-1-ol

SHHSOdXE NVWﬂH 80:! 'lVLLNElOd '9

SOHdNIANSdH01H0

07L

CHLORFENVINPHOS 141

5. POTENTIAL FOR HUMAN EXPOSURE

5.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT

Reliable evaluation of the potential for human exposure to chlorfenvinphos depends on the reliability of
supporting analytical data from environmental samples and biological specimens. In reviewing data on
chlorfenvinphos levels monitored in the environment, it should also be noted that the amount of chemical

identiﬁed analytically is not necessarily equivalent to the amount that is bioavailable.

5.4.1 Air

No information was located on the ambient concentrations of chlorfenvinphos in the atmosphere or on

concentrations associated with domestic or occupational indoor air exposures in the United States.

5.4.2 Water

No information was located on the ambient concentrations of chlorfenvinphos in drinking water, surface
water, or groundwater in the United States. Chlorfenvinphos was detected (concentration unspeciﬁed) in
surface water and groundwater samples collected at the only hazardous waste site where it was detected in

some environmental media (HazDat 1996).

Environmental monitoring data are available for surface waters from Canadian studies in the Great Lakes
region and from British Columbia. Braun and Frank (1980) analyzed pesticide residues in surface water
samples collected over a 3-year period (1975—77) in 11 agricultural watersheds in Southern Ontario, Canada.
Although chlorfenvinphos was known to have been used as a pesticide in at least one of the watersheds, it was
not detected in any surface water samples (detection limit 1 ug/L [1 ppb]). Frank et al. (1991) analyzed
pesticide residues in water samples collected over a 5-year period (1986—90) from the mouths of the

three major agricultural watershed rivers in Ontario, Canada: the Grand, the Saugeen, and the Thames. All
three rivers ﬂow into Lake Erie. Although it was known to have been used as a soil pesticide in the Thames
River basin in 1988, no chlorfenvinphos residues were detected in any water samples during the study period
(detection limit <1.0 ug/L [<1 ppb]). Most recently, Wan et al. (1994) studied residues of several
organophosphate pesticides including chlorfenvinphos in farm ditch water and farm soils in the lower Fraser
Valley of British Columbia, Canada, from July through December 1991. The farm ditches drained into three
rivers: the Fraser, the Niicomekl, and the Sumas. During the study period, no sales of chlorfenvinphos were

reported. Chlorfenvinphos was used as a soil insecticide in 1990, but was not recommended for this use in

CHLORFENVINPHOS 142

5. POTENTIAL FOR HUMAN EXPOSURE

Canada in 1991. Although chlorfenvinphos was not detected in any of the farm ditch water or sediment
samples analyzed at the 7 sampling sites, it was detected in 7% of the soil samples. Residue results obtained in
these Canadian studies may be inappropriate for estimating water residues in the United States, as

chlorfenvinphos was never registered for use as a soil insecticide in the United States (REFS 1995).
5.4.3 Sediment and Soil

Chlorfenvinphos was detected (concentration not speciﬁed) in topsoil and subsoil samples (>3 inches deep)
collected at one NPL hazardous waste site where it was detected in some environmental media (HazDat 1996).
No other information was located on the concentrations of chlorfenvinphos detected in soil or sediment

samples collected in the United States.

Environmental monitoring data are available, however, for agricultural soils from Canadian studies in the
Great Lakes region and from British Columbia. Chlorfenvinphos residues in organic farm soils of the Holland
Marsh in Ontario, Canada, were analyzed each fall from 1972 to 1975 and residue levels generally exceeded
0.1 ppm (Miles et al. 1978). The annual mean residues (dry weight basis) of chlorfenvinphos sampled in

13 farm soils were as follows: 1972, 0.12 ppm; 1973, 0.05 ppm; 1974, 0.36 ppm; and 1975, 0.13 ppm. Wan
et al. (1994) studied residues of several organophosphate pesticides including chlorfenvinphos in farm soils
from seven different sites in the lower Fraser Valley of British Columbia, Canada, from July through
December 1991. Chlorfenvinphos was used as a soil insecticide in 1990, but was not recommended for this
use in Canada, in 1991 (during the study period). Despite the fact that chlorfenvinphos was not used during
the study period, it was detected in 7% of the soil samples analyzed. The mean chlorfenvinphos concentration
found in soil at the Cloverdale site was 31 ug/kg (0.031 ppm), with a range of 12 to 60 ug/kg

(0012—0060 ppm). The authors believed that these residues were a carryover from the previous years.
Residue results obtained in these Canadian studies may be inappropriate for estimating soil residues in the
United States, as chlorfenvinphos was never registered for use as a soil insecticide in the United States (REFS
1995)

5.4.4 Other Environmental Media
Chlorfenvinphos was not monitored in many of the federal, regional, and state food studies conducted from the

late 19605 through the mid-19805 (Comeliussen 1970; Duggan and Comeliussen 1972; Duggan et a1. 1983;
Gartell et a1. 1986; Gunderson 1988; Hundley et al. 1988). The FDA's monitoring program for domestic and

CHLORFENVINPHOS 143

5. POTENTIAL FOR HUMAN EXPOSURE

imported food commodities detected Chlorfenvinphos in unspeciﬁed foods at unspeciﬁed concentrations
during ﬁscal years 1978—82 (Y ess et al. 1991a) and during ﬁscal years 1983—86 (Y ess et al. 1991b). During
1982—86, the FDA Los Angeles District Laboratory analyzed 19,851 samples of domestic and imported food
and feed commodities (Luke et a1. 1988). Chlorfenvinphos was not detected in any sample of the

6,391 domestic agricultural commodities or in any of the 12,044 imported agricultural commodities analyzed.
Chlorfenvinphos was detected in unspeciﬁed foods at unspeciﬁed concentrations and at an unspeciﬁed
detection frequency in 14,492 domestic and imported food samples analyzed as part of the FDA pesticide
monitoring program for 1986—87 (FDA 1988). In a pesticide residue screening program conducted in 1989—91
in San Antonio, Texas, on 6,970 produce samples, Chlorfenvinphos was detected (0.75 ppm detectionlimit) in
one produce sample of tomatoes (frequency of <0.5%) (Schattenburg and Hsu 1992). In a similar study
conducted by Agriculture Canada of 13,230 domestic and imported food items analyzed during the same
period (1989—91), chlorfenvinphos was not detected in any domestic foods, but was detected in 13 imported
food samples (frequency <0.1%) (Neidert et al. 1994). Detectable residues were found in fresh oranges,
peppers, pineapples, and spinach. As part of the FDA's Pesticide Monitoring Program for domestic and
imported foods, Chlorfenvinphos residues have been detected in unspeciﬁed foods at unspeciﬁed
concentrations and at unspeciﬁed detection frequencies during 1988—89, 1989—90, 1990—91, 1991—92,
1992-93 (FDA 1990, 1991, 1992, 1993, 1994), but residues were not detected in 1993—94 during the most
recent regulatory monitoring period (FDA 1995).

The effect of cooking on Chlorfenvinphos concentrations in raw foods was examined by Askew et al. (1968).
These authors spiked samples of raw potato and cabbage mash with 2 ppm of Chlorfenvinphos and boiled the
samples for 30 minutes to simulate the effect of cooking raw vegetables contaminated with Chlorfenvinphos.
Total residues were reduced by 37—53% for potato and 56—86% for cabbage mash. A cooking process such as
boiling leads to a partial reduction of Chlorfenvinphos residues, but does not completely eliminate the
pesticide. A similar study examined the effects of milk processing procedures on organophosphate residues in
milk (Skibniewska and Smoczynski 1985). These authors reported that boiling in an enamel vessel to
simulate home cooking, and three pasteurization procedures involving heating for 30 minutes at 62 °C, for

2 minutes at 72 °C, and for 5 seconds at 85 °C, resulted in about a 20% decrease in the residues of
organophosphates including Chlorfenvinphos. Reduction of the pesticide residues was more affected by the

duration of heating rather than the temperature to which the milk was heated.

Nagayama et al. (1989) studied the residue levels of Chlorfenvinphos on commercial tea leaves grown in Japan

and the leaching of the pesticide into tea. Chlorfenvinphos was detected at concentrations ranging from trace

CHLORFENVINPHOS 144

5. POTENTIAL FOR HUMAN EXPOSURE

to 3.4 ppm on tea leaves and more that 12% of the chlorfenvinphos was found to leach from the leaves into the

tea.

Heikes and Craun (1992) analyzed the residues of several pesticides including chlorfenvinphos in anhydrous
lanolin and lanolin-containing pharmaceutical preparation sampled from 1988 through 1992. Concentrations
of chlorfenvinphos in anhydrous lanolin samples collected in 1989 ranged from 0.60 to 5.9 mg/kg; those
collected in 1991 ranged from 0.81 to 10 mg/kg. In 1988, chlorfenvinphos was detected in a wide range of
pharmaceutical preparations including A & D ointment, analgesic balm, nitroglycerin cream, atropine sulfate
ointment, and dibucaine ointment at concentrations ranging from 0.08 to 1.1 mg/kg (ppm). In 1992,
chlorfenvinphos was detected in antibiotic, cold sore, and ophthalmic ointments at concentrations ranging

from trace to 0.32 mg/kg (ppm).

5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE

Currently, the general population is primarily exposed to chlorfenvinphos by ingesting food containing
chlorfenvinphos, particularly fresh fruits and vegetables imported from countries where this pesticide still is
used. In addition, the general population may be derrnally exposed to chlorfenvinphos concentrations in

lanolin and lanolin-containing pharmaceutical products.

No information is available on the concentrations of chlorfenvinphos in ambient air. However, because this
pesticide currently has no registered uses in the United States, the extent of exposure of the general population
to chlorfenvinphos from inhalation is probably insigniﬁcant. No information is available on the
concentrations of chlorfenvinphos in drinking water. Because chlorfenvinphos was not used as an agricultural
pesticide on crops in the United States, it was not monitored extensively in groundwater. As a result of its
relatively limited use, current exposure of the general population to chlorfenvinphos from consumption of

drinking water is probably negligible.

Chlorfenvinphos has been detected in both domestic and imported foods, but especially in imported fresh
fruits and vegetables (see Section 5.4.4). Thus, consumers can be exposed to chlorfenvinphos by ingesting
contaminated food. No information was available on the FDA-estimated daily food intakes of
chlorfenvinphos for different age/sex groups in the United States for ﬁscal years 1982—84 (Gunderson 1988)
or l986—9l (FDA 1993). However, because exposure to the general population from consumption of

chlorfenvinphos-contaminated foods comes primarily from imported foods and because residues in raw

CHLORFENVINPHOS 145

5. POTENTIAL FOR HUMAN EXPOSURE

vegetables and fruits are reduced during food preparation by washing and cooking procedures, the risk to the

general US. population appears negligible.

Workers who were involved in the manufacture, formulation, handling, or application of chlorfenvinphos are
likely to have been exposed to higher concentrations by dermal exposure and inhalation of chlorfenvinphos
particles than the general population. Workers who are currently involved in the disposal of chlorfenvinphos-
contaminated wastes are likely to be exposed to higher concentrations by dermal contact and inhalation of
chlorfenvinphos particles or chlorfenvinphos-contaminated soil particles than the general population.
Occupational exposure to chlorfenvinphos was reported to have occurred in workers in California who
handled ﬂea control products. However, chlorfenvinphos was not associated with statistically elevated

symptom frequency (Ames et al. 1989).

No information was found in the National Occupational Exposure Survey (N OES) conducted by NIOSH from
1981 to 1983 on the number of workers and the number of facilities where workers could be potentially
exposed to chlorfenvinphos in the United States (NOES 1990). NIOSH (1992) did not provide
recommendations for occupational exposure levels to chlorfenvinphos for a 10-hour time weighted average
(TWA) workday. An Occupational Safety and Health Administration (OSHA) permissible exposure limit
(PEL) for workplace air does not exist (OSHA 1974).

