DRAFT TOXICOLOGICAL PROFILE FOR HYDRAZINES Prepared by: Life Systems, Inc. Under Subcontract to: Clement International Corporation Under Contract No. 205-88-0608 Prepared for: U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service Agency for Toxic Substances and Disease Registry June 1994 *** DRAFT FOR PUBLIC COMMENT *** “AT. FOR I. DISCLAIMER The use of company or product name(s) is for identification only and does not imply endorsement by the Agency for Toxic Substances and Disease Registry. *** DRAFT FOR PUBLIC COMMENT *** UPDATE STATEMENT 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 Division of Toxicology/Toxicology Information Branch 1600 Clifton Road NE, E-29 Atlanta, Georgia 30333 R A 2 4 ol Ha TeE Fu él *** DRAFT FOR PUBLIC COMMENT *** FOREWORD The Superfund Amendments and Reauthorization Act (SARA) of 1986 (Public Law 99-499) amended the Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA or Superfund). Section 211 of SARA also amended Title 10 of the U. S. Code, creating the Defense Environmental Restoration Program. Section 2704(a) of Title 10 of the U. S. Code directs the Secretary of Defense to notify the Secretary of Health and Human Services of not less than 25 of the most commonly found unregulated hazardous substances at defense facilities. Section 2704(b) of Title 10 of the U. S. Code directs the Administrator of the Agency for Toxic Substances and Disease Registry (ATSDR) to prepare a toxicological profile for each substance on the list provided by the Secretary of Defense under subsection (b). Each profile must include the following: (A) The examination, summary, and interpretation of available toxicological information and epidemiological evaluations on a hazardous substance in order 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 which present a significant risk to human health of acute, subacute, and chronic health effects. (C) Where appropriate, identification of toxicological testing needed to identify the types or levels of exposure that may present significant risk of adverse health effects in humans. This toxicological profile is prepared in accordance with guidelines developed by ATSDR and 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 is intended to characterize succinctly the toxicological and adverse health effects information for the hazardous substance being described. Each profile identifies and reviews the key literature (that has been peer-reviewed) that describes a hazardous substance’s toxicological properties. Other pertinent literature is also presented but 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. Each toxicological profile begins with a public health statement, which 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 will be identified by ATSDR and the Environmental Protection Agency (EPA). The focus of the profiles is on health and toxicological information; therefore, we have included this information in the beginning of the document. *** DRAFT FOR PUBLIC COMMENT *** Foreword 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. We plan to revise these documents in response to public comments and as additional data become available. Therefore, we encourage comments that will make the toxicological profile series of the greatest use. Comments should be sent to: Agency for Toxic Substances and Disease Registry Division of Toxicology Mail Stop E-29 Atlanta, Georgia 30333 This profile reflects our assessment of all relevant toxicological testing and information that has been peer reviewed. It has been reviewed by scientists from ATSDR, the Centers for Disease Control and Prevention (CDC), and other Federal agencies. It has also been reviewed by a panel of nongovernment peer reviewers and is being made available for public review. Final responsibility for the contents and views expressed in this toxicological profile resides with ATSDR. David Satcher, M.D., Ph.D. Administrator Agency for Toxic Substances and Disease Registry *** DRAFT FOR PUBLIC COMMENT *** vii CONTRIBUTORS CHEMICAL MANAGER(S)/AUTHOR(S): Hugh Hansen, Ph.D. ATSDR, Division of Toxicology, Atlanta, GA Mr. Christopher Kirman Life Systems, Inc., Cleveland, OH THE PROFILE HAS UNDERGONE THE FOLLOWING ATSDR INTERNAL REVIEWS: L. Green Border Review. Green Border review assures the 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 endpoints. 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. 4. Quality Assurance Review. The Quality Assurance Branch assures that consistency across profiles is maintained, identifies any significant problems in format or content, and establishes that Guidance has been followed. *** DRAFT FOR PUBLIC COMMENT *** r - a a "k on - CONTENTS FOREWORD . ©. oot ee ee ee ee ee ee ee ee v CONTRIBUTORS .... cvvc voi wisn smsmomsmns sons hd MA MIRE FHI RATED THI ALG EHTS vii LIST OF FIGURES! ; 55 5.0 61 ¢ 55 50% 5 smd # 2% 8 0 20 0 Ha Mie 8 £68 882d sammm wens wsmen pou xiii LISTOF TABLES ..vvuvivsmrmrmrvrnsnsntasmmand ss nd®imswadbavimimemsmsss Xv 1. PUBLIC HEALTH STATEMENT . . su ainsi vs stat ttmsgumuivimsassnsnsssns 1 1.1 WHAT AREHYDRAZINES? . . coins vs ins as ms Ms H bm hm sos #0 s vB Ws E65 swe 1 1.2 WHAT HAPPENS TO HYDRAZINES WHEN THEY ENTER THE ENVIRONMENT? ..... 2 1.3 HOW MIGHT I BE EXPOSED TO HYDRAZINES? . . . . ... iii 3 1.4 HOW CAN HYDRAZINES ENTER AND LEAVE MY BODY? .................... 3 1.5 HOW CAN HYDRAZINES AFFECT MY HEALTH? . . ......... i. 4 1.6 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN EXPOSED TO HYDRAZINES? . oo 5s 54 5 1 wos 15.8 0 2% #0 prem ws sw ww wx wows moms 5 1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO PROTECT HUMANHEALTH? ovr mem stead #49 83 Mra ht ms smn smus esas 5 1.8 WHERE CAN I GET MORE INFORMATION? ........ iin 6 2. HEALTH EFFECTS .. o «vs ssw moms stds #30 0a ba ms GAN i HE Ma Ms MRE MEW tH 0s Wns 7 2.1 INTRODUCTION ...v' vv rmemonementanamensnsdinsmomuidsbsmsssmass 7 2.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE ................. 7 221 IhAalonEXPOSUIE . oc os niu namin sw sim sa vu vs usa sms apap w suman ris 8 2211 Dealh.. ov. v'winis ia isi aiF sa BERNIE IRIB IE RAGE REFS XSW 0 8 22.1.2 SyStemICEBIMECIS . «vi vivir rnin a mE REA BPE RE na 20 22.1.3 Tunological BIfects o.oo cnn rmensummmememsmanvnuensas 22 22.14 Neurological Effects : « csc vs vs ns nv ns nsnrmmsnsnsnsmpmns mens 22 2.2.1.5 Reproductive BIfects . . .. .. cui insmsmvavinsnsmsmonwsnsns 23 2.2.1.6 Developmental Effects ............ cotinine 23 2.2.1.7 Genotoxic Effects . . . .... 23 D218 CaNlBE vin i vi migs 08880 0A BEE GEREN Rs BFE GLEE S 00% pws 23 222 OralBIposUIE . . « vss scic sd dad ha SF REF FRIRIB IRIS 5B HR REPEL 5 KE 0 3 24 222.1 Death. .... 0 0 nimisims isan us hd RIFE BIE LE HEED WER BE 24 2.222 SystemICEIectS . .. «vio urn cmv vm naa cm mn ha 24 2.2.2.3 Immunological Effects ................ i... 40 2.2.2.4 Neurological Effects . . ............. BAL HHI BNE BE MLSE NE 40 22325 Reproductive Effects ....::. cv iivvononcurnsmrsnvaweninsmnsins 40 2.2.2.6 Developmental Effects . ................. ii. 41 2.2.2.7 Genotoxic Effects . ........ 41 2228 CAMIGEL vin os Brum 9 NT HE Hs 8s BEECH IR PLE AW LWA KE vw Hw An 41 223 Dermal BXposure . « . ass +s saan sh aio sis as sv wi Hews mua Nr HoH RE Wan wr 42 223.0 Detth...ccoiuionasans nin iF isi Hint Bi RAST IRB HEB HAY 0A 42 2232 Systemic BIfects . .. icv ini nn ir mini tr h RR RR IEA Ea ke 42 2.2.3.3 Immunological Effects ................. i. 45 2234 Neurological Effects . . . « : «vv vv vs vi nr nro rmsmue ns nr ns men vos 45 2.23.5 Reproductive Effects « : «cu vs vs vu vrsrrsnimnnscn momen nme 46 2.23.6 Developmental Bffects ............. co icine ussimininansran 46 2.2.3.7 Genotoxic Effects . .......... 46 22.3.8 CHLOE vuvwvwom amas Hines #481508 R Een ueB: Hien snns aes 46 *** DRAFT FOR PUBLIC COMMENT *** 3, 4. 5. 2.3 TOXICORINETIOS “vn 00 00 65 wa'%is 5 405 % ¢180 4 5000 505 0% 45.0% x v0 sn 5sesn ni 46 2.3.1 ADSOIPHONM + « cv wavs v6 550s uvueurmensmenenssnessusosessssesmen 46 2.3.1.1 Inhalation EXposure . .................. ui 46 23.1.2 OMIEXPOSUIC + «cons nivonsmonmsinsbdns snare vues ssnes nes 46 2.3.1.3 Dermal EXpOSUre . .............. iii 47 23.2 Distribution ......... 47 2.3.2.1 Inhalation EXpOSUTe . . ............. 00 47 2.3.2.2 Oral EXPOSUIE . . . o.oo v titi 47 2323 Dermal BRPOSUIE .... viv iv rumen russvamsmonsnssenssesas 47 2.3.2.4 Other Routes of EXpOSUre . .................uuinrnmno nu... 47 2.33 Metabolism . ..... LL. 48 234 EXCIZUOM . ovo rnin 00.008 20.95 5055 3 584 wr mam anes esas meds is sess s ss 51 2.3.4.1 Inhalation Exposure . .................... 51 2.3.4.2 Oral EXposure . ..............iiiii 51 2.3.43 Dermal EXPOSUIE . . . ...... oii 51 2344 OMErEXPOSUTE . uo: wus ininmrvrmemnunonssnsosonsmanmsssns 51 2.3.5 Mechanisms of Action . . . ........ LL... 52 24 RELEVANCE TO PUBLIC HEALTH . ........... cit, 53 2.5 BIOMARKERS OF EXPOSURE AND EFFECT . .........o ovum. 64 2.5.1 Biomarkers Used to Identify or Quantify Exposure to Hydrazines ............... 65 2.5.2 Biomarkers Used to Characterize Effects Caused by Hydrazines ................ 65 2.6 INTERACTIONS WITH OTHER SUBSTANCES . . . .... o.oo 65 2.7 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE . .............oo...... 66 2.8 METHODS FOR REDUCING TOXIC EFFECTS . . . . . otto ieee eee 66 2.8.1 Reducing Peak Absorption Following EXpOSure . ......................... 66 2.82 Reducing Body Burden ..................... 67 2.8.3 Interfering with the Mechanism of Action for Toxic Effects . . ................. 67 2.9 ADEQUACY OF THEDATABASE . . .........oiiiiii i, 68 2.9.1 Existing Information on Health Effects of Hydrazines ...................... 68 2.9.2 Identification of Data Needs . ...................0uuiuumninnnno.. 70 2.93 On-going Studies . ............... ii 74 CHEMICAL AND PHYSICAL INFORMATION . ...........i 77 30 CHEMICALIDERTITY .. viv vn vuiminnmaetnin nse soem sn aessmsse ss 77 3.2 PHYSICAL AND CHEMICAL PROPERTIES . . . . .......ouu i, 77 PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL . ...............oo. 81 4.1 PRODUCTION . ....... iti 81 42 IMPORT/EXPORT . . os s6 noo smsmennmennnsmsnesssssnensmonsessssssa 81 83 USE vis tu mi a sms 6s Rh br mv ms msm rm en FoR HE TH 88S % Roth barr asses 85 4.4 DISPOSAL .... oi 85 POTENTIAL FOR HUMAN EXPOSURE . . . ... ieee 87 50 OVERVIEW |, 0 vmrn on si tamanssssivensntnssssensssssessnssssnen nn 87 5.2 RELEASES TO THE ENVIRONMENT . . . ..........i 87 5.2.1 AI Lo 87 B22 WHEE ooo vv vv ra sma 0s 91405 8h hn nn mr rE ee Ee EEE gS oe 89 A 89 5.3 ENVIRONMENTAL FATE ................. i, 89 5.3.1 Transport and Partitioning . . ........................ 89 5.3.2 Transformation and Degradation . . . . ...................... .. . .. ... 94 53.21 AI wv unun sna sams 450 rm vn rE Re EEE EEE Es 94 5322 WRBE wun in ssauuuninn sos ms asses snsnsssssinsme enn eens 95 *** DRAFT FOR PUBLIC COMMENT *** xi 5323 Sediment and SOI .. ovo mins ns sr memems men wo ve sosnsamsseins 95 5.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT . . . .............. 96 BA] AIT + ott tts siti t essa r sre aaa a a ee 96 BAT WOOL vv vw sms sia ® SES EAE SME NE BEET He rms at BARRERA AB WW 96 543 Sedimentand Soil .......... iii iii ia ieee 96 5.4.4 Other Environmental Media . ....... «ie 96 5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE ................... 96 5.6 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES . . . ................... 97 5.7 ADEQUACY OF THE DATABASE . ........... tii 97 5.7.1 Identification of Data Needs . . . . . . . «itt ini 98 572 On-going Studies . ........ vcr tirana onsets nnn 99 6. ANALYTICAL METHODS . . . ttt 101 6.1 BIOLOGICAL MATERIALS . . . . tee eee ees 101 6.2 ENVIRONMENTAL SAMPLES . . . ttt es 101 6.3 ADEQUACY OF THE DATABASE . .......... tiie 106 6.3.1 Identification of Data Needs . . . . .. . «vite 106 632 On-goingStudies ............ criti iii 107 7. REGULATIONS AND ADVISORIES . . . . eee 109 8. REFERENCES . © i tt ttt tt tt ee ee ee ee ee eee eee eee 115 9. GLOSSARY . iii iti tit titties sisi a eee a eee 141 APPENDICES A. USER'S GUIDE . . vv « « +s tt osm ems osmein 3d sd a oi ais was ss sm sm vwemeeessid A-1 B. ACRONYMS, ABBREVIATIONS, AND SYMBOLS . ................ nn. B-1 C. PEER REVIEW . . oot ee ee eee eee ee C-1 *** DRAFT FOR PUBLIC COMMENT *** - A } = = =a H Tome Aa A oy JECT iy ipl j : pe = = mma i iN tp - = EL = fa = AE Sie Be Pi A= a Fa ah ET = : Fa [I E tae EE A xiii LIST OF FIGURES 2-1 Levels of Significant Exposure to Hydrazines - Inhalation ....................ooonnnn 15 2-2 Levels of Significant Exposure to Hydrazines - Oral . . ............. cnn 34 2-3 Existing Information on Health Effects of Hydrazines . ....................oovvnnnnnn 69 5-1 Frequency of NPL Sites with Hydrazines Contamination . ................coooueeen.. 88 *+* DRAFT FOR PUBLIC COMMENT *** 2-1 2-2 2-3 2-4 2-6 3-1 3-2 4-1 4-2 5-2 6-1 7-1 7-2 7-3 xv LIST OF TABLES Levels of Significant Exposure to Hydrazines - Inhalation . ............... coon. 9 Levels of Significant Exposure to Hydrazines - Oral . . .............coovvnn. 25 Levels of Significant Exposure to Hydrazines - Dermal . ..............c..ovounnnnn. 43 Genotoxicity of Hydrazines In Vitro . . ........... oii 60 Genotoxicity of Hydrazines In Vivo... ....... iii 62 On-going Studies on the Health Effects of Hydrazines . . ............ coon. 75 Chemical Identity of Hydrazines . ............ cotton nee. 78 Physical and Chemical Properties of Hydrazines ..................coinnnn.. 79 Facilities that Manufacture or Process Hydrazine . . .......... cin. 82 Facilities that Manufacture or Process 1,1-Dimethylhydrazine . ............. oon 84 Releases to the Environment from Facilities that Manufacture or Process Hydrazine ............ 90 Releases to the Environment from Facilities that Manufacture or Process 1,1-Dimethylyydrazine . . . . . 93 Analytical Methods for Determining Hydrazines in Biological Materials . . ................. 102 Analytical Methods for Determining Hydrazines in Environmental Samples . . . .. o.oo 104 Regulations and Guidelines Applicable to Hydrazines . ............... coven. 110 Regulations and Guidelines Applicable to 1,1-Dimethylhydrazine . ...................... 112 Regulations and Guidelines Applicable to 1,2-Dimethylhydrazine . ..... MERI A REEL Hy 114 *** DRAFT FOR PUBLIC COMMENT *** a “ | ro - 1. ; i Ee Te. n B = EE s - a 3 a . y a at I 1 3 - FH 1 - - » k - . Seti r "CH i ) | = . - } 1 A B wv 2 v I » u ale 4 = - - - B oo - rE = =" o B 7 uy - =r or Lan, fa . a - B - om 's --. - ’ t - . oy B . - oo a i=" eS na Ey: ate] 1. PUBLIC HEALTH STATEMENT This Statement was prepared to give you information about hydrazines and to emphasize the human health effects that may result from exposure to them. The Environmental Protection Agency (EPA) has identified 1,350 hazardous waste sites as the most serious in the nation. These sites comprise the "National Priorities List" (NPL): Those sites which are targeted for long-term federal cleanup activities. Hydrazines have been found in at least 8 of the sites on the NPL. However, the number of NPL sites evaluated for hydrazines is not known. As EPA evaluates more sites, the number of sites at which hydrazines are found may increase. This information is important because exposure to hydrazines may cause harmful health effects and because these sites are potential or actual sources of human exposure to hydrazines. 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 can be exposed to a substance only when you come in contact with it. You may be exposed by breathing, eating, or drinking substances containing the substance or by skin contact with it. If you are exposed to a substances such as hydrazines, many factors will determine whether harmful health effects will occur and what the type and severity of those health effects will be. These factors include the dose (how much), the duration (how long), the route or pathway by which you are exposed (breathing, eating, drinking, or skin contact), the other - chemicals to which you are exposed, and your individual characteristics such as age, gender, nutritional status, family traits, life-style, and state of health. 1.1 WHAT ARE HYDRAZINES? Hydrazines are chemical compounds that contain two nitrogen atoms joined by a single covalent bond. Three examples of hydrazines are: ® hydrazine - also known as diamine, diamide, anhydrous hydrazine, and hydrazine base ® 1,1-dimethylhydrazine - also known as unsymmetrical dimethylhydrazine, dimazine, and others ® 1,2-dimethylhydrazine - also known as symmetrical dimethylhydrazine, hydrazomethane, and others This document uses the term "hydrazines" to refer to hydrazine, 1,1-dimethylhydrazine, and 1,2-dimethylhydrazine, collectively. These hydrazines are somewhat similar in chemical structure and reactivity. However, there are some clear differences regarding their production, uses, and adverse health effects. It should be noted that there are many other *** DRAFT FOR PUBLIC COMMENT *** 2 1. PUBLIC HEALTH STATEMENT hydrazine compounds; however, these three hydrazines are discussed together in this document because they are of interest to the U.S. Department of Defense. Hydrazines are made by man from chemicals such as ammonia, dimethylamine, hydrogen peroxide, and/or sodium hypochlorite. A small amount of hydrazine occurs naturally in some plants. The amounts of hydrazine and 1,1-dimethylhydrazine produced in the United States in the mid-1960s to mid-1980s have been reported to range from 15 million to 38 million pounds and from 9,900 to 99,000 pounds per year, respectively. 1,2-Dimethylhydrazine is a research chemical and the quantities produced are likely to be much less. The amount of hydrazines currently produced is not available. In their pure form, hydrazines are clear, colorless liquids. These liquids can evaporate in air. Hydrazines smell like ammonia. Most people can smell hydrazine or 1,1-dimethylhydrazine when present at concentrations greater than 2-8 parts hydrazines per million parts of air (ppm). Hydrazines are highly reactive and flammable. Hydrazine has been used as fuel for many rockets and spacecraft, including the space shuttle. Hydrazine is used to treat boiler water to reduce corrosion, to reduce other chemicals, and to catalyze chemical reactions. It is also used as a medicine and to make other medicines, agricultural chemicals, and plastic foams. 1,1-Dimethylhydrazine is used to combine gases, develop photographs, make other chemicals, and regulate plant growth. Other uses are also possible. 1,2-Dimethylhydrazine has no commercial uses, but is used in labs to study colon cancer in experimental animals. For more information about the chemical properties and uses of hydrazines, see Chapters 3 and 4. 1.2 WHAT HAPPENS TO HYDRAZINES WHEN THEY ENTER THE ENVIRONMENT? Hydrazines can be released to the environment from places that make, process, or use these chemicals. One of the primary ways hydrazine and 1,1-dimethylhydrazine enter the environment is from their use as rocket fuels. Since 1,2-dimethylhydrazine is not used commercially and is produced only in small amounts, large releases of this chemical to the environment are not expected. Accidental spills and leaks from storage and waste sites may add to environmental levels of hydrazines. Most of the hydrazines are released directly to the air. They are quickly destroyed by reactive molecules normally present in air. Most of the hydrazines in air are gone within a few minutes or hours. Smaller amounts of hydrazines are also released directly to surface water and soil. Lab studies show that some of the hydrazines released to soil and water can evaporate in air. Hydrazines can also dissolve in water or bind to soil. The extent to which these processes occur depends on soil and water conditions. Hydrazines can move with water through soil as it flows underground. This is particularly true in sandy soils. In water and soil, some *** DRAFT FOR PUBLIC COMMENT *** 3 1. PUBLIC HEALTH STATEMENT microorganisms can break down hydrazines to form less toxic compounds. Most of the hydrazines in soil and water are gone within a few weeks. Hydrazines may become concentrated in some fish living in contaminated water. However, since most animals quickly digest and excrete hydrazines, high levels of these compounds are not expected to remain in their bodies. For more information on what happens to hydrazines in the environment, see Chapters 4 and 5. 1.3 HOW MIGHT | BE EXPOSED TO HYDRAZINES? You may be exposed to significant amounts of hydrazines if you work in a place that makes, processes, or uses hydrazines, especially if you do not use proper protective equipment. People who live near these places, or near accidental spills or hazardous waste sites contaminated with hydrazines, may also be exposed. However, since hydrazines stay in air, water, and soil only briefly, most people are not exposed to hydrazines from these sources. Small amounts of hydrazine and 1,1-dimethylhydrazine have been found in tobacco products. Therefore, people who chew tobacco, smoke cigarettes, or are exposed to cigarette smoke indirectly, may be exposed to small amounts of these chemicals. In the past, some people may have been exposed to 1,1-dimethylhydrazine in fruits sprayed with Alar®. 1,1-Dimethylhydrazine is sometimes found where Alar® is made or used. Since Alar® is no longer used on food plants in the United States, people are no longer exposed to 1,1-dimethylhydrazine from this source. However, Alar® is still used on some non-food plants. Therefore, some greenhouse workers who use Alar® may be exposed to small amounts of 1,1-dimethylhydrazine. Since 1,2-dimethylhydrazine is not used commercially, most people are not exposed to this chemical. 1,2-Dimethylhydrazine is used as a research chemical to produce colon cancer in lab animals. Therefore, lab workers who use 1,2-dimethylhydrazine for this purpose may be exposed to small amounts. For more information about how you can be exposed to hydrazines, see Chapter 5. 1.4 HOW CAN HYDRAZINES ENTER AND LEAVE MY BODY? Very little is known about how hydrazines enter and leave your body. Based on limited studies in animals, hydrazines are probably rapidly absorbed into your blood if you swallow them or if you get them on your skin. Based on their chemical and physical properties, hydrazines are also likely to be well-absorbed if you breathe them into your lungs. Once they are in your blood, hydrazines are probably carried to all tissues of your body. Animal studies suggest that soon after you are exposed, the levels of hydrazines in your blood and tissues will fall rapidly. This is because your body changes hydrazines into other compounds called metabolites. These metabolites are formed by reactions with enzymes and reactive *** DRAFT FOR PUBLIC COMMENT *** 4 1. PUBLIC HEALTH STATEMENT molecules in your body. Some of these metabolites can react with important molecules in your body and may harm you. Animal studies show that most metabolites and unchanged hydrazines leave your body in urine within one day. A small amount can also be found in the air you breathe out. For more information about how hydrazines can enter and leave your body, see Chapter 2. 1.5 HOW CAN HYDRAZINES AFFECT MY HEALTH? A small number of case studies of acute exposure in humans suggest that your lungs, liver, kidney, and central nervous system may be injured if you breathe in hydrazine or 1,1- dimethylhydrazine or get them on your skin. Similar effects have been observed in animals. Animal studies indicate that effects on the liver usually consist of fatty changes, but other effects have also been noted. Some animals developed convulsions, tremors, seizures, or other effects on the nervous system after breathing hydrazines. Serious effects on the reproductive system were sometimes observed in animals. These effects included decreased sizes of the ovaries and testes, and decreased sperm production. Some of these effects were seen in animals exposed to concentrations as low as 0.05-1 ppm hydrazine or 1,1- dimethylhydrazine in air for several months or more. Note that these concentrations are below those at which most people begin to smell hydrazines (2-8 ppm). A few studies in humans show that hydrazine or 1,1-dimethylhydrazine affects your nervous system. If you swallow hydrazines, you may experience an upset stomach, vomiting, uncontrolled shaking, lethargy (sluggishness), coma, and neuritis (an inflammation of your nerves). These effects usually occur soon after exposure, but some may be delayed. Hydrazine has been used in the past to treat cancer patients. These effects occurred in some patients that swallowed 0.2-0.7 milligrams hydrazine per kilogram of their body weight per day (mg/kg/day) for 1 month or more. Vitamin By; has been given to people exposed to these chemicals to reduce nervous system effects. Effects on the nervous system have also been seen in animals exposed to hydrazine and 1,1-dimethylhydrazine, but not to 1,2-dimethylhydrazine. If you are exposed to hydrazines, you may have an increased cancer risk. The cancer- causing effects of hydrazines have not been well studied in humans. However, many studies show that hydrazines can cause cancer in some animals after oral exposure to doses of 0.06-19 mg/kg/day or inhalation exposure to concentrations of 0.05-5 ppm. Tumors have been seen in many organs of animals exposed in this way, but were found most often in the lungs, blood vessels, or colon. Some of the cancers caused by 1,1-dimethylhydrazine may have been due to the presence of dimethylnitrosamine (a powerful carcinogen) as an impurity of this chemical. It is of particular concern that 1,2-dimethylhydrazine has caused colon cancer in lab animals following a single exposure. *** DRAFT FOR PUBLIC COMMENT *** 5 1. PUBLIC HEALTH STATEMENT Although it is hard to apply information from animal cancer studies directly to humans, several government agencies have considered all the cancer evidence and developed the following conclusions: ® The Department of Health and Human Services (DHHS) has determined that hydrazine and 1,1-dimethylhydrazine are known carcinogens. ® The International Agency for Research on Cancer (IARC) has determined that hydrazine, 1,1-dimethylhydrazine, and 1,2-dimethylhydrazine are probably carcinogenic to humans. ® EPA has determined that hydrazine, 1,1-dimethylhydrazine, and 1,2-dimethylhydrazine are probable human carcinogens. For more information about how hydrazines can affect your health, see Chapter 2. 1.6 1S THERE A MEDICAL TEST TO DETERMINE WHETHER | HAVE BEEN EXPOSED TO HYDRAZINES? If you are exposed to hydrazines, you can be tested for the presence of these chemicals or their metabolites in your blood, urine, or feces. These tests must be done soon after you are exposed (usually within 1 day). Exposure to some cancer drugs or other chemicals can produce hydrazines or their metabolites in your body. These tests cannot be used to tell how much hydrazines you were exposed to or if you are going to be ill. These tests are not usually done in a doctor’s office, but are sent to special labs for testing. For more information about tests for exposure to hydrazines, see Chapters 2 and 6. 1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO PROTECT HUMAN HEALTH? Several government regulatory agencies have taken action to protect people from excess exposure to hydrazines. EPA considers hydrazine and 1,1-dimethylhydrazine to be hazardous air pollutants. The Occupational Safety and Health Administration (OSHA) limits the amount of hydrazine and 1,1-dimethylhydrazine to 0.1 and 0.5 ppm, respectively, in workplace air for an 8-hour workday. The National Institute of Occupational Safety and Health (NIOSH) recommends that the levels of hydrazine and 1,1-dimethylhydrazine in workplace air not exceed 0.03 and 0.06 ppm, respectively, for a 2-hour period. The Food and Drug Administration (FDA) has ruled that hydrazine cannot be added to water for steam that will contact food. The EPA restricts the amount of hydrazines that may be released to the environment during burning or by disposal in landfills. For more information regarding the regulations and guidelines for hydrazines, see Chapter 7. *** DRAFT FOR PUBLIC COMMENT *** 6 1. PUBLIC HEALTH STATEMENT 1.8 WHERE CAN | 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 Clifton Road NE, E-29 Atlanta, Georgia 30333 (404) 639-6000 This agency can also provide you with information on the location of occupational and environmental health clinics. These clinics specialize in the recognition, evaluation, and treatment of illness resulting from exposure to hazardous substances. *** DRAFT FOR PUBLIC COMMENT *** 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 hydrazines. 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. The term "hydrazines" is a generic name used in this document to describe a group of three structurally related chemicals: hydrazine, 1,1-dimethylhydrazine, and 1,2-dimethylhydrazine. These three hydrazines were selected for inclusion in this document because they have been detected at hazardous waste sites and are of concern to the Department of Defense. Numerous other hydrazine derivatives exist as well. For example, the reader is referred to the Toxicological Profile for 1,2-Phenylhydrazine (ATSDR 1990) for information on this chemical. 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 exposure — inhalation, 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-effect levels (NOAELSs) or lowest-observed-adverse-effect levels (LOAELS) reflect the actual doses (levels of exposure) used in the studies. LOAELSs 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 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 (LOAELSs) or exposure levels below which no adverse effects (NOAELSs) 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. Levels of exposure associated with carcinogenic effects (Cancer Effect Levels, CELs) of hydrazines are indicated in Tables 2-1 and 2-2 and Figures 2-1 and 2-2. Because cancer effects could occur at lower exposure *** DRAFT FOR PUBLIC COMMENT *** 8 2. HEALTH EFFECTS levels, Figures 2-1 and 2-2 also show a range for the upper bound of estimated excess risks, ranging from a risk of 1 in 10,000 to 1 in 10,000,000 (10* to 107), as developed by EPA. Estimates of exposure levels posing minimal risk to humans (Minimal Risk Levels or MRLs) have been made for 1,1-dimethylhydrazine. 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 effect(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 1990a), 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 A). This guide should aid in the interpretation of the tables and figures for Levels of Significant Exposure and the MRLs. 2.2.1 Inhalation Exposure In their pure form, hydrazines are fairly volatile liquids (see Section 3.2), and therefore, inhalation exposures are of concern. Data regarding toxic effects in humans or animals after inhalation exposure to 1,2-dimethylhydrazine are lacking. However, data are available from human and animal studies regarding the toxic effects of inhaled hydrazine and 1,1-dimethylhydrazine. These studies are discussed below. 