5.6 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES

In the past, individuals who were occupationally exposed to chlorfenvinphos during its production,
formulation, packaging, distribution, use, or disposal, were exposed to higher-than-background concentrations

of chlorfenvinphos.

At the present time, several groups within the general population may receive potentially high exposures to
chlorfenvinphos. These groups include individuals living near chemical manufacturing or processing sites or
those currently involved in the disposal of chlorfenvinphos or chlorfenvinphos—contaminated materials, those
living on dairy, beef, sheep, or poultry farms where chlorfenvinphos was extensively used, and those living
near hazardous waste sites. Individuals living near these sites may be exposed to potentially higher
concentrations of chlorfenvinphos or its metabolites in their drinking water if they obtain tap water from wells
near these sources. Children playing in chlorfenvinphos-contaminated soils may consume this pesticide or its

degradation products from their exposed hands.

CHLORFENVINPHOS 146

5. POTENTIAL FOR HUMAN EXPOSURE

5.7 ADEQUACY OF THE DATABASE

Section 104(i)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with the
Administrator of EPA and agencies and programs of the Public Health Service) to assess whether adequate
information on the health effects of chlorfenvinphos is available. Where adequate information is not
available, ATSDR, in conjunction with the NTP, is required to assure the initiation of a program of research
designed to determine the health effects (and techniques for developing methods to determine such health

effects) of Chlorfenvinphos.

The following categories of possible data needs have been identiﬁed by a joint team of scientists from
ATSDR, NTP, and EPA. They are deﬁned as substance-speciﬁc informational needs that if met would
reduce the uncertainties of human health assessment. This deﬁnition should not be interpreted to mean that
all data needs discussed in this section must be ﬁlled. In the future, the identiﬁed data needs will be

evaluated and prioritized, and a substance-speciﬁc research agenda will be proposed.
5.7.1 Identification of Data Needs

Physical and Chemical Properties. As seen in Table 3-2, the relevant physical and chemical
properties of chlorfenvinphos are known (Bowman and Sans 1983; Domine et al. 1992; HSDB 1994;
Kenaga 1980; Merck 1989; Worthing 1983) and predicting the environmental fate and transport of this

compound based on the K00, KW, and Henry's law constant is possible. No further information is required.

Production, Import/Export, Use, Release, and Disposal. Chlorfenvinphos was introduced into the
United States in 1963 (Hayes 1982) by the Shell International Chemical Company, Ciba—Geigy AG, and by
Allied Chemical Corporation (Worthing 1983). No historic import/export information was available for this
chemical. In the United States, chlorfenvinphos use appears to have been limited to uses in dairies, feedlots,
or poultry yards to reduce adult ﬂy populations; in manure containment areas to reduce adult and larval ﬂy
populations; as a cattle and sheep dip to reduce ectoparasites, and as a wettable powder (WP), granular
form, or contained in a collar for killing ﬂeas and ticks in dogs (EPA 1994; REFS 1995). While
chlorfenvinphos has been extensively used in agricultural applications in other countries, especially for root
and cole crops, this pesticide was not used for crop applications in the United States (Farm Chemicals
Handbook 1984, 1993; Spencer 1982; The Agrochemicals Handbook 1991; Worthing 1983). More

complete information on the production and import/export of chlorfenvinphos would be useful to assess the

CHLORFENVINPHOS 147

5. POTENTIAL FOR HUMAN EXPOSURE

possible routes of exposure, potential for environmental contamination and human exposure. Information
on the number of producers and production sites, locations of production facilities, years of production, and
the volume of production in the United States would be helpful. Information on import/export volumes and
estimates of yearly usage during those years prior to the cancellation of its pesticide registration would also
be useful. While adequate information on disposal procedures exists (IRPTC 1985), more recent

information would be helpful.

According to the Emergency Planning and Community Right-to—Know Act of 1986, 42 U.S.C. Section
11023, industries are required to submit chemical release and off-site transfer information to the EPA. The
Toxics Release Inventory (TRI), which contains this information for 1993, became available in May of
1995. This database will be updated yearly and should provide a list of industrial production facilities and
emissions. No information is available from TRI93 because chlorfenvinphos is not one of the toxic

chemicals that producers currently are required to report (EPA 1995).

Environmental Fate. Information regarding the fate of chlorfenvinphos in the air was not located in the
literature. Given a vapor pressure ranging from 4x106 to 7.5x10“S mm Hg (Merck 1989; Worthing 1983),
chlorfenvinphos should exist in the atmosphere in the vapor phase, but will also partition to available
airborne particulates (Eisenreich et al. 1981). The solubility of 145 mg/L (Merck 1989) ensures that at least
partial removal of atmospheric chlorfenvinphos will occur by wet deposition. Based on these chemical and
physical properties, the atmospheric concentrations of chlorfenvinphos are expected to be low because
chlorfenvinphos is not highly volatile. Additional information would help predict the residence time and
distance of its aerial transport. The fate of chlorfenvinphos in water has been more extensively studied (see
Section 5.3.1) (Barba et al. 1991; Beynon et a1. 1971, 1973; Braun and Frank 1980; Frank et al. 1991; Wan
et a1. 1994), including information on its degradation under various environmental conditions. The fate of
chlorfenvinphos in soil, including information on its mobility and biodegradation, has also been well
documented (see Section 5.3.1) (Beynon et al. 1973; Edwards et al. 1971; Miles et al. 1979, 1983; Racke
1992; Rouchaud et al. 1988, 1989a, 1989b, 1989c, 1991, 1992a, 1992b; Williams 1975a). Additional
information on the degradation of chlorfenvinphos in air and groundwater would be helpful in estimating
exposure to chlorfenvinphos under various conditions of environmental release for purposes of planning and

conducting meaningful follow-up exposure and health studies.

Bioavailability from Environmental Media. Available information regarding the rate of

chlorfenvinphos absorption following inhalation, oral, and dermal contact has been discussed in the

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5. POTENTIAL FOR HUMAN EXPOSURE

Toxicokinetics section (see Section 2.3) (Hunter 1969; Hutson and Wright 1980; Pach et al. 1987).
Although no data on chlorfenvinphos' bioavailability from contaminated air are available, the bioavailability
from inhalation exposure is expected to be relatively low because the compound is likely to partition to
available particulates. No data are available on the bioavailability of Chlorfenvinphos from water, soil, or
plant material. Chlorfenvinphos is adsorbed moderately to soil (Beynon et al. 1973; Edwards et al. 1971;
Racke 1992). Chlorfenvinphos is expected to have reduced bioavailability from soil and water, since the
part that remains adsorbed to soil or sediment may be only partially bioavailable. Additional data on the
bioavailability of Chlorfenvinphos from environmental media and the difference in bioavailability from
different media would be helpful in assessing the potential body burdens that may occur as a result of

exposure to environmental concentrations.

Food Chain Bioaccumulation. The only information on bioconcentration factors for Chlorfenvinphos
was derived from equations based on information on physical and chemical properties (see Section 5.3.1)
Estimated whole-body concentration factors calculated for Chlorfenvinphos were signiﬁcant, but relatively
low, ranging from 37 to 460 (Mackay 1982; Veith et al. 1979; Veith et al. 1980 in Bysshe 1990). No
measured BCFs for any aquatic organisms were found in the literature. Available data indicate that
Chlorfenvinphos applied to plant foliage is transported across the cuticular membrane (Bauer and Schonherr
1992). Chlorfenvinphos applied to the soil is accumulated in the roots, stem and leaves of plants (Ritcey et
al. 1991; Rouchaud et al. 1989b; Suett 1974, 1975b). No information was found on the biomagniﬁcation of
Chlorfenvinphos in aquatic or terrestrial food chains. These data would be helpful in assessing the potential

for human exposure as a result of consuming contaminated food.

Exposure Levels in Environmental Media. No data were located on the concentrations of
Chlorfenvinphos in ambient air or in occupational settings; therefore, no estimate of inhalation exposure to
Chlorfenvinphos can be obtained for the general population, or for any occupationally exposed groups. No
data on the concentration of Chlorfenvinphos in drinking water, surface water, or groundwater in the United
States were located in the literature. Monitoring data for surface waters are available from several Canadian
studies conducted in the Great Lakes region and British Columbia; however, monitoring results from these
Canadian studies may be inappropriate for estimating water residues in the United States, as
Chlorfenvinphos was never registered for agricultural use as a soil insecticide. Current monitoring data on
the concentrations of Chlorfenvinphos in ambient air, in drinking water, surface water, groundwater, and in
soil from the United States would be helpful. Many of the federal, regional, and state food studies

conducted from the late 19605 through the mid-19805 did not monitor Chlorfenvinphos concentrations in

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5. POTENTIAL FOR HUMAN EXPOSURE

foods (Comeliussen 1970; Duggan and Comeliussen 1972; Duggan et al. 1983; Gartell et al. 1986;
Gunderson 1988; Hundley et a1. 1988), despite the fact that chlorfenvinphos was most extensively used in
the United States during this period (see Section 4.3). Recent FDA monitoring studies on imported and
domestic foods have detected chlorfenvinphos residues; however, the foods in which chlorfenvinphos was
detected and the residue concentrations were not speciﬁed (FDA 1990, 1991, 1992, 1993). Additional
quantitative information on chlorfenvinphos concentrations in food and the estimated daily human intake of

chlorfenvinphos from foods would be helpful in assessing current exposure levels to this pesticide.

Reliable monitoring data for the concentrations of chlorfenvinphos in contaminated media at hazardous
waste sites are needed so that the information obtained on levels of chlorfenvinphos in the environment can
be used in combination with the resulting body burden of chlorfenvinphos to assess the potential risk of

adverse health effects in populations living in the vicinity of hazardous waste sites.

Exposure Levels in Humans. No data on chlorfenvinphos levels in various human tissues and body
ﬂuids of unexposed populations, populations near hazardous waste sites, or occupationally exposed groups
in the United States are available. Although chlorfenvinphos is a hydrophilic substance, it has not been
widely found in human tissues because of its relatively short half-life. However, in a recent study conducted
in the Federal Republic of Germany, chlorfenvinphos was found in some of the 41 specimens of cervical
mucus, follicular and sperm ﬂuids, and human milk that were examined. Chlorfenvinphos concentrations of
13.66, 1.69, 2.02, and 1.89 ug/kg were detected in 4 of the 11 samples of cervical mucus. Chlorfenvinphos
was also detected at concentrations of 0.42 ug/kg in l of the 10 sperm ﬂuid samples and 1 of the 10 human
milk samples, respectively (Wagner et a1. 1990). Additional data on the concentrations of chlorfenvinphos
and its metabolites in body tissues and ﬂuids are needed to estimate the extent of exposure to
chlorfenvinphos. This information is necessary for assessing the need to conduct health studies on these

populations.

Exposure Registries. No exposure registries for chlorfenvinphos were located. This substance is not
currently one of the compounds for which a subregistry has been established in the National Exposure
Registry. The substance will be considered in the future when chemical selection is made for subregistries
to be established. The information that is amassed in the National Exposure Registry facilitates the
epidemiological research needed to assess adverse health outcomes that may be related to exposure to this

substance.

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5. POTENTIAL FOR HUMAN EXPOSURE

5.7.2 Ongoing Studies

A search of the Federal Research in Progress database (FEDRIP 1995) indicated that no research studies are

in progress to ﬁll the data gaps discusses in Section 5.7.1.

CHLORFENVINPHOS 151

6. ANALYTICAL METHODS

The purpose of this chapter is to describe the analytical methods that are available for detecting, and/or
measuring, and/or monitoring chlorfenvinphos, its metabolites, and other biomarkers of exposure and effect to
chlorfenvinphos. The intent is not to provide an exhaustive list of analytical methods. Rather, the intention is
to identify well-established methods that are used as the standard methods of analysis. Many of the analytical
methods used for environmental samples are the methods approved by federal agencies and organizations such
as EPA and the National Institute for Occupational Safety and Health (NIOSH). Other methods presented in
this chapter are those that are approved by groups such as the Association of Official Analytical Chemists
(AOAC) and the American Public Health Association (APHA). Additionally, analytical methods are included
that modify previously used methods to obtain lower detection limits, and/or to improve accuracy and

precision.

6.1 BIOLOGICAL SAMPLES

Few methods are available for the determination of chlorfenvinphos in biological samples. Some methods
which may be applicable to biological media are summarized in Table 6-1. Most methods involve an
extraction step followed by one or more puriﬁcation and fractionation procedures, then analysis, usually by
gas chromatography (GC). Two detection methods are commonly used, nitrogen-phosphorus detection (NPD)
(Thier and Zeumer 1987; Wagner et al. 1990) and ﬂame photometric detection (FPD) (Ivey et al. 1973). Both
of these methods are speciﬁc for phosphorus-containing compounds and are very sensitive (low— to sub-ppb

levels). Recovery, where reported, is very good (>80%).

Several cautions should be noted. First, the stability of chlorfenvinphos in biological media is unknown. The
cold-storage stability (5 to _—20 °C) of chlorfenvinphos in crops and soil has been reported (Kawar et al. 1973).
However, enzymes present in biological media may reduce levels of organophosphate pesticides (Singh et al.
1986). Second, it is difficult to eliminate or reduce interfering compounds and maintain acceptable recovery of
chlorfenvinphos. Quality control procedures are recommended to assure that the method performance is
acceptable. Third, other organophosphorus pesticides may co-elute with chlorfenvinphos (Sasaki et al. 1987),
so a confirmatory method is recommended A few methods are available for measuring metabolites of
chlorfenvinphos. Chlorfenvinphos undergoes biotransformation to a variety of polar metabolites including
diethyl phosphate. Methods for measurement of dialkyl phosphates involve extraction from urine using an ion

exchange resin and derivatization prior to GC analysis (Bradway et al. 1981; Lores and Bradway 1977). The

Table 6-1. Analytical Methods for Determining Chlorfenvinphos in Biological Samples

 

 

Sample

detection Percent
Sample matrix Preparation method Analytical method limit recovery Reference
Human milk, Solvent extraction; clean-up on Florisil GC/NPD 0.040 ug/kg No data Wagner et al. 1990;
cervical fluid, Thier and Zeumer
sperm fluid 1987
Flat liver, muscle, Solvent extration; clean-up GC/thermionic 0.10—0.02 ppm 92 (muscle, Hladka et al. 1975
whole blood detection liver)
Rat liver, blood Solvent extraction TLC/enzyme- sub-nanogram 94—96 (blood); Vitorovié 1982

inhibition detection levels 84—89 (liver)

Cattle and chicken Fat, skin: isolation by filtration through GC/FPD 0.001 ppm 83—100 lvey et al. 1973

fat, skin, muscle,
liver, heart, kidney,

feces

celite; solvent partition

Tissues, feces: solvent extraction;
solvent partition

All: clean—up on sodium sulfate/silicic
acid column

GC = gas chromatography; FPD = flame photometric detection; NPD = nitrogen/phosphorus detection; TLC = thin layer chromatography

SGOHLBW TVOIJJOVNV '9

SOHdNIANEdHOWHO

ZSl

CHLORFENVINPHOS 153

6. ANALYTICAL METHODS

performance of the methods is variable; extraction is not always complete, and GC interferences often present

problems.

6.2 ENVIRONMENTAL SAMPLES

Representative analytical methods for determining chlorfenvinphos in environmental samples are summarized
in Table 6—2. Methods involve solvent extraction, puriﬁcation and fractionation, and gas chromatographic
analysis. Although most methods for measuring chlorfenvinphos in environmental samples involve GC
coupled with speciﬁc detectors (including MS), other methods are available, including high-performance
liquid chromatography (HPLC) with ultraviolet (UV) detection (Bagon and Warwick 1982; Schlett 1991), and
thin layer chromatography (TLC) (Roberts and Stoydin 1976).

Methods for determining chlorfenvinphos in aqueous samples include solvent extraction (EPA 1992b; Wan et
a1. 1994) or isolation using solid phase extraction (SPE) (Schlett 1991). Further clean-up of the extract may
not be required prior to analysis by HPLC (Schlett 1991) or GC (EPA 1992b; Wan et a1. 1994). For GC
analysis, conﬁrmation using a second column is recommended (EPA 1992b; Wan et al. 1994). Detection

limits are in the sub-ppb range; recovery was not reported.

Similarly, methods for determining chlorfenvinphos in sediments, solid wastes, and soils use a solvent
extraction procedure. A variety of clean-up procedures are used, including Florisil column puriﬁcation
(Beynon et al. 1966), solvent partition (Miles et al. 1979; Williams 1975b), and gel permeation
chromatography (Wan et al. 1994). Extracts are analyzed by GC with electron capture detection (ECD)
(Beynon et al. 1966; Edwards et al. 1968) or phosphorus-speciﬁc detectors (Wan et a1. 1994; Williams
1975b). Detection limits are in the low-ppb range (1—20); recovery is excellent (295%).

A chemiluminscence assay has been developed that should be a useful screening tool for environmental
media. It is not as sensitive as GC methods, but is inexpensive, fast, and may be used as a portable detection
system (Moris et al. 1995). Capillary electrophoresis is a relatively new technique for environmental
analysis. It is rapid, but does not yet achieve detection limits needed for environmental analysis (Sﬁsse and

Miiller 1995).

Methods for determining chlorfenvinphos on a variety of foods and crops have been reported. Most involve

solvent extraction followed by clean-up using adsorption column techniques (FDA 1979; Kadenczki et al.

Table 6-2. Analytical Methods for Determining Chlorfenvinphos in Environmental Samples

 

 

Sample
Sample detection Percent
matrix Preparation method Analytical method limit recovery Reference
Workplace air Collection on filters/Tenax HPLC/UV 2 ug/m3 a No datab Bagon and WanNick
traps, desorption 1982
Drinking and Filtration; solid-phase HPLC/UV z0.025 No data Schlett 1991
surface water extraction (SPE) ug/L
Drinking and On-line enrichment (SPE) Thermospray LC/MS 15 ng/L 52 Sennert et al. 1995
surface water
Waste water Solvent extraction; optional Capillary GC/FPD; confirmation 2 ng/L No data EPA 1992b
(EPA Method clean-up using GPC and/or on second GC column
1657) SPE
Water and Water: solvent extraction Dual column/dual detector: 0.01 pg/L 99 (water); Wan et al. 1994
sediments Sediments: solvent capillary GC/NPD, FPD (water); 1 97 (soil);
extraction; clean-up by GPC pg/kg (soil, 96 (sediment)
sediment)
Solid wastes Solvent extraction; optional Capillary GC/NPD No data No data (SW-846) EPA
(EPA Method cleanup using Florisil column 1992a
8141A) or GPC
Soil Samples are tumbled with GC/ECD 0.01 ppm 95 Beynon et al. 1966
solvent; optional clean-up on
Florisil column
Soil Ultrasonic extraction; solvent GC No data 95 ave. Miles at al. 1979
partition
Soil Solvent extraction GC/ECD <0.02 ppm 95—1 15 Edwards et al. 1968
Pesticide Solvent extraction GC/FID Not 92—97 for mg Paterson 1970
formulations applicable quantities

SGOHlHW "IVOIUCIVNV '9

SOHdNIANBdHO'IHO

79L

Table 6-2. Analytical Methods for Determining Chlorfenvinphos in Environmental Samples (continued)

 

 

Sample
Sample detection Percent
matrix Preparation method Analytical method limit recovery Reference
Animal tissue, Solvent extraction; clean-up GC/thermoionic detection 0.001 ppm 73—87 (beef FDA 1979
milk on Florisil column ' (milk); fat); 84-1 05
0.005 ppm (milk)
(tissue)
Fruits and Solvent extraction Capillary GC/FPD; confirmation 10 pg/kg 90.5 Agiiera et al. 1993
vegetables by capillary GC/MS ~
Vegetables Solvent extraction and CO 0.02 mg/kg 85—97 ave. Frank et al. 1990
partition
Foods Solvent extraction; column capillary GC/FPD; confirmation :9 ppb 89—97 (trans Leoni et al. 1992
clean-up by GC/MS or GC/FPD (trans isomer);
isomer), :7 72—1 01 (cis
ppb (cis isomer)
isomer)
Fruits and Prepared food is adsorbed Capillary GC/PFD‘ or NPD 0.01 mg/kg -- 80—89 Kadenczki et al.
vegetables onto Florisil, extracted with 1992
solvent
Fruit (apples) Soxhlet extraction Capillary GC/NPD 0.099 98 Barrio et al. 1994
pg/mL
Crops (lipid- Solvent extraction; cleanup,‘ Capillary GC/FPD 1 ppb j 79 Nakamura et al.
containing) by solvent partitioning 1994
Milk Solvent extraction; clean-up GC/FPD or thermoionic, 20.01 81—96 Stijve 1984
by solvent partitioning detector; confirmation by TLC mg/kg
Pharmaceutic Disolution in solvent, Capillary GC/ELCD; <0.05 97-110 (all Heikes and Craun
als filtration; GPC clean-up confirmation by second column mg/kg ' pesticides) 1992

or MS

SGOHlEW "IVOILA'IVNV ‘9

SOHdNIANSdHOTHO

SSL

Table 6-2. Analytical Methods for Determining Chlorfenvinphos in Environmental Samples (continued)

 

 

Sample
Sample detection Percent
matrix Preparation method Analytical method limit recovery Reference
Cosmetics Solvent extraction utilizing GC/FPD 30.2 mg/kg 98-108 Specht 1990
adsorption columns; GPC
clean-up

 

6 Based on instrumental detection limits; value will vary with volume of air sampled.
b Desorption efficiency from Tenax is 100%.

GO = gas chromatography; ELCD = electrolytic conductivity detection; FlD = flame ionization detection; FPD = flame photometric detection;
GPC = gel permeation chromatography; HPLC = high performance liquid chromatography; LC = liquid chromatography; MS = mass
spectrometry; NPD = nitrogen/phosphorous detection; SPE = solid-phase extraction; TLC = thin layer chromatography; UV = visible/ultraviolet
detection

SGOHLBW WVOIM'IVNV '9

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99L

CHLORFENVINPHOS - 157

6. ANALYTICAL METHODS

1992; Leoni et al. 1992) or solvent partitioning (Frank et al. 1990; Stijve 1984). Chlorfenvinphos is
determined by GC with phosphorus-speciﬁc detectors (ﬂame photometric [FPD]; and nitrogen-phosphorus
[NPD]) (Agiiera et al. 1993; Leoni et al. 1992; Kadenczki et al. 1992; Stijve 1984). Chlorfenvinphos in
sample extracts is conﬁrmed using GC with MS (Agiiera et al. 1993; Leoni et al. 1992) or TLC (Stijve 1984).

Detection limits are in the low-ppb range; recovery is acceptable (>80%).

A summary of methods for determination of Chlorfenvinphos environmental degradation products is shown in
Table 6—3. The breakdown products 2,4-dichloroacetophenone, l-(2,4—dichlorophenyl)-l-ethan-l-ol, and
2,4—dichlorophenacyl chloride can be determined in soil and earthworms using solvent extraction and
GC/ECD (Edwards et al. 1968). Detection limits are approximately 0.05 ppm and recovery is excellent
(95—115%). The hydrolysis product 2,2',4'-trichloroacetophenone has been determined in corn extracts using
GC/ECD and GC/FPD. Detection limits are 0.02 ppm (ECD) and 0.002 (FPD), and recovery is excellent
(Beroza and Bowman 1966). Free and conjugated degradation products have been determined in soils and
crops by GC/ECD (Beynon et al. 1968). Free products are extracted with solvent; conjugated products are
hydrolyzed with sulfuric acid. Recovery is acceptable (80—100% for soils, 50—90% for crops); detection limits
range from 0.01 to 0.2 ppm for soils (varies with compound) and from 0.005 to 0.05 ppm for crops.
Degradation products, including soil-bound (polar) compounds, were determined by GC/ECD of soil extracts.
The polar compounds were methylated prior to GC analysis. Recovery is acceptable (65—105%); detection

limits are approximately 0.02 ppm.