2.2.1.1 Death A single case study was located which described the death of a male worker exposed to an undetermined concentration of hydrazine once a week for 6 months (Sotaniemi et al. 1971). Death was attributed to hydrazine exposure, resulting in severe lesions of the kidneys and lungs with complicating pneumonia. A number of animal studies have reported deaths after inhalation exposure to hydrazines. For example, one out of three dogs died within 3 days of intermittent exposure to 25 ppm 1,1-dimethylhydrazine (Rinehart et al. 1960). Nearly 100% (29/30) of mice exposed continuously to 140 ppm 1,1-dimethylhydrazine died within 2 weeks (Rinehart et al. 1960). Eight deaths were observed within 5 weeks in 30 mice exposed continuously to 75 ppm 1,1-dimethylhydrazine (Rinehart et al. 1960). Two of eight dogs exposed continuously to 1 ppm hydrazine progressively deteriorated and died after 16 weeks (Haun and Kinkhead 1973). Twenty-two out of 40 mice exposed continuously to 1 ppm hydrazine for 6 months died (Haun and Kinkhead 1973). Death in these mice was attributed to the hepatotoxic effects of hydrazine. In contrast, mortality was not increased in rats or monkeys exposed to 1 ppm hydrazine, suggesting that mice may be more sensitive to the lethal effects of hydrazine than other species. The mortality rates in rats, mice, dogs, and hamsters were not significantly affected by exposure to 5 ppm 1,1-dimethylhydrazine for 6 months (Haun et al. 1984). Mortality was 32-33% in hamsters exposed intermittently to 0.25 ppm hydrazine for 1 year compared to 19% in controls (Vernot et al. 1985). These studies indicate that exposure to relatively high concentrations of hydrazines in air can be lethal and suggest that hydrazine may be more toxic than 1,1-dimethylhydrazine. All LOAEL values from each reliable study for lethality are recorded in Table 2-1 and plotted in Figure 2-1. *** DRAFT FOR PUBLIC COMMENT *** TABLE 2-1. Levels of Significant Exposure to Hydrazines - Inhalation LOAEL (effect) Exposure Key to duration/ NOAEL Less serious Serious figure’ Species frequency System (ppm) (ppm) (ppm) Reference Form ACUTE EXPOSURE Death 1 Mouse 6-7 wk 140 (death in 29/30 Rinehart et al. 11DMH (cont) within 2 weeks) 1960 2 Dog 13-26 wk 25 (death in 1/3 Rinehart et al. 11DMH . 5d/wk within 3 days) 1960 * 6hr/d o = . a Neurological 3 3 Dog 13-26 wk 5 25 (depression, ataxia, Rinehart et al. 11DMH > 5d/wk salivation, emesis, 1960 & 6hr/d and seizures after © 3 days) oO 0 3 INTERMEDIATE EXPOSURE B Death 5 * 4 Mouse 6 mo 1 (death in 22/40) Haun and H * 5d/wk Kinkhead 1973 6hr/d or (cont) 5 Mouse 6-7 wk 75 (death in 8/30 Rinehart et al. 11DMH (cont) within 5 weeks) 1960 6 Dog 6 mo 1 (2/8 deaths after Haun and H 5d/wk 16 weeks) Kinkhead 1973 6hr/d or (cont) S103443 H1TV3H '¢ »»» LNIJWWOD O178Nd HOH 14VHA « « « TABLE 2-1. Levels of Significant Exposure to Hydrazines - Inhalation (continued) Exposure LOAEL (effect) Key to duration/ NOAEL Less serious Serious figure’ Species frequency System (ppm) (ppm) (ppm) Reference Form Systemic 7 Rat 6 mo Hemato 1 Haun and H 5d/wk Other 0.2 1 (decreased body Kinkhead 1973 6hr/d weight gain) or (cont) 8 Rat 6 mo Resp 0.05 (alveolar Haun et al. 1984 11DMH 5d/wk hyperplasia) 6hr/d Hemato 5 Hepatic 0.05" (fatty change in the liver) 9 Mouse 6 mo Hepatic 0.2° (moderate fatty 1 (severe fatty liver Haun and H 5d/wk liver change) change; cytoplasmic Kinkhead 1973 6hr/d vacuolization) or (cont) 10 Mouse 6 mo Resp 0.05 (lymphoid Haun et al. 1984 11DMH 5d/wk hyperplasia of the 6hr/d lung) Resp 0.5 (congestion and perivascular cuffing of the lung) Hepatic 0.05 (angiectasis in the Liver) Hepatic 0.5 (congestion of the Liver) Other 0.05 (hyaline degeneration of the gall bladder) Other 5 (body wt) 1 Dog 8.5 wk Hepatic 5 (mild cytoplasmic Haun 1977 11DMH 5d/wk degeneration of 6hr/d liver cord cells) or (cont) S103 HITVIH °C ol «x» LNJWWOD O178Nd HOd LIVHA » x» TABLE 2-1. Levels of Significant Exposure to Hydrazines - Inhalation (continued) Exposure LOAEL (effect) Key to duration/ NOAEL Less serious Serious figure’ Species frequency System (ppm) (ppm) (ppm) Reference Form 12 Dog 6 mo Hemato 0.2 1 (decreased Haun and H 5d/wk hemoglobin, Kinkhead 1973 6hr/d hematocrit, and or red blood cell (cont) count) Hepatic 0.2 1 (fatty changes) Other 0.2 1 (decreased body weight gain) 13 Dog 13-26 wk Resp 5 25 (alveolar Rinehart et al. 11DMH 5d/wk hemorrhage, 1960 6hr/d emphysema, and atelectasis) Cardio 25 Gastro 25 Hemato 5 (mild anemia) 25 (anemia) Hepatic 5 25 (hemosiderosis) Renal 25 Other 5 (13% body weight loss) 14 Dog 6 mo Hemat 5 Haun et al. 1984 11DMH 5d/wk Hepati 5 6hr/d Other 5 (body wt) 15 Hamster 6 mo Hemato 5 Haun et al. 1984 11DMH 5d/wk 6hr/d 16 Monkey 6 mo Hemato 1 Haun and H 5d/wk Hepatic 0.2 (slight to moderate Kinkhead 1973 6hr/d fatty liver or changes) (cont) Derm/oc 0.2 1 (minimal eye irritation) Other 1 (body wt) Neurological 17 Rat 6-7 wk 75 (occasional tremors) Rinehart et al. 11DMH (cont) 1960 S103443 H1TV3H '¢ LL » x» LNIJWWOD O178Nd HOH 14VHQA « « « TABLE 2-1. Levels of Significant Exposure to Hydrazines - Inhalation (continued) Exposure LOAEL (effect) Key to duration/ NOAEL Less serious Serious figure’ Species frequency System (ppm) (ppm) (ppm) Reference Form 18 Mouse 6-7 wk 75 (occasional tremors) Rinehart et al. 11DMH (cont) 1960 19 Dog 6 mo 0.2 1 (tonic convulsions) Haun and H 5d/wk Kinkhead 1973 6hr/d or cont 20 Dog 13-26 wk 5 Rinehart et al. 11DMH 5d/wk 1960 6hr/d Cancer 21 Rat 6 mo 0.05 (CEL: adenoma of the Haun et al. 1984 11DMH 5d/wk pancreas Islet 6hr/d cell; adenoma of the pituitary, and mononuclear cell leukemia) 22 Mouse 6 mo 0.05 (CEL: adenocarcinoma Haun et al. 1984 11DMH 5d/wk of the pituitary, 6hr/d hemangiosarcoma, and Kupfer cell sarcoma) 0.5 (CEL: thyroid follicular cell carcinoma) CHRONIC EXPOSURE Death 23 Hamster 1yr 0.25 (increased Vernot et al. H (inter- mortality) 1985 mittent) S103433 HLIVIH 'T zl TABLE 2-1. Levels of Significant Exposure to Hydrazines - Inhaiation (continued) LOAEL (effect) Exposure Key to duration/ NOAEL Less serious Serious figure’ Species frequency System (ppm) (ppm) (ppm) Reference Form Systemic 24 Rat 1yr Resp 1 5 (inflammation, Vernot et al. H (inter- hyperplasia, and 1985 mittent) metaplasia of the upper respiratory tract) . Hepatic 0.25 1 (focal cellular : change in females) ¥ 25 Mouse 1yr Resp 1 Vernot et al. H > (inter- Cardio 1 1985 ~ mittent) Gastro 1 3 Musc/skel 1 - Hepatic 1 e Renal 1 2 Derm/oc 1 oO oO 26 Mouse 1 yr Resp 5 (inflammation, Haun et al. 1984 11DMH 2 5d/wk hyperplasia, 2 6hr/d metaplasia, and 0 dysplasia of the A nasal mucosa) . Hepatic 5 (angiectasis in : liver) Other 5 (15% decreased body weight gain) 27 Dog 1yr Hepatic 0.25 1 (focal areas of Vernot et al. H (inter- highly vacuolated 1985 mittent) cells, elevated serum glutamic oxaloacetic transaminase) 28 Hamster 1 yr Hepatic 0.25 (amyloidosis, Vernot et al. H (inter- hemosiderosis, and 1985 mittent) bile duct hyperplasia) Renal 0.25 (amyloidosis and mineralization) Other 0.25 (up to 14% loss of body weight) S103443 H1TV3H 'C €l »» x LNIWWOD 2178Nd HOH L4VHA » » « TABLE 2-1. Levels of Significant Exposure to Hydrazines - Inhalation (continued) Exposure LOAEL (effect) Key to duration/ NOAEL Less serious Serious figure’ Species frequency System (ppm) (ppm) (ppm) Reference Form Reproductive 29 Rat 1 yr 5 (atrophy of the Vernot et al. H (inter- ovaries and 1985 mittent) inflammation of the endometrium and uterine tube) 30 Hamster 1 yr 0.25 1 (senile testicular Vernot et al. H (inter- atrophy) 1985 mittent) Cancer No 31 Rat 1 yr 1 (CEL: nasal Vernot et al. H & (inter- adenomatous polyps 1985 > mittent) in males) i 5 (CEL: thyroid . carcinoma in males) T m 32 Mouse 1 yr 5 (CEL: alveolar/ Haun et al. 1984 11DMH a 5d/wk bronchiolar o 6hr/d adenoma, hepato- cellular adenoma, lymphoma, papilloma of the nose, osteoma, and hemangioma predominantly in the liver) 33 Hamster 1 yr 5 (CEL: nasal Vernot et al. H (inter- adenomatous polyp) 1985 mittent) ‘The number corresponds to entries in Figure 2-1. sed to derive an intermediate inhalation minimal risk level (MRL) of 9x10 ppm for 1,1-dimethylhydrazine; dose adjusted for intermittent exposure and divided by an uncertainty factor of 1,000 (10 for use of a LOAEL, 10 for extrapolation from animals to humans, and 10 for human variability). Also adopted as the basis for derivation of an identical chronic inhalation MRL of 9x10°° ppm for 1,1-dimethylhydrazine. ‘Used to derive an intermediate inhalation minimal risk level of 2x10 ppm for hydrazine; dose divided by an uncertainty factor of 1,000 (10 for use of a LOAEL, 10 for extrapolation from animals to humans, and 10 for human variability). 11DMH = 1,1-dimethylhydrazine; Cardio = cardiovascular; CEL = cancer effect level; (cont) = continuous; d = day(s); Derm/oc = dermal/ocular; Gastro = gastrointestinal; H = hydrazine; Hemato = hematological; hr = hour(s); LOAEL = lowest-observed- adverse-effect level; mo = month(s); NOAEL = no-observed-adverse-effect level; ppm = parts per million; Resp = respiratory; wt = weight; wk = week(s); yr = year(s) vi » +» LNIWWOD J118Nd HOH LIVHA ws» FIGURE 2-1 Levels of Significant Exposure to Hydrazines — Inhalation ACUTE (14 Days) N & & Nd > SO (ppm) QF w 1,000 — 100 @m @ 2 @3¢ 10— Qad 1 he 0.1 0.01 — 0.001 — 0.0001 — Ke 0.00001 |— y d Dog @ LOAEL for serious effects (animals) | Minimal risk level ; ; for effects other s Hamster ( LOAEL for less serious effects (animals) 1 — Ww tha 0.500001 k Monkey O NOAEL (animals) i cancer m Mouse ¢ CEL — Cancer Effect Level (animals) 0.0000001 [— r Rat The number next to each point corresponds to entries in Table 2-1. 0.00000001 ‘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. 0.000000001 L— S1J33443 H1TV3aH 'T Sl «x» LNIWINOD O178Nd HOH 14VHA » « » FIGURE 2-1 Levels of Significant Exposure to Hydrazines — Inhalation (Continued) INTERMEDIATE (15-364 Days) Systemic N » @ X © & & o © NA & 2 © So & N 2 © QO > AS & x £ & & F (ppm) & C 0 RS ® 1,000 — 100 — ®:n @® Qi Qa @13¢ QQ 13d 6+ QO 13d @13d O14 Oss Qe Q@ria OQ13da Q14d —@6d @ 4m 12d Qrek Orr (Pad 1 @ o Q 16m Qo @on Qo 10m O 12d O 12d @ 16k Sin 01 ® @ 10m (er | @ 1om Qe ! 1 0.01 — | | 1 I | i 0.001 [— i 0.0001 — bs I K 1 0.00001 }— 3y < d Dog @ LOAEL for serious effects (animals) | Minimal risk level s Hamster ( LOAEL for less serious effects (animals) 1 for effects other Hl th 0.000001 k Monkey O NOAEL (animals) “w than cancer m Mouse $ CEL - Cancer Effect Level (animals) 0.0000001 [— ¢ Ral The number next to each point corresponds to entries in Table 2-1. 0.00000001 ‘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. 0.000000001 L_ S103443 HiTVEH “Z gi » xs LNIJWWOD O1N18Nd HOd L4VHA « « « FIGURE 2-1 Levels of Significant Exposure to Hydrazines — Inhalation (Continued) INTERMEDIATE (15-364 Days) Systemic 3 ; &° . © Re & (ppm) O° J or? 1,000 — 100 = @ em @17r 10 aa QO 14d O1om QO 20d 1 —Q@ 12d QO 16k Qn @1%d $ O 12d On O1ed 0.1 @ om @ 2m $n 0.01 — 0.001 — 0.0001 — Ke 0.00001 }— y d Dog @ LOAEL for serious effects (animals) | Minimal risk level 0.000001 — s Hamster ( LOAEL for less serious effects (animals) < Rr silects cies ‘ k Monkey O NOAEL (animals) m Mouse b CEL - Cancer Effect Level (animals) 0.0000001 [— r Rat The number next to each point corresponds to entries in Table 2-1. 0.00000001 — *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. 0.000000001 L_ S103443 HAVaH T Ll) »»» LNIJWWOD 21N18Nd HO L4VHA ws» FIGURE 2-1 Levels of Significant Exposure to Hydrazines — Inhalation (Continued) CHRONIC (2365 Days) Systemic » & & 3 & SF °° SF of x > oO Ky @ . oO & © & N 2 KR $8 &

5x/wk c w 5 Dog (GW) 2 wk 60 (2/2 deaths) Wilson 1976 12DMH o 1x/wk 8 : 2 Systemic g 6 Rat (GW) Once Hepatic 27 81 (fatty liver) Preece et al. HS 5 1992 : 7 Rat (GW) Once Hepatic 49 (increased Marshall et al. HS lipogenesis) 1983 8 Rat (G) 4d Gastro 25 (proliferative foci Caderni et al. 12DMH 2x in colon) 1991 9 Dog (GW) 2 wk Hepatic 60 (hepatic Wilson 1976 12DMH 1x/wk degeneration and hemorrhagic necrosis) Other 60 (weight loss) Developmental 10 Hamster (GW) Once 166 Schiller et al. H Gd 12 1979 S103443 H1TV3IH '¢C SC »»» LNIJWWOD JIT8Nd HOH 14VHA ww TABLE 2-2. Levels of Significant Exposure to Hydrazines - Oral (continued) LOAEL (effect) Exposure Key to duration/ NOAEL Less serious Serious figure’ Species Route frequency System (mg/kg/day) (mg/kg/day) (mg/kg/day) Reference Form 1" Hamster (GW) Once 68 Schiller et al. 12DMH Gd 12 1979 Cancer 12 Rat (G) Once 30 (CEL: colon Craven and 12DMH adenocarcinomas) DeRubertis 1992 13 Rat (GW) Once 15.8 (CEL: colon tumors) Watanabe et al. 12DMH 1985 14 Rat (GW) Once 15.8 (CEL: colon tumors) Schiller et al. 12DMH 1980 INTERMEDIATE EXPOSURE Death 15 Rat (GW) 10 wk 13.6 (100% mortality) Teague et al. 12DMH 1x/wk 1981 16 Gn pig (GW) 7-10 wk 60 (5/6 deaths) Wilson 1976 12DMH 1x/wk 17 Mouse (F) 6 wk 5.1 (100% mortality Visek et al. 12DMH ad lib in males) 1991 4.5 (100% mortality in females) 18 Mouse (GW) 25 wk 2.3 (38/50 deaths by Biancifiori 1970 HS 1x/d 80 weeks) (inter- mittent) 19 Mouse (GW) 4-21 wk 33 (2/5 died) Roe et al. 1967 11DMH 5x/wk 20 Dog (GW) 4-10 wk 15 (9/10 died) Wilson 1976 12DMH 1x/wk 21 Hamster (GW) 15-20 wk 4.9 (32/35 died by Biancifiori 1970 HS 1x/d week 50) (inter- mittent) S103443 H1TV3H °C 9z «xx LNIWWOD 2178Nd HOH LdVHA «4» « TABLE 2-2. Levels of Significant Exposure to Hydrazines - Oral (continued) Exposure LOAEL (effect) Key to duration/ NOAEL Less serious Serious figure’ Species Route frequency System (mg/kg/day) (mg/kg/day) (mg/kg/day) Reference Form 22 Pig (GW) 10 wk 60 (5/8 died) Wilson 1976 12DMH 1x/wk Systemic 23 Rat (W) <10 mo Hepatic 4.2 (severe Bedell et al. 12DMH hepatotoxicity) 1982 24 Rat (GW) 9 wk Other 15 30 (10% decreased body Barbolt and 12DMH 1x/wk weight gain) Abraham 1980 25 Gn pig (GW) 7-10 wk Hepatic 30 (hepatic necrosis Wilson 1976 12DMH 1x/wk and ascites) Other 30 (severely decreased body weight gain) 26 Mouse (F) 6 wk Other 0.74 1.4 (decreased food Visek et al. 12DMH ad lib consumption, body 1991 weight gain (25%), and relative organ weights in males) 27 Mouse (F) 5 mo Cardio 0.75 1.6 (myocytolysis, Visek et al. 12DMH ad lib fibrosis, and 1991 calcification) Hepatic 0.75" (mild hepatitis) 1.6 (hepatitis, centrilobular necrosis, and hepatocellular hypertrophy) Renal 0.75 1.6 (interstitial nephritis and pyelonephritis) Other 0.75 (small decreases in 1.6 (decreases in food food consumption, body weight gain (10%), and relative organ weights) consumption, body weight gain (28%), and relative organ weights) S103443 H1TV3H °C LT »»» LNIWWOD 2178Nd HOH 14VHA « « « TABLE 2-2. Levels of Significant Exposure to Hydrazines - Oral (continued) Exposure LOAEL (effect) Key to duration/ NOAEL Less serious Serious figure’ Species Route frequency System (mg/kg/day) (mg/kg/day) (mg/kg/day) Reference Form 28 Mouse (GW) 25 wk Other 1.1 (brown degeneration Biancifiori 1970 HS 1x/d of the adrenals in (inter- females) mittent) 9.3 (no effects on the thyroid) 29 Dog (GW) 4-10 wk Hepatic 5 (mild hepatic Wilson 1976 12DMH 1x/wk fibrosis, hemosiderosis, and ascites) 15 (hepatic failure) 30 Hamster (GW) 15-20 wk Hepatic 4.9 (cirrhosis, cell Biancifiori 1970 HS 1x/d proliferation, (inter- degenerative mittent) changes) Other 5.3 (no lesions in the thyroid or adrenals) 31 Pig (GW) 10 wk Hepatic 30 (focal megalocytosis Wilson 1976 12DMH 1x/wk and postfibrotic necrosis of the liver) Immunological 32 Rat (GW) 5 wk 27.1 Locniskar et al. 12DMH 1x/wk 1986 Neurological 33 Human (C) NS 0.2 (paresthesia, Ochoa et al. HS lethargy, nausea, 1975 vomiting, and sensorimotor abnormalities) 34 Human (C) 1-6 mo 0.6 (nausea, vomiting, Gershanovich et HS 3x/d dizziness, al. 1981 excitement, insomnia, and polyneuritic syndrome) S.1J3443 HIVaIH CT 8¢ TABLE 2-2. Levels of Significant Exposure to Hydrazines - Oral (continued) LOAEL (effect) Exposure Key to duration/ NOAEL Less serious Serious figure’ Species Route frequency System (mg/kg/day) (mg/kg/day) (mg/kg/day) Reference Form 35 Human (C) 1-47 d 0.6 (dizziness) Spremulli et al. HS 3x/d 1979 36 Human (c) 30d 0.7 (nausea, transient Chlebowski et HS 3x/d dizziness) al. 1984 Reproductive : 37 Mouse (GW) 25 wk 9.3 Biancifiori 1970 HS : 1x/d g (inter- > mittent) 3 3 38 Hamster (GW) 15-20 wk 5:3 Biancifiori 1970 HS X 1x/d 3 (inter- @ mittent) = 2 Cancer o s 39 Rat (GW) 10 wk 4.5 (CEL: liver Teague et al. 12DMH m 1x/wk angiosarcoma, 1981 = cholangioma, * hepatocel lular 3 carcinoma, bowel adenocarcinoma) 13.6 (CEL: ear canal papi l Loma) 40 Rat (GW) 4-8 wk 30 (CEL: colon and Wilson 1976 12DMH 1x/wk squamous cell carcinoma of the ear) 41 Rat (GW) 5 wk 27.1 (CEL: carcinomas Locniskar et al. 12DMH 1x/wk of the colon and 1986 small intestine) 42 Rat (GW) 10 wk 9 (CEL: colorectal Thorup et al. 12DMH 1x/wk adenoma, 1992 adenocarcinoma, and signet ring cell carcinoma) S103443 H1TV3H 'C 6¢ »%» LNIJWWOD 2118Nd HOH 14VHA » « TABLE 2-2. Levels of Significant Exposure to Hydrazines - Oral (continued) Exposure LOAEL (effect) Key to duration/ NOAEL Less serious Serious figure’ Species Route frequency System (mg/kg/day) (mg/kg/day) (mg/kg/day) Reference Form 43 Rat (W) <10 mo 4.2 (CEL: angiosarcoma Bedell et al. 12DMH of the liver and 1982 lung, hepatocellular carcinoma, renal adenoma and mesenchymal tumors) 44 Rat (GW) 10 wk 30 (CEL: Asano and 12DMH 1x/wk gastrointestinal Pollard 1978 adenocarcinomas) 45 Rat (GW) 9 wk 30 (CEL: Abraham et al. 12DMH 1x/wk gastrointestinal 1980 adenomas and adenocarcinomas) 46 Rat (G) 11 wk 3 (CEL: hemangioendo- Druckrey 1970 12DMH 1x/wk theliomas of the or 5d/wk liver) 21 (CEL: carcinomas of the colon, small intestine, and rectum) 47 Rat (GO) 5 wk 30 (CEL: adenomas Calvert et al. 12DMH 1x/wk and adenocarcinomas 1987 of the small intestine and colon) 48 Rat (GW) 9 wk 15 (CEL: colon adenoma Barbolt and 12DMH 1x/wk and adenocarcinoma) Abraham 1980 30 (CEL: duodenal adenocarcinoma) 49 Gn pig (GW) 7-10 wk 30 (CEL: hepatomas and Wilson 1976 12DMH 1x/wk bile duct cell carcinomas) 50 Mouse (GW) 40 wk 16.7 (CEL: lung adenomas Roe et al. 1967 H 5x/wk and adeno- carcinomas) S123443 H1VaH CT 0€ TABLE 2-2. Levels of Significant Exposure to Hydrazines - Oral (continued) Exposure LOAEL (effect) Key to duration/ NOAEL Less serious Serious figure’ Species Route frequency System (mg/kg/day) (mg/kg/day) (mg/kg/day) Reference Form 51 Mouse (GW) 40 wk 33 (CEL: lung adenomas Roe et al. 1967 11DMH 5x/wk and adeno- carcinomas) 52 Mouse (GW) 24 wk 30 (CEL: angiosarcomas Izumi et al. 12DMH 1x/wk predominantly in 1979 the liver, adenomas and adenocarcinomas : of the lungs and * large intestines, 5 and squamous cell - > carcinomas of the -) anus) 3 BS 53 Mouse (G) 4-11 mo 9 (CEL: adeno- Bhide et al. HS e 6x/wk carcinomas of the 1976 @ lungs and breast) 2 54 Mouse (W) 10-48 wk 1.9 (CEL: hemangiomas Izumi et al. 12DMH o and hemangioendo- 1979 theliomas m predominantly in 2 the liver, adenomas * and adenocarcinomas : of the lungs) 15.2 (CEL: adenomas and adenocarcinomas of the large intestine and squamous cell carcinomas of the anus) 55 Mouse (GW) 46 wk 9.3 (CEL: pulmonary Biancifiori and HS 1x/d adenomas and Ribacchi 1962 adenocarcinomas) 56 Mouse (GW) 25 wk 2.3 (CEL: hepatomas) Biancifiori 1970 HS 1x/d (inter- mittent) 57 Mouse (GW) 36 wk 9.2 (CEL: lung adenomas Biancifiori et HS 7d/wk adenocarcinomas, al. 1964 1x/d hepatomas) S103443 H1TV3H 'C LE TABLE 2-2. Levels of Significant Exposure to Hydrazines - Oral (continued) «»» LNIJWWWOD J178Nd HOH L4VHA « « « Exposure LOAEL (effect) Key to duration/ NOAEL Less serious Serious figure’ Species Route frequency System (mg/kg/day) (mg/kg/day) (mg/kg/day) Reference Form 58 Mouse (W) 33-48 wk 0.46 (CEL: lung adenomas Yamamoto and HS and adeno- Weisburger 1970 carcinomas) CHRONIC EXPOSURE Death 59 Mouse (W) Lifetime 0.95 (100% mortality Toth and Patil 12DMH by week 70) 1982 Systemic 60 Mouse (W) 2yr Resp 9.5 Steinhoff et al. HH ad lib Cardio 9.5 1990 Gastro 9:5 Musc/skel 9.5 Hepatic 9.5 Renal 9.5 Derm/oc 9.5 Other 1.9 9.5 (reduced body weight gain by 10%, and ruffled coats) Cancer 61 Rat (GW) 68 wk 12 (CEL: lung adenomas Biancifiori et HS 1x/d and carcinomas) al. 1966 (inter- mittent) 62 Mouse (W) Lifetime 1.9 (CEL: lung adenomas) Toth 1972b H 63 Mouse (G) 13-18 mo 9 (CEL: adeno- Bhide et al. HS 6x/wk carcinomas of the 1976 lungs and breast) 64 Mouse (W) Lifetime 5.6 (CEL: lung adenomas Toth 1969 HS ad lib and adeno- carcinomas) 65 Mouse (GW) 55 wk 9 (CEL: lung tumors) Maru and Bhide HS 5d/wk 1982 1x/d S103443 H1TV3H °C EE «xx LNIWWOD O118Nd HOd L4VHA «x « TABLE 2-2. Levels of Significant Exposure to Hydrazines - Oral (continued) LOAEL (effect) Exposure Key to duration/ NOAEL Less serious Serious figure’ Species Route frequency System (mg/kg/day) (mg/kg/day) (mg/kg/day) Reference Form 66 Mouse (W) Lifetime 19 (CEL: angiosarcomas Toth 1973a 11DMH ad lib predominantly in the liver, hepatomas, adenomas and adenocarcinomas of the lungs, and adenomas of the kidneys) 67 Mouse (W) Lifetime 0.059 (CEL: angiomas and Toth and Patil 12DMH angiosarcomas) 1982 68 Hamster (W) 2 yr 8.3 (CEL: hepatocellular Bosan et al. HS ad lib carcinoma, adrenal 1987 cortical adenoma) 69 Hamster (W) Lifetime 1.1 (CEL: angiosarcomas Toth 1972 12DMH predominantly in the liver) *The number corresponds to entries in Figure 2-2. Used to derive an intermediate oral Minimal Risk uncertainty factor of 1,000 (10 for use of a LOAEL, 12DMH = 1,2-dimethylhydrazine; 11DMH = 1,1-dimethylhydrazine; ad lib = CEL = cancer effect level; d = day(s); Derm/oc = dermal /ocular; (F) = Gd = gestation day(s); Gn pig = guinea pig; HH = hydrazine hydrate; LDs = lethal dose (50% kill); LOAEL = (GO) = gavage (oil); (GW) = gavage (water); H Level (MRL) of 8x10" mg/kg/day for 1,2-dimethylhydrazine; dose divided by an 10 for extrapolation from animals to humans, and 10 for human variability). ad libitum; (C) = capsule; Cardio = cardiovascular; feed; (G) = gavage (not specified); Gastro = gastrointestinal; = hydrazine; HS = hydrazine sulfate; Lowest -observed-adverse-effect level; mg/kg/day = milligram per kilogram per day; mo = month(s); Musc/Skel = musculoskeletal; NOAEL = no- observed-adverse-effect level; NS = not specified; Resp = Respiratory; (W) = drinking water; wk = week(s); x time(s); yr = year(s) S103443 H1TV3aH °C £€ »«x LNFWINOD J178Nd HOH 14VHA wus FIGURE 2-2 Levels of Significant Exposure to Hydrazines — Oral ACUTE (<14 Days) Systemic > A s° & Q & © & » 2 °F ¢ & (mg/kg/day) ® ¥ o* F* ® 1,000 ~ @% 3m in . [Ye Q 10s 100 ®: Or ® 6 Psa Oris Him Qe or $ 12r 10 — Hn 13 dprar 1 — 0.1— 0.01 ~~ 0.001 — 0.0001 |— Key d Dog HM L0s0 0.00001 |— g Guinea Pig @ LOAEL for serious effects (animals) s Hamster ( LOAEL for less serious effects (animals) 0.000001 — m Mouse O NOAEL (animals) r Rat AA LOAEL for serious effects (humans) 0.0000001 — p Pig A LOAEL for less serious effects (humans) 4 CEL - Cancer Effect Level (animals) 0.00000001 — The number next to each point corresponds to entries in Table 2-2. “Doses represent the lowest dose tested per study that produced a tumorigenic 0.000000001 response and do not imply the existence of a threshold for the cancer end point. S103443 H1TV3aH “¢ ve «x» LINIJWWOD O118Nd HO 1dVHA wv» FIGURE 2-2 Levels of Significant Exposure to Hydrazines — Oral (Continued) INTERMEDIATE (15-364 Days) Systemic 8 WW 2D o 2 & RY X $F @ (mg/kg/day) <7 FF Q¢ 1,000 — 100 — 16g 22p ® @ om ° @®25¢ ®3r 10 | @200 @ sr @ 204 92: @ im @ 20 @ 30s @ 2 ISH gn 27m @2/m 1 27m 27m Oa2mm i 01 | i 0.01 — ! i 0.001 |— 4 0.0001 |— Key d Dog Hl LDs50 0.00001 — g Guinea Pig @ LOAEL for serious effects (animals) s Hamster (D LOAEL for less serious effects (animals) 0.000001 — m Mouse QO NOAEL (animals) r Rat /\ LOAEL for serious effects (humans) | Pig A LOAEL for less serious effects (humans) 0.0000001 p @ CEL - Cancer Effect Level (animals) 0.00000001 — The number next to each point corresponds to entries in Table 2-2. ’ *Doses represent the lowest dose tested per study that produced a tumorigenic 0.000000001 L_ response and do not imply the existence of a threshold for the cancer end point. S103443 H1TV3H 'C S€ «++ LNIWWOD J178Nd HOH L4VHA wu FIGURE 2-2 Levels of Significant Exposure to Hydrazines — Oral (Continued) (mg/kg/day) ot 1,000 100 10 0.1 0.01 0.001 0.0001 0.00001 0.000001 0.0000001 0.00000001 0.000000001 — — INTERMEDIATE (15-364 Days) Systemic NS . » “© & ° & S&P » & & EF <& ® 2g 24 (Oar O 28m 3 2 Om Qaos QO 38s sm @27/m 26m (27m @ 28m Ax A» Asks Ax Key d Dog Ml Loso g Guinea Pig @ LOAEL for serious effects (animals) s Hamster ( LOAEL for less serious effects (animals) m Mouse O NOAEL (animals) r Rat A LOAEL for serious effects (humans) p Pig A LOAEL for less serious effects (humans) $ CEL - Cancer Effect Level (animals) The number next to each point corresponds to entries in Table 2-2. ‘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. S103443 HITV3IH ¢ 9g «ux LNIJWWOD 2118Nd HOH 14VHA wus FIGURE 2-2 Levels of Significant Exposure to Hydrazines — Oral (Continued) INTERMEDIATE (15-364 Days) < & Kd (mg/kg/day) © 1,000 — 100 — 0 5m $= wo Gar Qu Qs ow Qo Pu 50m 54m 39r 48r 10 53m @ ssn @sm 42r 39r 43r @ ar ; @ sim @ som @ som 0.11 0.01 — 0.001 |— 0.0001 |— Key d Dog HM Loso 0.00001 — g Guinea Pig @ LOAEL for serious effects (animals) s Hamster (D LOAEL for less serious effects (animals) 0.000001 — m Mouse oO NOAEL (animals) r Rat /\ LOAEL for serious effects (humans) 0.0000001 F— p Pig A LOAEL for less serious effects (humans) ) @ CEL - Cancer Effect Level (animals) 0.00000001 — The number next to each point corresponds to entries in Table 2-2. *Doses represent the lowest dose tested per study that produced a tumorigenic 0.000000001 N response and do not imply the existence of a threshold for the cancer end point. S103443 H1TV3H 'C LE +++ INIWWOD J178Nd HO4 L4VHA ww FIGURE 2-2 Levels of Significant Exposure to Hydrazines — Oral (Continued) CHRONIC (2365 Days) Systemic N 3 F&F » & & & & O < RS Q &° a° & A N & & & > (mg/kg/day) XP & w® cid 1,000 ~ 100 — 10 Oem Qem Qsm Qeom Qeom Oeom eom (om onde Poin em $i Qe6om ou ® — —@ 59m 0.1— $e 0.04 7 0.001 — 0.0001 |— Koy 10 104 0.00001 — | d Dog MH Loso Estimated Estimated g Guinea Pig @ LOAEL for serious effects (animals) 10-6 — Upper-Bound 10 10-6 —-{ Upper-Bound 0.000001 — s Hamster @ LOAEL for less serious effects (animals) Human Estraled Human ] m Mouse O NOAEL (animals) | Cancer 5 UpverBoung 10° Cancer r Rat A LOAEL for serious effects (humans) 10 Risk Levels 10” a Risk Levels 0.0000001 [— p Pig A LOAEL for less serious effects (humans) forH c 7 for 11DMH $ CEL — Cancer Effect Level (animals) 107 10-6 Road! og 10~ 0.00000001 — The number next to each point corresponds to entries in Table 2-2. for 12DMH ‘Doses represent the lowest dose tested per study that produced a tumorigenic 7 0.000000001 response and do not imply the existence of a threshold for the cancer end point. 10 S103443 H1TV3H 2 8€ 39 2. HEALTH EFFECTS Respiratory Effects. No adverse histological effects were observed in the lungs of mice exposed to 9.5 mg/kg/day hydrazine via the drinking water for 2 years (Steinhoff et al. 1990). No other studies were located regarding respiratory effects in animals ingesting hydrazines. Cardiovascular Effects. Focal myocytolysis, fibrosis, and calcification of the heart were observed in mice receiving 1.6 mg/kg/day 1,2-dimethylhydrazine in the feed for 5 months (Visek et al. 1991). These effects were not observed in mice receiving 0.75 mg/kg/day. No adverse histological effects were observed in the hearts of mice receiving 9.5 mg/kg/day hydrazine in the drinking water for 2 years (Steinhoff et al. 1990). These data are too limited to make firm conclusions regarding the cardiovascular effects of hydrazines. Gastrointestinal Effects. Although oral exposure to hydrazine has produced nausea in humans, this effect is probably due to effects on the central nervous system and is therefore discussed in Section 2.2.2.4. Proliferative foci were noted in the colons of rats receiving 2 doses of 25 mg/kg 1,2-dimethylhydrazine within a 4-day period (Caderni et al. 1991). No adverse histological effects were observed in the gastrointestinal tracts of mice receiving 9.5 mg/kg/day hydrazine in the drinking water for 2 years (Steinhoff et al. 1990). These data are too limited to make firm conclusions regarding the gastrointestinal effects of hydrazines. Hematological Effects. No studies were located regarding the hematological effects in animals after oral exposure to hydrazines. Musculoskeletal Effects. No adverse effects were observed in the muscle tissue of mice receiving 9.5 mg/kg/day hydrazine in the drinking water for 2 years (Steinhoff et al. 1990). No other studies were located regarding the effects of hydrazines on the musculoskeletal system. Hepatic Effects. A number of studies in animals have reported effects on the liver after oral exposure to hydrazines. In rats and mice, relatively mild effects on the liver such as megamitochondria formation, increased lipogenesis, and fatty changes occurred following acute exposure to 49-650 mg/kg/day hydrazine (Marshall et al. 1983; Preece et al. 1992; Wakabayashi et al. 1983). More notable effects, including degeneration, hemorrhage, and necrosis of the liver, were observed in dogs administered weekly doses of 60 mg/kg 1,2-dimethylhydrazine for 2 weeks (Wilson 1976). Intermediate duration exposure to 1,2-dimethylhydrazine produced liver damage (hemosiderosis, necrosis, hepatitis, fibrosis, ascites and/or failure) in rats receiving 4.2 mg/kg/day (Bedell et al. 1982), guinea pigs receiving 30 mg/kg/day or more (Wilson 1976), mice receiving 0.75 mg/kg/day or more (Visek et al. 1991), dogs receiving 5 mg/kg/day or more (Wilson 1976), and pigs receiving 30 mg/kg/day (Wilson 1976). Cirrhosis, reticuloendothelial cell proliferation, bile duct proliferation, and degenerative fibrous cells were observed in the livers of hamsters exposed to 4.9 mg/kg/day hydrazine for 15-20 weeks (Biancifiori 1970). No adverse effects were observed in the livers of mice receiving 9.5 mg/kg/day hydrazine for 2 years (Steinhoff et al. 1990). Collectively, these data indicate that hydrazine and 1,2-dimethylhydrazine are hepatotoxic by the oral route. Based on a LOAEL of 0.75 mg/kg/day for hepatic effects in mice (Visek et al. 1991), an intermediate oral MRL of 8x10" mg/kg/day was calculated for 1,2-dimethylhydrazine as described in footnote "b" in Table 2-2. Renal Effects. Interstitial nephritis and pyelonephritis were observed in mice receiving 1.6 mg/kg/day 1,2-dimethylhydrazine in feed for 5 months (Visek et al. 1991). These effects were not observed in mice similarly exposed to 0.75 mg/kg/day 1,2-dimethylhydrazine. No adverse effects were noted in the kidneys of mice receiving 9.5 mg/kg/day hydrazine in the drinking water for 2 years (Steinhoff et al. 1990). These data are too limited to make firm conclusions, but suggest that 1,2-dimethylhydrazine is toxic to the kidneys, whereas hydrazine is not. Dermal/Ocular Effects. No adverse effects were observed in the skin and eyes of mice receiving 9.5 mg/kg/day hydrazine in the drinking water for 2 years (Steinhoff et al. 1990). No other studies were located regarding dermal/ocular effects in animals after oral exposure to hydrazines. *** DRAFT FOR PUBLIC COMMENT *** 40 2. HEALTH EFFECTS Other Systemic Effects. Body weight loss and decreased body weight gain were reported in animals exposed orally to 1,2-dimethylhydrazine and hydrazine. Weight loss was noted in dogs receiving 2 weekly doses of 60 mg/kg/day (Wilson 1976). Decreased body weight gains were reported for intermediate duration exposure to 1,2-dimethylhydrazine for rats receiving 30 mg/kg/day (Barbolt and Abraham 1980), guinea pigs receiving 30 mg/kg/day (Wilson 1976), and in mice receiving 0.75 mg/kg/day or more (Visek et al. 1991). Decreased body weight gain was also noted in mice chronically exposed to 9.5 mg/kg/day hydrazine in the drinking water for 2 years (Steinhoff et al. 1990). No significant effect on body weight gain was noted in mice receiving 1.9 mg/kg/day. Decreases in body weight were often accompanied by decrements in food intake, organ weights, and altered physical appearance, and therefore probably represent signs of general toxicity. In some cases, decreased body weight gain may be secondary to an underlying disease (e.g., cancer). Degeneration of the adrenals was noted in female mice exposed to 1.1 mg/kg/day or more hydrazine for 25 weeks (Biancifiori 1970). No adverse effects were noted in the thyroid of mice exposed to 9.3 mg/kg/day hydrazine for 25 weeks. Similarly, no effects were observed in the thyroid or adrenals of hamsters exposed to 5.3 mg/kg/day hydrazine for 15-20 weeks (Biancifiori 1970). 