6.3 ADEQUACY OF THE DATABASE

Section 104(i)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with the
Administrator of EPA and agencies and programs of the Public Health Service) to assess whether adequate
information on the health effects of chlorfenvinphos is available. Where adequate information is not
available, ATSDR, in conjunction with the NTP, is required to assure the initiation of a program of research
designed to determine the health effects (and techniques for developing methods to determine such health

effects) of chlorfenvinphos.

The following categories of possible data needs have been identiﬁed by a joint team of scientists from
ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would reduce

the uncertainties of human health assessment. This deﬁnition should not be interpreted to mean that

Table 6-3. Analytical Methods for Determining Biomarkers for Chlorfenvinphos

 

 

Sample
detection Percent
Sample matrix Preparation method Analytical method limit recovery Reference
Acetylcholinesterase No data No data Zwiener and Ginsburg 1988
in erythrocytes
Free tryptophan in Spectrophotometry No data No data Dudka and Szczepaniak 1993
plasma
Urine levels of Solvent extraction; GC/FPD 0.002 ppm 97% Hunter et al. 1972
desethyl methyation
Chlorfenvinphos
metabolite
Blood levels of Headspace GC/FID;GC/ No data No data Klys 1985
Chlorfenvinphos thermionic detection

 

GC = gas chromatography; FlD = flame ionization detection

SCIOHJBW 'lVOliA'lVNV '9

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99L

CHLORFENVINPHOS 159

6. ANALYTICAL METHODS

all data needs discussed in this section must be ﬁlled. In the future, the identiﬁed data needs will be evaluated

and prioritized, and a substance-speciﬁc research agenda will be proposed.

6.3.1 Identification of Data Needs

Methods for Determining Biomarkers of Exposure and Effect. Few methods are available for
measuring exposure to chlorfenvinphos. These are summarized in Table 6-4. Blood levels of
chlorfenvinphos were determined in a case of human poisoning (Klys 1985); however, sensitivity and
reliability were not reported. Chlorfenvinphos is metabolized in the body to esters of phosphoric acid, and
methods are available for determining urine levels of these metabolites (Bradway et a1. 1981; Lores and
Bradway 1977). However, these phosphate compounds are not speciﬁc for chlorfenvinphos, but are common
to all organophosphate pesticides. Decreased levels of acetylcholinesterase in plasma or erythrocytes have
been reported to be indicative of chlorfenvinphos poisoning (Zwiener and Ginsberg 1988). Again, this assay is
not speciﬁc for chlorfenvinphos. An increase in the level of tryptophan aﬁer exposure to chlorfenvinphos has
been reported in rats (Dudka and Szczepaniak 1993). Good precision and accuracy were reported for the
method; however, speciﬁc values were not given. It is not known if the available analytical methods will be
sensitive enough to measure chlorfenvinphos levels in body tissues and ﬂuids of the background population.
Since chlorfenvinphos is apparently not produced or imported into this country, it should not be necessary to
determine these background levels. It would be helpﬁil to have methods which would perrnit assessment of

the severity of exposure of a highly exposed population.

Methods for Determining Parent Compounds and Degradation Products in Environmental
Media. Methods are available for determining chlorfenvinphos in water, soils and sediments, and foods
(Table 6-2). A summary of available methods for determining the environmental degradation products of
chlorfenvinphos in soils (Beynon et a1. 1968; Rouchaud et a1. 1988), crops (Beynon et a1. 1968; Beroza and
Bowman 1966), and worms (Edwards et a1. 1968) is shown in Table 6-3. Sensitive methods (sub-ppb levels)
are available for determining chlorfenvinphos in water; however, better information is needed regarding the
recovery and precision of the methods (EPA 1992b; Schlett 1991; Wan et a1. 1994). Methods for determining
chlorfenvinphos in soils and sediments are sensitive (low ppb levels) and good recovery (295%) has been
reported (Beynon et a1. 1966; Edwards et al. 1968; Wan et a1. 1994). Methods for measuring chlorfenvinphos
in some foods are sensitive (low ppb levels) with acceptable recovery (72—105%) (Agiiera et a1. 1993; FDA
1979; Frank et al. 1990; Kadenczki et a1. 1992; Leoni et al. 1992; Stijve 1984). Available methods have

Table 6-4. Analytical Methods for Determining Environmental Degradation Products of Chlorfenvinphos

 

 

Sample
detection Percent
Sample matrix Preparation method Analytical method limit recovery Reference
Soil, worms Solvent extraction GC/ECD 20.05 ppm No data Edwards et al.
1968
Soil Solvent extraction; clean-up on alumina GC/ECD 0.01—0.2 ppm 80—100 Beynon et al.
1968
Crops Maceration with solvent; clean-up on GC/ECD 0.005—0.15 50—90 Beynon et al.
alumina. Hydrolysis of conjugates are ppm 1968
hydrolyzed with sulfuric acid/heat;
solvent extraction; clean-up on alumina
Soil Solvent extraction; solvent partition; GC/ECD; ~0.02 mg/kg 65—105 Rouchaud et al.
clean-up by TLC. confirmation by 1988
Soil bound compounds: extraction at GC/MS
basic pH; pH adjustment and solvent
extraction; clean-up by TLC; methylation
Corn Sample is blended with solvent GC/ECD; GC/FPD 0.02 ppm 94—101 Beroza and
(ECD); Bowman 1966
0.002 ppm
(FPD)

 

G0 = gas chromatography; ECD = electron capture detection; FPD = flame photometric detection; MS = mass spectrometry; TLC = thin layer

chromatography

SGOHlHW 'IVOIM'IVNV '9

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CHLORFENVINPHOS 161

6. ANALYTICAL METHODS

sufficient sensitivity for measuring chlorfenvinphos in water, soils and sediments, and foods at background
levels. Information on the precision of these methods would be helpful. No methods are available for
measuring chlorfenvinphos in ambient air. Given its low volatility, chlorfenvinphos is not likely to be detected
in ambient air. Methods are available for monitoring occupational exposure to chlorfenvinphos (Bagon and
Warwick 1982). Research investigating the relationship between levels of chlorfenvinphos measured in water,

soils and sediments, and food and health effects would be helpful.

6.3.2 Ongoing Studies

No ongoing studies involving chlorfenvinphos were located.

 

CHLORFENVINPHOS 163

7. REGULATIONS AND ADVISORIES

The national regulations and guidelines regarding chlorfenvinphos in air, food, and other media are
summarized in Table 7-1. No international or state regulations were identiﬁed for chlorfenvinphos, nor were

regulations and guidelines identiﬁed for chlorfenvinphos in air or water.

ATSDR has not derived MRLs for inhalation exposure for any duration of exposure.

An acute oral MRL of 0.002 mg/kg/day for chlorfenvinphos has been developed from a LOAEL of
2.4 mg/kg/day, based on adverse neurological effects in rats (Barna and Simon 1973).

An intermediate oral MRL of 0.002 mg/kg/day for chlorfenvinphos has been developed from a LOAEL of
1.5 mg/kg/day, based on adverse immunological/lymphoreticular effects in mice (Kowalczyk-Bronisz et al.

1992).

A chronic oral MRL of 0.0007 mg/kg/day for chlorfenvinphos has been developed from a LOAEL of
0.7 mg/kg/day, based on adverse neurological effects in rats (Ambrose et al. 1970).

No reference concentration or dose exists for chlorfenvinphos, and no IARC or EPA cancer classiﬁcation

exists.

Chlorfenvinphos is one of the chemicals regulated under "The Emergency Planning and Community Right-to-
Know Act of 1986" (EPCRA) (EPA 1987). Section 313 of Title III of EPCRA requires owners and operators
of certain facilities that manufacture, import, process, or otherwise use the chemicals on this list to report

annually their release of those chemicals to any environmental media.
An Occupational Safety and Health Administration (OSHA) permissible exposure limit (PEL) for
chlorfenvinphos does not exist, nor is it regulated by the Clean Water Effluent Guidelines contained in Title

40, Sections 400-475, of the Code of Federal Regulations.

Tolerances for chlorfenvinphos in agricultural products have been established (EPA 1982b).

CHLORFENVINPHOS

7. REGULATIONS AND ADVISORIES

164

Table 7-1. Regulations and Guidelines Applicable to Chlorfenvinphos

 

 

ﬂency Description Information References
INTERNATIONAL
IARC Carcinogenic classification None
NATIONAL
Regulations:
a. Food
FDA FDA action level None
EPA OPTS Tolerances for Related Pesticide Yes 40 CFR 180.3, EPA 1976
Chemicals
Tolerance Range for Agriculture 0.005-02 ppm 40 CFR 180.322, EPA 1982b
Products
b. Other
EPA Carcinogen Classification None IRIS 1995
Reference Dose (RfD) None IRIS 1995
Reference Concentration (RfC) None IRIS 1995
EPA OERR Threshold Planning Quantity 500 lb. 40 CFR 355, App A, EPA 1987
Reportable Quantity 500 lb. 40 CFR 355, App A, EPA 1996
App. B - National Priorities List Yes 40 CFR 300, EPA 1992d

 

EPA = Environmental Protection Agency; FDA = Food and Drug Administration; IARC = International Agency for
Research on Cancer; IRIS = Integrated Risk Information System; LDR = Land Disposal Restrictions; NIOSH =
National Institute for Occupational Safety and Health; OERR = Office of Emergency and Remedial Response;
OSW = Office of Solid Wastes; REL = Recommended Exposure Limit; TWA = time-weighted average

CHLORFENVINPHOS 165

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*Endo G, Horiguchi S, Kiyota I, et al. 1988. Serum cholinesterase and erythrocyte acetylcholinesterase
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*EPA. 1994. Response to Freedom of Information (FOI) request for chlofrenvinphos.

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Protection Agency. Washington D. C.

*EPA. 1996. National Oil and Hazardous Substances Contigency Plan; National Priorities List Update.
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*Farm Chemicals Handbook. 1984. Chlorfenvinphos. Farm Chemicals Handbook, Pesticide Dictionary,
1984. Willoughby, OH: Meister Publishing Co., C50-C51.

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*Wan MT, Szeto S, Price P. 1994. Organophosphorus insecticide residues in farm ditches of the Lower
Fraser Valley of British Columbia. J Environ Sci Health, Part B: Pestic Food Contam Agric 29(5):917-949.

*Wiaderkiewicz R, Walter Z, Reimschussel W. 1986. Sites of methylation of DNA bases by the action of
organophosphorus insecticides in vitro. Acta Biochim Pol 33(2):73-85.

*Williams JH. 1975a. Persistence of chlorfenvinphos in soils. Pestic Sci 6(5):501-509.

*Williams JH. 1975b. The role of organic matter in pesticide behavior. Report - Welsh Soils Discussion
Group 16:107-119.

*Williams MW, Fuyat HN, Fitzhugh CG. 1959. The subacute toxicity of four organic phosphates to dogs.
Toxicol Appl Pharmacol 1:1-7.

*Williams PL, Burson JL, eds. 1985. Industrial toxicology: Safety and health applications in the workplace.
New York, NY: Van Nostrand Reinhold Company.

*Woo OF. 1990. Organophosphates. In: Olsen KR, ed. Poisoning and drug overdose. lst ed. San
Francisco Bay Area Regional Poison Control Center. Norwalk, CT: Appleton and Lange, 225-229, 394.