2.2.2.3 Immunological Effects No studies were located regarding immunological effects in humans after oral exposure to hydrazines. A single study in rats reported that splenic natural killer cell activity was not affected after exposure to 27.1 mg/kg/day 1,2-dimethylhydrazine once a week for 5 weeks (Locniskar et al. 1986). This NOAEL value is recorded in Table 2-2 and plotted in Figure 2-2. 2.2.2.4 Neurological Effects Ingestion of hydrazine (estimated between a mouthful and a cupful) resulted in several neurological effects including episodes of violent behavior, ataxia, coma, convulsions, hypesthesia of the hands, and paraesthesia of the arms and legs (Reid 1965). Confusion, lethargy, restlessness, paresthesia, and neurogenic atrophy were observed in a 24-year-old male who swallowed a mouthful of hydrazine (Harati and Niakan 1986). Hydrazine has been used as a chemotherapeutic agent in human cancer patients. Neurological side effects have been observed in some human cancer patients (4-50%) treated with 0.2-0.7 mg/kg/day hydrazine as hydrazine sulfate for intermediate durations (Chlebowski et al. 1984; Gershanovich et al. 1976, 1981; Ochoa et al. 1975; Spremulli et al. 1979). For the most part, the neurological effects were relatively mild (lethargy, nausea, vomiting, dizziness, excitement, insomnia); however, two studies reported more serious effects (paresthesia, sensorimotor abnormalities, polyneuritis) (Gershanovich et al. 1976; Ochoa et al. 1975). The appearance of more serious effects in these two studies may be related to increased exposure duration. For example, Gershanovich et al. (1976, 1981) noted that polyneuritis developed only in patients receiving uninterrupted treatment with hydrazine for 2-6 months. The treatment duration used by Chlebowski et al. (1984) and Spremulli et al. (1979), which was less than 2 months in both studies, may have been sufficiently short enough to prevent the development of more serious neurological effects. Limitations in the findings of these studies lie in the fact that the test subjects were generally not healthy prior to hydrazine exposure. Therefore it is possible that some of the observed effects may be attributable to the underlying disease. However, taken together, these studies strongly suggest that the central nervous systems is a target of hydrazine in humans after oral exposure. The highest NOAEL values and all LOAEL values for neurological effects resulting from oral exposure to hydrazines are recorded in Table 2-2 and plotted in Figure 2-2. No studies were located regarding the neurological effects in animals after oral exposure to hydrazines. 2.2.2.5 Reproductive Effects No studies were located regarding the reproductive effects in humans after oral exposure to hydrazines. *** DRAFT FOR PUBLIC COMMENT *** 41 2. HEALTH EFFECTS A single animal study reported no histopathological lesions in the ovaries of mice and hamsters exposed to 9.3 or 5.3 mg/kg/day hydrazine, respectively, for 15-25 weeks (Biancifiori 1970). However, the findings of this study are limited since reproductive function was not assessed. These NOAEL values for reproductive effects are recorded 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 after oral exposure to hydrazines. A single study in hamsters reported no evidence of developmental toxicity or teratogenicity following exposure to a single dose of 166 mg/kg hydrazine or 68 mg/kg 1,2-dimethylhydrazine on day 12 of gestation (Schiller et al. 1979). Although these data are limited, they suggest that fetal development is not adversely affected by hydrazine or 1,2-dimethylhydrazine. These NOAEL values for developmental effects resulting from oral exposure to hydrazines are recorded in Table 2-2 and plotted in Figure 2-2. 2.2.2.7 Genotoxic Effects No studies were located regarding genotoxic effects in humans after oral exposure to hydrazines. Alkylation of liver DNA was reported in rats acutely exposed to 30-90 mg/kg hydrazine for 1-3 days (Becker et al. 1981; Bosan et al. 1986). Micronuclei were observed in the bone marrow of mice exposed to a single oral dose of 10-50 mg/kg 1,2-dimethylhydrazine (Albanese et al. 1988; Ashby and Mirkova 1987). However, micronuclei were not observed in the bone marrow of rats after a single oral dose of 50-80 mg/kg 1,2-dimethylhydrazine (Ashby and Mirkova 1987). These data indicate that hydrazine and 1,2-dimethylhydrazine are genotoxic by the oral route. Furthermore, species differences may exist between rats and mice regarding their sensitivity to the genotoxic effects of 1,2-dimethylhydrazine. Other genotoxicity studies are discussed in Section 2.4. 2.2.2.8 Cancer No studies were located regarding carcinogenic effects in humans after oral exposure to hydrazines. Adenomas and adenocarcinomas of the colon have been observed in rats following a single oral exposure to 15.8-30 mg/kg 1,2-dimethylhydrazine (Craven and DeRubertis 1992; Schiller et al. 1980; Watanabe et al. 1985). Colon tumors are not common to rats, and were not observed in the control animals of these studies. Several tumor types have been observed in animals after intermediate-duration exposure to hydrazines. Exposure to 0.46-16.7 mg/kg/day hydrazine for 24-48 weeks produced a statistically significant increase in the incidence of lung, liver, and breast tumors in mice (Bhide et al. 1976; Biancifiori 1970; Biancifiori and Ribacchi 1962; Biancifiori et al. 1964; Roe et al. 1967; Yamamoto and Weisburger 1970). A single study also reported an increased incidence of lung tumors in mice after exposure to 33 mg/kg/day 1,1-dimethylhydrazine for 40 weeks (Roe et al. 1967). A large number of studies have reported tumors in rodents after intermediate exposure to 1,2-dimethylhydrazine. Statistically significant increases were reported for tumor incidences of the blood vessels (Bedell et al. 1982; Druckrey 1970; Izumi et al. 1979; Teague et al. 1981), liver (Bedell et al. 1982; Teague et al. 1981; Wilson 1976), lung (Izumi et al. 1979), kidney (Bedell et al. 1982), ear duct (Teague et al. 1981; Wilson 1976), and most notably the intestines, colon, and anus (Abraham et al. 1980; Asano and Pollard 1978; Barbolt and Abraham 1980; Calvert et al. 1987; Druckrey 1970; Izumi et al. 1979; Locniskar et al. 1986; Teague et al. 1981; Thorup et al. 1992; Wilson 1976). Doses of 1,2-dimethylhydrazine resulting in increased tumor incidence ranged from 1.9 mg/kg/day to 30 mg/kg/day. *** DRAFT FOR PUBLIC COMMENT *** 42 2. HEALTH EFFECTS Chronic oral exposure to hydrazines has also resulted in statistically significant increases in the incidence of tumors in rodents. Exposure to 1.9-12 mg/kg/day hydrazine resulted in lung tumor formation in rats and mice (Biancifiori et al. 1966; Bhide et al. 1976; Maru and Bhide 1982; Toth 1969, 1972b). In hamsters, exposure to 8.3 mg/kg/day hydrazine produced an increased incidence of liver and kidney tumors (Bosan et al. 1987). The difference in target organ specificity for the carcinogenic effects of hydrazine may represent an important species difference between hamsters and other laboratory rodents. Several tumor types, including those of the blood vessels, lung, kidney, and liver were noted at elevated incidences in mice chronically exposed to 19 mg/kg/day 1,1-dimethylhydrazine in the drinking water (Toth 1973a). Studies have reported a statistically significant increase in the incidence of blood vessel tumors in mice exposed to 0.059 mg/kg/day 1,2-dimethylhydrazine (Toth and Patil 1982) and in hamsters exposed to 1.1 mg/kg/day 1,2-dimethylhydrazine in the drinking water for life (Toth 1972c¢). Collectively, these data indicate that hydrazines are carcinogenic by the oral route following acute, intermediate, or chronic exposure, and are capable of producing tumors in multiple tissue sites in several different animal species. Clearly, 1,2-dimethylhydrazine is the most potent carcinogen of the three hydrazines, since significant tumor incidences have been reported following single doses (Craven and DeRubertis 1992; Schiller et al. 1980; Watanabe et al. 1985) and at very low chronic doses (Toth and Patil 1982). Hydrazine and 1,1-dimethylhydrazine are less potent carcinogens, producing tumors primarily in the lungs (Bhide et al. 1976; Biancifiori et al. 1966; Maru and Bhide 1982; Roe et al. 1967). All CEL values from each reliable study resulting from oral exposure to hydrazines are recorded in Table 2-2 and plotted in Figure 2-2. The EPA has derived oral slope factors of 30 (mg/kg/day)’ for hydrazine based on liver tumors, 2.6 (mg/kg/day)" for 1,1-dimethylhydrazine based on tumors of the cardiovascular system, and 37 (mg/kg/day)" for 1,2-dimethylhydrazine based on tumors of the cardiovascular system (HEAST 1992; IRIS 1993). Doses of hydrazine, 1,1-dimethylhydrazine, and 1,2-dimethylhydrazine corresponding to excess cancer risks of 10% to 107 are shown in Figure 2-2. 2.2.3 Dermal Exposure 2.2.3.1 Death No studies were located regarding lethal effects in humans after dermal exposure to hydrazines. In rabbits and guinea pigs, the dermal LDy, values ranged from 93-190 mg/kg, 1,341-1,680 mg/kg, and 158-563 mg/kg for hydrazine, 1,1-dimethylhydrazine, and 1,2-dimethylhydrazine, respectively (Rothberg and Cope 1956). One out of four dogs administered a single dermal dose of 300 mg/kg 1,1-dimethylhydrazine died 6 hours after exposure (Smith and Clark 1971). All dogs (3/3) exposed to a single dermal dose of 1,800 mg/kg 1,1-dimethylhydrazine died within 6 hours. In dogs exposed to hydrazine, 2/3 died following exposure to a single dermal dose of 96 mg/kg (Smith and Clark 1972). Additional deaths were noted in this study at higher dermal doses of hydrazine. These data indicate that acute dermal exposure to large doses of hydrazines can be lethal. These LOAEL values are recorded in Table 2-3. 2.2.3.2 Systemic Effects No studies were located regarding respiratory, cardiovascular, gastrointestinal, musculoskeletal, hepatic, renal, or other systemic effects in humans or animals after dermal exposure to hydrazines. All LOAEL values for hematological and dermal/ocular effects from each reliable study are recorded in Table 2-3. *** DRAFT FOR PUBLIC COMMENT *** TABLE 2-3. Levels of Significant Exposure to Hydrazines - Dermal Exposure LOAEL (effect) duration/ NOAEL Less serious Serious Species frequency System Reference Form ACUTE EXPOSURE Death Rabbit Once 563 (LD50) Rothberg and 12DMH mm’/kg Cope 1956 . Rabbit Once 1341 (LD50) Rothberg and 11DMH 3 mm’/kg Cope 1956 § Rabbi t Once , 93 (LD50) Rothberg and H 5 mm°/kg Cope 1956 3 Gn pig Once 190 (LD50) Rothberg and H o mm’/kg Cope 1956 T c @ Gn pig Once 1680 (LD50) Rothberg and 11DMH 5 mm’/kg Cope 1956 Q 2 Gn pig Once 158 (LD50) Rothberg and 12DMH 3 mm’/kg Cope 1956 m 2 Dog Once 300 (1/4 deaths) smith and Clark 11DMH * mg/kg 1971 * * Dog Once 96 (2/3 deaths) Smith and Clark H mg/kg 1972 Systemic Human Once Derm/oc 1% (positive eczematous van Ketel 1964 HH HS reaction in patch test) Human Once Derm/oc 0.0005% (contact dermatitis) Suzuki and HS HH Ohkido 1979 Human Once Derm/oc 1% (eczematous reaction Frost and Hjorth H to patch test) 1959 S103443 H1TV3IH 'C £v » x» LNJWWOD O178Nd HOH L4VHA «x» TABLE 2-3. Levels of Significant Exposure to Hydrazines - Dermal (continued) Exposure LOAEL (effect) duration/ NOAEL Less serious Serious Species frequency System (mg/kg/day) (mg/kg/day) (mg/kg/day) Reference Form Human (occup) Derm/oc 1% (contact dermatitis) Wrangsjo and HS Martensson 1986 Human (occup) Derm/oc 0.03% (allergic contact Hovding 1967 HH HS dermatitis) Rabbit Once Derm/oc 3 (corneal damage, Rothberg and H uL conjunctivitis, Cope 1956 erythema of eyelids) Rabbit Once Derm/oc 93 (skin discoloration) Rothberg and H mm’/kg Cope 1956 Rabbit Once Derm/oc 3 (mild conjunctivitis Rothberg and 12DMH uL and erythema of Cope 1956 eyelids) Rabbit Once Derm/oc 3 (mild conjunctivitis Rothberg and 11DMH uL and erythema of Cope 1956 eyelids) Gn pig Once Derm/oc 190 (skin discoloration) Rothberg and H mm’/kg Cope 1956 Dog Once Hemato 300 (decreased smith and 11DMH mg/kg thromboplastin Castaneda 1970 generation time) Derm/oc 300 (corneal swelling) mg/kg Dog Once Derm/oc 300 (slight irritation Smith and Clark 11DMH mg/kg of the skin) 1971 Dog Once Derm/oc 96 (discoloration and Smith and Clark H mg/kg edema of the skin) 1972 11DMH = 1,1-dimethylhydrazine; 12DMH = 1,2-dimethylhydrazine; Derm/oc = dermal/ocular; Gn pig = guinea pig; H = hydrazine; Hemato = hematological; HH = hydrazine hydrate; HS = hydrazine sulfate; LD50 = lethal dose (50% kill); LOAEL = lowest-observed-adverse-effect level; mg/kg = milligram per kilogram; mm’/kg = cubic millimeters per day; NOAEL = no-observed-adverse-effect level; (Occup) = occupational; pL = microliter(s) S103443 H1TV3IH °C 45 2. HEALTH EFFECTS Hematological Effects. No studies were located regarding hematological effects in humans after dermal exposure to hydrazines. Data in animals regarding hematological effects are limited to a single study. A decreased thromboplastin generation time was noted in dogs exposed to a single dose of 300 mg/kg 1,1-dimethylhydrazine (Smith and Castaneda 1970). No other blood coagulation parameters were significantly affected. Dermal/Ocular Effects. Dermal exposure to hydrazine produces contact dermatitis. A number of studies have reported contact dermatitis in humans after dermal exposure to solutions containing 0.00005% to 1% hydrazine (Frost and Hjorth 1959; Hovding 1967; Suzuki and Ohkido 1979; Van Ketel 1964; Wrangsjo and Martensson 1986). These studies clearly indicate that hydrazine is a sensitizing agent. A single application of 3 pL of hydrazine, 1,1-dimethylhydrazine, or 1,2-dimethylhydrazine directly to the eyes produced conjunctivitis and erythema of the eyelids in rabbits (Rothberg and Cope 1956). Corneal damage was also noted in rabbits exposed to hydrazine, but not in rabbits exposed to 1,1-dimethylhydrazine or 1,2-dimethylhydrazine. Exposure to a single dermal dose of 93-190 mg/kg hydrazine resulted in discoloration of the exposed area in rabbits and guinea pigs (Rothberg and Cope 1956). Dermal discoloration and edema of the skin (application area) were observed in dogs dermally exposed to a single dose of 96 mg/kg hydrazine or more (Smith and Clark 1972). Discoloration was also observed in dogs after dermal exposure to a single dose of 300 mg/kg 1,1-dimethylhydrazine (Smith and Clark 1971). Dermal exposure to a single dose of 5 mmole/kg 1,1-dimethylhydrazine produced corneal swelling in dogs (Smith and Castaneda 1970). Although the ocular effects observed in this study may have resulted from hydrazine that was absorbed systemically, it is also possible that direct exposure of the eyes to hydrazine vapors was responsible for this effect. These data indicate that hydrazine and 1,1-dimethylhydrazine are skin irritants, and that all three hydrazines can produce effects on the eyes. 2.2.3.3 Immunological Effects Data regarding the immunological effects of hydrazines in humans after dermal exposure are limited to a single case study. A female laboratory worker intermittently exposed to an undetermined amount of hydrazine developed a lupus erythematosus-like disease (Reidenberg et al. 1983). Symptoms included a photosensitive rash, fatigue, anthragias, and a breaking off of frontal hair. The subject also possessed antinuclear antibodies and antibody to DNA. A positive skin patch test response was obtained after a dermal challenge to hydrazine was administered. The authors concluded that hydrazine can induce a lupus erythematosus-like disease in predisposed persons. In support of this view, a number of other hydrazine derivatives have been linked to the induction of lupus erythematosus in humans (Pereyo 1986). As discussed in Section 2.2.3.2, dermal exposure to hydrazine also produces allergic contact dermatitis in humans. No data were located regarding the immunological effects in animals after dermal exposure to hydrazines. 2.2.3.4 Neurological Effects Data regarding neurological effects of hydrazines in humans after dermal exposure to hydrazines are limited to two case studies. A man who suffered burns during an industrial hydrazine explosion became comatose 14 hours after the explosion (Kirklin et al. 1976). Rapid recovery from the coma was facilitated by pyridoxine treatment. Another man who suffered burns during an industrial 1,1-dimethylhydrazine explosion exhibited abnormal EEG readings and narcosis within 40 hours after exposure (Dhennin et al. 1988). Recovery from these symptoms was also facilitated by pyridoxine treatment. Several months after the incident the latter worker developed polyneuritis. The findings from these studies are limited because the subjects were burn patients. The trauma from the burns may have played a role in some of the neurological effects observed. In addition, pyridoxine is also known to produce neurological effects at high doses, and may have been partially responsible for the delayed polyneuritis. *** DRAFT FOR PUBLIC COMMENT *** 46 2. HEALTH EFFECTS Mild convulsions were noted in 3/13 dogs receiving a single dermal dose of 300-1800 mg/kg 1,1-dimethylhydrazine (Smith and Clark 1971). Similarly, convulsions were noted in 3/25 dogs administered a single dermal dose of 96-480 mg/kg hydrazine (Smith and Clark 1972). The data from animal studies support the findings of the human case studies which indicate that hydrazine and 1,1-dimethylhydrazine adversely affect the central nervous system following large dermal exposures. No studies were located regarding the following effects in humans or animals after dermal exposure to hydrazines: 2.2.3.5 Reproductive Effects 2.2.3.6 Developmental Effects 2.2.3.7 Genotoxic Effects Genotoxicity studies are discussed in Section 2.4. 2.2.3.8 Cancer No studies were located regarding cancer effects in humans or animals after dermal exposure to hydrazines. 2.3 TOXICOKINETICS Overview No data were located regarding the toxicokinetics of hydrazines in humans after inhalation, oral, or dermal exposure to hydrazines. Inhalation, oral, and dermal studies in animals indicate that hydrazines are rapidly absorbed into the blood. Animal studies also indicate that hydrazines readily distribute to tissues without preferential accumulation at any specific site. Hydrazines with a free amino group are able to react with endogenous alpha-keto acids, and in so doing produce a variety of adverse health effects. In vivo and in vitro studies indicate that hydrazines are metabolized by several pathways, both enzymatic and nonenzymatic. Free radical and carbonium ion intermediates are produced during the metabolism of hydrazines, and may also be involved in adverse health effects produced by exposure to hydrazines. Limited data from animal studies indicate that metabolites of hydrazines are excreted principally in the urine and expired air. 2.3.1 Absorption 2.3.1.1 Inhalation Exposure No studies were located regarding absorption in humans after inhalation exposure to hydrazines. A single study was located which investigated the absorption of hydrazine in the lungs. Groups of 8 rats were exposed to concentrations of 10, 60, or 500 ppm hydrazine in a nose-only chamber of 1 hour (Llewellyn et al. 1986). Based on the levels of hydrazine and its metabolites excreted in the urine within 48 hours, the absorption of hydrazine was estimated to be at least 8.4-29.5%. However, because a large percentage of the dose may have been retained in the body or excreted by fecal or pulmonary routes, absorption in the lungs is probably significantly higher than 8.4-29.5%. 2.3.1.2 Oral Exposure No studies were located regarding absorption in humans after oral exposure to hydrazines. *** DRAFT FOR PUBLIC COMMENT *** 47 2. HEALTH EFFECTS A single study in animals was located which investigated the oral absorption of hydrazine. Groups of 15 rats were administered a single dose of hydrazine, ranging from 2.9-81 mg/kg (Preece et al. 1992). Based on the levels of hydrazine and its metabolites excreted in the urine within 24 hours, at least 19-46% of the administered dose was absorbed. However, since the analytical method employed in this study cannot detect certain metabolites of hydrazine, and since 24 hours may have been too short a time period to collect all urinary metabolites, the absorption of hydrazine in the gastrointestinal tract is most likely higher than 19-46%. 2.3.1.3 Dermal Exposure No studies were located regarding absorption in humans after dermal exposure to hydrazines. Two studies in dogs reported that hydrazine and 1,1-dimethylhydrazine were detected in the blood within 30 seconds of exposure to a single dermal dose (Smith and Clark 1971, 1972). In dogs exposed to a single dermal dose of 96-480 mg/kg hydrazine reported maximum levels of hydrazine in the blood (approximately 70 pg/L) 3 hours after exposure (Smith and Clark 1972). Similarly, in dogs exposed to a single dermal dose of 300-1,800 mg/kg 1,1-dimethylhydrazine, the highest levels of 1,1-dimethylhydrazine (approximately 130 pg/mL) were detected 3 hours after exposure (Smith and Clark 1971). These data indicate that hydrazine and 1,1-dimethylhydrazine are rapidly absorbed from the skin into the blood. However, these studies do not provide enough information to estimate the extent to which hydrazine and 1,1-dimethylhydrazine are absorbed. 2.3.2 Distribution 2.3.2.1 Inhalation Exposure No studies were located regarding distribution in humans or animals after inhalation exposure to hydrazines. 2.3.2.2 Oral Exposure No studies were located regarding distribution in humans after oral exposure to hydrazines. A single study in animals reported limited information on the distribution of hydrazine after oral exposure. Following a single oral dose of 2.9-81 mg/kg hydrazine, peak levels of hydrazine in the plasma and liver of rats were achieved within 30 minutes (Preece et al. 1992). These levels ranged from approximately 1-2.5 nmol/mL and 1.3-2.3 nmol/g, respectively. The levels of hydrazine in other tissues were not reported. 2.3.2.3 Dermal Exposure No studies were located regarding distribution in humans or animals after dermal exposure to hydrazines. 2.3.2.4 Other Routes of Exposure No studies were located regarding distribution in humans after exposure to hydrazines by other routes. In rats administered a single dose of 9.9 mg/kg hydrazine by subcutaneous injection, hydrazine was observed to rapidly distribute to tissues (Kaneo et al. 1984). Maximum tissue levels were observed within 30 minutes in the liver, lung, plasma, and particularly the kidney. Hydrazine was detected in the brain of rats at levels of 0.5-1 ug/g following intravenous injection of 5.1 mg/kg hydrazine (Matsuyama et al. 1983). The levels of hydrazine in various tissues in rats were reported to decrease with half-times ranging from 2.3 to 3.3 hours (Kaneo et al. 1984). In a series of experiments, groups of rats, rabbits, cats, dogs, and monkeys were administered a single intraperitoneal dose of 1,1-dimethylhydrazine ranging from 10 to 50 mg/kg (Back et al. 1963). The plasma levels of 1,1-dimethylhydrazine in all species reached maximum values within 1 hour of the injection, *** DRAFT FOR PUBLIC COMMENT *** 48 2. HEALTH EFFECTS accounting for up to 14.3% of the dose in dogs and 8.7% of the dose in cats. Plasma levels were not detectable in rats after 2-24 hours, indicating that 1,1-dimethylhydrazine was rapidly distributed to tissues or was excreted. Plasma levels in monkeys tended to drop off after 1 hour and were not detectable after 24 hours. In a limited study, male rats were subcutaneously injected with 50 mg/kg 1,1-dimethylhydrazine or 100 mg/kg 1,2-dimethylhydrazine (Fiala and Kulakis 1981). Plasma levels of these two hydrazines decreased rapidly after exposure, with half-times of approximately 1 hour for each chemical. In rats administered a single dose of 0.78-80 mg/kg 1,1-dimethylhydrazine by intraperitoneal injection, approximately 71.1% of the dose was retained in the body after 4 hours (Mitz et al. 1962), and approximately 7.1-38.7% of the dose was retained in the body after 53 hours (Dost et al. 1966). Low levels of 1,1-dimethylhydrazine (approximately 0.1-3.1% of the dose) were detected in tissues (brain, liver, kidney, heart, blood) of rats administered a single dose of 11-60 mg/kg 1,1-dimethylhydrazine by intraperitoneal injection (Mitz et al. 1962; Reed et al. 1963). Preferential accumulation of 1,1-dimethylhydrazine was not observed in any organ. Although higher concentrations of 1,1-dimethylhydrazine were detected in the liver and colon of rabbits within 2 hours after receiving a single intravenous or intraperitoneal dose (Back et al. 1963), this was not judged to be evidence of preferential accumulation by the authors. The highest levels in these rabbits were detected in the liver (8.9%) and colon (11.6%) after 2 hours, whereas other tissue levels ranged from 0.02-4.18% of the dose. These data indicate that hydrazines distribute rapidly to all tissues without preferential accumulation following injection of a single dose. Furthermore, tissue levels of hydrazine and 1,1-dimethylhydrazine tend to reach maximal values within 1 hour and are generally not detectable after 24 hours. 2.3.3 Metabolism Several enzymatic and nonenzymatic pathways are involved in the metabolism of hydrazines. Although the extent to which each pathway contributes to total metabolism may depend somewhat on the route of exposure (a first-pass metabolic effect for oral exposure, for example), the types of pathways involved and metabolites formed do not appear to be dependent on route. Therefore this section discusses the data without reference to route of exposure. While the metabolic pathways of hydrazine, 1,1-dimethylhydrazine, and 1,2-dimethylhydrazine are similar in some ways, there are some important differences. Therefore, data from in vivo and in vitro studies regarding the metabolism of hydrazine, 1,1-dimethylhydrazine, and 1,2-dimethylhydrazine are discussed separately, below. Hydrazine. In rats exposed to 10-500 ppm hydrazine for 1 hour, approximately 2-10% of the inhaled dose was excreted in the urine unchanged, 1.7-4% as acetyl hydrazine, and 4.5-11.4% as diacetyl hydrazine (Llewellyn et al. 1986). In rats exposed to a single dose of 16-64 mg/kg hydrazine, approximately 20% was excreted in the urine as an unspecified hydrazine derivative, 30% was excreted in the urine unchanged, and 25% of the nitrogen in hydrazine was released in expired air as nitrogen gas (Springer et al. 1981). In rats administered a single dose of 2-81 mg/kg hydrazine, a small percentage of the dose (1-19%) was recovered in the urine as acetyl hydrazine and/or diacetyl hydrazine within 24-48 hours of exposure (Kaneo et al. 1984; Llewellyn et al. 1986; Preece et al. 1992). Following exposure to larger doses of 427 mg/kg hydrazine, a number of metabolites were excreted in the urine, including acetyl hydrazine, diacetyl hydrazine, pyruvate hydrazone, urea, and a cyclic compound (1,4,5,6-tetrahydro-6-oxo-3-pyridazine carboxylic acid, a product of the reaction between 2-oxoglutarate and hydrazine) (Preece et al. 1991). These data indicate that hydrazine undergoes acetylation and can react with cellular molecules in vivo. Hydrazine is rapidly metabolized by rat liver microsomes in vitro (Timbrell et al. 1982). Oxygen, nicotinamide-adenine dinucleotide phosphate (NADPH), and active enzyme were required for maximal activity. Metabolism of hydrazine by rat liver hepatocytes was increased when rats were pretreated with cytochrome P-450 inducers (phenobarbital and rifampicin), and was decreased by the addition of cytochrome P-450 inhibitors (metyrapone and piperonyl butoxide) (Noda et al. 1987). Cytochrome P-450 inhibitors and inducers were also reported to increase and decrease hydrazine toxicity, respectively, indicating a relationship between *** DRAFT FOR PUBLIC COMMENT *** 49 2. HEALTH EFFECTS metabolism and toxicity (Timbrell et al. 1982). Free radical formation was reported to occur when hydrazine was incubated with purified NADPH-cytochrome P-450 reductase (Noda et al. 1988). This reaction required NADPH and oxygen, was stimulated by FAD, inhibited by superoxide dismutase, and was unaffected by carbon monoxide. Free radicals were also noted when hydrazine was metabolized in perfused rat livers (Sinha 1987). These free radicals included acetyl, hydroxyl, and hydrogen radicals, the type of which was dependent upon the addition of an activating system (horseradish peroxidase or copper ion) to the perfusate. The occurrence of an acetyl radical suggests that hydrazine is acetylated prior to radical formation. These data indicate that hydrazine is metabolized by cytochrome P-450, but that transformation via other enzyme systems (peroxidases) or nonenzymatic reactions (copper ion-mediated) may occur as well. The formation of free radicals during the metabolism of hydrazine may be important to the mechanism of action of hydrazine toxicity. 1,1-Dimethylhydrazine. In rats administered a single dose of 0.78-60 mg/kg 1,1-dimethylhydrazine, approximately 12-27% of the dose was detected in expired air as carbon dioxide (Dost et al. 1966; Reed et al. 1963). Four hours after receiving a single dose of 40 mg/kg 1,1-dimethylhydrazine less than 2% of the dose was released in expired air (Mitz et al. 1962). Approximately, 3-10% and 20-25% of the dose was recovered in the urine as the glucose hydrazone of 1,1-dimethylhydrazine and an unidentified metabolite (Mitz et al. 1962). The authors speculated that the unidentified metabolite was another hydrazone of 1,1-dimethylhydrazine. These data indicate that 1,1-dimethylhydrazine undergoes demethylation and can react with cellular molecules in vivo. N-demethylation of 1,1-dimethylhydrazine by rat and hamster liver microsomes in vitro required the presence of NADPH and oxygen and was decreased by the addition of flavin-containing monooxygenase inhibitor (methimazole), but not by the addition of cytochrome P-450 inhibitors (Prough et al. 1981). 1,1-Dimethylhydrazine was also noted to be a good substrate for N-oxidation by amine oxidase (Prough 1973). In rat liver microsomes and S-9 fractions, both a nonenzymatic and an enzymatic component were identified for the metabolism of 1,1-dimethylhydrazine (Godoy et al. 1983). Formaldehyde was produced by both components, although the nonenzymatic component dominated the formation of a reactive protein-binding species. In contrast, rat liver slices metabolized 1,1-dimethylhydrazine to carbon dioxide and did not generate any reactive protein-binding species (Godoy et al. 1983), suggesting that in vitro metabolic studies may not be presenting an accurate picture of 1,1-dimethylhydrazine metabolism as it occurs in vivo. The formation of formaldehyde by rat colon microsomes was decreased by the addition of lipoxygenase and cyclooxygenase inhibitors (indomethacin and eicosatetranoic acid) and was stimulated by the addition of fatty acids, suggesting that lipoxygenase and cyclooxygenase may be involved in the colonic metabolism of 1,1-dimethylhydrazine (Craven et al. 1985). Several studies have shown that the reactive binding species generated by 1,1-dimethylhydrazine metabolism may be free radical intermediates. Rat liver microsomes and rat hepatocytes are capable of metabolizing 1,1-dimethylhydrazine to form methyl radical intermediates (Albano et al. 1989; Tomasi et al. 1987). The formation of these radicals was inhibited by the addition of inhibitors of cytochrome P-450 (SKF 525A, metyrapone, and carbon monoxide) and inhibitors of the flavin-containing monooxygenase system (methimazole). The formation of free radicals could also be supported nonenzymatically by the presence of copper ion (Tomasi et al. 1987). These data indicate that at least two independent enzyme systems and one nonenzymatic pathway may be involved in the metabolism of 1,1-dimethylhydrazine. 