*Worthing CR. 1987. Chlorfenvinphos. The Pesticide Manual 107.

*Worthing CR, ed. 1983. Chlorfenvinphos. In: The Pesticide Manual, A Wbrld Compendium, Seventh
edition. The British Crop Protection Council.

*Wysocka—Paruszewska BA, Osicka A, Brzezinski J. 1980. An evaluation of the toxicity Of thiuram in
combination with other pesticides. Arch Toxicol, Suppl. 4:449-451.

CHLOHFENWNPHOS 180

& REFERENCES

*Wysocki J, Kalina Z, Owczarzy I. 1987. Effect of organophosphoric pesticides on the behaviour of
NBT-Dye reduction and E Rosette Formation Tests in Human Blood. Int Arch Occup Environ Health
59:63-71.

*Yess NJ, Houston MG, Gunderson EL. 1991a. Food and Drug Administration pesticide residue monitoring
of foods: 1978-1982. J Assoc Off Anal Chem 74(2):265-272.

*Yess NJ, Houston MG, Gunderson EL. 1991b. Food and Drug Administration pesticide residue monitoring
of foods: 1983-1986. J Assoc Off Anal Chem 74(2):273-280.

Yoshikawa H, Yoshida M, Hara 1. 1990. Electroretinographic changes induced by organophosphorus
pesticides in rats. J Toxicol Sci 15(2):87-95.

*Zwiener RJ, Ginsburg CM. 1988. Organophosphate and carbamate poisoning in infants and children.
Pediatrics 8(1):121-126.

CHLORFENVINPHOS 181

9. GLOSSARY

Acute Exposure—Exposure to a chemical for a duration of 14 days or less, as speciﬁed in the Toxicological
Proﬁles.

Adsorption Coefﬁcient (Km)——-The ratio of the amount of a chemical adsorbed per unit weight of organic
carbon in the soil or sediment to the concentration of the chemical in solution at equilibrium.

Adsorption Ratio (Kd)—The amount of a chemical adsorbed by a sediment or soil (i.e., the solid phase)
divided by the amount of chemical in the solution phase, which is in equilibrium with the solid phase, at a
ﬁxed solid/solution ratio. It is generally expressed in micrograms of chemical sorbed per gram of soil or
sediment.

Bioconcentration Factor (BCF)—The quotient of the concentration of a chemical in aquatic organisms at a
speciﬁc time or during a discrete time period of exposure divided by the concentration in the surrounding
water at the same time or during the same period.

Cancer Effect Level (CEL)—The lowest dose of chemical in a study, or group of studies, that produces
signiﬁcant increases in the incidence of cancer (or tumors) between the exposed population and its appropriate
control.

Carcinogen—A chemical capable of inducing cancer.
Ceiling Value—A concentration of a substance that should not be exceeded, even instantaneously.
Chronic Exposure—Exposure to a chemical for 365 days or more, as speciﬁed in the ToxicolOgical Proﬁles.

Developmental Toxicity—The occurrence of adverse effects on the developing organism that may result
from exposure to a chemical prior to conception (either parent), during prenatal development, or postnatally to
the time of sexual maturation. Adverse developmental effects may be detected at any point in the life span of
the organism.

Embryotoxicity and Fetotoxicity—Any toxic effect on the conceptus as a result of prenatal exposure to a
chemical; the distinguishing feature between the two terms is the stage of development during which the insult
occurred. The terms, as used here, include malformations and variations, altered growth, and in utero death.

EPA Health Advisory—An estimate of acceptable drinking water levels for a chemical substance based on
health effects information. A health advisory is not a legally enforceable federal standard, but serves as
technical guidance to assist federal, state, and local ofﬁcials.

Immediately Dangerous to Life or Health (IDLH)—The maximum environmental concentration of a
contaminant from which one could escape within 30 min without any escape-impairing symptoms or
irreversible health effects.

Intermediate Exposure—Exposure to a chemical for a duration of 15—364 days, as speciﬁed in the
Toxicological Proﬁles.

CHLORFENWNPHOS 182

9 GLOSSARY

Immunologic Toxicity—The occurrence of adverse effects on the immune system that may result from
exposure to environmental agents such as chemicals.

In Vitro—Isolated from the living organism and artiﬁcially maintained, as in a test tube.
In Viva—Occurring within the living organism.

Lethal Concentrationm) (LCLo)—The lowest concentration of a chemical in air which has been reported to
have caused death in humans or animals.

Lethal Concentration” (LC50)—A calculated concentration of a chemical in air to which exposure for a
speciﬁc length of time is expected to cause death in 50% of a deﬁned experimental animal population.

Lethal Dose“), (LDL0)—The lowest dose of a chemical introduced by a route other than inhalation that is
expected to have caused death in humans or animals.

Lethal Dosem) (LDso)—The dose of a chemical which has been calculated to cause death in 50% of a deﬁned
experimental animal population.

Lethal Timem) (LT50)—A calculated period of time within which a speciﬁc concentration of a chemical is
expected to cause death in 50% of a deﬁned experimental animal population.

Lowest-Observed-Adverse-Effect Level (LOAEL)——The lowest dose of chemical in a study, or group of
studies, that produces statistically or biologically signiﬁcant increases in frequency or severity of adverse
effects between the exposed population and its appropriate control.

Malformations—Permanent structural changes that may adversely affect survival, development, or function.

Minimal Risk Level—An estimate of daily human exposure to a dose of a chemical that is likely to be
without an appreciable risk of adverse noncancerous effects over a speciﬁed duration of exposure.

Mutagen—A substance that causes mutations. A mutation is a change in the genetic material in a body cell.
Mutations can lead to birth defects, miscarriages, or cancer.

Neurotoxicity—The occurrence of adverse effects on the nervous system following exposure to chemical.

No—Observed-Adverse—Effect Level (N OAEL)——The dose of chemical at which there were no statistically or
biologically signiﬁcant increases in frequency or severity of adverse effects seen between the exposed
population and its appropriate control. Effects may be produced at this dose, but they are not considered to be
adverse.

Octanol-Water Partition Coefficient (Kow)—The equilibrium ratio of the concentrations of a chemical in
n-octanol and water, in dilute solution.

Permissible Exposure Limit (PEL)—An allowable exposure level in workplace air averaged over an 8-hour
shift.

q1*—The upper-bound estimate of the low-dose slope of the dose-response curve as determined by the
multistage procedure. The q1* can be used to calculate an estimate of carcinogenic potency, the incremental
excess cancer risk per unit of exposure (usually ug/L for water, mg/kg/day for food, and ug/m3 for air).

CHLORFENVINPHOS 183

9. GLOSSARY

Reference Dose (Rﬂ))—An estimate (with uncertainty spanning perhaps an order of magnitude) of the daily
exposure of the human population to a potential hazard that is likely to be without risk of deleterious effects
during a lifetime. The Rﬂ) is operationally derived from the NOAEL (from animal and human studies) by a
consistent application of uncertainty factors that reﬂect various types of data used to estimate Rst and an
additional modifying factor, which is based on a professional judgment of the entire database on the chemical.
The RtDs are not applicable to nonthreshold effects such as cancer.

Reportable Quantity (RQ)——The quantity of a hazardous substance that is considered reportable under
CERCLA. Reportable quantities are (1) 1 pound or greater or (2) for selected substances, an amount
established by regulation either under CERCLA or under Sect. 31 1 of the Clean Water Act. Quantities are
measured over a 24-hour period.

Reproductive Toxicity—The occurrence of adverse effects on the reproductive system that may result from
exposure to a chemical. The toxicity may be directed to the reproductive organs and/or the related endocrine
system. The manifestation of such toxicity may be noted as alterations in sexual behavior, fertility, pregnancy
outcomes, or modiﬁcations in other functions that are dependent on the integrity of this system.

Short-Term Exposure Limit (STEL)—The maximum concentration to which workers can be exposed for up
to 15 min continually. No more than four excursions are allowed per day, and there must be at least 60 min
between exposure periods. The daily TLV-TWA may not be exceeded.

Target Organ Toxicity—This term covers a broad range of adverse effects on target organs or physiological
systems (e.g., renal, cardiovascular) extending from those arising through a single limited exposure to those
assumed over a lifetime of exposure to a chemical.

Teratogen—A chemical that causes structural defects that affect the development of an organism.

Threshold Limit Value (TLV)—A concentration of a substance to which most workers can be exposed
without adverse effect. The TLV may be expressed as a TWA, as a STEL, or as a CL.

Time-Weighted Average (TWA)——An allowable exposure concentration averaged over a normal 8-hour
workday or 40-hour workweek.

Toxic Dose ('I‘D50)—A calculated dose of a chemical, introduced by a route other than inhalation, which is
expected to cause a speciﬁc toxic effect in 50% of a deﬁned experimental animal population.

Uncertainty Factor (UF)—A factor used in operationally deriving the RfD from experimental data. UFs are
intended to account for (1) the variation in sensitivity among the members of the human population, (2) the
uncertainty in extrapolating animal data to the case of human, (3) the uncertainty in extrapolating from data
obtained in a study that is of less than lifetime exposure, and (4) the uncertainty in using LOAEL data rather
than NOAEL data. Usually each of these factors is set equal to 10.

 

CHLORFENVINPHOS A4

APPENDIX A

ATSDR MINIMAL RISK LEVEL

The Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA) [42 U.S.C. 9601
et seq.], as amended by the Superfund Amendments and Reauthorization Act (SARA) [Pub. L. 99—499],
requires that the Agency for Toxic Substances and Disease Registry (ATSDR) develop jointly with the US.
Environmental Protection Agency (EPA), in order of priority, a list of hazardous substances most commonly
found at facilities on the CERCLA National Priorities List (NPL); prepare toxicological proﬁles for each
substance included on the priority list of hazardous substances; and assure the initiation of a research program

to ﬁll identiﬁed data needs associated with the substances.

The toxicological proﬁles include an examination, summary, and interpretation of available toxicological
information and epidemiologic evaluations of a hazardous substance. During the development of
toxicological proﬁles, Minimal Risk Levels (MRLs) are derived when reliable and sufﬁcient data exist to
identify the target organ(s) of effect or the most sensitive health effect(s) for a speciﬁc duration for a given
route of exposure. An MRL is an estimate of the daily human exposure to a hazardous substance that is likely
to be without appreciable risk of adverse noncancer health effects over a speciﬁed duration of exposure.
MRLs are based on noncancer health effects only and are not based on a consideration of cancer effects.
These substance-speciﬁc estimates, which are intended to serve as screening levels, are used by ATSDR
health assessors to identify contaminants and potential health effects that may be of concern at hazardous

waste sites. It is important to note that MRLs are not intended to deﬁne clean—up or action levels.

MRLs are derived for hazardous substances using the no—observed-adverse-effect level/uncertainty factor
approach. They are below levels that might cause adverse health effects in the people most sensitive to such
chemical-induced effects. MRLs are derived for acute (1—14 days), intermediate (15—364 days), and chronic
(365 days and longer) durations and for the oral and inhalation routes of exposure. Currently, MRLs for the
dermal route of exposure are not derived because ATSDR has not yet identiﬁed a method suitable for this
route of exposure. MRLs are generally based on the most sensitive chemical-induced end point considered to
be of relevance to humans. Serious health effects (such as irreparable damage to the liver or kidneys, or birth
defects) are not used as a basis for establishing MRLs. Exposure to a level above the MRL does not mean that

adverse health effects will occur.