1,2-Dimethylhydrazine. In vivo studies indicate that 1,2-dimethylhydrazine is metabolized to form azomethane, azoxymethane, methylazoxymethanol, ethane, and carbon dioxide. In rats administered a single dose of 20-200 mg/kg 1,2-dimethylhydrazine, approximately 4-24 % and 14-23% of the dose was detected in expired air as carbon dioxide and azomethane, respectively (Fiala et al. 1976; Harbach and Swenberg 1981). Azoxymethane and methylazoxymethanol were detected in the urine of rats injected receiving 21 mg/kg 1,2-dimethylhydrazine (Fiala et al. 1977). It has been proposed that 1,2-dimethylhydrazine undergoes sequential oxidations to form azomethane, which in turn is metabolized to form azoxymethane, and then methylazoxymethanol (Druckrey 1970). Ethane was detected in the expired air of rats exposed to a single dose of 9-91 mg/kg 1,2-dimethylhydrazine (Kang et al. 1988). The authors proposed that ethane was formed by a *** DRAFT FOR PUBLIC COMMENT *** 50 2. HEALTH EFFECTS dimerization of methyl radicals originating from 1,2-dimethylhydrazine metabolism. These data indicate that oxidation can occur at both the nitrogen and the carbon of 1,2-dimethylhydrazine in vivo, and suggest that free radicals may be formed as well. Human colon microsomes and human colon cancer cells were capable of generating formaldehyde from 1,2-dimethylhydrazine in vitro (Newaz et al. 1983). The formation of formaldehyde was decreased by the addition of cytochrome P-450 inhibitors and was increased by the pretreatment of cancer cells with cytochrome P-450 inducers. Interestingly, the authors noted a gradient with respect to 1,2-dimethylhydrazine metabolism activity in the colon (ascending < transverse < descending). Other studies have reported that the greatest capacity to produce DNA-binding intermediates from 1,2-dimethylhydrazine is in the ascending colon of humans (Autrup et al. 1980a). Rat colon epithelial cells were found to metabolize 1,2-dimethylhydrazine to azoxymethane, methylazoxymethanol, and a reactive binding species (Glauert and Bennink 1983). In the hamster colon cells, surface columnar epithelial cells were found to metabolize 1,2-dimethylhydrazine 2-3 times as well as crypt cells (Sheth-Desai et al. 1987). In addition, metabolism was inhibited by a dehydrogenase inhibitor (pyrazole). In a rat liver perfusion study, the metabolites of 1,2-dimethylhydrazine were identified as 1,2-dimethylhydrazine, azomethane, azoxymethane, and methylazoxymethanol (Wolter et al. 1984). Rat liver microsomes were found to metabolize 1,2-dimethylhydrazine to azomethane (N-N oxidation) and formaldehyde (C-N oxidation) (Erikson and Prough 1986). These activities were increased in rats pretreated with cytochrome P-450 inducers (phenobarbital) indicating the involvement of this enzyme. Mitochondrial amine oxidase demonstrated considerable activity as well (Coomes and Prough 1983; Erikson and Prough 1986), although 1,2-dimethylhydrazine was not as good a substrate for this enzyme as was 1,1-dimethylhydrazine (Prough 1973). Likewise, 1,2-dimethylhydrazine was not as good a substrate as 1,1-dimethylhydrazine for flavin- containing monooxygenase-mediated metabolism (Prough et al. 1981) or colonic cyclooxygenase and lipoxygenase (Craven et al. 1985). Since 1,2-dimethylhydrazine is a potent colon carcinogen while 1,1-dimethylhydrazine is not carcinogenic for the rodent colon, the significance of these findings is uncertain. Reactive intermediates are formed during the metabolism of 1,2-dimethylhydrazine. In vitro studies indicate that methylazoxymethane can form a reactive species (probably a methyldiazonium ion) either spontaneously (Nagasawa and Shirota 1972) or enzymatically by alcohol dehydrogenase and/or cytochrome P-450 (Feinberg and Zedeck 1980; Sohn et al. 1991). Other in vitro studies suggest that free radicals are formed during the metabolism of 1,2-dimethylhydrazine. For example, as observed with 1,1-dimethylhydrazine, the formation of methyl free radicals from 1,2-dimethylhydrazine in rat liver microsomes and rat hepatocytes was inhibited by cytochrome P-450 inhibitors (SKF 525A, metyrapone, and carbon monoxide) (Albano et al. 1989; Tomasi et al. 1987). However, unlike 1,1-dimethylhydrazine, the formation of methyl radicals was not decreased by the addition of a flavin-containing monooxygenase inhibitor (methimazole), suggesting that this enzyme is not involved in the production of free radicals from 1,2-dimethylhydrazine. Carbon-centered radicals were observed when 1,2-dimethylhydrazine was metabolized by horseradish peroxidase (Augusto et al. 1985; Netto et al. 1987). These data indicate some differences exists between the enzyme systems involved in metabolism of 1,2-dimethylhydrazine and 1,1-dimethylhydrazine to reactive intermediates. Reactive intermediate produced during the metabolism of 1,2-dimethylhydrazine are most likely responsible for DNA adducts observed in vivo (Becker et al. 1981; Netto et al. 1992; Pozharisski et al. 1975) and in vitro (Autrup et al. 1980a; Harris et al. 1977; Kumari et al. 1985). Regardless of the identity of the reactive species (methyldiazonium ion or methyl fee radical) it is clear that the metabolism of 1,2-dimethylhydrazine is essential for its carcinogenicity. Inhibition of metabolism by disulfiram and other thiono sulfur compounds (Fiala et al. 1977) resulted in inhibition of DNA alkylation (Swenberg et al. 1979) and colon carcinogenicity (Wattenberg 1975). Moreover, azoxymethane and methylazoxymethanol, two metabolites of 1,2-dimethylhydrazine, are also potent colon and liver carcinogens (Williams and Weisburger 1991). *** DRAFT FOR PUBLIC COMMENT *** 51 2. HEALTH EFFECTS 2.3.4 Excretion 2.3.4.1 Inhalation Exposure No studies were located regarding excretion in humans after inhalation exposure to hydrazines. Forty-eight hours after a 1 hour exposure to 10-500 ppm hydrazine, approximately 8.4-29.5% of the inhaled dose was excreted in the urine of rats (Llewellyn et al. 1986). Most of the recovered dose was excreted during the first 24 hours. Three metabolites were identified in the urine as unchanged hydrazine, acetyl hydrazine, and diacetyl hydrazine. No other studies were located regarding excretion in animals after inhalation exposure to hydrazine. 2.3.4.2 Oral Exposure No studies were located regarding excretion in humans after oral exposure to hydrazines. A single study was located that reported excretion in animals after oral exposure to hydrazine. Twenty-four hours after receiving a single oral dose of 2.9-81 mg/kg hydrazine, approximately 19-46% of the dose was recovered in the urine of exposed rats (Preece et al. 1992). Two metabolites were identified in the urine as unchanged hydrazine and acetyl hydrazine. Fecal excretion and release of the compound in expired air were not investigated in this study. 2.3.4.3 Dermal Exposure No studies were located regarding excretion in humans after dermal exposure to hydrazines. Data in animals regarding the excretion of hydrazines are limited to two studies. In dogs administered a single dermal dose of 300-1,800 mg/kg 1,1-dimethylhydrazine, levels of up to 600 ug/mL 1,1-dimethylhydrazine were detected in the urine within 5 hours (Smith and Clark 1971). Similarly, in dogs administered a single dermal dose of 96-480 mg/kg hydrazine, levels of up to 70 pg/mL were detected in the urine within 3 hours (Smith and Clark 1972). However, neither of these studies examined fecal excretion nor did they provide sufficient information to estimate the fraction of the dose excreted in the urine. 2.3.4.4 Other Exposure No studies were located regarding excretion in humans after other exposures to hydrazines. The levels of hydrazine in the blood were reported to decrease in a biphasic manner in rats administered 16-64 mg/kg hydrazine via indwelling catheters, with halftimes of 0.74 and 26.9 hours (Springer et al. 1981). In dogs administered a single dose of 16-64 mg/kg hydrazine via an indwelling cannula, approximately 25% and 50% of the dose was recovered within 48 hours in the expired air and urine, respectively (Springer et al. 1981). Forty-eight hours after receiving a single intravenous dose of 2-12 mg/kg hydrazine, rats excreted approximately 13.8-37.3% of the dose in the urine (Llewellyn et al. 1986). Approximately 29.2% of a single subcutaneous dose of 9.9 mg/kg hydrazine was excreted in the urine of rats after 48 hours (Kaneo et al. 1984). Although these data are limited due to the lack of information on fecal excretion, they suggest that the majority of an absorbed dose of hydrazine is excreted in the urine, but that a significant fraction of the dose may be released in expired air. In rats administered a single dose of 0.78-80 mg/kg 1,1-dimethylhydrazine, approximately 18.9-76% of the carbon dose was recovered in the urine and 2-23% of the carbon dose was excreted in expired air within 4-53 hours (Dost et al. 1966; Mitz et al. 1962; Reed et al. 1963). Approximately 34.8-39.1% of the carbon dose was excreted in the urine within 5 hours in dogs intraperitoneally injected with 50 mg/kg 1,1-dimethylhydrazine (Back et al. 1963). Approximately 37.2-51.2% of the carbon dose was recovered in the *** DRAFT FOR PUBLIC COMMENT *** 52 2. HEALTH EFFECTS urine within 6 hours in cats intraperitoneally injected with 10-50 mg/kg 1,1-dimethylhydrazine (Back et al. 1963). These studies typically employed a carbon radiolabel (*4C-1,1-dimethylhydrazine). This radiolabel can become separated from the rest of the molecule during the demethylation of 1,1-dimethylhydrazine; therefore, these studies may not accurately depict the metabolic fate of the nitrogen contained within the dose. In addition, fecal excretion of 1,1-dimethylhydrazine was not determined in these studies. Despite these limitations, these data suggest that the majority of the carbon from an absorbed dose of 1,1-dimethylhydrazine is excreted in the urine, but that a significant fraction of the carbon dose may be released in expired air. In rats and mice administered a single subcutaneous dose of 15-225 mg/kg 1,2-dimethylhydrazine, approximately 13-47% of the carbon dose was released in expired air as azomethane and carbon dioxide within 24 hours (Fiala et al. 1976, 1977; Harbach and Swenberg 1981; Hawks and Magee 1974). Approximately 10-25% of a 15-21 mg/kg dose of 1,2-dimethylhydrazine was excreted in the urine (Fiala et al. 1977; Hawks and Magee 1974). A single study reported that only 0.4-0.9% of a single 200 mg/kg dose of 1,2-dimethylhydrazine was excreted in the bile of rats with 24 hours (Hawks and Magee 1974). As noted above for 1,1-dimethylhydrazine, the findings from these studies are limited since they employed a carbon radiolabel (*C-1,2-dimethylhydrazine) only, and therefore may not accurately depict the metabolic fate of the dose expressed in terms of nitrogen. Despite this limitation, these data suggest that a significant fraction of the carbon dose of 1,2-dimethylhydrazine may be released in expired air and urine, whereas fecal excretion is relatively low. 2.3.5 Mechanisms of Action Studies in animals indicate that hydrazines are rapidly absorbed from the skin (Smith and Clark 1971, 1972), and presumably in the lungs and gastrointestinal tract as well. Although the mechanism by which hydrazines are absorbed into the blood has not been studied, this most likely occurs by passive diffusion. A number of studies have investigated the mechanism by which hydrazines produce adverse health effects. These data suggest there are at least two distinct mechanisms of action for hydrazines; one involving the direct binding of those hydrazines with a free amino group (hydrazine and 1,1-dimethylhydrazine) to key cellular molecules, and the other involving the generation of reactive species such as free radical intermediates or methyldiazonium ions as a result of metabolism. Studies which support the existence of these mechanisms are discussed below. In vitro studies have shown that hydrazine reacts with alpha-keto acids to form hydrazone compounds (O’Leary and Oikemus 1956). By binding to keto acids and forming hydrazones, hydrazine inhibited oxygen consumption with mitochondrial substrates in vitro (Fortney 1967). This mechanism may well account for the hyperlactemic and hypoglycemic effects of hydrazine observed in humans (Ochoa et al. 1975) and dogs in vivo (Fortney 1967). Hydrazine and 1,1-dimethylhydrazine can form hydrazones with vitamin Bg derivatives (Cornish 1969). By binding to vitamin By derivatives, hydrazine and 1,1-dimethylhydrazine are able to inhibit reactions that require vitamin By as a cofactor. These reactions include transamination reactions, decarboxylation and other transformations of amino acids, the metabolism of lipids and nucleic acids, and glycogen phosphorylase (NRC 1989). Deficiency of vitamin Bg can produce convulsions, dermatitis, and anemia. These data suggest that the convulsions and anemia observed in animal studies are the result of the formation of hydrazone derivatives of vitamin By. In addition, some authors have proposed that a free amino group, as found in hydrazine and 1,1-dimethylhydrazine, is required for hydrazone formation (Cornish 1969). This would explain why convulsions are associated with exposures to hydrazine and 1,1-dimethylhydrazine, and not 1,2-dimethylhydrazine. It should be noted that pyridoxine (one of the forms of vitamin Bg) is commonly used to treat humans exposed to hydrazine or 1,1-dimethylhydrazine. A number of in vitro studies have reported the production of reactive intermediates during the metabolism of hydrazines (see Section 2.3.3). Evidence for the production of radicals including methyl, acetyl, hydroxyl, and hydrogen radicals has been observed during the metabolism of hydrazine (Ito et al. 1992; Noda et al. 1988; *** DRAFT FOR PUBLIC COMMENT *** 53 2. HEALTH EFFECTS Runge-Morris et al. 1988; Sinha 1987), 1,1-dimethylhydrazine (Albano et al. 1989; Tomasi et al. 1987), and 1,2-dimethylhydrazine (Albano et al. 1989; Augusto et al. 1985; Netto et al. 1987; Tomasi et al. 1987). Multiple pathways, including both enzymatic and nonenzymatic, appear to be involved in free radical generation. Free radicals have been implicated in protein damage (hemoglobin) associated with hydrazine in human erythrocytes (Runge-Morris et al. 1988), suggesting that free radicals may be involved in the anemic effects of hydrazines observed in animals in vivo (Haun and Kinkhead 1973; Rinehart et al. 1960). It has also been proposed that metabolism of 1,2-dimethylhydrazine yields a reactive, methyldiazonium ion (Feinberg and Zedeck 1980; Sohn et al. 1991). The production of reactive species during the metabolism of hydrazines may also explain their genotoxic effects, such as the formation of DNA adducts in vivo (Becker et al. 1981; Beranek et al. 1983; Bolognesi et al. 1988; Bosan et al. 1986; Netto et al. 1992; Pozharisski et al. 1975; Quintero-Ruiz et al. 1981). DNA adducts may well be responsible for gene mutations observed in a number of in vitro studies (DeFlora and Mugnoli 1981; Kerklaan et al. 1983; Levi et al. 1986; Malaveille et al. 1983; Noda et al. 1986; Oravec et al. 1986; Parodi et al. 1981; Rogers and Back 1981; Sedgwick 1992; Wilpart et al. 1983), and may also serve as the initiating event for cancers induced by hydrazines in vivo. 2.4 RELEVANCE TO PUBLIC HEALTH Data regarding the toxic effects of hydrazines in humans are limited to a few case studies of accidental exposure and chemotherapy trials in cancer patients. Studies consistently indicate that the central nervous system is the primary target for hydrazine and 1,1-dimethylhydrazine following inhalation, oral, and dermal exposures. In some cases, neurological effects were delayed, but for the most part were observed either during exposure or soon after. Quantitative data on human exposures are available only for oral exposures for intermediate- durations. Studies in animals, which support the findings from human studies, report neurological effects following inhalation, dermal, and parenteral exposures to hydrazine and 1,1-dimethylhydrazine. Neurological effects do not appear to be of concern following exposure to 1,2-dimethylhydrazine. Effects on the liver have been consistently reported in animal studies following exposure to all three hydrazines. Limited studies in animals suggest that exposure to hydrazines by the inhalation, oral, and parenteral route may cause reproductive and developmental effects. A number of species-, sex-, and strain-specific differences have been observed for sensitivity to the toxic effects of hydrazines. All three hydrazines are carcinogenic in animals following oral and inhalation exposures. 1,2-Dimethylhydrazine is a potent carcinogen in animals and can induce tumors following single oral or parenteral doses. Data regarding the toxicokinetics of hydrazines are limited, but suggest that in animals hydrazines are rapidly absorbed and distributed to all tissues, and that metabolites are excreted largely in the urine or released in expired air. Limited data in humans suggest that people with a slow acetylator genotype do not clear hydrazine from the body as well as those who are fast acetylators, and therefore may be more susceptible to the toxic effects of hydrazine. Minimal Risk Levels for Hydrazines Inhalation MRLs ® An MRL of 2x10* ppm has been derived for intermediate inhalation exposure to hydrazine. This MRL is based on a LOAEL of 0.2 ppm for moderate fatty liver changes observed in female mice (Haun and Kinkhead 1973). In this study, groups of 40 female ICR mice were exposed to either 0, 0.2, or 1 ppm hydrazine continuously, or to 0, 1, or 5 ppm intermittently. The authors also investigated the effects of inhaled hydrazine in other species. In support of this MRL, fatty liver changes were also observed in dogs exposed to 1 ppm hydrazine for 6 months, and in monkeys exposed to 0.2 ppm for 6 months. *** DRAFT FOR PUBLIC COMMENT *** 54 2. HEALTH EFFECTS ® An MRL of 9x10° ppm has been derived for intermediate inhalation exposure to 1,1-dimethylhydrazine. This MRL is based on a LOAEL of 0.05 ppm for fatty liver changes in male rats (Haun et al. 1984). In this study, a large number (200/group) of male CDF F-344/CrIBR rats were exposed to either 0, 0.05, 0.5, or 5 ppm 1,1-dimethylhydrazine for 6 hours/day, 5 days/week for 6 months. Although the effect was observed only at the low dose, the MRL is supported by other studies in humans (Petersen et al. 1970; Shook and Cowart 1957), mice (Haun et al. 1984) and dogs (Haun 1977; Rinehart et al. 1960) that indicate that the liver is a target of 1,1-dimethylhydrazine after inhalation exposure. ® An MRL of 9x10 ppm has been derived for chronic inhalation exposure to 1,1-dimethylhydrazine. This MRL is based on the same rat study (Haun et al. 1984), doses and exposure regimens that are described above for the derivation of the intermediate inhalation MRL. In rats, a 6-month exposure may reasonably be considered chronic in nature, especially when definitive, longer-duration studies are lacking. In the only longer- duration inhalation study on 1,1-dimethylhydrazine that was located, mice exposed to 5 ppm (the only concentration tested) for 6 hours/day, 5 days/week for 1 year displayed increased angiectasis of the liver (17/190 compared with 6/191 for controls) (Haun et al. 1984). While providing evidence that the liver is a principal target organ of chronic inhalation exposure to 1,1-dimethylhydrazine, this limited study was not adequate serve as the basis for a chronic inhalation MRL. However, the fact that the treatment-induced relative increase in liver angiectasis was equal to or smaller than that observed after only 6 months of exposure (Haun et al. 1984) supports foregoing the inclusion of an additional uncertainty factor in the extrapolation of this chronic MRL. A chronic inhalation MRL for hydrazine was not similarly extrapolated from the intermediate MRL value presented above (Haun and Kinkhead 1973) because increased death was observed in hamsters exposed for 1 year to nearly the same dose (0.25 ppm, the lowest dose tested) (Vernot et al. 1985). No inhalation MRLs were derived for exposures to hydrazines for acute durations. Although data from animal study indicates that inhalation exposure to 1,1-dimethylhydrazine produces adverse effects on the central nervous system following acute exposure (Rinehart et al. 1960) this study does not define the threshold exposure level for these effects with confidence. Acute inhalation studies for the other hydrazines were not located. Oral MRLs ® An MRL of 8x10“ mg/kg/day has been derived for intermediate oral exposure to 1,2-dimethylhydrazine. This MRL is based on a LOAEL of 0.75 mg/kg/day for mild hepatitis in mice (Visek et al. 1991). In this study, groups of 25 male mice were administered 0, 0.75, 1.6, or 2.7 mg/kg/day 1,2-dimethylhydrazine in the diet for 5 months. This MRL is supported by studies reporting LOAELSs for hepatic effects ranging from 4.2-30 mg/kg/day 1,2-dimethylhydrazine in several other species, including rats (Bedell et al. 1992), guinea pigs (Wilson 1976), dogs (Wilson 1976), and pigs (Wilson 1976). No oral MRLs were derived for exposures to hydrazine or 1,1-dimethylhydrazine for acute and chronic durations. Although data are available for neurological effects in humans after intermediate duration exposure to hydrazine (Chlebowski et al. 1984; Gershanovich et al. 1976, 1981; Ochoa et al. 1975; Spremulli et al. 1979), these effects were judged to be serious in some cases (Gershanovich et al. 1976; Ochoa et al. 1975). Studies in animals have reported effects on the liver following acute (Marshall et al. 1983; Wakabayashi et al. 1983; Wilson 1976) and intermediate-duration exposures (Biancifiori 1970). However, these data do not define the threshold dose for hepatic effects with confidence. Death. Data regarding the lethal effects of hydrazines in humans are limited to a single case study involving’ inhalation exposure to hydrazine. Death was reported in a male worker exposed to an undetermined concentration of hydrazine once a week for 6 months (Sotaniemi et al. 1971). Death in this case was due to *** DRAFT FOR PUBLIC COMMENT *** 55 2. HEALTH EFFECTS lesions of the kidneys and lungs with complicating pneumonia. The effects on the kidneys and lungs, as well as effects in other tissues, were comparable to those observed in animals exposed to hydrazine. Therefore, death in this case is most likely attributed to hydrazine exposure. A number of animal studies have reported acute lethality after all routes of exposure to hydrazines. For inhalation exposures, deaths were observed in dogs and mice after acute exposure to 25-140 ppm 1,1-dimethylhydrazine (Rinehart et al. 1960). For oral exposures, doses of 133 mg/kg hydrazine, 533 mg/kg/day 1,1-dimethylhydrazine, and 11.7-90 mg/kg 1,2-dimethylhydrazine caused deaths in mice and/or dogs (Roe et al. 1967; Visek et al. 1991; Wilson 1976). For dermal exposures, LDs, values ranging from 93-1,680 mg/kg were reported for all three hydrazines in rabbits and guinea pigs (Rothberg and Cope 1956). Deaths were noted in dogs after application of a single dose of 96 mg/kg hydrazine or 300 mg/kg 1,1-dimethylhydrazine (Smith and Clark 1971, 1972). A large number of studies have reported deaths in several animal species following injections of 8-400 mg/kg/day hydrazine (Bodansky 1923; Lee and Aleyassine 1970; O’Brien et al. 1964; Roberts and Simonsen 1966; Rothberg and Cope 1956; Wakebayashi et al. 1983), 71-125 mg/kg/day 1,1-dimethylhydrazine (Back and Thomas 1962; Furst and Gustavson 1967; Geake et al. 1966; O’Brien et al. 1964; Rothberg and Cope 1956), and 44-60 mg/kg 1,2-dimethylhydrazine (Rothberg and Cope 1956; Wilson 1976). These doses are comparable to those producing death following oral exposure, suggesting that hydrazines are absorbed fairly well by the oral route. Limited information from a single oral study suggests that male animals are more sensitive to the lethal effects of hydrazine than females (Visek et al. 1991). A number of studies have reported increased mortality following exposure to hydrazines for intermediate durations. Following inhalation exposures, increased mortality was noted in mice and dogs exposed to 1 ppm hydrazine (Haun and Kinkhead 1973), and in mice exposed to 75 ppm 1,1-dimethylhydrazine (Rinehart et al. 1960), but not in several species following intermediate exposure to 0.05-5 ppm 1,1-dimethylhydrazine (Haun et al. 1984). Oral exposures of 2.3-4.9 mg/kg/day hydrazine (Biancifiori 1970), 33 mg/kg/day 1,1-dimethylhydrazine (Roe et al. 1967), and 4.5-60 mg/kg/day 1,2-dimethylhydrazine (Teague et al. 1981; Visek et al. 1991; Wilson 1976) caused deaths in a number of animal species. Increased mortality was observed in several animal species after injections of 20-21.8 mg/kg/day hydrazine (Bodansky 1923; Patrick and Back 1965), 30 mg/kg/day 1,1-dimethylhydrazine (Cornish and Hartung 1969), and 15-60 mg/kg/day 1,2-dimethylhydrazine (Wilson 1976). The oral and injection dose ranges producing death in animals are comparable for all three hydrazines, and suggest that the potencies of hydrazine, 1,1-dimethylhydrazine, and 1,2-dimethylhydrazine are similar. Data regarding lethality effects in animals after chronic exposure to hydrazines are limited to two studies. Mortality was significantly increased in hamsters exposed to 0.25 ppm hydrazine in air for 1 year (Vernot et al. 1985), and in mice exposed to 0.95 mg/kg/day hydrazine via the drinking water (Toth and Patil 1982). These exposures are notably lower than those producing fatalities after acute and intermediate duration exposure to hydrazine. Systemic Effects Respiratory Effects. Data regarding the respiratory effects of hydrazines in humans are limited to a single case study involving inhalation exposure to hydrazine. Pneumonia, tracheitis, and bronchitis were observed in a man occupationally exposed to an undetermined concentration of hydrazine in air once a week for 6 months (Sotaniemi et al. 1971). Hyperplasia was observed in the lungs of rats and mice exposed to 0.05 ppm 1,1-dimethylhydrazine for 6 months (Haun et al. 1984). Lung irritation and damage has been noted in dogs after intermediate- duration exposure to 25 ppm 1,1-dimethylhydrazine, but not 5 ppm 1,1-dimethylhydrazine (Rinehart et al. 1960). Similarly, pulmonary effects were observed in rats chronically exposed to 5 ppm hydrazine, but not in mice chronically exposed to 1 ppm hydrazine (Vernot et al. 1985). Effects on the nasal mucosa, including inflammation, hyperplasia, and dysplasia were noted in mice chronically exposed to 5 ppm 1,1-dimethylhydrazine (Haun et al. 1984). Pulmonary edema, congestion, and pneumonia were observed in rats injected with 20 mg/kg/day hydrazine but not in rats injected with 10 mg/kg/day hydrazine (Patrick and Back *** DRAFT FOR PUBLIC COMMENT *** 56 2. HEALTH EFFECTS 1965). No adverse effects were observed in the lungs of mice exposed to 9.5 mg/kg/day hydrazine via the drinking water for 2 years (Steinhoff et al. 1990). These data suggest that effects on the lungs and upper respiratory tract are of concern primarily following inhalation exposures to hydrazines. Cardiovascular Effects. Data regarding the cardiovascular effects of hydrazines in humans are limited to a single case study involving inhalation exposure to hydrazine. Intermittent exposure of a worker to an undetermined concentration of hydrazine in air for 6 months produced atrial fibrillation, enlargement of the heart, and degeneration of heart muscle fibers (Sotaniemi et al. 1971). The findings from animal studies have been inconsistent. No adverse effects were noted on the cardiovascular system of dogs exposed to 25 ppm 1,1-dimethylhydrazine or mice exposed to 1 ppm hydrazine for intermediate and chronic durations (Rinehart et al. 1960; Vernot et al. 1985). Mice exposed to 0.05-5 ppm 1,1-dimethylhydrazine for 6 months to 1 year had abnormally dilated blood vessels (angiectesis) (Haun et al. 1984). Focal myocytolysis, fibrosis, and calcification of the heart were noted in mice receiving 1.6 mg/kg/day 1,2-dimethylhydrazine in the feed for 5 months (Visek et al. 1991). Slight accumulation of fat was observed in the myocarium of monkeys receiving 5 mg/kg/day hydrazine by intraperitoneal injection for 1-4 weeks (Patrick and Back 1965). Changes in blood pressure were noted in dogs following a single injection of 100 mg/kg 1,1-dimethylhydrazine (Back and Thomas 1962). Cardiovascular effects were not observed in mice receiving 0.75 mg/kg/day 1,2-dimethylhydrazine (Visek et al. 1991). No adverse effects were observed in the hearts of rats injected with 20 mg/kg/day hydrazine for 5 weeks (Patrick and Back 1965) or in mice receiving 9.5 mg/kg/day hydrazine in the drinking water for 2 years (Steinhoff et al. 1990). The findings of the animal studies, although inconsistent, suggest that the cardiovascular effects observed in the human case study are related to exposure. Gastrointestinal Effects. Oral exposure to hydrazine has produced nausea and vomiting in human cancer patients. These effects could be due to direct irritation of the gastrointestinal tract, but could also be due to effects on the central nervous system. Studies in animals generally have not reported effects on the gastrointestinal system following intermediate and chronic inhalation exposures to 25 ppm 1,1-dimethylhydrazine (Rinehart et al. 1960) or 1 ppm hydrazine (Vernot et al. 1985). Similarly, chronic oral exposure to 9.5 mg/kg/day were without effect on the gastrointestinal system of mice (Steinhoff et al. 1990). Proliferation, dysplasia, and hyperplasia of the colon mucosa has been observed in rats orally exposed to 25 mg/kg 1,2-dimethylhydrazine or injected with 15-20 mg/kg 1,2-dimethylhydrazine (Caderni et al. 1991; Decaens et al. 1989; Wargovich et al. 1983). These effects are most likely precursors of carcinogenic lesions induced by 1,2-dimethylhydrazine in this tissue site. Although these data suggest that the gastrointestinal system is not a primary target of the noncarcinogenic effects of hydrazines, this is not certain, particularly for 1,2-dimethylhydrazine. Hematological Effects. No studies were located regarding hematological effects in humans after exposure to hydrazines. Studies in dogs indicate that inhalation exposure for intermediate-durations to relatively high concentrations of hydrazine (1-5 ppm), but not 1,1-dimethylhydrazine, produces anemia (Haun and Kinkhead 1973; Haun et al. 1984; Rinehart et al. 1960). Signs of anemia were not observed in dogs exposed to 0.2 ppm hydrazine. Hematological effects (decreased thromboplastin generation time) were also noted in dogs exposed to a single dermal dose of 5 mmol/kg 1,1-dimethylhydrazine (Smith and Castaneda 1970). However, hematological effects have not been observed in other species. For example, rats, hamsters, and monkeys exposed to 1 ppm hydrazine or 5 ppm 1,1-dimethylhydrazine for 6 months (Haun and Kinkhead 1973; Haun et al. 1984) and rats and monkeys injected with 10-50 mg/kg/day 1,1-dimethylhydrazine (Cornish and Hartung 1969; Patrick and Back 1965) did not exhibit any hematological effects. These data suggest that dogs may be particularly sensitive to the hematological effects of hydrazines. Currently, it is not known if dogs are good animal models for the hematological effects of hydrazines in humans, therefore, it is uncertain if this effect is of concern to humans exposed to hydrazines. Musculoskeletal Effects. No studies were located regarding musculoskeletal effects in humans after exposure to hydrazines. Data in animals are limited to a single study. No adverse effects were observed in the muscle tissue of mice chronically exposed to 9.5 mg/kg/day hydrazine (Steinhoff et al. 1990). These data are too limited to determine