CHLORFENVINPHOS A.2

APPENDIX A

MRLs are intended only to serve as a screening tool to help public health professionals decide where to look
more closely. They may also be viewed as a mechanism to identify those hazardous waste sites that are not
expected to cause adverse health effects. Most MRLs contain a degree of uncertainty because of the lack of
precise toxicological information on the people who might be most sensitive (e.g., infants, elderly,
nutritionally or immunologically compromised) to the effects of hazardous substances. ATSDR uses a
conservative (i.e., protective) approach to address this uncertainty consistent with the public health principle of
prevention. Although human data are preferred, MRLs often must be based on animal studies because
relevant human studies are lacking. In the absence of evidence to the contrary, ATSDR assumes that humans
are more sensitive to the effects of hazardous substance than animals and that certain persons may be
particularly sensitive. Thus, the resulting MRL may be as much as a hundredfold below levels that have been

shown to be nontoxic in laboratory animals.

Proposed MRLs undergo a rigorous review process: Health Effects/MRL Workgroup reviews within the
Division of Toxicology, expert panel peer reviews, and agencywide MRL Workgroup reviews, with
participation ﬁom other federal agencies and comments from the public. They are subject to change as new
information becomes available concomitant with updating the toxicological proﬁles. Thus, MRLs in the most
recent toxicological proﬁles supersede previously published levels. For additional information regarding
MRLs, please contact the Division of Toxicology, Agency for Toxic Substances and Disease Registry, 1600
Clifton Road, Mailstop E-29, Atlanta, Georgia 30333.

CHLORFENVINPHOS A-3

MINIMAL RISK LEVEL (MRL) WORKSHEET

Chemical name: Chlorfenvinphos

CAS number: 470-90-6

Date: August 21, 1996

Proﬁle status: Final

Route: [] Inhalation [x] Oral

Duration: [x] Acute []Intermediate [] Chronic
Key to ﬁgure: 13

Species: Rat

MRL: 0.002 [x] mg/kg/day [] ppm [] mg/m3

Reference: Bama J, Simon G. 1973. The effect of chlorfenvinphos insecticide in small often repeated dose.
Cereal Research Commun. Vol.1, No. 3: 33—44. -

Exmrimental desigp (human study details or strain, number of animals per exposure/control group, sex, dose
administration details):

Two groups (SS/group) of adult female albino (Wistar) rats weighing 208 g were orally administered Birlane®
(chlorfenvinphos) at dose of 0 or 2.4 mg/kg/day in the diet for 10 days. The study was designed to investigate
the effects of oral chlorfenvinphos on body weightincrease, the gastrointestinal absorption of glucose, Na“,

and Ca2+, as well as he effects of oral chlorfenvinphos on plasma and erythrocyte cholinesterase activity levels.

Effects noted in study and corresponding dpses:

Plasma cholinesterase activity was inhibited by 52% while erythrocyte cholinesterase activity level was
inhibited by 30% at a dose of 2.4 mg/kg/day (the only dose tested). Gastrointestinal (g.i.) absorption of
glucose was increased by 30% over control values while Na+ absorption was decreased by 32% below control
values. Gastrointestinal absorption of Ca2+ and body weight increases were unaffected by chlorfenvinphos
exposure. These changes in the gastrointestinal absorption of glucose and Na+ were not considered
statistically signiﬁcant (P>0.05) by the investigators.

Dose endppint used for MRL derivation:

[] NOAEL [x] LOAEL

2.4 mg/kg/day; 30% decrease in erythrocyte cholinesterase activity in female rats.
Uncertainty factors used in MRL derivation:

[] 1 [] 3 [x] 10 (for use of a LOAEL)

[] 1 [] 3 [x] 10 (for extrapolation from animals to humans)

[] 1 [] 3 [x] 10 (for human variability)

Was a conversion factor used from ppm in food or water to a mgzpody weight dosg?
If so, explain: No, the doses used are author-provided.

CHLORFENVINPHOS A-4

APPENDIX A

If an inhalation study in animals, list conversion factors used in determining human equivalent dose: Not

applicable.

Was a conversion used from intermittent to continuous exposure?
Not applicable.

Other additional studies or mrtinent information that lend support to this MRL:

Neurological effects, mediated by cholinesterase inhibition, is the principal and most sensitive toxicological
consequence of acute-duration exposure to chlorfenvinphos in humans (Cupp et al. 1975; Pach et al. 1987).
Chlorfenvinphos also inhibits noradrenaline in the central nervous system (Brzezinski 1978). Human subjects,
exposed to large acute doses of chlorfenvinphos, exhibited severe cholinergic signs. These cholinergic signs
were relieved by the administration of atropine and/or pralidoxime, indicating cholinesterase inhibition
etiology (Cupp et al. 1975; Pach et al. 1987). In rats, relatively moderate to low doses (2.4—30 mg/kg) of oral
chlorfenvinphos signiﬁcantly inhibited cholinesterase activities in a number of tissue including the brain,
erythrocyte, and plasma (Osumi et al. 1975 ; Osicka—Koprowska et al. 1984; Puzynska 1984). An acute-
duration oral study also found alterations in noradrenaline level in rat brain following exposure to
chlorfenvinphos. A chlorfenvinphos dose of 13 mg/kg decreased noradrenaline levels in rat brains by 20%, as
compared to control rats. According to the investigators, chlorfenvinphos accelerated the rate of NA
disappearance from the brain (Brzezinski 1978).

Therefore, it is appropriate to base the acute oral MRL for chlorfenvinphos on cholinesterase inhibition.

It should be noted that a study by Osumi et al. (1975) which determined a NOAEL of 1 mg/kg/day and a
LOAEL of 2 mg/kg/day for 38% inhibition of brain cholinesterase in rats was not used to calculate an acute
oral MRL because of the gavage (oral) route of administration of the test substance which was deemed less
appropriate by the ATSDR MRL Workgroup. An oral feeding study is preferred by the ATSDR MRL
Workgroup.

Agency Contact (Chemical Manager): Alfred Dorsey.

CHLOHFENVINPHOS A-5

APPENDIX A

MINIMAL RISK LEVEL (MRL) WORKSHEET

Chemical name: Chlorfenvinphos

CAS number: 470-90-6

Date: August 21, 1996

Proﬁle status: Final

Route: [] Inhalation [x] Oral

Duration: [] Acute [x]Intermediate [] Chronic
Key to ﬁgure: 23

Species: Mouse

MRL: 0.002 [x] mg/kg/day [] ppm [1 mg/m3

Reference: Kowalczyk—Bronisz S, Gieldanowski J, Bubak , Kotz J. 1992. Studies on the effect of pesticide
chlorfenvinfos on mouse immune system. Arc Immunol Ther Exp (Warsz) 40(5-6):283-289.

Exmrimental design (human study details or strain, number of animals per exposure/control group, sex, dose
administration details):

The authors investigated the effect of chlorfenvinphos on mouse immune system. In the study, male and
female inbred C57BL/6 mice and (C57BL/6 x DBA/2)F1 (BDFl/Iiw) hybrids mice (6-8 weeks old) were
orally dosed with chlorfenvinphos (suspended in 1% methylcellulose solution) and evaluated for 5 days for the
effect of chlorfenvinphos exposure on the mouse immune system. The rats were exposed to oral
chlorfenvinphos doses of 0, 1.5, 3, and 6 mg/kg (0, 1/ 100, 1/50, and 1/25 LDSO) daily for 3 months; control
group was given 1% methylcellulose. Then exposed and control mice were immunized by intraperitoneal
injections of 0.2 mL 10% SRBC. IgM-PFC (plaque-forming or antibody-producing cells) number in spleen
cell suspension was tested on day 4 after immunization and the procedure repeated 3 weeks after the exposure
to chlorfenvinphos had been ceased. Exposed and control groups were subjected to immunological tests and
hematological examinations. Lymphatic organs were histologically examined.

Effects noted in study and corresponding doses:

A dose-related decrease in number of hemolysin producing cells was observed: plaque-fomiing cells (PFC)
were 58% at the 6 mg/kg dose group and 85% at the 3 mg/kg dose level as compared to control values.
Chlorfenvinphos treatment also caused reduction in E rosettes forming cell number by 30% at the 6 mg/kg
dose level and by 25% at the 3 mg/kg dose level. Increases in Interlukin-l (ll—1) activity and DTH reaction
were observed 24 hours after challenge. Spleen colonies were stimulated as evidenced by the increase of
endogenous spleen colonies and exogenous spleen colonies (CFU-S) increased 190% at the 1.48 mg/kg dose
level and 137% at the 6 mg/kg dose level, and 162% at 1.5 mg/kg dose level and 70% at the 6 mg/kg dose
level, respectively). When the IgM PFC number was tested 3 weeks latter, after the exposure to
chlorfenvinphos in the small dose (1.5 mg/kg), and increase (about 40%) in plaques number was observed.
There was a 50% reduction in thymus weight at the 1.5 mg/kg dose level as compared to controls as well as
signiﬁcant involution of thymus was noted.

Dose endpoint used for MRL derivation:

[] NOAEL [x] LOAEL

CHLOHFENVINPHOS A-6

APPENDIX A

1.5 mg/kg/day; 190% increase of spleen endogenous colonies; 162% increase of spleen exogenous colonies;
50% reduction in thymus weight.

Uncertainty factors used in MRL derivation:

[] 1 [] 3 [x] 10 (for use of a LOAEL)
[] 1 [] 3 [x] 10 (for extrapolation from animals to humans)
[] 1 [] 3 [x] 10 (for human variability)

Was a conversion factor used from ppm in food or water to a mgzpody weight dose?

If so, explain: Doses were provided as 1/ 100, 1/50, and 1/25 of the LD50 (148 mg/kg) by the authors, resulting
in doses of 1.5, 3, and 6 mg/kg, respectively.

If an inhalation study in animals, list conversion factors used in determining human equivalent dose: Not

applicable.

Was a conversion used from intermittent to continuous exmsure?
Not applicable.

Other additional studies or mrtinpnt information that lend support to this MRL:

In other studies, adverse immunolymphoreticular effects has been associated with exposure to oral
chlorfenvinphos. In an intermediate-duration dietary study with albino (Wistar) rats, there was a signiﬁcant
and irreversible reduction in relative spleen weight of female rats given 23 mg/kg/day chlorfenvinphos for

12 weeks (Ambrose et a1. 1970). A study was undertaken to evaluate selected serological and
cytoimmunological reactions in rabbits subjected to a long-term poisoning with subtoxic oral doses (10 mg/kg
in a soya oil solution with a small amount of food) of chlorfenvinphos for 90 days. Chlorfenvinphos treatment
signiﬁcantly elevated serum hemagglutinin level (16%) and hemolysin activity (66%, P<0.05) as well as
increased the number of nucleated lymphoid cells producing hemolytic antibody to sheep erythrocytes as
compared to controls (treated 906, P<0.05 and controls 618). Spleen cytomorphology changes, manifested
mainly as transformation of primary follicles into secondary ones with well developed germinal centers, were
also observed (Roszkowski 1978).

Therefore, it is appropriate to base the intermediate oral MRL for chlorfenvinphos on immunological effects.

Agency Contact (Chemical Manager): Alfred Dorsey.

CHLORFENVINPHOS A-7

APPENDIX A

MINIMAL RISK LEVEL (MRL) WORKSHEET

Chemical name: Chlorfenvinphos

CAS number: 470-90-6

Date: August 21, 1996

Proﬁle status: Final

Route: [] Inhalation [x] Oral

Duration: [] Acute []Intermediate [x] Chronic
Key to ﬁgure: 34

Species: Rat

MRL: 0.0007 [x] mg/kgday [] ppm [] mg/m3

Reference: Ambrose AM, Larson PS, Borzelleca JF, Hennigar GR. 1970. Toxicologic studies on
diethyl—1-(2,4-dichlorophenyl)—2-chloroviny1 phosphate. Toxicology and Applied Pharmacology, 17:323-336.