if effects on the musculoskeletal system are of concern in humans exposed to hydrazines. *** DRAFT FOR PUBLIC COMMENT *** 57 2. HEALTH EFFECTS Hepatic Effects. Data regarding the hepatic effects of hydrazines in humans are limited to a single case study. Areas of focal necrosis and cell degeneration were noted in the liver of a worker exposed to an undetermined concentration of hydrazine in air once a week for 6 months (Sotaniemi et al. 1971). These effects on the liver, however, were not contributing factors in the worker’s death. A large number of studies in animals were located regarding the hepatotoxic effects of hydrazines. Multiple effects on the liver (hemosiderosis, degeneration, fatty changes, elevated serum enzymes, hyperplasia) have been observed in a number of species following inhalation exposure to 0.25-5 ppm hydrazine (Haun and Kinkhead 1973; Vernot et al. 1985) or 0.05-25 ppm 1,1-dimethylhydrazine (Haun 1977; Haun et al. 1984; Rinehart et al. 1960). Hepatotoxic effects (fatty changes, degeneration, necrosis, hemosiderosis, hepatitis, fibrosis) were also observed in animals following oral exposure to 4.9-650 mg/kg/day hydrazine (Biancifiori 1970; Marshall et al. 1983; Preece et al. 1992; Wakabayashi et al. 1983) and 0.75-60 mg/kg/day 1,2-dimethylhydrazine (Bedell et al. 1982; Visek et al. 1991: Wilson 1976). Similar effects were observed in animals receiving injection of 5-45 mg/kg/day hydrazine (Bodansky 1923; Patrick and Back 1965; Reinhardt et al. 1965b; Warren et al. 1984) or 3-333 mg/kg/day 1,2-dimethylhydrazine (Dixon et al. 1975; Pozharisski et al. 1976; Wilson 1976). Species differences in sensitivity were noted in individual studies, but these were not consistently observed across studies. Although data are lacking on the hepatic effects of 1,2-dimethylhydrazine by the inhalation route and 1,1-dimethylhydrazine by the oral route, these data clearly indicate that the liver is an important target organ and that hepatic effects are of potential concern for humans exposed to hydrazines. Renal Effects. Data regarding the renal effects of hydrazines in humans are limited to a single case study. This study reported severe renal effects (tubular necrosis, hemorrhaging, inflammation, discoloration, enlargement) in a worker after exposure to an undetermined concentration of hydrazine (Sotaniemi et al. 1971). The renal effects were a significant factor in the worker’s death. Renal effects have been observed in several animal studies. Following inhalation exposure to 0.25 ppm hydrazine, mild effects were noted in the kidneys of hamsters (Vernot et al. 1985). Similarly, signs of mild renal toxicity were observed in rats and dogs injected with 16-64 mg/kg/day hydrazine (Dominguez et al. 1962; Van Stee 1965) or 50 mg/kg/day 1,1-dimethylhydrazine (Cornish and Hartung 1969). More severe effects (nephritis) were noted in the kidneys of mice orally exposed to 1.6 mg/kg/day 1,2-dimethylhydrazine (Visek et al. 1991) and in dogs and monkeys injected with 20-28 mg/kg/day hydrazine (Bodansky 1923; Patrick and Back 1965). However, no effects were observed in the kidneys of dogs exposed to 25 ppm 1, 1-dimethylhydrazine by the inhalation route (Rinehart et al. 1960), in mice exposed to 0.75 mg/kg/day 1,2-dimethylhydrazine or 9.5 mg/kg/day hydrazine by the oral route (Steinhoff et al. 1990; Visek et al. 1991), or in rats injected with 20 mg/kg/day hydrazine (Patrick and Back 1965). These animal studies support the findings of the human case study and suggest that the kidney is an important target organ, at least following exposure to high doses of hydrazines. Dermal/Ocular Effects. Several studies were located regarding dermal/ocular effects in humans after exposure to hydrazines. Conjunctivitis was consistently observed in a worker repeatedly exposed to an undetermined concentration of hydrazine (Sotaniemi et al. 1971). Contact dermatitis has been observed in humans after dermal exposure to dilute solutions containing hydrazine (Hovding 1967; Suzuki and Ohkido 1979; Wrangsjo and Martensson 1986). Eye irritation was noted in monkeys exposed to 1 ppm hydrazine in air but not in monkeys exposed to 0.2 ppm hydrazine (Haun and Kinkhead 1973). Dermal effects (discoloration, irritation) and ocular effects (corneal swelling) were also observed in dogs, rabbits, and guinea pigs after dermal exposure to hydrazine, 1,1-dimethylhydrazine, and 1,2-dimethylhydrazine (Rothberg and Cope 1956; Smith and Castaneda 1970; Smith and Clark 1971, 1972). However, by the oral route, no effects were observed in the skin of mice exposed to 9.5 mg/kg/day hydrazine (Steinhoff et al. 1990). These data indicate that direct contact with hydrazines causes irritation of the skin and eyes. Other Systemic Effects. No studies were located regarding other systemic effects in humans after exposure to hydrazines. A large number of studies in animals exposed orally or by injection to hydrazines have reported decreased body weight gain. For example, oral exposure to 0.75-60 mg/kg/day 1,2-dimethylhydrazine (Barbolt and Abraham 1980; Visek et al. 1991; Wilson 1976), 5 mg/kg/day 1,1-dimethylhydrazine (Haun et al. 1984), or 9.5 mg/kg/day hydrazine (Steinhoff et al. 1990) decreased body weight gain in a number of animal species. Similarly, injection of 5-10 mg/kg/day hydrazine (Patrick and Back 1965), 10 mg/kg/day 1,1-dimethylhydrazine *** DRAFT FOR PUBLIC COMMENT *** 58 2. HEALTH EFFECTS (Patrick and Back 1965), or 60 mg/kg/day 1,2-dimethylhydrazine (Wilson 1976) decreased animal body weight gain. These decreases in body weight gain are most likely due, at least in part, to decreased food intake. The decreased food intake may be due to taste aversion in feed studies, however, the appearance of this effect in animal exposed by other routes suggests that appetite may be decreased. Alternatively, decreases in body weight gain may be secondary to an underlying disease (e.g., cancer). Immunological Effects. Very little information is available regarding immunological effects of hydrazines. Several studies in humans indicate that dermal exposure to hydrazine produces contact dermatitis (Hovding 1967; Suzuki and Ohkich 1979; Wrangsjo and Martensson 1986). In addition, there are some data from case studies in humans that suggest that exposure to hydrazine and other hydrazine derivatives can produce a lupus erythematosus-like disease (Pereyo 1986; Reidenberg et al. 1983). However, this possibility warrants further investigation before firm conclusions can be made. A single study in animals reported no effect in the splenic natural killer cell activity in rats orally exposed to 27.1 mg/kg/day 1,2-dimethylhydrazine (Locniskar et al. 1986). However, in mice injected with 75 mg/kg/day 1,1-dimethylhydrazine, a decreased T helper cell count was observed (Frazier et al. 1991). In vitro studies have reported that 1,1-dimethylhydrazine induces immunomodulation (enhancing some immune functions while diminishing others) in mouse lymphocytes and splenocytes (Bauer et al. 1990; Frazier et al. 1992). These data are limited, but suggest that humans exposed to hydrazines may be at risk of developing immunological effects. Neurological Effects. Neurological effects have been noted in humans after inhalation, oral, and dermal exposure to hydrazines. For inhalation exposure, these effects included nausea, vomiting, tremors, and impairment of cognitive functions (Richter et al. 1992; Sotaniemi et al. 1971). Neurological symptoms of nausea, vomiting, dizziness, excitement, lethargy, and neuritis have been reported in some cancer patients treated orally with 0.2-0.7 mg/kg/day hydrazine (Chlebowski et al. 1984; Gershanovich et al. 1976, 1981; Ochoa et al. 1975; Spremulli et al. 1979). Dermal exposure to hydrazine or 1, 1-dimethylhydrazine as a result of an industrial explosion produced narcosis, coma, and polyneuritis in two workers (Dhennin et al. 1988; Kirklin et al. 1976). Neurological effects (depression, seizures, convulsions, tremors, lethargy, behavioral changes) have also been observed in a number of animal species following inhalation exposure to 1 ppm hydrazine (Haun and Kinkhead 1973), and 25-75 ppm 1,1-dimethylhydrazine (Rinehart et al. 1960). Effects on the central nervous system were also observed in dogs after dermal exposure to 96-480 mg/kg hydrazine (Smith and Clark 1972) or 300-1800 mg/kg 1,1-dimethylhydrazine (Smith and Clark 1971). Similar neurological effects were noted in animals after injection of 16-350 mg/kg/day hydrazine (Floyd 1980; Mizuno et al. 1989; Patrick and Back 1965) or 4-125 mg/kg/day 1,1-dimethylhydrazine (Furst and Gustavson 1967; Geake et al. 1966; Goff et al. 1967, 1970; Minard and Mushahwar 1966; O’Brien et al. 1964; Reynolds et al. 1964; Segerbo 1979; Sterman and Fairchild 1967). The studies in humans and animals convincingly demonstrate that the central nervous system is a target for persons exposed to hydrazine or 1,1-dimethylhydrazine. However, based on the mechanism by which hydrazine and 1,1-dimethylhydrazine affect the central nervous system, neurological effects do not appear to be of concern for humans exposed to 1,2-dimethylhydrazine. Developmental Effects. Data regarding the developmental effects of hydrazines are limited to two animal studies. Signs of developmental toxicity or teratogenicity were not observed in hamsters exposed to a single dose of 166 mg/kg hydrazine or 68 mg/kg 1,2-dimethylhydrazine on day 12 of gestation (Schiller et al. 1979). However, increased prenatal and perinatal mortality was reported in rats injected with 8 mg/kg/day hydrazine (Lee and Aleyassine 1970). No studies were located which investigated the developmental effects of 1,1-dimethylhydrazine. The data in animals are inconsistent between routes of exposure and are too limited to permit firm conclusions regarding the potential for developmental effects in humans exposed to hydrazines. Reproductive Effects. Data regarding the reproductive effects of hydrazines are limited to a few animal studies. Reproductive effects (ovarian and testicular atrophy, endometrial inflammation, aspermatogenesis) were observed in hamsters exposed to 1-5 ppm hydrazine by the inhalation route (Vernot et al. 1985). The incidence of endometrial cysts was significantly elevated in female mice exposed to 0.05 ppm 1,1-dimethylhydrazine (Haun et al. 1984). Sperm abnormalities and decreased caudal epididymal sperm counts were noted in mice *** DRAFT FOR PUBLIC COMMENT *** 59 2. HEALTH EFFECTS injected with 8 mg/kg/day hydrazine or 12.5-68.8 mg/kg/day 1,1-dimethylhydrazine (Wyrobek and London 1973). These effects were not observed in hamsters exposed to 0.25 ppm hydrazine by the inhalation route (Vernot et al. 1985) or in mice and hamsters exposed to 5.3-9.5 mg/kg/day hydrazine by the oral route (Biancifiori 1970). No studies were located regarding the reproductive effects of 1,2-dimethylhydrazine. In addition, no studies were located which investigated effects of hydrazines on reproductive function. Despite the inconsistency of the findings from animal studies, the serious nature of the reproductive effects observed in the positive studies makes them one of concern for humans exposed to hydrazine. Genotoxic Effects. No studies were located regarding genotoxic effects in humans after exposure to hydrazines. Studies regarding the genotoxic effects in animals after oral or injection exposure to hydrazines are summarized in Table 2-4, while in vitro studies are presented in Table 2-5. These findings are discussed below. Data from in vivo studies indicate that hydrazines are alkylating agents. The methylation of tissue DNA was reported in animals exposed orally to hydrazine (Becker et al. 1981; Bosan et al. 1986) or by injection to hydrazine (Bosan et al. 1986; Quintero-Ruiz et al. 1981) or 1,2-dimethylhydrazine (Beranek et al. 1983; Bolognesi et al. 1988; Hawks and Magee 1974; Netto et al. 1992; Pozharisski et al. 1975; Rogers and Pegg 1977). The mechanism by which adducts are formed may involve the generation of reactive species (methyldiazanium ions or methyl free radicals) (Albano et al. 1989; Augusto et al. 1985; Feinberg and Zedeck 1980; Netto et al. 1987, 1992). The formation of methyl adducts with DNA bases in vivo may be one of the mechanisms by which hydrazines have produced DNA damage (Parodi et al. 1981), gene mutations (Jacoby et al. 1991; Winton et al. 1990; Zeilmaker et al. 1991; Zijlstra and Vogel 1988), micronuclei (Albanese et al. 1988; Ashby and Mirkova 1987), and sister chromatid exchange (Couch et al. 1986; Neft and Conner 1989). In vivo studies on the genotoxicity of hydrazines have largely reported positive results, although hydrazine did not induce unscheduled DNA synthesis in mouse sperm cells (Sotomayor et al. 1982). In addition, 1,2-dimethylhydrazine failed to induce micronuclei in rat bone marrow cells, even though this effect has been observed in mouse bone marrow cells (Albanese et al. 1988; Ashby and Mirkova 1987). A large number of in vitro studies have reported genotoxic effects for all three hydrazines. Hydrazines produced methyl adducts in DNA from human cells (Autrup et al. 1980a; Harris et al. 1977; Kumari et al. 1985) and in free DNA (Bosan et al. 1986; Lambert and Shank 1988), but adducts were not noted in Chinese hamster V79 cells (Boffa and Bolognesi 1986). Gene mutations have been observed in human teratoma cells (Oravec et al. 1986), mouse lymphoma cells (Rogers and Back 1981), and in several strains of bacteria (DeFlora and Mugnoli 1981; Kerklaan et al. 1983; Levi et al. 1986; Malaveille et al. 1983; Noda et al. 1986; Parodi et al. 1981; Sedgwick 1992; Wilpart et al. 1983). Other genotoxic effects observed in mammalian cells exposed to hydrazines include sister chromatid exchange (MacRae and Stich 1979), transformation (Kumari et al. 1985), and unscheduled DNA synthesis (Mori et al. 1988). In vitro studies regarding the genotoxic effects of hydrazines have generally reported positive results, with and without metabolic activation. Taken together with the in vivo studies discussed above, these data clearly indicate that all three forms of hydrazine are genotoxic. Cancer. Although no significant increase in cancer mortality was observed in a single epidemiology study of workers exposed to hydrazine (Wald et al. 1984), a large number of studies in animals have reported increased tumor incidence following inhalation, oral, and parenteral exposures to hydrazines. Following inhalation exposures to 5 ppm hydrazine, increased nasal and thyroid tumor incidences were reported in mice and hamsters (Vernot et al. 1985). Tumors of the lung, nasal passage ways, bone, pancreas, pituitary, blood vessels, liver, and thyroid, and leukemia were observed at an increased incidence in mice or rats exposed to 0.05-5 ppm 1,1-dimethylhydrazine (Haun et al. 1984). It is possible that some of the carcinogenic effects of impure grades of 1,1-dimethylhydrazine may be attributable to the presence of dimethylnitrosamine, a potent carcinogen, as a contaminant (Haun 1977). *** DRAFT FOR PUBLIC COMMENT *** »% x LNIJWWOD O1T8Nd HOH L4VHA « « « TABLE 2-4. Genotoxicity of Hydrazine In Vivo Species (test system) End point Results Reference Form Mammalian cells: Rat liver and colon DNA alkylation + Netto et al. 1992 12DMH Rat liver DNA alkylation + Bosan et al. 1986 H Rat liver, kidney and intestines DNA alkylation + Pozharisski et al. 1975 12DMH Rat liver DNA alkylation + Becker et al. 1981 H Rat liver DNA alkylation + Beranek et al. 1983 12DMH Mouse liver DNA alkylation + Quintero-Ruiz et al. 1981 HS Rat liver, kidney, and colon DNA damage + Bolognesi et al. 1988 12DMH Mouse liver and lung DNA damage + Parodi et al 1981 11DMH Mouse liver and lung DNA damage + Parodi et al 1981 12DMH Mouse liver and lung DNA damage + Parodi et al 1981 HH Mouse lung, liver, and kidney Decreased DNA content + D’Souza and Bhide 1975 HS Mouse intestine Gene mutation + Winton et al. 1990 12DMH Rat colon Gene mutation + Jacoby et al. 1991 12DMH Rat colon Gene mutation + Jacoby et al. 1991 12DMH Rat colon Gene mutation + Llor et al. 1991 12DMH Mouse colon Inhibition of DNA repair + Koval 1984 12DMH Rat bone marrow Micronuclei - Albanese et al. 1988 12DMH Mouse bone marrow Micronuclei + Albanese et al. 1988 12DMH Mouse bone marrow Micronuclei + Ashby and Mirkova 1987 12DMH Mouse colon Sister chromatid exchange + Couch et al. 1986 12DMH Mouse bone marrow, lung, Sister chromatid exchange + Neft and Conner 1989 12DMH liver, and kidney Mouse blood and spleen Sister chromatid exchange + Neft and Conner 1989 12DMH lymphocytes Mouse sperm Unscheduled DNA synthesis - Sotomayor et al. 1982 H Mouse sperm Dominant lethal mutation - Brusick and Matheson 1976 11DMH SLO3443 H1IVaH CT 09 «»% LINIWWOD O178Nd HO4 14VHA «wu» TABLE 2-4. Genotoxicity of Hydrazine In Vivo (continued) Species (test system) End point Results Reference Form Nonmammalian cells: Drosophila melanogaster Drosophila melanogaster Host-mediated assays: Mouse Gene mutation - Gene mutation - Zijlstra and Vogel 1988 Zijlstra and Vogel 1988 Gene mutation (Escherichia coli) + Zeilmaker et al. 1991 11DMH 12DMH 12DMH - = negative result; + = positive result 11DMH = 1,1-dimethylhydrazine; 12DMH = 1,2-dimethylhydrazine; DNA = deoxyribonucleic acid; H = hydrazine; HH = hydrazine hydrate; HS = hydrazine sulfate S103443 H1TV3IH 'C 19 »»» LINIJWWOD O178Nd HOH LIVHA wx» TABLE 2-5. Genotoxicity of Hydrazine In Vitro With Without Species (test system) End point activation activation Reference Form Prokaryotic organisms: Salmonella typhimurium Gene mutation + + Parodi et al 1981 HH S. Typhimurium Gene mutation + + DeFlora and Mugnoli 1981 HH S. Typhimurium Gene mutation + + Wilpart et al. 1983 12DMH S. Typhimurium Gene mutation No data - Pence 1985 12DMH S. Typhimurium Gene mutation + + Parodi et al 1981 12DMH S. Typhimurium Gene mutation + - Malaveille et al. 1983 12DMH S. Typhimurium Gene mutation + - Kerklaan et al. 1983 12DMH S. Typhimurium Gene mutation + + DeFlora and Mugnoli 1981 12DMH S. Typhimurium Gene mutation + + DeFlora and Mugnoli 1981 11DMH S. Typhimurium Gene mutation + + Parodi et al 1981 11DMH S. Typhimurium Gene mutation - - Brusick and Matheson 1976 11DMH Saccharomyas cerevisiae Gene mutation - - Brusick and Matheson 1976 11DMH Photobacterium leiognathi Gene mutation No data + Levi et al. 1986 H Escherichia coli Gene mutation + No data Noda et al. 1986 B E. coli Gene mutation No data + Sedgwick 1992 12DMH E. coli Gene mutation No data + Sedgwick 1992 11DMH E. coli Gene mutation - - Brusick and Matheson 1976 11DMH Mammalian cells: Human colon DNA alkylation No data + Autrup et al. 1980a 12DMH Human bronchi DNA alkylation + No data Harris et al. 1977 12DMH Human fibroblasts DNA alkylation No data + Kumari et al. 1985 12DMH Human fibroblasts DNA alkylation No data + Kumari et al. 1985 11DMH Human teratoma Gene mutation + No data Oravec et al. 1986 12DMH Human fibroblasts Transformation No data + Kumari et al. 1985 12DMH Human fibroblasts Transformation No data + Kumari et al. 1985 11DMH V79 Chinese hamster DNA alkylation + - Boffa and Bolognesi 1986 12DMH Mouse lymphoma Gene mutation No data + Rogers and Back 1981 H Mouse lymphoma Gene mutation No data + Rogers and Back 1981 12DMH Mouse lymphoma Gene mutation No data + Rogers and Back 1981 11DMH Mouse lymphoma Gene mutation + + Brusick and Matheson 1976 11DMH SLO HITVIH 2 c9 » x» LNIWWOD O1T78Nd HOH LJVHA ww» TABLE 2-5. Genotoxicity of Hydrazine In Vitro (continued) Results With Without Species (test system) End point activation activation Reference Form Chinese hamster ovary Sister chromatid No data + MacRae and Stich 1979 H exchange Chinese hamster ovary Sister chromatid + + MacRae and Stich 1979 12DMH exchange Mouse hepatocytes Unscheduled DNA No data + Mori et al. 1988 HS synthesis Mouse hepatocytes Unscheduled DNA No data + Mori et al. 1988 HH synthesis Mouse hepatocytes Unscheduled DNA No data + Mori et al. 1988 12DMH synthesis Rat hepatocytes Unscheduled DNA No data + Mori et al. 1988 12DMH synthesis Human diploid W1-38 Unscheduled DNA - (+) Brusick and Matheson 1976 11DMH synthesis Mouse hepatocytes Unscheduled DNA No data + Mori et al. 1988 11DMH synthesis Noncellular assays: Calf thymus DNA DNA alkylation + - Bosan et al. 1986 H Calf thymus DNA DNA alkylation + - Lambert and Shank 1988 H Plasmid DNA DNA damage No data + Yamamoto and Kawanishi H 1991 Plasmid DNA DNA damage No data + Kawanishi and Yamamoto 11DMH 1991 Plasmid DNA DNA damage No data + Kawanishi and Yamamoto 12DMH 1991 - = negative result; + = positive result; (+) = weakly positive result 11DMH = 1,1-dimethylhydrazine; 12DMH = 1,2-dimethylhydrazine; DNA = deoxyribonucleic acid; H = hydrazine; HH = hydrazine hydrate; HS = hydrazine sulfate S103443 H1TV3H '¢C €9 64 2. HEALTH EFFECTS Following oral exposures, doses of 0.46-16.7 mg/kg/day hydrazine increased the incidence of liver, kidney, breast, and particularly lung tumors in several animal species (Bhide et al. 1976; Biancifiori 1970; Biancifiori and Ribacchi 1962; Biancifiori et al. 1964, 1966; Bosan et al. 1987; Maru and Bhide 1982; Roe et al. 1967; Yamamoto and Weisburger 1970). Oral exposure to 33 mg/kg/day 1,1-dimethylhydrazine increased the incidence of lung tumors in mice (Roe et al. 1967). Multiple tumor types, but most notably colon and blood vessel tumors, were induced in several animal species exposed to oral doses of 0.059-30 mg/kg/day 1,2-dimethylhydrazine (Abraham et al. 1980; Asano and Pollard 1978; Barbolt and Abraham 1980; Bedell et al. 1982; Calvert et al. 1987; Izumi et al. 1979; Locniskar et al. 1986; Teague et al. 1981; Thorup et al. 1992; Toth and Patil 1982; Wilson 1976). Colon tumors were also induced after single oral doses of 15.8-30 mg/kg 1,2-dimethylhydrazine (Craven and DeRubertis 1992; Schiller et al. 1980; Watanabe et al. 1985). A large number of studies have reported the carcinogenic effects of 1,2-dimethylhydrazine by the injection route. These studies have reported an induction of tumor types similar to those reported for oral exposure following single injections of 15-143 mg/kg 1,2-dimethylhydrazine (Barnes et al. 1983; Decaens et al. 1989; Fujii and Komano 1989; Glauert and Weeks 1989; Karkare et al. 1991; Sunter and Senior 1983; Toth et al. 1976; Wargovich et al. 1983) and repeated injections of 3-40 mg/kg/day (Andrianopoulos et al. 1990; Barsoum et al. 1992; Decaens et al. 1989; Druckrey 1970; Hagihara et al. 1980; Nelson et al. 1992; Pozharisski et al. 1976; Shirai et al. 1983; Vinas-Salas et al. 1992). Peripheral nerve sheath tumors were observed in hamsters injected with 32.5 mg/kg/day 1,1-dimethylhydrazine (Ernst et al. 1987). Several government departments and regulatory offices have evaluated the evidence regarding the carcinogenicity of hydrazines. The Department of Health and Human Services has determined that hydrazine and 1,1-dimethylhydrazine are known carcinogens (NTP 1991). The International Agency for Research on Cancer has determined that hydrazine, 1,1-dimethylhydrazine, and 1,2-dimethylhydrazine are probably carcinogenic to humans (Group 2B) (IARC 1987). The EPA has determined that hydrazine, 1,1-dimethylhydrazine, and 1,2-dimethylhydrazine are probable human carcinogens (Group B2) (HEAST 1992; IRIS 1993). 2.5 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). 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 (NAS/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 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 hydrazine are discussed in Section 2.5.1. 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 *** DRAFT FOR PUBLIC COMMENT *** 65 2. HEALTH EFFECTS health impairment (e.g., DNA adducts). Biomarkers of effects caused by hydrazine are discussed in Section 2.5.2. 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 2.7, "Populations That Are Unusually Susceptible." 2.5.1 Biomarkers Used to Identify or Quantify Exposure to Hydrazines Methods exist for measuring the levels of hydrazines and their metabolites in the plasma of humans (Blair et al. 1985) and in tissues, urine, and expired air of animals (Alvarez de Laviada et al. 1987; Back et al. 1963; Dost et al. 1966; Fiala and Kulakis 1981; Fiala et al. 1976; Harbach and Swenberg 1981; Kaneo et al. 1984; Kang et al. 1988; Matsuyama et al. 1983; Preece et al. 1991; Reed et al. 1963; Springer et al. 1981). These studies have employed colorimetric, chromatographic, and nuclear magnetic resonance techniques. However, the levels of hydrazines or their metabolites in tissues and excretia cannot presently be used to quantify past exposures. The detection of hydrazines and some of their metabolites (for example, azomethane and azoxymethane from 1,2-dimethylhydrazine) is a fairly specific biomarker of exposure. However, hydrazine is a metabolite of drugs such as isoniazid and hydralazine (Blair et al. 1985). Therefore, care must be taken to ensure that exposure to these drugs has not occurred. Other metabolites of hydrazines (for example, carbon dioxide and nitrogen) are endogenous to the body, and therefore, cannot be used as specific biomarkers of exposure. 2.5.2 Biomarkers Used to Characterize Effects Caused by Hydrazines Effects on the liver are associated with exposure to hydrazines in humans (Sotaniemi et al. 1971) and animals (Haun and Kinkhead 1973; Rinehart et al. 1960; Vernot et al. 1985; Wilson 1976). Therefore, assessment of serum transaminase activities may be useful in revealing liver damage in people exposed to hydrazines. Neurological effects are often observed following exposure to hydrazine and 1,1-dimethylhydrazine in humans (Chlebowski et al. 1984; Gershanovich et al. 1976; Ochoa et al. 1975; Richter et al. 1992; Sotaniemi et al. 1971) and animals (Haun and Kinkhead 1973; Rinehart et al. 1960). The mechanism by which hydrazine and 1,1-dimethylhydrazine produces neurological effects involves binding to vitamin Bg derivatives. Therefore, assessment of vitamin Bg status either by direct measurement in the blood, tryptophan load tests, or measurements of vitamin B-dependent activities in plasma or erythrocytes may serve to indicate if vitamin Bg status has been compromised by hydrazine or 1,1-dimethylhydrazine. DNA adducts have been observed in animals exposed hydrazines in vivo (Becker et al. 1991; Bosan et al. 1986; Beranek et al. 1983; Bolognesi et al. 1988; Netto et al. 1992; Pozharisski et al. 1975; Quintero-Ruiz et al. 1981; Rogers and Pegg 1977). However, these are somewhat difficult to detect and quantitate, and therefore, may not be useful as biomarkers of effect. An increased incidence of colon tumors is the most consistent effect observed following exposure to 1,2-dimethylhydrazine in animals (Abraham et al. 1980; Asano and Pollard 1978; Barbolt and Abraham 1980; Calvert et al. 1987; Izumi et al. 1979; Locniskar et al. 1986; Teague et al. 1981; Thorup et al. 1992; Wilson 1976). Simple tests for occult blood in the stools can be used as a preliminary screen for intestinal tumors. However, these types of effects can be caused by exposures to a large number of agents, and in no way are these biomarkers specific for the effects of hydrazines. 2.6 INTERACTIONS WITH OTHER SUBSTANCES No studies were located regarding interactions in humans or animals after exposure to hydrazine or 1,1-dimethylhydrazine. On the other hand, a large number of studies are available in animals regarding the interactions of various treatments on 1,2-dimethylhydrazine-induced colon cancer. For example, high fat diets, high cholesterol diets, potassium chloride, caffeine, vitamin C, iron, ethoxyquin, and colorectal surgery were all found to increase the incidence, multiplicity, or malignancy of 1,2-dimethylhydrazine-induced intestinal tumors *** DRAFT FOR PUBLIC COMMENT *** 66 2. HEALTH EFFECTS (Balansky et al. 1992; Bansal et al. 1978; Cruse et al. 1982; Locniskar et al. 1986; Nelson et al. 1992; Shirai et al. 1985; Siegers et al. 1992), whereas aspirin, bran, pectin, calcium, vitamin C, vitamin D, vitamin E, carbon tetrachloride, carbon disulfide, sodium selenate, butylated hydroxytoluene, corn oil, and calcium chloride were all found to decrease the incidence of these tumors (Balansky et al. 1992; Barnes et al. 1983; Barsoum et al. 1992; Belleli et al. 1992; Calvert et al. 1987 ; Colacchio et al. 1989; Craven and DeRubertis 1992; Heitman et al. 1992; Shirai et al. 1985). Other studies have reported that bran, beta-carotene, butylated hydroxyanisole, propyl gallate, and stress had no significant effect on tumors of the colon induced by 1,2-dimethylhydrazine (Andrianopoulos et al. 1990; Barbolt and Abraham 1980; Colacchio et al. 1989; Shirai et al. 1985; Thorup et al. 1992). A number of mechanisms are possible for these interactions including but not limited to interference with the metabolism of 1,2-dimethylhydrazine (Fiala et al. 1977), action as a scavenger for free radicals produced during 1,2-dimethylhydrazine metabolism, and influences at the post-initiation stage of colon carcinogenesis. 2.7 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE A susceptible population will exhibit a different or enhanced response to hydrazine than will most persons exposed to the same level of hydrazine in the environment. Reasons include genetic make-up, developmental stage, age, health and nutritional status (including dietary habits that may increase susceptibility, such as inconsistent diets or nutritional deficiencies), and substance exposure history (including smoking). These parameters result in decreased function of the detoxification and excretory processes (mainly hepatic, renal, and respiratory) or the pre-existing compromised function of target organs (including effects or clearance rates and any resulting end-product metabolites). For these reasons we expect the elderly with declining organ function and the youngest of the population with immature and developing organs will generally be more vulnerable to toxic substances than healthy adults. Populations who are at greater risk due to their unusually high exposure are discussed in Section 5.6, "Populations With Potentially High Exposure." Data from a single human study indicate that people with a slow acetylator genotype may be unusually susceptible to the effects of hydrazine. A pronounced accumulation of hydrazine was noted in the plasma of slow acetylator patients treated with isoniazid compared to those patients that were rapid acetylators (Blair et al. 1985). However, such a mechanism is speculative and warrants further investigation. In animals, a number of studies have reported differences in susceptibility to the toxic effects of hydrazines with respect to species (Haun and Kinkhead 1973; Rinehart et al. 1960; Vernot et al. 1985; Wilson 1976), strain (Asano and Pollard 1978; Bhide et al. 1976; Teague et al. 1981; Toth 1969), sex (Bhide et al. 1976; Biancifiori 1970; Teague et al. 1981; Visek et al. 1991), and age (Wakabayashi et al. 1983). Some of the differences in susceptibility may be related to differences in ability to metabolize hydrazines; however, many other differences still lack a satisfactory explanation. 2.8 METHODS FOR REDUCING TOXIC EFFECTS This section will describe clinical practice and research concerning methods for reducing toxic effects of exposure to hydrazine. 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 hydrazine. When specific exposures have occurred, poison control centers and medical toxicologists should be consulted for medical advice. 