Exmrimental design (human study details or strain, number of animals per exposure/control group, sex, dose
administration details):

The authors conducted toxicological studies with chlorfenvinphos in weaning albino (W istar) rats. In the
study, four matched groups of weaning albino (Wistar) rats (30 rats/sex/group) were culled to a narrow
starting weight range and fed daily GC-4072 (technical chlorfenvinphos) doses of O, 0.7, 2.1, 7, or

21 mg/kg/day (males) or 0, 0.8, 2.4, or 8, or 24 mg/kg/day (females) in the diet for 104 weeks. An additional
group of non-littermate rats (30/sex) were administered 21 mg/kg/day (males) or 24 mg/kg/day (females)
chlorfenvinphos for 104 weeks. Plasma and erythrocyte cholinesterase (ChE) activity levels were obtained
from 4 rats of each sex per dose group at 1, 4, 8, and 12 weeks. At 13 weeks, 4 rats/sex/dose group were
sacriﬁced for histopathologic examination. At 13 weeks, 4 rats/sex/dose group were sacriﬁced for
histopathologic examination. The rats in the 21 mg/kg/day (males) and 24 mg/kg/day (females) were
sacriﬁced on the 95th week while all other dose group animals were sacriﬁced on the end of the study

(104 weeks). At each autopsy, relative organ weights were determined for heart and kidneys. All animals
sacriﬁced in moribund condition as well as those sacriﬁced at week 13, 95, and 104 weeks were examined
grossly and microscopically and organs (heart, lungs, liver, kidney, urinary bladder, spleen, stomach, small
and large intestine, skeletal muscle, skin, bone marrow, pancreas, thyroid, adrenal, pituitary) from these
animals were histopathologically examined. Chlorfenvinphos signiﬁcantly decreased body weight gain of
females at the 8 and 24 mg/kg/day dose groups from the 26th week till towards the end of the study, although,
the decreased body weight gain became not statistically signiﬁcant at the end of the study. Increased relative
liver weights were observed in males at the 7 mg/kg/day dose level but no other signs of hepatopathology was
reported. No consistent difference in body weight gains in males, survival of the test animals, food
consumption, or mortality was evident at all dose levels tested, as compared to undosed controls. Essentially,
no gross or microscopic histopathology were evident in all the organs (heart, lungs, liver, kidney, urinary
bladder, spleen, stomach, small and large intestine, skeletal muscle, skin, bone marrow, pancreas, thyroid,
adrenal, pituitary) tissues examined. No changes in organ-to—body weight were observed in the heart, kidney,
spleen and testes (Ambrose et a1. 1970).

Dose endpoint used for MRL derivation:

[] NOAEL [x] LOAEL

CHLORFENVINPHOS A-8

APPENDIX A

0.7 mg/kg/day; 45% inhibition of plasma cholinesterase activity; 33% inhibition of erythrocyte cholinesterase
activity

Uncertainty factors gsﬂ in MRL derivgtjgm:

[] 1 [] 3 [x] 10 (for use of a LOAEL)
[] 1 [] 3 [x] 10 (for extrapolation from animals to humans)
[] l [] 3 [x] 10 (for human variability)

Was a conversi factor m in r w ' t w i t o ‘7
If so, explain: Doses, provided as food concentrations (10, 30, 100, or 300 ppm), were converted to doses
in mg/kg/day using rat daily food intake factor for chronic Wistar rat obtained from EPA (1988).

CALCULATIONS: 10 ppm =10 mg/kg; Male - 10 mg/kg x 0.07 mg/kg/day (chronic male Wistar rat food
factor) = 0.7 mg/kg/day; 30 ppm = 2.1 mg/kg/day; 100 ppm = 7 mg/kg/day; 300 ppm = 21 mg/kg/day:
Female —- 10 mg/kg x 0.08 mg/kg/day (chronic female Wistar rat food factor) = 0.8 mg/kg/day; 30 ppm =
2.4 mg/kg/day; 100 ppm = 7 mg/kg/day; 300 ppm = 24 mg/kg/day.

    

If an inhalati n stud ' : Not
applicable.

Was a conversion useg from intermittent to continuous exmsum? Not applicable.

Other ditional ' s or i inf i a is M '

Although the neurological effects of human prolonged exposure to low oral doses of chlorfenvinphos is not
known due to a dearth of studies, acute-duration exposure data indicate that neurological effects, mediated by
cholinesterase inhibition, is the most sensitive toxicological consequence of human exposure to
chlorfenvinphos(Cupp et a1. 1975; Pach et a]. 1987; Taitelman 1992). Similarly, chlorfenvinphos significantly
inhibited both plasma and erythrocyte cholinesterase activities in Beagle dogs (2/sex) fed daily
chlorfenvinphos doses of 0, 0.3, 2, or 10 mg/kg/day (males), or 0, 1.5, 10, or 50 mg/kg/day (females) in the
diet (moist) for 104 weeks. Plasma cholinesterase activities were signiﬁcantly inhibited at all dietary levels
through week 39 of the study; 49% inhibition at the 0.3 mg/kg/day (males) and 1.5 mg/kg/day (females) dose
levels. Erythrocyte cholinesterase activity was signiﬁcantly and consistently inhibited (36%) during the ﬁrst
12 weeks only in the 10 mg/kg/day (males) and 50 mg/kg/day (females) dose levels (Ambrose et al. 1970).

Therefore, it is considered appropriate to use this endpoint for developing a chronic oral MRL for
chlbrfenvinphos.

Agency gongct (Qhemical Manager): Alfred Dorsey.

CHLORFENVINPHOS 3-1

APPENDIX B

USER'S GUIDE
Chapter 1
Public Health Statement

This chapter of the proﬁle is a health effects summary written in non-technical language. Its intended
audience is the general public especially people living in the vicinity of a hazardous waste site or chemical
release. If the Public Health Statement were removed from the rest of the document, it would still
communicate to the lay public essential information about the chemical.

The major headings in the Public Health Statement are useful to ﬁnd speciﬁc topics of concern. The topics are
written in a question and answer format. The answer to each question includes a sentence that will direct the
reader to chapters in the proﬁle that will provide more information on the given topic.

Chapter 2
Tables and Figures for Levels of Signiﬁcant Exposure (LSE)

Tables (2-1, 2-2, and 2-3) and ﬁgures (2—1 and 2-2) are used to summarize health effects and illustrate
graphically levels of exposure associated with those effects. These levels cover health effects observed at
increasing dose concentrations and durations, differences in response by species, minimal risk levels (MRLs)
to humans for noncancer endpoints, and EPA's estimated range associated with an upper— bound individual
lifetime cancer risk of l in 10,000 to 1 in 10,000,000. Use the LSE tables and ﬁgures for a quick review of the
health effects and to locate data for a speciﬁc exposure scenario. The LSE tables and ﬁgures should always be
used in conjunction with the text. All entries in these tables and ﬁgures represent studies that provide reliable,
quantitative estimates of No—Observed-Adverse- Effect Levels (NOAELs), Lowest-Observed- Adverse-Effect
Levels (LOAELs), or Cancer Effect Levels (CELs).

The legends presented below demonstrate the application of these tables and ﬁgures. Representative
examples of LSE Table 2-1 and Figure 2-1 are shown. The numbers in the left column of the legends
correspond to the numbers in the example table and ﬁgure.

LEGEND
See LSE Table 2-1

(1) Route of Exposure One of the ﬁrst considerations when reviewing the toxicity of a substance using
these tables and ﬁgures should be the relevant and appropriate route of exposure. When sufficient data
exists, three LSE tables and two LSE ﬁgures are presented in the document. The three LSE tables
present data on the three principal routes of exposure, i.e., inhalation, oral, and dermal (LSE Table 2-1,
2-2, and 2-3, respectively). LSE ﬁgures are limited to the inhalation (LSE Figure 2-1) and oral (LSE
Figure 2-2) routes. Not all substances will have data on each route of exposure and will not therefore
have all ﬁve of the tables and ﬁgures.

(2) Exposure Period Three exposure periods — acute (less than 15 days), intermediate (15—3 64 days), and
chronic (365 days or more) are presented within each relevant route of exposure. In this example, an

CHLORFENVINPHOS B-2

(3)

(4)

(5)

(6)

(7)

(8)

(9)

(10)
(11)

APPENDIX B

inhalation study of intermediate exposure duration is reported. For quick reference to health effects
occurring from a known length of exposure, locate the applicable exposure period within the LSE table
and ﬁgure.

Health Effect The major categories of health effects included in LSE tables and ﬁgures are death,
systemic, immunological, neurological, developmental, reproductive, and cancer. NOAELs and
LOAELs can be reported in the tables and ﬁgures for all effects but cancer. Systemic effects are further
deﬁned in the "System" column of the LSE table (see key number 18).

Key to Figure Each key number in the LSE table links study information to one or more data points
using the same key number in the corresponding LSE ﬁgure. In this example, the study represented by
key number 18 has been used to derive a NOAEL and a Less Serious LOAEL (also see the 2 "18r" data
points in Figure 2—1).

Smcies The test species, whether animal or human, are identiﬁed in this column. Section 2.5,
"Relevance to Public Health," covers the relevance of animal data to human toxicity and Section 2.3,
"Toxicokinetics," contains any available information on comparative toxicokinetics. Although
NOAELs and LOAELs are species speciﬁc, the levels are extrapolated to equivalent human doses to
derive an MRL.

Exposure Frequency/Duration The duration of the study and the weekly and daily exposure regimen are
provided in this column. This permits comparison of NOAELs and LOAELs ﬁom different studies. In
this case (key number 18), rats were exposed to toxaphene via inhalation for 6 hours per day, 5 days per
week, for 3 weeks. For a more complete review of the dosing regimen refer to the appropriate sections
of the text or the original reference paper, i.e., Nitschke et al. 1981.

System This column further deﬁnes the systemic effects. These systems include: respiratory,
cardiovascular, gastrointestinal, hematological, musculoskeletal, hepatic, renal, and dermal/ocular.
"Other" refers to any systemic effect (e.g., a decrease in body weight) not covered in these systems. In
the example of key number 18, l systemic effect (respiratory) was investigated.

NOAEL A No-Observed-Adverse-Effect Level (N OAEL) is the highest exposure level at which no
harmful effects were seen in the organ system studied. Key number 18 reports a NOAEL of 3 ppm for
the respiratory system which was used to derive an intermediate exposure, inhalation MRL of 0.005 ppm
(see footnote "b").

LOAEL A Lowest—Observed-Adverse-Ef’fect Level (LOAEL) is the lowest dose used in the study that
caused a harmful health effect. LOAELs have been classiﬁed into "Less Serious" and "Serious" effects.
These distinctions help readers identify the levels of exposure at which adverse health effects ﬁrst
appear and the gradation of effects with increasing dose. A brief description of the speciﬁc endpoint
used to quantify the adverse effect accompanies the LOAEL. The respiratory effect reported in key
number 18 (hyperplasia) is a Less serious LOAEL of 10 ppm. MRLs are not derived from Serious
LOAELs.

Reference The complete reference citation is given in Chapter 8 of the proﬁle.

CEL A Cancer Effect Level (CEL) is the lowest exposure level associated with the onset of
carcinogenesis in experimental or epidemiologic studies. CELs are always considered serious effects.

CHLORFENVINPHOS B-3

APPENDIX B

The LSE tables and ﬁgures do not contain NOAELs for cancer, but the text may report doses not
causing measurable cancer increases.

(12) Footnetes Explanations of abbreviations or reference notes for data in the LSE tables are found in the
footnotes. Footnote "b" indicates the NOAEL of 3 ppm in key number 18 was used to derive an MRL
of 0.005 ppm.

LEGEND
See Figure 2-1

LSE ﬁgures graphically illustrate the data presented in the corresponding LSE tables. Figures help the reader
quickly compare health effects according to exposure concentrations for particular exposure periods.

(13) Expesure Period The same exposure periods appear as in the LSE table. In this example, health effects
observed within the intermediate and chronic exposure periods are illustrated.