2.8.1 Reducing Peak Absorption Following Exposure No data were located regarding methods for reducing absorption after inhalation exposure to hydrazines. There are several methods by which the absorption of hydrazines can be reduced in the gastrointestinal tract. Induced emesis, gastric lavage, use of saline cathartics, or activated charcoal are all methods which are commonly used to decrease the gastrointestinal absorption of compounds such as hydrazines (Bronstein and Currance 1988; Sittig 1991; Stutz and Janusz 1988). In general, these treatments are most effective when used *** DRAFT FOR PUBLIC COMMENT *** 67 2. HEALTH EFFECTS within a few hours after oral exposure. In some cases, these treatments may be contraindicated. For example, some authors contend that emesis should not be induced (Bronstein and Currance 1988). In addition, emesis should not be induced in obtunded, comatose, or convulsing patients. Oils should not be used as a cathartic, since they may enhance the gastrointestinal absorption of hydrazines. Saline cathartics should be used with caution in patients with impaired renal function. Following dermal or ocular exposures to hydrazines, there are several methods by which absorption can be reduced. All contaminated clothing should be removed, and contacted skin should be washed immediately with soap and water (Bronstein and Currance 1988; Haddad and Winchester 1990; Sittig 1991; Stutz and Janusz 1988). Eyes that have come in contact with hydrazines should be flushed with copious amounts of water. Contact lenses should be removed prior to flushing with water. Proparacaine hydrochloride may be used to assist eye irrigation (Bronstein and Currance 1988). 2.8.2 Reducing Body Burden Elimination of hydrazines in the urine may be enhanced by forced diuresis and acidification of the urine (Haddad and Winchester 1990). Hemodialysis and peritoneal dialysis may also be helpful, but this has not been fully studied. Activated charcoal is sometimes administered in serial doses to minimize the enterohepatic recirculation of persistent chemicals. Data regarding the enterohepatic recirculation of hydrazines were not located. However, available data suggest that hydrazines are readily cleared from the body since the levels in various tissues in animals are usually not detectable after 24 hours. In addition, studies in rats indicate that only a small percentage of a dose of 1,2-dimethylhydrazine (0.4-0.9%) is excreted in the bile (Hawks and Magee 1974). Therefore, it is not likely that efforts to minimize enterohepatic recirculation of hydrazines would be of much use. 2.8.3 Interfering with the Mechanism of Action for Toxic Effects There are at least two distinct mechanisms by which hydrazines produce adverse health effects. Methods for interfering with these mechanisms are discussed below. The first mechanism involves the reaction of hydrazine or 1,1-dimethylhydrazine with endogenous alpha-keto acids such as vitamin By (pyridoxine). The formation of hydrazones of pyridoxine is the proposed mechanism by which hydrazine and 1,1-dimethylhydrazine produce neurological effects. Several studies have reported successful treatment of neurological effects in humans exposed to hydrazine and 1,1-dimethylhydrazine with pyridoxine (Dhennin et al. 1988; Ellenhorn and Barceloux 1988; Haddad and Winchester 1990; Kirklin et al. 1976). In addition, several animal studies reported that pyridoxine diminished, and in some cases completely abolished the lethal and neurological effects of hydrazine and 1,1-dimethylhydrazine (Geake et al. 1966; Lee and Aleyassine 1970; O’Brien et al. 1964; Segerbo 1979). However, treatment with pyridoxine is not without risk. For example, some authors suggested that pyridoxine is also capable of producing neuropathy (Harati and Niakan 1986). This effect has been noted in humans exposed to hydrazines and treated with pyridoxine (Dhennin et al. 1988; Harati and Niakan 1986; Ochoa et al. 1975), but it is difficult to ascribe this effect to exposure to either hydrazines or pyridoxine alone. It is possible that the adverse effects of pyridoxine treatment may be associated with treatments using large doses. Evidence of a therapeutic window have been reported in animal studies (Geake et al. 1966). Studies in animals have also reported that the hydrazones of pyridoxine are more toxic than the corresponding hydrazine (Furst and Gustavson 1967). These data indicate that pyridoxine should be used with caution and that all potential risks and benefits should be considered prior to treatment. In any case, treatment with pyridoxine would not be expected to be beneficial for exposures to 1,2-dimethylhydrazine since this compound, unlike hydrazine and 1,1-dimethylhydrazine, does not form hydrazines. The second mechanism by which hydrazines produce adverse health effects involves the generation of free radical intermediates. Free radicals have been detected during the metabolism of hydrazines in vitro (Albano et al. 1989; Augusto et al. 1985; Ito et al. 1992; Netto et al. 1987; Noda et al. 1988; Runge-Morris et al. 1988; Sinha 1987; Tomasi et al. 1987). Therefore, treatment with agents that act as free radical scavengers could *** DRAFT FOR PUBLIC COMMENT *** 68 2. HEALTH EFFECTS offer a protective effect. In vitro studies have shown that glutathione is an effective scavenger of the free radicals produced from the metabolism of 1,1-dimethylhydrazine and 1,2-dimethylhydrazine (Tomasi et al. 1987). A number of animal studies have reported that aspirin, vitamin C, vitamin E, and butylated hydroxytoluene decreased the incidence, multiplicity, or malignancy of 1,2-dimethylhydrazine-induced intestinal tumors (Belleli et al. 1992; Colacchio et al. 1989; Cook and McNamara 1980; Craven and DeRubertis 1992; Shirai et al. 1985). It is possible that this protective effect may occur via inhibition of metabolic activation or a free radical scavenging mechanism, and if so, treatment would be most effective if administered relatively soon after exposure; however, the mechanism is not known conclusively and warrants further investigation. Since reactive intermediates are (methyldiazonium ions or free radicals) produced as a result of the metabolism of hydrazines, the administration of inhibitors of the cytochrome P-450 or the flavin-containing monooxygenase system offer may some protective effect. For example, disulfiram, an inhibitor of cytochrome P45011E1 (Guengerich et al. 1991), decreased the oxidation of azomethane (a metabolite of 1,2-dimethylhydrazine) to azoxymethane (Fiala et al. 1977), and the further oxidation of azoxymethane to methylazoxymethanol (Fiala 1977). The inhibition of the activation pathway of 1,2-dimethylhydrazine by disulfiram resulted in decreased DNA methylation in the liver and colon of rats (Swenberg et al. 1979), and inhibition of 1,2-dimethylhydrazine- induced colon carcinogenesis (Wattenberg 1975). Although disulfiram is a toxic compound which is known to inhibit other enzyme systems, it has been used in humans as an alcohol deterrent (Ellenhorn and Barceloux 1988). In cases of significant exposure to 1,2-dimethylhydrazine, the potential benefits of disulfiram in preventing colon cancer may outweigh the potential risk of adverse toxic effects. 2.9 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 hydrazine 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 hydrazine. 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. 2.9.1 Existing Information on Health Effects of Hydrazines The existing data on health effects of inhalation, oral, and dermal exposure of humans and animals to hydrazine are summarized in Figure 2-3. The purpose of this figure is to illustrate the existing information concerning the health effects of hydrazine. Each dot in the figure indicates that one or more studies provide information associated with that particular effect. The dot does not imply anything about the quality of the study or studies. Gaps in this figure should not be interpreted as "data needs." A data need, as defined in ATSDR’s Decision Guide for Identifying 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. As shown in Figure 2-3, data are available in humans regarding lethal, neurological, and carcinogenic effects after inhalation exposure to hydrazines. Data are also available for the systemic effects observed in humans exposed to hydrazines by the inhalation route for intermediate-durations. By oral route, information is only available for the neurological effects in humans exposed to hydrazines. Acute systemic, immunological, and neurological effects have been reported in humans after dermal exposure to hydrazines. *** DRAFT FOR PUBLIC COMMENT *** 69 2. HEALTH EFFECTS FIGURE 2-3. Existing Information on Health Effects of Hydrazines | SYSTEMIC 4 S/S) S SS ELLE Inhalation | ® ® # ® Oral ® Dermal @ | © HUMAN SYSTEMIC / & g i £) A £/ « SEE SESE Inhalation | ®| ®| ®| © ® ® ® Oral o/lo|o0o|0|0|O0|O0O|O OO Dermal o| O® ® ANIMAL @ Existing Studies *** DRAFT FOR PUBLIC COMMENT *** 70 2. HEALTH EFFECTS Considerably more information on the health effects of hydrazines are available from animal studies. These are data for all effect categories from animal studies for oral exposure to hydrazines. The lethal, neurological, reproductive, carcinogenic, and systemic effects for all exposure durations are available from studies in animals exposed to hydrazines by the inhalation route. For dermal exposures to hydrazines, animal data are available regarding the lethal, neurological, and acute systemic effects. 2.9.2 Identification of Data Needs Acute-Duration Exposure. Data are available for the acute toxicity of hydrazine in humans after inhalation and dermal exposures, and in several animal species after oral and dermal exposures. Although a human case study suggests neurological effects are of concern following inhalation exposure to hydrazine (Frierson 1965), quantitative data are not available for the acute toxicity of hydrazine after inhalation exposure. Data from animal studies (rats, dogs) indicate that the liver is the primary target organ after oral exposures (Marshall et al. 1983; Preece et al. 1992; Wakabayashi et al. 1983), and that the skin is the most sensitive target in humans and animals (rabbits, guinea pigs, dogs) following dermal exposures (Hovding 1967; Suzuki and Ohkido 1979). These data do not sufficiently define the threshold dose for these effects, and do not support the derivation of an MRL. Data are available for the acute toxicity of 1,1-dimethylhydrazine after inhalation exposure in humans, and inhalation, oral, and dermal exposures in animals. A human case study suggests that neurological effects are of concern following acute inhalation exposure to 1,1-dimethylhydrazine (Frierson 1965). Data from a study in dogs indicate that the central nervous system is affected following inhalation of 1,1-dimethylhydrazine (Rinehart et al. 1960). This finding is supported by data in rats, mice, cats, and monkeys acutely exposed to 1,1-dimethylhydrazine by injection (Furst and Gustavson 1967; Furst et al. 1969; Geake et al. 1966; Goff et al. 1967, 1970; Minard and Mushahwar 1966; O’Brien et al. 1964; Reynolds et al. 1963, 1964; Segerbo 1979; Sterman and Fairchild 1967). Data regarding the effects of acute oral exposure to 1,1-dimethylhydrazine are limited to a lethality study in mice (Roe et al. 1967). Animal studies (rabbits, dogs) have reported hematological and ocular effects following dermal exposure to 1,1-dimethylhydrazine (Rothberg and Cope 1956; Smith and Castaneda 1970; Smith and Clark 1971). These studies do not define the threshold for effect with confidence, and do not support the derivation of an MRL. Data are available for the acute toxicity of 1,2-dimethylhydrazine in animals after acute oral and dermal exposures. No human studies were located regarding the acute toxicity of 1,2-dimethylhydrazine. Two studies in rats and dogs were located which reported effects on the colon, liver, and body weight after oral exposure (Caderni et al. 1991; Wilson 1976). Studies in rabbits and guinea pigs indicate that acute dermal exposure to 1,2-dimethylhydrazine can product irritation and death (Rothberg and Cope 1956). These studies do not define the effect level for 1,2-dimethylhydrazine with confidence, and do not support the derivation of an MRL. Studies are also available on the carcinogenic effects of 1,2-dimethylhydrazine after acute oral exposure (Craven and DeRubertis 1992; Schiller et al. 1980; Watanabe et al. 1985). No animal studies were located regarding the effects of acute inhalation exposure to 1,2-dimethylhydrazine. Additional animal studies which investigate the acute effects of hydrazines after inhalation, oral, and dermal exposures would better define the threshold dose for adverse health effects. Such studies would be useful in predicting adverse health effects in humans acutely exposed to hydrazines at hazardous waste sites by similar routes. Intermediate-Duration Exposure. Data are available on the toxicity of hydrazine and 1,1-dimethylhydrazine in humans and several animal species after intermediate-duration exposure by the inhalation and oral routes. These studies reported effects on the central nervous system in humans following oral exposure (Chlebowski et al. 1984; Gershanovich et al. 1976, 1981; Ochoa et al. 1975) and in animals (rats, mice, dogs) after inhalation exposure (Haun and Kinkhead 1973), and effects on the liver in animals (mice, dogs, monkeys, rats) after inhalation exposure (Biancifiori 1970; Haun and Kinkhead 1973; Haun et al. 1984; Rinehart et al. 1960). The data were sufficient to support the derivation of inhalation MRLs of 2x10* ppm for hydrazine and *** DRAFT FOR PUBLIC COMMENT *** 71 2. HEALTH EFFECTS 9x10 ppm for 1,1-dimethylhydrazine based on hepatic effects. No data were located regarding the toxicity of hydrazine or 1,1-dimethylhydrazine following dermal exposure for an intermediate exposure. Studies are also available for the carcinogenic effects of hydrazine and 1,1-dimethylhydrazine after intermediate-duration exposures (Biancifiori 1970; Bhide et al. 1976; Haun et al. 1984; Roe et al. 1967). No studies were located regarding the toxicity of 1,2-dimethylhydrazine in humans after intermediate exposure. Data regarding the toxicity of 1,2-dimethylhydrazine in animals after intermediate-duration exposure are limited to those by the oral route. These studies have generally reported hepatic effects in rats, guinea pigs, mice, and pigs (Bedell et al. 1982; Visek et al. 1991; Wilson 1976), and support the derivation of an intermediate oral MRL of 8x10 mg/kg/day for 1,2-dimethylhydrazine. In addition, a large number of studies report the carcinogenic effects of 1,2-dimethylhydrazine after intermediate exposures (Izumi et al. 1979; Teague et al. 1981; Wilson 1976). Additional studies in animals which investigate the effects of hydrazines after intermediate-duration inhalation, oral, and dermal exposures would better define the threshold dose for adverse health effects. Such studies would be useful in predicting adverse health effects in humans exposed for intermediate-durations to hydrazines at hazardous waste sites by similar routes. Chronic-Duration Exposure and Cancer. Data are available on the toxicity of hydrazine and 1,1-dimethylhydrazine in animals after chronic-duration exposure by the inhalation and oral routes. Effects on the liver, lung, and body weight gain are the most consistent findings observed in rats, mice, dogs, and hamsters (Haun et al. 1984; Steinhoff et al. 1990; Vernot et al. 1985). However, these studies alone do not define the threshold dose level for these effects with confidence, and therefore do not by themselves support the derivation of an MRL. However, in the case of 1,1-dimethylhydrazine, they do permit the adoption of the intermediate inhalation MRL as a value also appropriate for the chronic inhalation MRL. Despite this, data regarding the noncarcinogenic effects of 1,2-dimethylhydrazine after chronic exposures are largely lacking. Additional studies which investigate the effects of hydrazines in animals after chronic inhalation, oral, and dermal exposures would help define the threshold dose for adverse health effects. Such studies would be useful in predicting adverse health effects in humans chronically-exposed to hydrazines at hazardous waste sites by similar routes. As discussed in the previous sections, hydrazines can cause cancer in animals following acute or intermediate duration exposure by the oral and inhalation route. In addition, a number of studies reported carcinogenic effects in a number of animal species exposed to hydrazine (Bhide et al. 1976; Bosan et al. 1987; Maru and Bhide 1982; Toth 1969, 1972b; Vernot et al. 1985), 1,1-dimethylhydrazine (Haun et al. 1984; Toth 1973a), and 1,2-dimethylhydrazine (Toth and Patil 1982), following chronic oral and inhalation exposures. These studies demonstrate that hydrazines are carcinogenic in animals following chronic oral and inhalation exposures. Epidemiological studies which investigate the carcinogenic effects in humans exposed occupationally or therapeutically to hydrazine would confirm whether or not the cancer effects observed in animal studies also occur in humans. Genotoxicity. Data regarding the genotoxicity of hydrazines in humans are not available. A large number of studies are available that report the genotoxic effects of hydrazines in animals in vivo (Albanese et al. 1988; Ashby and Mirkova 1987; Becker et al. 1981; Beranek et al. 1983; Bolognesi et al. 1988; Bosan et al. 1986; Couch et al. 1986; Jacoby et al. 1991; Netto et al. 1992; Parodi et al. 1981; Pozharisski et al. 1975; Quintero- Ruiz et al. 1981; Winton et al. 1990; Zeilmaker et al. 1991; Zijlstra and Vogel 1988) and in a number of cell lines in vitro (Autrup et al. 1980a; Bosan et al. 1986; DeFlora and Mugnoli 1981; Harris et al. 1977; Kerklaan et al. 1983; Kumari et al. 1985; Lambert and Shank 1988; Levi et al. 1986; Malaveille et al. 1983; Noda et al. 1986; Oravec et al. 1986; Parodi et al. 1981; Rogers and Back 1981; Sedgwick 1992; Wilpart et al. 1983). These studies convincingly demonstrate that all three hydrazines are genotoxic. Additional genotoxicity studies in humans exposed to hydrazines, either occupationally, therapeutically, or by living near hazardous waste sites, would determine whether or not the effects observed in animals and in cells are also observed in humans. *** DRAFT FOR PUBLIC COMMENT *** 72 2. HEALTH EFFECTS Reproductive Toxicity. Data regarding the reproductive toxicity of hydrazines in humans are not available. Data regarding the reproductive effects of hydrazines are limited to a few animal studies following inhalation, oral, and parenteral routes of exposure to hydrazine (Biancifiori 1970; Vernot et al. 1985; Wyrobek and London 1973) and inhalation exposure to 1,1-dimethylhydrazine (Haun et al. 1984). The serious nature of the effects caused by the inhalation of hydrazines suggests they may be of concern in humans exposed at hazardous wastes sites. Studies that investigate the reproductive effects of 1,2-dimethylhydrazine by all routes of exposure, and additional studies that investigate the reproductive effects of hydrazine, and 1,1-dimethylhydrazine, particularly those which also evaluate reproductive function over several generations, would be valuable in determining if the reproductive system is adversely affected in humans exposed to hydrazines. Developmental Toxicity. Data regarding the developmental toxicity of hydrazines in humans are not available. Data regarding the developmental effects of hydrazines are limited to a few animal studies which report increased fetal and neonatal mortality following exposure to hydrazine and 1,2-dimethylhydrazine by the oral and parenteral routes (Lee and Aleyassine 1970; Schiller et al. 1979). Studies that investigate the developmental effects of 1,1-dimethylhydrazine for any exposure route, as well as multigenerational studies that better define the dose-response relationship for the developmental effects of hydrazine and 1,2-dimethylhydrazine for any exposure route would be useful in determining whether developmental effects are of concern in humans exposed to hydrazines. Immunotoxicity. The data regarding the immunological effects of hydrazines are limited. There is some suggestive evidence from human studies that exposure to hydrazine and other hydrazine derivatives can produce a lupus erythematosus-like disease (Pereyo 1986; Reidenberg et al. 1983). Data in animals reported immunological effects in mice with parenteral exposure to 1,1-dimethylhydrazine (Frazier et al. 1991) but not in rats with oral exposure to 1,2-dimethylhydrazine (Locniskar et al. 1986). In vitro studies suggest 1,1-dimethylhydrazine produces immunomodulatory effects (Bauer et al. 1990; Frazier et al. 1992). Additional case studies in humans and studies in animals which better define the dose-response relationship for the immunological effects of hydrazines would help determine if these effects are of concern to humans exposed to hydrazines. Neurotoxicity. Data are available for the neurological effects of hydrazines in humans following inhalation, oral, and dermal routes of exposures to hydrazine (Chlebowski et al. 1984; Gershanovich et al. 1976, 1981; Haun and Kinkhead 1973; Ochoa et al. 1975; Richter et al. 1992; Sotaniemi et al. 1971; Spremulli et al. 1979) and 1,1-dimethylhydrazine (Dhennin et al. 1988; Kirklin et al. 1976; Rinehart et al. 1960). Effects on the central nervous system were also observed in animals following dermal and parenteral exposures to hydrazine (Floyd 1980; Mizuno et al. 1989; Patrick and Back 1965; Smith and Clark 1972) and 1,1-dimethylhydrazine (Furst and Gustavson 1967; Geake et al. 1966; Goff et al. 1970; Minard and Mushahwar 1966; O’Brien et al. 1964; Reynolds et al. 1964; Segerbo 1979; Smith and Clark 1971). Although these studies convincingly demonstrate that the central nervous system is a primary target of hydrazine and 1,1-dimethylhydrazine, these data do not define the threshold dose for neurological effects with confidence. Additional studies which better define the threshold dose for the neurological effects of hydrazine and 1,1-dimethylhydrazine would be useful in determining the risk of neurological effects in humans exposed to these hydrazines. Studies on 1,2-dimethylhydrazine in animals may determine if neurological effects are of concern for humans exposed to this chemical. Epidemiological and Human Dosimetry Studies. Only one epidemiological study was located regarding the effects of hydrazine. This study showed no significant increase in cancer mortality in 427 hydrazine workers (Wald et al. 1984). However, the number of deaths examined was relatively small and the follow-up period may not have been sufficient for detecting a weak carcinogenic effect. Additional epidemiological studies investigating the neurological, hepatic, renal, and carcinogenic effects of hydrazines, particularly studies which also provide quantitative information on exposure, would be valuable in estimating the risk of adverse health effects in persons exposed to hydrazines in the workplace or at hazardous waste sites. *** DRAFT FOR PUBLIC COMMENT *** 73 2. HEALTH EFFECTS Biomarkers of Exposure and Effect: Exposure. Methods are available for determining the levels of hydrazine in the plasma of humans (Blair et al. 1985), and the levels of all three hydrazines and their metabolites and in tissues, urine, and expired air of animals (Alvarez de Laviada et al. 1987; Back et al. 1963; Dost et al. 1966; Fiala et al. 1976; Harbach and Swenberg 1981; Kaneo et al. 1984; Kang et al. 1988; Matsuyama et al. 1983; Preece et al. 1991; Reed et al. 1963; Springer et al. 1981). The detection of hydrazines and some of their metabolites (for example, the metabolites of 1,2-dimethylhydrazine - azoxymethane and methylazoxymethanol) are fairly specific for exposures to hydrazines. However, it should be kept in mind that treatment with certain drugs such as isoniazid or hydralazine can result in the presence of hydrazine in human plasma (Blair et al. 1985), therefore care should be taken to ensure subjects have not been exposed to these drugs. Other metabolites of hydrazines (for example, carbon dioxide and nitrogen) are endogenous to the body, and therefore, cannot be used as specific biomarkers of exposure. Studies which investigate the quantitative relationship between exposure intensity, time since exposure, and the levels of hydrazines or their unique metabolites detected in biological samples, particularly in the urine, would be useful for estimating human exposures to hydrazines in the workplace or at hazardous waste sites. Studies that identify biomarkers of exposure that are specific to hydrazines could lead to the development of a reliable method for estimating recent exposures to hydrazines. Effect. Exposure to hydrazine and 1,1-dimethylhydrazine is associated with the development of neurological and hepatic effects in humans (Chlebowski et al. 1984; Gershanovich et al. 1976; Ochoa et al. 1975; Richter et al. 1992; Sotaniemi et al. 1971) and animals (Haun and Kinkhead 1973; Rinehart et al. 1960; Vernot et al. 1985; Wilson 1976). Studies which investigate if serum transaminase levels or vitamin By status could be used to predict effects of hydrazines could be useful. However, these effects are not specific to exposures to hydrazines. The carcinogenic effects of hydrazines have also been amply demonstrated in animal studies (Abraham et al. 1980; Asano and Pollard 1978; Barbolt and Abraham 1980; Calvert et al. 1987; Izumi et al. 1979; Locniskar et al. 1986; Teague et al. 1981; Thorup et al. 1992; Wilson 1976). Studies which investigate if tests for occult blood in stools could be used to predict intestinal tumors induced by 1,2-dimethylhydrazine could be useful. However, the etiology of colon cancer is multifactional and may not be related to exposures to 1,2-dimethylhydrazine. Studies which identify biomarkers of effect that are specific to exposures to hydrazines could lead to the development of a reliable method for predicting past exposures to hydrazines. Absorption, Distribution, Metabolism, and Excretion. Data regarding the toxicokinetics of hydrazines are limited to in vitro metabolic assays (Albano et al. 1989; Augusto et al. 1985; Coomes and Prough 1983; Craven et al. 1985; Erikson and Prough 1986; Godoy et al. 1983; Glauert and Bennink 1983; Netto et al. 1987; Newaz et al. 1983; Noda et al. 1987, 1988; Prough 1973; Prough et al. 1981; Sheth-Desai et al. 1987; Sinha 1987; Timbrell et al. 1982; Tomasi et al. 1987; Wolter et al. 1984) and in vivo studies in rats exposed via inhalation (Llewellyn et al. 1986), rats exposed orally (Preece et al. 1992), dogs exposed dermally (Smith and Clark 1971, 1972), and in several species exposed by parenteral routes (Back et al. 1963; Dost et al. 1966; Fiala et al. 1976; Harbach and Swenberg 1981; Kaneo et al. 1984; Mitz et al. 1962; Reed et al. 1963; Springer et al. 1981). ° These studies invariably employed a single radiolabel (either “C or *N), and therefore in the case of 1,1-dimethylhydrazine and 1,2-dimethylhydrazine, the metabolic fate data (expressed as a carbon or nitrogen dose) were often incomplete. Studies which investigate the toxicokinetics of hydrazines for all routes and durations, particularly those which employ both a carbon and nitrogen label, would enhance the current understanding of the metabolic fate of hydrazines in humans exposed at hazardous waste sites. Comparative Toxicokinetics. Studies in humans (Dhennin et al. 1988; Kirklin et al. 1976; Sotaniemi et al. 1971) and several animal species (Biancifiori 1970; Haun and Kinkhead 1973; Marshall et al. 1983; Rinehart et al. 1960; Vernot et al. 1985; Wakabayashi et al. 1983) indicate that the liver and central nervous system are the primary target organs affected following oral, inhalation, and dermal exposures to hydrazine and 1,1-dimethylhydrazine. Studies in several animal species indicate that the intestinal tract and liver are the primary target organs affected following oral exposure to 1,2-dimethylhydrazine (Bedell et al. 1992; Wilson et al. 1976). Data regarding the toxicokinetics of hydrazines are lacking in humans and are limited in animals. These data are not sufficient to conclude which animal species is the best model for modelling human *** DRAFT FOR PUBLIC COMMENT *** 74 2. HEALTH EFFECTS exposures. Similarly, these data do not reveal the basis of species differences in the toxicokinetics of hydrazines which underlie the species differences in toxicity. For example, dogs appear to be particularly sensitive to the hematological effects of hydrazine and 1,1-dimethylhydrazine (Haun and Kinkead 1973; Haun et al. 1984; Rinehart et al. 1960; Smith and Castaneda 1970). Additional studies which investigate the toxicokinetics in multiple species, including humans or human tissues, would be useful in developing an appropriate animal model for humans exposed to hydrazines at hazardous waste sites. Methods for Reducing Toxic Effects. General methods exist for reducing the absorption of chemicals from the eyes, skin, and gastrointestinal tract (Bronstein and Currance 1988; Sittig 1991; Stutz and Janusz 1988). However, none of these methods are specific for exposures to hydrazines. No data were located for reducing body burden after exposure to hydrazines. Pyridoxine, which interferes with the mechanism of action of hydrazine and 1,1-dimethylhydrazine, is often administered to humans exposed to these hydrazines (Dhennin et al. 1988; Kirklin et al. 1976). However, exposure to pyridoxine may also be associated with adverse health effects. Additional studies that investigate the threshold dose for adverse effects of pyridoxine, and studies that investigate alternative agents that interfere with the mechanism of action of hydrazines could lead to a safer method of treatment. Inhibitors of metabolic activation (Fiala et al. 1977) and free radical scavengers may also be useful in interfering with the mechanism of action of hydrazines (Belleli et al. 1992; Colacchio et al. 1989; Cook and McNamara 1980; Craven and DeRubertis 1992; Shirai et al. 1985; Tomasi et al. 1987). Additional studies that investigate the effects of metabolic inhibitors and various free radical scavengers in humans occupationally exposed to hydrazines, and in animals could lead to other methods of interfering with the mechanism of action of hydrazines. 2.9.3 On-going Studies A number of researchers are continuing to investigate the toxicity and toxicokinetics of 1,2-dimethylhydrazine. Table 2-6 summarizes studies sponsored by agencies of the U.S. federal government. *** DRAFT FOR PUBLIC COMMENT *** 75 2. HEALTH EFFECTS TABLE 2-6. On-going Studies on the Health Effects of Hydrazines Investigator Affiliation Research description Sponsor Brasitus, TA University of Chicago Colonic epithelial cell plasma membranes NIH, NCI in rats treated with 1,2-dimethylhydrazine Goldman, P Harvard School of Metabolism of 1,2-dimethylhydrazine by rat NIH, NCI Public Health intestinal bacteria Kazarinoff, MN Cornell University Induction of ornithine decarboxylase by USDA 1,2-dimethylhydrazine McGarrity, TJ ~~ Milton S Hershey Cellular changes in 1,2-dimethylhydrazine- NIH, NCI Medical Center induced colon tumors in the rat Pretlow, TP Case Western Reserve Colonic putative preneoplastic foci in NIH, NCI University rats by metabolite, azoxymethane Shank, RC University of California Environmental hydrazines and methylation of NIH, NIEHS DNA in rats and hamsters Strobel, HW University of Texas Identification of cytochrome P-450 isozymes NIH, NCI Medical School involved in the metabolism of 1,2-dimethylhydrazine Sources: CRISP (1993) NCI NIH National Cancer Institute; NIEHS = National Institute of Environmental Health Sciences; National Institute of Health; USDA = U.S. Department of Agriculture *** DRAFT FOR PUBLIC COMMENT *** 77 3. CHEMICAL AND PHYSICAL INFORMATION 3.1 CHEMICAL IDENTITY Information regarding the chemical identity of hydrazine is located in Table 3-1. 