(14) Health Effect These are the categories of health effects for which reliable quantitative data exists. The
same health effects appear in the LSE table.

(15) Levels of Exposure concentrations or doses for each health effect in the LSE tables are graphically

displayed in the LSE ﬁgures. Exposure concentration or dose is measured on the log scale y axis.
Inhalation exposure is reported in mg/m3 or ppm and oral exposure is reported in mg/kg/day.

(16) NOAEL In this example, 18r NOAEL is the critical endpoint for which an intermediate inhalation
exposure MRL is based. As you can see from the LSE ﬁgure key, the open-circle symbol indicates to a
NOAEL for the test species-rat. The key number 18 corresponds to the entry in the LSE table. The
dashed descending arrow indicates the extrapolation from the exposure level of 3 ppm (see entry 18 in
the Table) to the MRL of 0.005 ppm (see footnote "b" in the LSE table).

(17) CEL Key number 38r is 1 of 3 studies for which Cancer Effect Levels were derived. The diamond
symbol refers to a Cancer Effect Level for the test species-mouse. The number 38 corresponds to the
entry in the LSE table.

(18) Estimated Upmr-Bound Human Cancer Risk Levels This is the range associated with the upper-bound
for lifetime cancer risk of 1 in 10,000 to 1 in 10,000,000. These risk levels are derived from the EPA's
Human Health Assessment Group's upper-bound estimates of the slope of the cancer dose response
curve at low dose levels (q,*).

(19) Key to LSE Figure The Key explains the abbreviations and symbols used in the ﬁgure.

 

 

 

 

TABLE 2-1. Levels of Significant Exposure to [Chemical x] — Inhalation

 

 

 

          

Exposure LOAEL (effect)
Key to frequency/ NOAEL . _
figurea Species duration System (ppm) Less serious (ppm) Serious (ppm) Reference
INTERMEDIATE EXPOSURE
Systemic 1 t 1 1 1 t
18 Rat 13 wk Resp 3b 10 (hyperplasia) Nitschke et al.
5d/wk 1981
6hﬂd

 

CHRONIC EXPOSURE

 

Cancer 1
38 Rat 18 mo 20 (CEL, multiple Wong et al. 1982
5d/wk organs)
7hr/d
39 Rat 89—104 wk 10 (CEL, lung tumors, NTP 1982
5d/wk nasal tumors)
6hdd
40 Mouse 79—103 wk 10 (CEL, lung tumors, NTP 1982
5d/wk hemangiosarcomas)
6hr/d

 

a The number corresponds to entries in Figure 2-1.

° Used to derive an intermediate inhalation Minimal Risk Level (MRL) of 5 x 10 pprna, dose adjusted for intermittent exposure and divided
by an uncertainty factor of 100 (10 for extrapolation from animal to humans, 10 for human variability).

8 XIGNEddV

SOHdNIANEHHO'IHO

 

 

 

—-—> Figure 2-1. Levels of Significant Exposure to [Chemical X] — Inhalation

 

 

 

 

 

 

Acute Intermediate
(s1 4 days) (1 5-364 days)
Systemic Systemic
\ \
. '0 . ’0 . 0
a g9 3" cs“
\0 \0 \0 \° , o *
s ‘\"” 0° s \‘Q’ a?" 0““ «06 c?"
-—> (ppm) 02> Q58 06* do 099 0s QQ Q9 ((9
Q Q ~2~ O <2~ ‘2‘ ~2~ ‘2‘ O
1 0000
1000 o .
O . 037m 0
100 . o O . 30' 34r
17r 0 20m 0 0 20m 31r O 0 35m 0
‘6' 249 18r 0 229 21 r 0 28m 0 29r O 27r 40m .
1 Br 22 34, 39r
1 Q _ 33r
Q 18r
1 I
. 10'4 —
l
0.1 I 1 0-5
V
0.01
Key 1 0-6
0001 r Rat . LOAEL for serious effects (animals) : Minimal risk level for effects 10-7
m Mouse 0 LOAEL for less serious effects (animals) I otherthan cancer
0'0001 h Rabbit O NOAEL (animals)
9 Guinea Pig CEL - Cancer Effect Level The number next to each point
0-00001 k Monkey . corresponds to entries in the
accompanying table.
0.000001
’ Doses represent the lowest dose tested per study that produced a tumorigenic response and do not imply
the existence of a threshold for the cancer end point.
0.0000001

 

 

 

 

Estimated
Upper Bound
Human Cancer
Risk Levels

4—

 

 

8 XIGNEddV

SOHleANEHHO'IHO

9'8

CHLORFENVINPHOS 3.6

APPENDIX B

Chapter 2 (Section 2.5)
Relevance to Public Health

The Relevance to Public Health section provides a health effects summary based on evaluations of existing
toxicologic, epidemiologic, and toxicokinetic information. This summary is designed to present interpretive,
weight-of-evidence discussions for human health endpoints by addressing the following questions.

1. What effects are known to occur in humans?
2. What effects observed in animals are likely to be of concern to humans?

3. What exposure conditions are likely to be of concern to humans, especially around hazardous waste
sites?

The section covers endpoints in the same order they appear within the Discussion of Health Effects by Route
of Exposure section, by route (inhalation, oral, dermal) and within route by effect. Human data are presented
ﬁrst, then animal data. Both are organized by duration (acute, intermediate, chronic). In vitro data and data
from parenteral routes (intramuscular, intravenous, subcutaneous, etc.) are also considered in this section. If
data are located in the scientiﬁc literature, a table of genotoxicity information is included.

The carcinogenic potential of the proﬁled substance is qualitatively evaluated, when appropriate, using
existing toxicokinetic, genotoxic, and carcinogenic data. ATSDR does not currently assess cancer potency or
perform cancer risk assessments. Minimal risk levels (MRLs) for noncancer endpoints (if derived) and the
endpoints from which they were derived are indicated and discussed.

Limitations to existing scientiﬁc literature that prevent a satisfactory evaluation of the relevance to public
health are identiﬁed in the Data Needs section.

Interpretation of Minimal Risk Levels

Where sufﬁcient toxicologic information is available, we have derived minimal risk levels (MRLs) for
inhalation and oral routes of entry at each duration of exposure (acute, intermediate, and chronic). These
MRLs are not meant to support regulatory action; but to acquaint health professionals with exposure levels at
which adverse health effects are not expected to occur in humans. They should help physicians and public
health ofﬁcials determine the safety of a community living near a chemical emission, given the concentration
of a contaminant in air or the estimated daily dose in water. MRLs are based largely on toxicological studies
in animals and on reports of human occupational exposure.

MRL users should be familiar with the toxicologic information on which the number is based. Chapter 2.5,
"Relevance to Public Health," contains basic information known about the substance. Other sections such as
2.7, "Interactions with Other Substances," and 2.8, "Populations that are Unusually Susceptible" provide
important supplemental information.

MRL users should also understand the MRL derivation methodology. MRLs are derived using a modiﬁed
version of the risk assessment methodology the Environmental Protection Agency (EPA) provides (Barnes and
Dourson 1988) to determine reference doses for lifetime exposure (Rst).

CHLORFENVINPHOS 3-7

APPENDIX B

To derive an MRL, ATSDR generally selects the most sensitive endpoint which, in its best judgement,
represents the most sensitive human health effect for a given exposure route and duration. ATSDR cannot
make this judgement or derive an MRL unless information (quantitative or qualitative) is available for all
potential systemic, neurological, and developmental effects. If this information and reliable quantitative data
on the chosen endpoint are available, ATSDR derives an MRL using the most sensitive species (when
information ﬁom multiple species is available) with the highest NOAEL that does not exceed any adverse
effect levels. When a NOAEL is not available, a lowest-observed-adverse—eﬂ‘ect level (LOAEL) can be used
to derive an MRL, and an uncertainty factor (UF) of 10 must be employed. Additional uncertainty factors of
10 must be used both for human variability to protect sensitive subpopulations (people who are most
susceptible to the health effects caused by the substance) and for interspecies variability (extrapolation from
animals to humans). In deriving an MRL, these individual uncertainty factors are multiplied together. The
product is then divided into the inhalation concentration or oral dosage selected from the study. Uncertainty
factors used in developing a substance-speciﬁc MRL are provided in the footnotes of the LSE Tables.

 

CHLORFENVINPHOS 0-1

ACGIH
ADME
atm
ATSDR
BCF
BSC

C

CDC
CEL
CERCLA
CFR
CLP

cm

CNS

d

DHEW
DHHS
DOL
ECG
EEG
EPA
EKG

F

F]
FAO
FEMA
FIF RA
fpm

ft

FR

APPENDIX C

ACRONYMS, ABBREVIATIONS, AND SYMBOLS

American Conference of Governmental Industrial Hygienists
Absorption, Distribution, Metabolism, and Excretion
atmosphere

Agency for Toxic Substances and Disease Registry
bioconcentration factor

Board of Scientiﬁc Counselors

Centigrade

Centers for Disease Control

Cancer Effect Level

Comprehensive Environmental Response, Compensation, and Liability Act
Code of Federal Regulations

Contract Laboratory Program

centimeter

central nervous system

day

Department of Health, Education, and Welfare
Department of Health and Human Services
Department of Labor

electrocardiogram

electroencephalogram

Environmental Protection Agency

see ECG

Fahrenheit

ﬁrst ﬁlial generation

Food and Agricultural Organization of the United Nations
Federal Emergency Management Agency

Federal Insecticide, Fungicide, and Rodenticide Act
feet per minute

foot

Federal Register

gram

gas chromatography

generation

high-performance liquid chromatography

hour

Immediately Dangerous to Life and Health
International Agency for Research on Cancer
International Labor Organization

inch

adsorption ratio

kilogram

metric ton

organic carbon partition coefﬁcient

CHLORFENVINPHOS

mm
mm Hg
mmol

mo
mppcf
MRL

MS
NIEHS
NIOSH
NIOSHTIC
ng

nm
NHANES
nmol
NOAEL
NOES
NOHS

ppm

ppt
REL

RTECS
sec
SCE
SIC

APPENDIX C

octanol-water partition coefﬁcient

liter

liquid chromatography

lethal concentration, low

lethal concentration, 50% kill

lethal dose, low

lethal dose, 50% kill
lowest-observed-adverse—effect level

Levels of Signiﬁcant Exposure

meter

milligram

minute

milliliter

millimeter

millimeters of mercury

millimole

month

millions of particles per cubic foot

Minimal Risk Level

mass spectrometry

National Institute of Environmental Health Sciences
National Institute for Occupational Safety and Health
NIOSH's Computerized Information Retrieval System
nanogram

nanometer

National Health and Nutrition Examination Survey
nanomole

no—observed-adverse-effect level

National Occupational Exposure Survey

National Occupational Hazard Survey

National Priorities List

National Research Council

National Technical Information Service

National Toxicology Program

Occupational Safety and Health Administration
permissible exposure limit

picogram

picomole

Public Health Service

proportionate mortality ratio

parts per billion

parts per million

parts per trillion

recommended exposure limit

Reference Dose

Registry of Toxic Effects of Chemical Substances
second

sister chromatid exchange

Standard Industrial Classiﬁcation

CHLORFENVINPHOS

SMR
STEL
STORET
TLV
TSCA

1:-< onus: °\°|/\/\ IIIVV

1:
005

APPENDIX C

standard mortality ratio

short term exposure limit
STORAGE and RETRIEVAL
threshold limit value

Toxic Substances Control Act
Toxics Release Inventory
tirne—weighted average
United States

uncertainty factor

year

World Health Organization
week

greater than

greater than or equal to
equal to

less than

less than or equal to
percent

alpha

beta

delta

gamma

micrometer
microgram

C-3

a U. 3. GOVERNMENT PRINTING OFFICE: 1997-538-161

NT?
1741

.r

U‘ C BERKELEY LIBRARIES

~ W WWIIWIIW

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