3.2 PHYSICAL AND CHEMICAL PROPERTIES Information regarding the physical and chemical properties of hydrazine is located in Table 3-2. *** DRAFT FOR PUBLIC COMMENT *** xxx INSWIWOD OMENd HOH L4VHQA xxx TABLE 3-1. Chemical Identity of Hydrazines Characteristic Hydrazine 1,1-Dimethylhydrazine 1,2-Dimethylhydrazine References Synonym(s) Diamine; diamide; Hydrazine, 1,1-dimethyl; Hydrazine, 1,2-dimethyl; HSDB 1993 anhydrous hydrazine; DMH; unsymmetrical DMH; symmetrical hydrazine base dimethylhydrazine; dimethylhydrazine; SDMH; UDMH; dimazine; and others hydrazomethane; and others Registered trade name(s) Levoxir®; SCAV-0X; No data No data HSDB 1993; Zerox; Oxytreat 35 WHO 1987 Chemical formula HN, CHN, CGHN, HSDB 1993 HC | Chemical structure H,N-NH, N- NH, CH, - NH - NH - CH, IARC 1974 / HC Identification numbers: CAS registry 302-01-2 57-14-7 540-73-8 HSDB 1993 NIOSH RTECS MU7175000 MV2450000 MV2625000 HSDB 1993 EPA hazardous waste u133 uosgs uosg9 HSDB 1993 OHM/TADS No data No data No data DOT/UN/NA/IMCO shipping UN2029, UN2030 UN1163 UN2382 HSDB 1993 IMCO 3.1 IMCO 3.2 IMCO 3.1 IMCO 8.2 NA 9188 HSDB 544 528 4039 HSDB 1993 NCI No data No data No data 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/TADS = Oil and Hazardous Materials/Technical Assistance Data System; RTECS = Registry of Toxic Effects of Chemical Substances NOILYWHOANI TYOISAHd ANV TVOIN3HO '€ 8. xxx INSWWOO OMENd HOH LIVHA xxx TABLE 3-2. Physical and Chemical Properties of Hydrazines Property Hydrazine 1,1-Dimethylhydrazine 1,2-Dimethylhydrazine Reference Molecular weight 32.05 60.10 60.10 HSDB 1993 Color Colorless Colorless Colorless HSDB 1983 Physical state Liquid Liquid Liquid HSDB 1993 Melting point 2C -58°C gC HSDB 1993 Boiling point 113.5°C 639°C 81°C WHO 1987 Density 1.0036 g/mL at 25°C 0.7914 g/mL at 25°C 0.8274 g/mL at 20°C HSDB 1993; WHO 1987 Odor Ammoniacal, Ammoniacal, Ammoniacal HSDB 1993; WHO 1987 pungent, fishy fishy Odor threshold: Water 160 mg/L No data No data Amoore and Hautala 1983 Air 3-4 mg/m? 12-20 mg/m No data Ruth 1986 Solubility: Water Miscible Miscible Miscible Budavari et al. 1989; HSDB 1993 Organic solvent(s) Partition coefficients: Log K,, Log K Vapor pressure Henry's law constant Autoignition temperature Flashpoint Flammability limits Conversion factors Explosive limits Miscible with alcohol, insoluble in chloroform and ether -3.08 -1.07 No data 10.4-16 mmHg at 20°C No data No data 38° C (open cup) 1.8-100% 1 ppm = 1.31 mg/m? 1 mg/m’ = 0.76 ppm 4.7-100% Miscible with alcohol, ether, dimethyl formamide and hydrocarbons No data No data 157 mmHg at 25°C No data 24 C -15° C (closed cup) No data 1 ppm = 2.5 mg/m? 1 mg/m’ = 0.407 ppm 2-95% Miscible with alcohol, ether, dimethyl formamide and hydrocarbons No data No data 68 mmHg at 24°C No data No data <23° C (closed cup) No data 1 ppm = 2.5 mg/nT 1 mg/n? = 0.407 ppm No data ACGIH 19912, 1991b; Budavari et al. 1989 Radding et al. 1977; Poitrast et al. 1988 HSDB 1993; Verschueren 1983; WHO 1987 HSDB 1993; WHO 1987 WHO 1987 HSDB 1993; Verschueren 1983; WHO 1987 ACGIH 1991a, 1991b NOILYWHOSNI TVOISAHd ANY TYOINIHO '€ 6. 81 4. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 4.1 PRODUCTION For most uses, hydrazine is produced as hydrazine hydrate in a formulation with water. The hydrate may be produced commercially by three methods: the Raschig process, the ketazine process, and the peroxide process. The Raschig process, the original commercial production process for hydrazine, involves oxidation of ammonia to chloramine with sodium hypochlorite, then further reaction of the chloramine with excess ammonia and sodium hydroxide to produce an aqueous solution of hydrazine with sodium chloride as a by-product. Fractional distillation of the product yields hydrazine hydrate solutions. Currently, most hydrazine is produced by the ketazine process, which is a variation of the Raschig process. Ammonia is oxidized by chlorine or chloramine in the presence of an aliphatic ketone, usually acetone. The resulting ketazine is then hydrolyzed to hydrazine. In the peroxide method, hydrogen peroxide is used to oxidize ammonia in the presence of a ketone. Anhydrous hydrazine is the formulation used in rocket fuels and is produced by dehydration of the hydrate by azeotropic distillation with aniline as an auxiliary fluid (Budavari et al. 1989; IARC 1974; Schmidt 1988; WHO 1987). 1,1-Dimethylhydrazine is currently prepared commercially by a modified Raschig process: reacting dimethylamine with the chloramine produced from ammonia and sodium hypochlorite. Formerly, it was prepared by the reduction of dimethylnitrosamine or by the reductive catalytic alkylation of carboxylic acid hydrazides with formaldehyde and hydrogen, followed by basic hydrolysis (Budavari et al. 1989; EPA 1984a; EPA 1992b; IARC 1974; Schmidt 1988). 1,2-Dimethylhydrazine may be prepared from dibenzoylhydrazine or by electrosynthesis from nitromethane (Budavari et al. 1989). The only current commercial producer of hydrazine in the United States is Olin Corporation in Lake Charles, Louisiana. The chemical was also produced by Fairmount Chemical Company, Inc., Newark, New Jersey as recently as 1987. 1,1-Dimethylhydrazine is produced by Olin and Uniroyal Chemical Company, Inc., Geismar, Louisiana. 1,2-Dimethylhydrazine is not commercially produced. 1,2-Dimethylhydrazine is commercially supplied in gram quantities as a research chemical only. Estimates of past production (based on anhydrous hydrazine, although most production was of the hydrate) indicate that United States production volume was about 7,000 metric tons (15 million pounds) per year in the mid-1960s and increased to 17,000 metric tons (37 million pounds) per year in the mid-1970s. Production capacity in the U.S. was estimated at 17,240 metric tons (38 million pounds) in 1979 and about 14,000 metric tons (30 million pounds) in 1984, the most recent year for which information was located. 1,1-Dimethylhydrazine production volume was estimated to be at least 45 metric tons (99,000 pounds) in 1977 and more than 4.5 metric tons (9,900 pounds) in 1982 (HSDB 1993; Schmidt 1988; SRI 1987, 1988, 1992; WHO 1987). Information on current production volume is not publicly available for either hydrazine or 1,1-dimethylhydrazine (EPA 1991d). Tables 4-1 and 4-2 list information on United States companies that reported the manufacture and use of hydrazine and 1,1-dimethylhydrazine, respectively, in 1990 (TRI90 1992). The Toxics Release Inventory (TRI) data should be used with caution since only certain types of facilities are required to report. This is not an exhaustive list. 4.2 IMPORT/EXPORT There is some indication that hydrazine was imported into the United States from Japan during the 1970s (IARC 1974), but no data were located on past or current U.S. import or export quantities of hydrazine or 1,1-dimethylhydrazine. *** DRAFT FOR PUBLIC COMMENT *** »»% LNIJWWOD O118Nd HOH LAVHA wx» TABLE 4-1. Facilities that Manufacture or Process Hydrazine® Range of maximum amounts Facility Location’ on site in pounds Activities and uses HALL CHEMICAL CO. ARAB PLANT ARAB, AL No Data As a processing aid 3M DECATUR, AL 10,000-99,999 Import, for on-site use/processing, as a reactant OLIN CORP. MC INTOSH, AL 100,000-999,999 In re-packaging OCCIDENTAL CHEMICAL CORP. SHEFFIELD, AL 10,000-99,999 As a processing aid GREAT LAKES CHEMICAL CO. EL DORADO EL DORADO, AR 10,000-99,999 As a formulation component PLANT GREAT LAKES CHEMICAL CORP. SOUTH EL DORADO, AR 10,000-99,999 As a processing aid PLANT DEEPWATER IODIDES INC. CARSON, CA 10,000-99,999 As a reactant TRIANGLE PWC INC. PITTSBURG, CA 1,000-9,999 As a reactant GENCORP AEROJET PROPULSION DIV. RANCHO CORDOVA, CA 1,000-9,999 In ancillary or other uses STAMFORD CHEMICALS CORP. STAMFORD, CT No Data As a reactant STAMFORD CHEMICALS CORP. STAMFORD, CT 1,000-9,999 As a reactant MARTIN MARIETTA SPACE LAUNCH SYSTEMS CAPE CANAVERAL AF, FL 100,000-999,999 In ancillary or other uses 3M CORDOVA, IL 10,000-99,999 As a reactant SUNDSTRAND AEROSPACE ROCKFORD, IL 10,000-99,999 In ancillary or other uses AMOCO PETROLEUM ADDITIVES CO. WOOD RIVER, IL 10,000-99,999 As a reactant VANDERBILT CHEMICAL CORP. MURRAY, KY 10,000-99,999 As a reactant UNIROYAL CHEMICAL CO. INC. GEISMAR, LA 100,000-999,999 As a reactant OLIN CORP. LAKE CHARLES PLANT SHELL OIL CO. NORCO MFG. COMPLEX - EAST CHEMET CORP. ICI AMERICAS INC. ICI RESINS US KOCH REFINING KOCH CHEMICAL CO. DIV. MOBAY CORP. AG CHEM. DIV. FAIRMOUNT CHEMICAL CO. INC. DEGUSSA CORP. METZ DIV. CIBA-GEIGY CORP. TOMS RIVER PLANT NORWICH EATON PHARMACEUTICALS INC. OLIN CORP. LUBRIZOL PETROLEUM CHEMICALS CO. HALL CHEMICAL CoO. SEASON-ALL INDUSTRIES INC. AMERICAN PLATING INC. BILCHEM LTD. TRAYBOR INC. DREXEL CHEMICAL CoO. LAKE CHARLES, LA NORCO, LA ATTLEBORO, MA WILMINGTON, MA WHITEHALL, MI KANSAS CITY, MO NEWARK, NJ SOUTH PLAINFIELD, NJ TOMS RIVER, NJ NORWICH, NY ROCHESTER, NY PAINESVILLE, OH WICKLIFFE, OH INDIANA, PA ZELIENOPLE, PA PONCE, PR ROCK HILL, SC MEMPHIS, TN 1,000, 000-9, 999,999 1,000-9,999 1,000-9,999 1,000-9,999 10,000-99,999 100,000-999,999 10,000-99,999 10, 000-99, 999 10, 000-99, 999 1,000-9,999 10,000-99, 999 10,000-99,999 No Data 100-999 100-999 10,000-99,999 10,000-99,999 10,000-99,999 Produce, for sale/distribution, in ancillary or other uses As a processing aid As a reactant As a reactant As a processing aid, in ancillary or other uses As a reactant As a reactant, as a formulation component, in re-packaging As a reactant, as a processing aid As a reactant As a reactant As a reactant, as a formulation component As a reactant As a processing aid As a processing aid As a processing aid As a reactant As a reactant a As reactant IVS0dSIa ANV ‘ISN ‘1H0dX3/LHOdI ‘NOILONAOHd ‘v [4°] +x» LNIJWWOD O178Nd HOH 14VHA » « « VELSICOL CHEMICAL CORP. GREAT LAKES CHEMICAL CORP. AMOCO CHEMICAL CO. CHOCOLATE BAYOU PLANT EXXON BAYTOWN REFINERY EXXON CHEMICAL AMERICAS BAYTOWN CHEMICAL PLANT EXXON CHEMICAL CO. BAYTOWN OLEFINS PLANT MOBAY CORP. MOBIL OIL CORP. BEAUMONT REFINERY SANDOZ CROP PROTECTION CORP. SHELL OIL CO. DEER PARK MFG. COMPLEX BASF CORP. ASHLAND CHEMICAL INC. DREW DIV. CONTINENTAL PRODUCTS OF TEXAS CALGON CORP. HOECHST CELANESE CHEMICAL GROUP INC. CLEAR LAKE PLANT LUBRIZOL PETROLEUM CHEMICALS CO. BAYPORT PLANT CHEMTREAT INC. MERCK & CO. INC. MOBAY CORP. MEMPHIS, TN NEWPORT, TN ALVIN, TX BAYTOWN, TX BAYTOWN, TX BAYTOWN, TX BAYTOWN, TX BEAUMONT, TX BEAUMONT, TX DEER PARK, TX FREEPORT, TX HOUSTON, TX ODESSA, TX PASADENA, TX PASADENA, TX PASADENA, TX ASHLAND, VA ELKTON, VA NEW MARTINSVILLE, WV 1,000-9,999 1,000-9,999 10,000-99, 999 100-999 0-99 1,000-9,999 1,000, 000-9,999,999 1,000-9,999 10,000-99,999 10, 000-99, 999 1,000-9,999 10,000-99,999 100-999 10,000-99,999 1,000-9,999 10,000-99,999 10, 000-99, 999 10, 000-99, 999 100, 000-999, 999 In ancillary or As a processing As a processing As a processing In ancillary or In ancillary or other uses aid aid aid other uses other uses Produce, for sale/distribution In ancillary or As a reactant As a processing other uses aid As a manufacturing aid As a formulation component, in re- packaging As a formulation component, in re- packaging In ancillary or As a reactant other uses As a formulation component As a reactant As a reactant Derived from TRIFO (1992) Post office state abbreviations used IVS0dSIA ANV ‘ISN ‘LHOdX3/LHOdWI ‘NOILONAOHd £8 » xe LNIWWOD O1N8Nd HOd LIVHA wwe TABLE 4-2. Facilities that Manufacture or Process 1,1-Dimethyl Hydrazine’ Range of maximum amounts Facility Location’ on site in pounds Activities and uses OLIN CORP. MC INTOSH, AL 100,000-999,999 GENCORP AEROJET PROPULSION DIV. UNIROYAL CHEMICAL CO. INC. OLIN CORP. LAKE CHARLES PLANT RANCHO CORDOVA, CA GEISMAR, LA LAKE CHARLES, LA 1,000-9,999 100, 000-999, 999 100, 000-999, 999 In re-packaging, import, for on-site use/processing In ancillary or other uses As a reactant Produce, for sale/distribution Derived from TRI9O (1992) post office state abbreviations used IvSOdSIa ANY ‘ISN ‘1H0dX3/LHOdWI ‘NOILONAOYHd 'v v8 85 4. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 4.3 USE Hydrazine (anhydrous or as the hydrate) has numerous commercial uses. The principal current use for hydrazine is as an intermediate in the production of agricultural chemicals such as maleic hydrazide. It is also used as an intermediate in the manufacture of chemical blowing agents which are used in the production of plastics such as vinyl flooring and automotive foam cushioning, as a corrosion inhibitor and water treatment agent, as a rocket propellant, and, to a lesser extent, as a reducing agent, in nuclear fuel reprocessing, as a polymerization catalyst, as a scavenger for gases, and several other uses. It has also been used as a medication for sickle cell disease and cancer. From the late 1950s through the 1960s, the primary use of hydrazine was as a rocket propellant. In 1964, 73% of the hydrazine consumed in the United States was used for this purpose. By 1982, other commercial uses dominated the market; 40% of the hydrazine consumed was used in agricultural chemicals, about 33% for blowing agents, 15% as a corrosion inhibitor in boiler water and only 5% as an aerospace propellant (Budavari et al. 1989; Fajen and McCammon 1988; HSDB 1993; Schmidt 1988; WHO 1987). 1,1-Dimethylhydrazine is used mainly as a component of jet and rocket fuels. Other uses include an adsorbent for acid gases, a stabilizer for plant growth regulators, an intermediate for organic chemical synthesis, and in photography. 1,2-Dimethylhydrazine is used only as a research chemical and has no known commercial uses (ACGIH 1991a; Budavari et al. 1989; HSDB 1993). 4.4 DISPOSAL Hydrazine, 1,1-dimethylhydrazine, 1,2-dimethylhydrazine, and wastes containing these chemicals are classified as hazardous wastes by EPA. Generators of waste containing these contaminants must conform to EPA regulations for treatment, storage, and disposal (see Chapter 7). Liquid injection or fluidized bed incineration methods are acceptable disposal methods for these wastes. Oxidation of spills of hydrazine fuels with sodium or calcium hypochlorite or hydrogen peroxide prior to disposal has been recommended. However, incomplete reaction of 1,1-dimethylhydrazine with hypochlorite leads to formation of several by-products, including carcinogenic N-nitrosoalkylamines. Ozonation of wastewater containing hydrazine fuels has been shown to reduce concentrations of the fuels, their associated impurities, and oxidation products to environmentally acceptable levels. Biodegradation is also an acceptable treatment for wastewaters containing hydrazine wastes (Brubaker 1988; EPA 1991a; HSDB 1993; Jody et al. 1988; WHO 1987). According to the TRI, about 36,800 pounds of hydrazine and 8,500 pounds of 1,1-dimethylhydrazine were transferred to landfills and/or treatment/disposal facilities in 1990 (see Section 5.2) (TRI90 1992). Of this quantity, about 11,400 pounds of hydrazine were discharged to publicly owned treatment works (POTW). *** DRAFT FOR PUBLIC COMMENT *** 87 5. POTENTIAL FOR HUMAN EXPOSURE 5.1 OVERVIEW Hydrazine and 1,1-dimethylhydrazine are industrial chemicals that enter the environment primarily by emissions from their use as aerospace fuels and from industrial facilities that manufacture, process, or use these chemicals. Treatment and disposal of wastes containing these chemicals also contributes to environmental concentrations. These chemicals may volatilize to the atmosphere from other media and may sorb to soils. These chemicals degrade rapidly in most environmental media. Oxidation is the dominant fate process, but biodegradation occurs in both water and soil at low contaminant concentrations. The half-lives in air range from less than 10 minutes to several hours, depending on ozone and hydroxyl radical concentrations. Half-lives in other media range up to several weeks, under various environmental conditions. Bioconcentration does occur, but biomagnification through the food chain is unlikely. Human exposure to hydrazine and 1,1-dimethylhydrazine is mainly in the workplace or in the vicinity of aerospace or industrial facilities or hazardous waste sites where contamination has been detected. These chemicals have not been detected in ambient air, water, or soil. Humans may also be exposed to small amounts of these chemicals by using tobacco products. Hydrazine has been identified in at least 4 of the 1,350 hazardous waste sites that have been proposed for inclusion on the NPL (HazDat 1993). 1,1-Dimethylhydrazine and 1,2-dimethylhydrazine have been identified in at least 3 and 1 of these sites, respectively. However, the number of sites evaluated for these chemicals 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 Hydrazine occurs naturally as a product of nitrogen fixation by some algae and in tobacco plants (IARC 1974). However, the major environmental sources of hydrazine are anthropogenic. There are no known natural sources of dimethylhydrazines. The estimated total annual environmental release of hydrazine and 1,1- dimethylhydrazine from manufacture and processing reported to the TRI were about 30,000 and 4,000 pounds, respectively, in 1988 (EPA 1991d). However, more recent data reported to the TRI indicate that environmental releases from manufacture and use of these chemicals total about 29,000 and 700 pounds, respectively (TRI90 1992). 1,1-Dimethylhydrazine may also be released to the environment from the application of daminozide (Alar®), a growth enhancer which contains about 0.005% 1,1-dimethylhydrazine as a contaminant to nonfood plants (EPA 1992c). 5.2.1 Air The major sources of hydrazine releases to air are expected to be from its use as an aerospace propellant and boiler water treatment agent (HSDB 1993). Burning of rocket fuels containing hydrazine and/or 1,1-dimethylhydrazine reportedly produces exhaust gases containing trace amounts of unchanged fuel (IARC 1974). Emissions are also expected from the production and processing of hydrazine (EPA 1991d; WHO 1987). It has been estimated, based on data from Germany, that 0.06-0.08 kg of hydrazine are emitted to the air for every metric ton produced, and an additional 0.02-0.03 kg are emitted for every metric ton subjected to handling and further processing (WHO 1987). On this basis, assuming production volume of about 14,000 metric tons (30 million pounds) (see Section 4.1) and handling or processing of the product, emissions to the air may range from 1,100 to 1,500 kg (500-680 pounds) annually. Atmospheric releases of hydrazine may also occur from tobacco smoking (see Section 5.4.4) and hazardous waste sites at which this chemical has been detected (HSDB 1993; WHO 1987). *** DRAFT FOR PUBLIC COMMENT *** » x» LNIJWWOD O118Nd HOH L4VHA « « « FIGURE 5-1. FREQUENCY OF NPL SITES WITH HYDRAZINES CONTAMINATION * FREQUENCY BEA 1 sITE Fa 2 SITES ¥Derived from HazDat 1993 JHNSOdX3 NVIWNH HOH TVILNILOd SG 88 89 5. POTENTIAL FOR HUMAN EXPOSURE Release of 1,1-dimethylhydrazine to the atmosphere is expected to occur primarily from its use as an aerospace propellant (HSDB 1993). Release of this chemical and 1,2-dimethylhydrazine may also occur from hazardous waste sites at which they have been detected. As shown in Tables 5-1 and 5-2, an estimated total of 27,200 pounds of hydrazine and 460 pounds of 1,1-dimethylhydrazine, amounting to about 94% and 65% of the total environmental releases, respectively, were discharged to the air from manufacturing and processing facilities in the United States in 1990 (TRI90 1992). The TRI data should be used with caution since only certain types of facilities are required to report. This is not an exhaustive list. 5.2.2 Water Releases of hydrazine and 1,1-dimethylhydrazine to water may occur during production, processing, use, or disposal of the chemical. Hydrazine was detected at a concentration of 0.01 mg/L in effluent from one industrial facility (EPA 1984b). However, since these chemicals are rapidly oxidized in water (see Section 5.3.2.2), the unreacted compounds are not likely to persist in detectable concentrations. As shown in Tables 5-1 and 5-2, an estimated total of 1,400 pounds of hydrazine and 250 pounds of 1,1-dimethylhydrazine, amounting to about 5% and 35% of the total environmental releases, respectively, were discharged to surface water from manufacturing and processing facilities in the United States in 1990 (TRI90 1992). An additional 423 pounds of hydrazine (1% of the total) were discharged by underground injection. The TRI data should be used with caution since only certain types of facilities are required to report. This is not an exhaustive list. 5.2.3 Sail No data were located documenting release of hydrazine or dimethylhydrazines to soil. However, releases to soil may occur from spills and leakage of underground storage tanks during the use of hydrazine and 1,1-dimethylhydrazine as rocket propellants (Street and Moliner 1988). Deposition from air is not expected to be significant (see Section 5.3.1). Hydrazine and dimethylhydrazines may be released to soil from hazardous waste sites at which these chemicals have been detected. 1,1-Dimethylhydrazine may also be released to soil from the application of daminozide (Alar) as a growth enhancer on nonfood plants. The use of this chemical on food products was voluntarily cancelled in 1989 by the manufacturer (Uniroyal Chemical Company) (EPA 1992c). Daminozide contains about 0.005% 1,1-dimethylhydrazine as an impurity and about 0.012% of a daminozide solution that hydrolyzes to 1,1-dimethylhydrazine after 24 hours (EPA 1992c). No data were located on the amount of daminozide used annually, but it is estimated that, in 1989, 90% of potted chrysanthemums and 40-50% of 65 million square feet of bedding plants were treated with this chemical. As shown in Tables 5-1 and 5-2, 5 pounds of hydrazine (<0.1% of the total environmental release) and no 1,1-dimethylhydrazine were reported discharged to land from manufacturing and processing facilities in the United States in 1990 (TRI90 1992). The TRI data should be used with caution since only certain types of facilities are required to report. This is not an exhaustive list. 5.3 ENVIRONMENTAL FATE 5.3.1 Transport and Partitioning Hydrazine or dimethylhydrazines released to water or soil may volatilize into air or sorb onto soil. These chemicals have low vapor pressures and are miscible in water (see Table 3-2). Therefore, volatilization is not expected to be an important removal process. Reported evaporation rates from aqueous solutions under *** DRAFT FOR PUBLIC COMMENT *** »»» LNJWWOD O178Nd HOH L4VHA «x « TABLE 5-1. Releases to the Environment from that Manufacture or Process Hydrazine Facilities Reported amounts released in pounds off-site Underground Total POTW waste Facility Location’ Air injection Water Land environment® transfer transfer HALL CHEMICAL CO. ARAB ARAB, AL 250 0 0 0 250 0 0 PLANT 3M DECATUR, AL 500 0 0 0 500 0 2,900 OLIN CORP. MC INTOSH, AL 2 0 0 0 3 0 1 OCCIDENTAL CHEMICAL SHEFFIELD, AL 7s 0 1,050 0 1,125 0 0 CORP. GREAT LAKES CHEMICAL CO. EL DORADO, AR 17 0 0 0 17 0 0 EL DORADO PLANT GREAT LAKES CHEMICAL EL DORADO, AR 1 0 0 0 1 0 0 CORP. SOUTH PLANT DEEPWATER IODIDES INC. CARSON, CA 250 0 0 0 250 5 0 TRIANGLE PWC INC. PITTSBURG, CA 0 0 0 0 0 0 0 GENCORP AEROJET RANCHO CORDOVA, CA 255 0 0 0 255 0 8,400 PROPULSION DIV. STAMFORD CHEMICALS CORP. STAMFORD, CT 0 0 0 0 0 0 0 STAMFORD CHEMICALS CORP. STAMFORD, CT 5 0 0 0 5 0 0 MARTIN MARIETTA SPACE CAPE CANAVERAL, FL 10 0 0 0 10 0 0 LAUNCH SYSTEMS 3M CORDOVA, IL 0 0 0 0 0 0 0 SUNDSTRAND AEROSPACE ROCKFORD, IL 500 0 0 0 500 0 0 AMOCO PETROLEUM WOOD RIVER, IL 10 0 80 0 90 2,700 0 ADDITIVES CO. VANDERBILT CHEMICAL MURRAY, KY 1 0 0 0 1 0 0 CORP. UNIROYAL CHEMICAL CO. GEISMAR, LA 302 0 0 0 302 0 0 INC. OLIN CORP. LAKE CHARLES LAKE CHARLES, LA 1,855 0 1 0 1,856 0 87 PLANT SHELL OIL CO. NORCO MFG. NORCO, LA 160 0 0 0 160 0 0 COMPLEX - EAST CHEMET CORP. ATTLEBORO, MA 0 0 0 0 0 0 0 ICI AMERICAS INC. ICI WILMINGTON, MA 19 0 0 0 19 0 0 RESINS US KOCH REFINING KOCH WHITEHALL, MI 10 0 0 0 10 5 0 CHEMICAL CO. DIV. MOBAY CORP. AG CHEM. KANSAS CITY, MO 539 0 0 0 539 0 0 DIV. FAIRMOUNT CHEMICAL CO. NEWARK, NJ 1,000 0 0 0 1,000 250 0 INC. JHNSOdX3 NVINNH HO4 TVILNILOd S 06 TABLE 5-1. Releases to the Environment from Facilities That Manufacture or Process Hydrazine (Continued) Reported amounts released in pounds «»» LINIWWOD O118Nd HOd LdVHA www off-site Underground Total POTW waste Facility Location’ Air injection Water Land environment® transfer transfer DEGUSSA CORP. METZ DIV. SOUTH PLAINFIE, NJ 1,000 0 0 0 1,000 250 0 CIBA-GEIGY CORP. TOMS TOMS RIVER, NJ 10 0 18 5 2 0 747 RIVER PLANT NORWICH EATON NORWICH, NY 101 0 0 0 101 0 2,176 PHARMACEUTICALS INC. OLIN CORP. ROCHESTER, NY 60 0 0 0 60 2 0 LUBRIZOL PETROLEUM PAINESVILLE, OH 50 0 0 0 50 0 0 CHEMICALS CO. HALL CHEMICAL CO. WICKLIFFE, OH 250 0 0 0 250 0 0 SEASON-ALL INDUSTRIES INDIANA, PA 0 0 0 0 0 0 0 INC. AMERICAN PLATING INC. ZELIENOPLE, PA 0 0 0 0 0 5 750 BILCHEM LTD. PONCE, PR 0 0 0 0 0 0 0 TRAYBOR INC. ROCK HILL, SC 5 0 0 0 5 7,900 0 DREXEL CHEMICAL CO. MEMPHIS, TN 255 0 5 0 260 250 0 VELSICOL CHEMICAL CORP. MEMPHIS, TN 3,703 0 0 0 3,703 0 0 GREAT LAKES CHEMICAL NEWPORT, TN 1 0 0 0 1 0 0 CORP. AMOCO CHEMICAL CO. ALVIN, TX 255 0 5 0 260 0 0 CHOCOLATE BAYOU PLANT EXXON BAYTOWN REFINERY BAYTOWN, TX 0 0 0 0 0 0 0 EXXON CHEMICAL AMERICAS BAYTOWN, TX 0 0 0 0 0 0 0 BAYTOWN CHEMICAL PLANT EXXON CHEMICAL CO. BAYTOWN, TX 0 0 0 0 0 0 0 BAYTOWN OLEFINS PLANT MOBAY CORP. BAYTOWN, TX 11,878 0 250 0 12,128 0 8,604 MOBIL OIL CORP. BEAUMONT BEAUMONT, TX 250 0 0 0 250 0 0 REFINERY SANDOZ CROP PROTECTION BEAUMONT, TX 5 5 5 0 15 0 0 CORP. SHELL OIL CO. DEER PARK DEER PARK, TX 543 0 0 0 543 0 0 MFG. COMPLEX BASF CORP. FREEPORT, TX 405 0 0 0 405 0 0 ASHLAND CHEMICAL INC. HOUSTON, TX 21 0 0 0 21 0 23 DREW DIV. CONTINENTAL PRODUCTS OF ODESSA, TX 0 0 0 0 0 0 0 TEXAS 34NSOdX3 NVIWNH HO4 TVILN3LOd °S L6 «++ LNIWWOD J118Nd HOH L4VHA wus TABLE 5-1. Releases to the Environment from Facilities That Manufacture or Process Hydrazine (Continued) Reported amounts released in pounds Off-site Underground Total POTW waste Facility Location’ Air injection Water Land environment’ transfer transfer CALGON CORP. PASADENA, TX 0 0 0 0 0 0 0 HOECHST CELANESE PASADENA, TX 5 418 0 0 423 0 224 CHEMICAL GROUP INC. CLEAR LAKE PLANT LUBRIZOL PETROLEUM PASADENA, TX 500 0 0 0 500 0 1,562 CHEMICALS CO. BAYPORT PLANT CHEMTREAT INC. ASHLAND, VA 0 0 0 0 0 0 0 MERCK & CO. INC. ELKTON, VA 1,260 0 0 0 1,260 0 0 MOBAY CORP. NEW MARTINSVIL, WV 864 0 0 0 864 0 0 Derived from TRI9O (1992) ®Post office state abbreviations used POTW = publicly-owned treatment works JHNSOdX3 NVYIWNH HO4 TVILN3LOd °§ [4 «we LINIJWWOD O118Nd HO 14VHA wus TABLE 5-2. Releases to the Environment from Facilities that Manufacture or Process 1,1-Dimethyl Hydrazine® Reported amounts released in pounds off-site Underground Total POTW waste Facility Location’ Air injection Water Land environment® transfer transfer OLIN CORP. MC INTOSH, AL 5 0 0 0 5 c 39 GENCORP AEROJET RANCHO CORDOVA, CA nN 0 0 0 3n 0 8,400 PROPULSION DIV. UNIROYAL CHEMICAL CO. GEISMAR, LA -104 0 0 0 104 c 0 INC. OLIN CORP. LAKE CHARLES LAKE CHARLES, LA 43 0 250 0 293 0 68 PLANT Derived from TRI9O (1992) post office state abbreviations used POTW = publicly-owned treatment works JUNSOdX3 NVINNH HO4 TVILNILOd '§ £6 94 5. POTENTIAL FOR HUMAN EXPOSURE laboratory conditions were 0.49 mg/cm? min for hydrazine and 13 mg/cm’ min for 1,1-dimethylhydrazine (EPA 1984a). The significance of these values to environmental conditions is unknown. Data from other studies indicate that volatilization of these chemicals from water increases with higher concentrations of the chemical and in the presence of sunlight (due to increased temperature of the hydrazine pool). Based on air dispersion modeling, volatilization of hydrazine from surface soil following a spill is expected to be sufficient (16-100 mg/cm’ h) to generate a short-term ambient air concentration of 4 mg/m? up to 2 km downwind of the spill under worst-case meteorological conditions (MacNaughton et al. 1981). Degradation of hydrazine would likely reduce the concentration within several hours (see Section 5.3.2.1). Atmospheric transport of hydrazine or dimethylhydrazines may occur, but transport will be limited by the high reactivity of the chemicals in the atmosphere (see Section 5.3.2.1). No data were located on deposition of hydrazine or dimethylhydrazines from air to water or soil, but deposition would also be limited by their high reactivity. Hydrazine undergoes complex interactions with soils, including both reversible physical sorption and irreversible chemisorption to colloids (Mansell et al. 1988). In a study on the adsorption and leaching characteristics of hydrazine fuels, no adsorption of 1,1-dimethylhydrazine was observed on sand, with almost 100% of the chemical leaching with water (Braun and Zirrolli 1983). In three other soils, adsorption ranged from 26% to 80%. No correlation between adsorption and soil organic content or pH was observed. The mechanisms of attenuation in soil materials were not reported. However, reported results of additional hydrazine adsorption studies with clays and soils indicate that adsorption may be correlated with soil organic matter and clay content and is highly dependent on pH; hydrazine appears to be adsorbed by different mechanisms under acidic and alkaline conditions (Moliner and Street 1989b). In a study of hydrazine in aqueous systems, the chemical was reported to be absorbed by guppies from a 0.5 mg/L solution (Slonim and Gisclard 1976). After 96 hours, the hydrazine concentration in fish was 144 pg/g, indicating a moderate tendency to bioconcentrate. However, bioconcentration of hydrazine and dimethylhydrazines is not expected to be important in aquatic systems due to the rapid degradation of these chemicals in water (see Section 5.3.2.2). 5.3.2 Transformation and Degradation 5.3.2.1 Air Hydrazine and dimethylhydrazines degrade rapidly in air through reactions with ozone, hydroxyl (OH) radicals, and nitrogen dioxide (WHO 1987). The reaction of hydrazine and 1,1-dimethylhydrazine with ozone is probably the major fate of these chemicals in the atmosphere. The reaction rate constant for hydrazine, derived from its decay rate in the presence of excess ozone, was about 3x10"? cm® molecules” and for 1,1-dimethylhydrazine the rate was greater than 1x10"'* cm® molecules” (Atkinson and Carter 1984). Major reaction products were hydrogen peroxide for the hydrazine reaction and dimethylnitrosamine (about 60%) for the 1,1-dimethylhydrazine reaction. Estimated atmospheric half-lives ranged from less than 10 minutes for hydrazine during an ozone pollution episode to less than 2 hours under usual conditions, with a half-life about one-tenth that time for 1,1-dimethylhydrazine (Tuazon et al. 1981). Reported results of additional studies indicate a reaction rate constant for hydrazine of 2.5x10"'¢ cm® molecules”, resulting in an estimated half-life of less than 1 minute (Stone 1989). The reported measured rate constant for reaction of hydrazine with atmospheric hydroxyl (OH) radicals producing ammonia and nitrogen gas was 6.1x10"! cm® molecule’'s" (Harris et al. 1979). The rate constant for 1,1-dimethylhydrazine was not measured, since the chemical decomposed rapidly in the test system, but the value was estimated at 5x10" cm® molecules’. Assuming an average OH radical concentration of about 10° molecule/cm’, the tropospheric half-lives of both chemicals due to reaction with OH were estimated to be about 3 hours. The half-lives are expected to range from less than 1 hour in polluted urban air to 3-6 hours in less polluted atmospheres (Tuazon et al. 1981). *** DRAFT FOR PUBLIC COMMENT *** 95 5. POTENTIAL FOR HUMAN EXPOSURE Hydrazine and 1,1-dimethylhydrazine react rapidly with nitrogen oxides in both the light and dark, with a half- life of about 2 hours for hydrazine and less than 10 minutes for 1,1-dimethylhydrazine (Pitts et al. 1980). Hydrazine and 1,1-dimethylhydrazine may also be removed from the atmosphere by autoxidation. In a dark reaction chamber, the approximate half-lives of hydrazine ranged from 1.8 to 5 hours, with the lower value measured at higher humidity. Reported values for 1,1-dimethylhydrazine under similar conditions were 5.9.9 hours. Surface interactions are important in controlling the rates of these reactions (Stone 1989). Although data were not located for 1,2-dimethylhydrazine, this chemical is expected to be degraded in the atmosphere by undergoing the same reactions as hydrazine and 1,1-dimethylhydrazine, although the rate and extent of degradation may be different. 5.3.2.2 Water Hydrazine and 1,1-dimethylhydrazine degrade in aqueous systems, but the rate of degradation is dependent on specific aquatic environmental factors, including pH, hardness, temperature, oxygen concentration, and the presence of organic matter and metal ions (Moliner and Street 1989a; Slonim and Gisclard 1976; WHO 1987). Oxidation and biodegradation are the primary removal mechanisms. Reaction of hydrazine with dissolved oxygen is catalyzed by metal ions, particularly copper (EPA 1984a). The reaction rate is strongly influenced by pH; degradation proceeds more rapidly in alkaline solutions. Hydrazine is rapidly removed from polluted waters, with less than one-third of the original concentration remaining in dirty river water after 2 hours (Slonim and Gisclard 1976). More than 90% of the hydrazine added to pond or chlorinated, filtered county water disappeared after 1 day. However, chlorinated, filtered, and softened city water contained almost the original amount of hydrazine after 4 days. Organic matter in the water and hardness were reported to be the major factors in the differing rates of degradation. The primary reaction pathway for hydrazine degradation in water produces nitrogen gas and water (Moliner and Street 19892). In oxygen-deficient waters or in the presence of metal ions which serve as catalysts, ammonia may also be produced. The reaction of 1,1-dimethylhydrazine with dissolved oxygen in water may proceed by a process catalyzed by copper ions or by an uncatalyzed reaction (Banerjee et al. 1984). The products include dimethylnitrosamine, formaldehyde, dimethylamine, and other related chemicals. Dimethylnitrosamine did not form in dilute solutions which might be encountered in ambient waters, but was reported in concentrated solutions which could be present in the vicinity of spills (EPA 1984a). The reported half-life of 1,1-dimethylhydrazine in ponds and seawaters ranged from 10-14 days, presumably due to reaction with oxygen and other free radicals (EPA 1984a). Biodegradation may be a significant removal process at low hydrazine concentrations in ambient waters, but at higher concentrations the chemical is toxic to microorganisms. In the presence of bacterial cells, more than 90% of the hydrazine was degraded in six water samples containing 11 pg/mL of the chemical within 2 hours (Ou and Street 1987b). Lower degradation rates were reported with increasing hydrazine concentrations. No degradation was reported for incubation of these waters without bacteria. Additional studies indicate that hydrazine and 1,1-dimethylhydrazine are toxic to bacterial populations. Concentrations of hydrazine and 1,1-dimethylhydrazine which reduced bacterial metabolism by 50% ranged from 14.6 to 145 mg/L and 19.2-9,060 mg/L, respectively (Kane and Williamson 1983). Thus, biological treatment would not be useful for spills of these chemicals into the aquatic environment. 5.3.2.3 Sediment and Soil Hydrazine appears to degrade more rapidly in soil than in water, with oxidation and biodegradation as the main removal processes. Hydrazine applied to nonsterile Arredondo soil (fine sand) at concentrations of 10, 100, and 500 pg/g was completely degraded in 1.5 hours, 1 day, and 8 days, respectively (Ou and Street 1987a). *** DRAFT FOR PUBLIC COMMENT *** 96 5. POTENTIAL FOR HUMAN EXPOSURE Comparison to degradation rates in sterile soils indicated that autoxidation appeared to be the major factor contributing to disappearance of the chemical, but the authors attributed about 20% of removal to biodegradation. Several heterotrophic soil bacteria were reported to degrade hydrazine, indicating that microbial degradation may contribute to removal of the chemical from soil (Ou 1987). 5.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT 5.4.1 Air No monitoring data were located for hydrazine or dimethylhydrazines in ambient air. Since these chemicals are readily degraded in the atmosphere (see Section 5.3.2.1), they are not expected to be present at measurable levels, except in the vicinity of production or processing facilities or spills. 5.4.2 Water No monitoring data were located for hydrazine or dimethylhydrazines in ambient water. Since these chemicals are readily degraded in aquatic systems (see Section 5.3.2.2), they are not expected to be present at measurable levels, except in the vicinity of production or processing facilities, spills or, possibly, at hazardous waste sites. 5.4.3 Sediment and Soil No data were located documenting hydrazine or dimethylhydrazine concentrations in ambient soil or sediments. Since these chemicals are readily degraded in soil (see Section 5.3.2.3), they are not expected to be present at measurable levels, except in the vicinity of production or processing facilities, spills, or hazardous waste sites. 5.4.4 Other Environmental Media Hydrazine and 1,1-dimethylhydrazine have been detected in tobacco. 1,1-dimethylhydrazine was reported at concentrations ranging from not detected to 147 ng/g in various types of tobacco in the United States (Schmeltz et al. 1977). Mainstream smoke from blended U.S. cigarettes contained an average of 31.5 ng of hydrazine per cigarette (Liu et al. 1974). Sidestream smoke may have higher hydrazine concentrations. The authors reported 94.2 ng of hydrazine in sidestream smoke from one cigarette. Although hydrazine may be an impurity in maleic hydrazide, a pesticide formerly used on tobacco plants, reports on studies of tobacco from both treated and untreated plants indicate that the application of maleic hydrazide is not the major source of hydrazine in tobacco. It has been suggested that these chemicals may be produced in tobacco by bacterial or enzymatic processes which occur during curing (Schmeltz et al. 1977). 1,1-Dimethylhydrazine has been detected in several food products due to its presence as an impurity (about 0.005%) in daminozide (Alar)®, a plant growth enhancer. 1,1-Dimethylhydrazine was detected in several processed fruits at maximum levels ranging from 0.007 to 0.60 ppm (Saxton et al. 1989). The fruits had been treated with, and contained residues of, daminozide. It appears that during thermal processing, some of the daminozide degrades to 1,1-dimethylhydrazine, adding to the quantity of 1,1-dimethylhydrazine already present. However, daminozide is no longer used on food plants in the United States, since its registered uses for food products were voluntarily cancelled in 1989 (EPA 1992c). Therefore, 1,1-dimethylhydrazine is no longer expected to be present in foods prepared from food plants grown in the United States. 5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE Exposure of the general population to hydrazine and dimethylhydrazines is expected to be extremely low (WHO 1987). Due to the high reactivity of these chemicals, they are unlikely to remain in environmental media for extended periods. These chemicals have not been detected in ambient air, water, or soil. *** DRAFT FOR PUBLIC COMMENT *** 97 5. POTENTIAL FOR HUMAN EXPOSURE Occupational exposures to hydrazine and 1,1-dimethylhydrazine may occur in facilities that manufacture, process, transport, or use these chemicals. The National Institute for Occupational Safety and Health (NIOSH) conducted a National Occupational Exposure Survey (NOES) during 1981-1983 and estimated that 59,675 and 2,197 workers were potentially exposed to hydrazine and 1,1-dimethylhydrazine, respectively, at that time (EPA 1991d). Since most hydrazine production processes involve closed systems, the potential for exposure is generally low (Fajen and McCammon 1988). The greatest potential for exposure probably occurs during process stream sampling, with measured time-weighted average (TWA) concentrations ranging from 0.04 to 0.27 ppm and excursions up to 0.91 ppm. Workplace breathing zone air levels of hydrazine and 1,1-dimethylhydrazine ranged from 0.22 to 1.98 ppm and 0.23-4.61 ppm, respectively, in a rocket propellant plant (Cook et al. 1979). Workers in facilities where exposure to these chemicals is possible are required to wear protective respirators. Analysis of samples from within the respirators indicated that these chemicals are not usually present at detectable levels. Thus, routine exposure to these levels is not expected, but respirator failures and other accidental exposures may OCCU. Occupational exposures may also occur to military and civilian personnel during the use of these chemicals as aerospace propellants. Exposure to workers may occur during loading or unloading of propellants, transfer operations, or testing of spacecraft components that use hydrazine fuels (Fajen and McCammon 1988). Although full-body supplied-air suits are usually worn during these operations, spills and other accidents may lead to short-term, acute exposures, rather than longer-term, low-level exposures. Exposure may also result from the use of hydrazine as an oxygen scavenger in boiler systems (Fajen and McCammon 1988). Long-term concentrations in areas where hydrazine was added to the boiler systems were generally below 0.1 ppm, but short-term concentrations ranged up to 0.23 ppm. In addition, those individuals who work as daminozide applicators in greenhouses may be exposed to 1,1-dimethylhydrazine (EPA 1992c). 5.6 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES Populations with potentially high exposures to hydrazine or 1,1-dimethylhydrazine include those exposed occupationally (see Section 5.5), people living or working near military or aerospace installations using these chemicals as fuels, or people living near hazardous waste sites where these chemicals have been detected. Others who may be exposed to these chemicals at above ambient levels include individuals who chew or smoke tobacco and those exposed to sidestream smoke (see Section 5.4.4). Furthermore, hydrazine is a metabolite of several drugs (e.g., hydralazine, isoniazid) and individuals taking these drugs may be exposed to hydrazine, based on the detection of hydrazine in the urine of patients taking hydralazine (Timbrell and Harland 1979). 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 hydrazines 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 hydrazines. 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. *** DRAFT FOR PUBLIC COMMENT *** 98 5. POTENTIAL FOR HUMAN EXPOSURE 5.7.1 Identification of Data Needs Physical and Chemical Properties. The physical and chemical properties of hydrazine and dimethylhydrazines are sufficiently well characterized to allow estimation of their environmental fate (see Table 3-2) (HSDB 1993; IARC 1974; Verschueren 1983). On this basis, it does not appear that further research in this area is required. Production, Import/Export, Use, Release, and Disposal. Hydrazine is produced at one facility and 1,1-dimethylhydrazine is produced at two locations (SRI 1992). However, production volume and import and export information are not available. This information would be useful in assessing potential exposure to workers and the general population. Since 1,2-dimethylhydrazine is produced only in gram quantities for research, additional information is not required. According to the Emergency Planning and Community Right-to-Know Act of 1986, 42 U.S.C. Section 11023, industries are required to submit substance release and off-site transfer information to the EPA. The Toxics Release Inventory (TRI), which contains this information for 1990, became available in May of 1992. This database is updated yearly and should provide a list of industrial production facilities and emissions. Environmental Fate. The environmental fate of hydrazine and 1,1-dimethylhydrazine has been well defined (Atkinson and Carter 1984; EPA 1984a; Moliner and Street 1989a, 1989b; Ou and Street 1987a, 1987b; Stone 1989; WHO 1987). These chemicals are highly reactive and degrade readily in environmental media. Thus, they are not likely to be present in air or water and it is not likely that exposure to the general population is of concern. Nevertheless, because these chemicals may migrate to groundwater, additional studies might be useful to assess the potential for transport of these chemicals from hazardous waste sites. Bioavailability from Environmental Media. Hydrazine is known to be absorbed following inhalation (Llewellyn et al. 1986), oral (dissolved in water) (Preece et al. 1992), and dermal (Smith and Clark 1971, 1972) exposures. Little is known about the absorption of 1,1-dimethylhydrazine and 1,2-dimethylhydrazine, but based on their chemical properties, the absorption is most likely similar to hydrazine. No information was located on the bioavailability of hydrazine or dimethylhydrazines from environmental media. This information would be helpful in evaluating the impact of environmental exposures on human health. Food Chain Bioaccumulation. Hydrazine in water may bioconcentrate in aquatic organisms to a moderate degree (Slonim and Gisclard 1976), but, due to its high reactivity, the chemical is rapidly degraded in aquatic systems and food chain bioaccumulation is unlikely. Exposure Levels in Environmental Media. Hydrazine and dimethylhydrazines have not been detected in ambient air, water, or soil, since they are highly reactive and degrade readily in environmental media. Hydrazine and 1,1-dimethylhydrazine have been detected in workplace air and in tobacco (Cook et al. 1979; Schmeltz et al. 1977). Since these chemicals are highly reactive and exposure of the general population is not expected to be of concern, monitoring of ambient environmental media does not appear to be required. However, monitoring of workplace air would help to determine potential sources and magnitude of exposure. Reliable monitoring data for the levels of hydrazine and dimethylhydrazines in contaminated media at hazardous waste sites are also needed so that the information obtained on levels of these chemicals in the environment can be used in combination with the known body burden of hydrazine to assess the potential risk of adverse health effects in populations living in the vicinity of hazardous waste sites. Exposure Levels in Humans. Hydrazine and dimethylhydrazines have not been detected in human tissues as a result of exposure to these chemicals from environmental media. Hydrazine has been detected in the urine of individuals taking medications (hydralazine) which may metabolize to hydrazine (Timbrell and Harland 1979). Since hydrazine and dimethylhydrazines are rapidly metabolized in vivo, it is unlikely that any free chemical would be present in biological tissues within a few days after environmental exposure. Studies which investigate *** DRAFT FOR PUBLIC COMMENT *** 99 5. POTENTIAL FOR HUMAN EXPOSURE the levels of hydrazines in humans within the first few days after exposure, along with their relationship to exposure levels, would be useful. This information is necessary for assessing the need to conduct health studies on these populations. Exposure Registries. No exposure registries for hydrazine 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. 5.7.2 On-going Studies No information was located regarding on-going studies on the environmental fate or exposure levels of hydrazine or dimethylhydrazines. *** DRAFT FOR PUBLIC COMMENT *** 101 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 hydrazine, 1,1-dimethylhydrazine, 1,2-dimethylhydrazine, their metabolites, and other biomarkers of exposure and effect these chemicals. 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 MATERIALS Spectrophotometric methods, high performance liquid chromatography (HPLC), and gas chromatography (GC) may be used to detect and measure hydrazine and dimethylhydrazines in biological materials (Amlathe and Gupta 1988; Alvarez de Laviada et al. 1987; Fiala and Kulakis 1981; Preece et al. 1992; Reynolds and Thomas 1965; Timbrell and Harland 1979). The spectrophotometer measures the absorbance of light at a particular wavelength, thereby identifying and quantifying the presence of a compound that absorbs at that wavelength. The chromatograph separates complex mixtures of organics and allows individual compounds to be identified and quantified by a detector. An electrochemical detector (ED), nitrogen phosphorus detector (NPD), or flame ionization detector (FID) may be used to identify hydrazine or dimethylhydrazine or their derivatives. When unequivocal identification is required, a mass spectrometer (MS) coupled to the GC column may be employed. Prior to GC or spectrophotometric analysis, hydrazine and dimethylhydrazines must be separated from the biological sample matrix and derivatives of the compounds must be prepared. Separation is usually effected by precipitation of residual protein with acid and extraction of interfering lipids with methylene chloride (Alvarez de Laviada et al. 1987; Preece et al. 1992; Reynolds and Thomas 1965; Timbrell and Harland 1979). Hydrazine and 1,1-dimethylhydrazine, but not 1,2-dimethylhydrazine, may then be derivatized with an aldehyde such as pentafluorobenzaldehyde or p-dimethylaminobenzaldehyde. Details of selected analytical methods for hydrazine and dimethylhydrazines in biological samples are summarized in Table 6-1. Accurate analysis of hydrazine and dimethylhydrazines in biological samples is complicated by the tendency of these chemicals to autoxidize during storage (Preece et al. 1992). Thus, derivatization should be completed as rapidly as possible, before autoxidation can occur. 6.2 ENVIRONMENTAL SAMPLES Determination of hydrazine and dimethylhydrazines in air, water, soil, food, and tobacco is also carried out by spectrophotometry, GC or HPLC analysis (Amlathe and Gupta 1988; ASTM 1991b; Holtzclaw et al. 1984; Leasure and Miller 1988; Liu et al. 1974; NIOSH 1977a, 1977b, 1984; Rutschmann and Buser 1991; Schmetlz et al. 1977; Wright 1987). Several representative methods for quantifying these chemicals in each of these media are summarized in Table 6-2. EPA-validated methods are not available for analysis of hydrazine or dimethylhydrazines in any environmental medium. Although two EPA methods (8250 and 8270) are recommended for analysis of 1,1-dimethylhydrazine in wastes (EPA 1990e), these methods do not list 1,1-dimethylhydrazine as an analyte (EPA 1990¢c, 1990d) and do not appear to be suitable methods for analysis of this compound, since 1,1-dimethylhydrazine is likely to degrade in the GC analysis unless it has been derivatized. **» DRAFT FOR PUBLIC COMMENT *** xxx LINTJWINOD O1M18Nd HOH 14VHQA xxx TABLE 6-1. Analytical Methods for Determining Hydrazine, 1,1-Dimethylhydrazine, and 1,2-Dimethylhydrazine in Biological Samples* Sample detection Percent Sample matrix Preparation method Analytical method limit recovery Reference Urine Precipitate residual protein with GC/NPD 8 pmol ® 79 +14 Preece et al. hydrochloric acid and ammonium 1992 sulfate; extract interfering lipids with methylene chloride; derivatize aqueous fraction with pentafluoro- benzaldehyde; extract with ethyl acetate. Urine Extract with methylene chloride; GC/NPD 0.05 pg/mL No data Timbrell and discard extract; derivatize aqueous Harland 1979 fraction with p-chlorobenzaldehyde; extract with methylene chloride; dry and dissolve in ethyl acetate. Urine Deproteinate with trichloroacetic Spectrophotometry 0.065 pg/mL 99.4-100 Amlathe and acid; derivatize with vanillin in Gupta 1988 ethanol; acidify with sulfuric acid. Urine © Dilute with deionized water. Ion-exchange 8 ng "sample No data Fiala and HPLC/ECD Kulakis 1981 Plasma Precipitate residual protein GC/MS =~20 nmol/mL ° 10349 Preece et al. Liver Tissue with hydrochloric acid and 1992 ammonium sulfate; extract interfering lipids with methyl- ene chloride; derivatize aqueous fraction with pentafluoro- benzaldehyde; extract with chloroform. SAOHL3N TVOILATYNY 9 col xxx INWOOD O1N8Nd HOH L4VHA xxx TABLE 6-1. Analytical Methods for Determining Hydrazine, 1,1-Dimethylhydrazine, and 1,2-Dimethylhydrazine in Biological Samples (continued) Sample detection Percent Sample matrix Preparation method Analytical method limit recovery Reference Plasma © None Ion-exchange 8 ng®sample No data Fiala and HPLC/ED Kulakis 1981 Serum Acidify; derivatize with p-dimethyl- Spectrophotometry 0.025 pg®sample ~~ No data Alvarez Liver/brain aminobenzaldehyde in ethanol. de Laviada tissue et al. 1987 Serum Treat with trichloroacetic acid; Spectrophotometry 0.05 pg/mL ° No data Reynolds and centrifuge; derivatize supernatant with p-dimethylaminobenzaldehyde in ethanol. Thomas 1965 * Applicable to hydrazine only unless otherwise noted. ® Lowest detected amount. ¢ Method applicable to 1,1-dimethylhydrazine and 1,2-dimethylhydrazine as well as hydrazine. ED = electrochemical detector; GC = gas chromatography; HPLC = high performance liquid chromatography; MS = mass spectroscopy; NPD = nitrogen-phosphorus detector. SAOHL3NW TVOILATYNY ‘9 £01 xxx INJWINOD O1N8Nd HOH 14VHQA xxx TABLE 6-2. Analytical Methods for Determining Hydrazine, 1,1-Dimethylhydrazine, and 1,2-Dimethylhydrazine in Environmental Samples® Sample detection Percent Sample matrix Preparation method Analytical method limit recovery Reference Air Collect in bubbler with hydrochloric Spectrophotometry 0.9 pg/sample No data NIOSH 1984 acid; neutralize with sodium hydroxide; derivatize with p-dimethylaminobenz- aldehyde; dilute with glacial acetic acid. Air® Adsorb on sulfuric acid-coated silica GC/FID 0.002 mg/m 3¢ No data NIOSH 1977b gel; elute with water; derivatize with (hydrazine) 2-furaldehyde; extract with ethyl 0.04 mg/m 3° acetate (1,1-dimethyl- hydrazine) Air? Collect in bubbler with hydrochloric Spectrophotometry 0.02 mg/m 3 No data NIOSH 1977a acid; derivatize with phosphomolybdic acid Air® Collect in a microimpinger containing GC/NSD 4 ppb 97-104 Holtzclaw acetone and glacial acetic acid to (5 pg/m? et al. 1984 trap and derivatize in one step Water Acidify with hydrochloric acid; Spectrophotometry 5 pg/L 97.5-100.3 ASTM 1991b derivatize with p-dimethylamino- benzaldehyde Water Derivatize with vanillin in ethanol; Spectrophotometry 0.065 ppm 99.2-100.4 Amlathe and acidify with sulfuric acid Gupta 1988 SAOH.L3IN TVOILATYNY ‘9 OL xxx INTFWWOD O118Nd HOH 14vdA xxx TABLE 6-2. Analytical Methods for Determining Hydrazine, 1,1-Dimethylhydrazine, and 1,2-Dimethylhydrazine in Environmental Samples (continued) Sample detection Percent Sample matrix Preparation method Analytical method limit recovery Reference Soil® Extract with sulfuric acid; derivatize GC/TID 0.1 ppm 98-100 Leasure and with 2,4-pentanedione (hydrazine) (hydrazine) Miller 1988 0.5 ppm 94-101 (1,1-dimethyl- (1,1-dimethyl- hydrazine) hydrazine) Food Extract with L-ascorbic acid; GC/ECD 10 ppb 72-122 Wright 1987 derivatize with 2-nitrobenzaldehyde; cleanup on alumina column Food * Derivatize with pentafluorobenzoyl GC/MS 0.01 ppm 24-100 Rutschmann and chloride; extract with methylene Buser 1991 chloride Tobacco/ Derivatize with pentafluorobenzaldehyde; GC/ECD 0.1 ng/cigarette No data Liu et al. 1974 tobacco smoke enrich the resulting decafluorobenz- aldehyde azine by thin layer chromatrography; extract with ether * Applicable to hydrazine only unless otherwise noted. ® Applicable to hydrazine and 1,1-dimethylhydrazine. ¢ Lower limit of range. d Applicable to 1,1-dimethylhydrazine only. ECD = electron capture detection; FID = flame ionization detector; GC = gas chromatography; MS = mass spectroscopy; NSD = nitrogen specific detector; TID = thermionic ionization detector SAOHL3NW TVOILATYNY 9 Sot 106 6. ANALYTICAL METHODS Separation of hydrazine and dimethylhydrazines from environmental samples is by acid extraction when necessary. Air samples are usually collected in a bubbler with acid or on an acid-coated silica gel (NIOSH 1977a, 1977b, 1984). When GC is employed, detection may be by electron capture detector (ECD), FID, nitrogen-specific detector (NSD), thermionic ionization detector (TID), and/or MS as described above (Section 6.1). Accurate determination of hydrazine and dimethylhydrazines in environmental samples is also complicated by the susceptibility of these chemicals to oxidization. Air samples must be analyzed immediately after collection (Cook et al. 1979). Degradation of hydrazine in aqueous samples can be prevented by acidification with sulfuric acid (WHO 1987). 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 hydrazines 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 hydrazines. 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. 6.3.1 Identification of Data Needs Methods for Determining Biomarkers of Exposure and Effect. Methods are available for determining the levels of hydrazine, 1,1-dimethylhydrazine, and 1,2-dimethylhydrazine in biological samples, including urine, plasma, serum, liver tissue, and brain tissue (Alvarez de Laviada et al. 1987; Amlathe and Gupta 1988; Fiala and Kulakis 1981; Preece et al. 1992; Reynolds and Thomas 1965; Timbrell and Harland 1979). These methods generally employ standard chromatographic and spectrophotometric procedures with detection limits ranging from 0.02-0.065 pg/mL, and therefore, most likely are sufficiently sensitive to measure levels at which biological effects occur following recent exposures. The limited data available indicate that these methods are accurate and reliable if analyses are performed rapidly, before autoxidation can occur. The background levels of hydrazines in biological samples in the general population have not been determined, and if present at all, are most likely present at levels below current detection limits. The detection limits for current methods are sufficiently sensitive to detect levels at which effects occur. Since hydrazines can occur in the body following exposure to drugs such as isoniazid and hydralazine (Timbrell and Harland 1979), and many of the metabolites of hydrazines are ubiquitous or may occur following exposure to other chemicals, measures should be taken to ensure exposure to these confounding chemicals has not occurred. Other metabolites such as azomethane, azoxymethane, and methylozoxymethanol are unique to exposure to 1,2-dimethylhydrazine. Studies which identify specific biomarkers for past exposure to hydrazines, in conjunction with the development of accurate and reliable methods for detecting such biomarkers, would be useful in estimating exposure to hydrazines at hazardous waste sites. The effects of hydrazines have been fairly well characterized in humans and animals, and include neurological, hepatic, and carcinogenic effects (Chlebowski et al. 1984; Gershanovich et al. 1976; Haun and Kinkhead 1973; Rinehart et al. 1960; Thorup et al. 1992; Wilson 1976). Methods exist for measuring serum transaminase levels, vitamin Bg status, and occult blood in stool samples, all of which may serve as biomarkers of effect for hydrazines. Although these methods are fairly accurate and reliable, none of them are specific for effects of hydrazines. Studies which identify biomarkers of effect that are specific to hydrazines, in conjunction with the *** DRAFT FOR PUBLIC COMMENT *** 107 6. ANALYTICAL METHODS development of accurate and reliable methods for detecting such biomarkers, would be useful in determining if individuals have been exposed to predicting recent exposures to hydrazines at hazardous waste sites. Methods for Determining Parent Compounds and Degradation Products in Environmental Media. Analytical methods are available to detect and quantify hydrazine and dimethylhydrazines in air, water, soil, food, and tobacco (Amlathe and Gupta 1988; ASTM 1991b; Holtzclaw et al. 1984; Leasure and Miller 1988; Liu et al. 1974; NIOSH 1977a, 1977b, 1984; Rutschmann and Buser 1991; Wright 1987). Air is the medium of most concern for human exposure to this chemical. Exposure may also occur from water, especially in the vicinity of hazardous waste sites or industrial sources. The existing analytical methods can provide determinations for these chemicals at levels sufficiently low to meet regulatory requirements (NIOSH 1977a, 1977b, 1984). Assuming that an adequate quantity of air is passed through the collector (for example: a volume of at least 41 m’ is required to detect a level equivalent to the intermediate inhalation MRL of 9x10 ppm for 1,1-dimethylhydrazine, assuming a detection limit of 0.9 pg/sample), current methods are sufficiently sensitive to measure levels near the MRL value for 1,1-dimethylhydrazine. However, their tendency to degrade and their chemical reactivity limit the accuracy of analyses of these chemicals in all media. Improved methods of extraction and analysis that minimize these reactions would enhance recovery of these chemicals from environmental samples and provide a better estimate of environmental levels, especially in drinking water and soil at hazardous waste sites. ‘ In addition, methods are available to measure degradation products of hydrazine and dimethylhydrazines (see Section 5.3.2) in environmental samples and can be used to determine the environmental impact of these chemicals. 6.3.2 On-going Studies On-going studies to improve analytical methods for hydrazine and dimethylhydrazines includes continuing research to improve HPLC columns and EDs. In addition, the Naval Research Laboratory has been investigating pattern recognition techniques using microsensors capable of measuring hydrazine in air at ppb concentrations (Anon 1987). These improvements are designed to overcome sampling problems and increase sensitivity and reliability of the analyses. *** DRAFT FOR PUBLIC COMMENT *** 109 7. REGULATIONS AND ADVISORIES Because of its potential to cause adverse health effects in exposed people, numerous regulations and advisories have been established for hydrazines by various international, national and state agencies. Major regulations and advisories pertaining to hydrazine, 1,1-dimethylhydrazine, and 1,2-dimethylhydrazine are summarized in Tables 7-1, 7-2, and 7-3, respectively. ATSDR has derived an intermediate inhalation MRL of 2x10* ppm for hydrazine. The MRL is based on a LOAEL of 0.2 ppm for fatty liver changes in female mice (Haun and Kinkhead 1973). The LOAEL was divided by an uncertainty factor of 1,000 (10 for use of a LOAEL, 10 for extrapolation from animals to humans, and 10 for human variability). ATSDR has derived intermediate and chronic inhalation MRLs of 9x10 ppm for 1,1-dimethylhydrazine. These MRLs are based on a LOAEL of 0.05 for fatty liver changes in male rats (Haun et al. 1984). The LOAEL was adjusted for intermittent exposure (6 hours/day, 5 days/week), and divided by an uncertainty factor of 1,000 (10 for use of a LOAEL, 10 for extrapolation from animals to humans, and 10 for human variability). ATSDR has derived an intermediate oral MRL of 8x10 mg/kg/day for 1,2-dimethylhydrazine. The MRL is based on a LOAEL of 0.75 mg/kg/day for mild hepatitis in male mice (Visek et al. 1991). The LOAEL was divided by an uncertainty factor of 1,000 (10 for use of a LOAEL, 10 for extrapolation from animals to humans, and 10 for human variability). *** DRAFT FOR PUBLIC COMMENT *** 110 7. REGULATIONS AND ADVISORIES TABLE 7-1. Regulations and Guidelines Applicable to Hydrazine Agency Description Information References INTERNATIONAL IARC Carcinogenic classification Group 2B? IARC 1987 NATIONAL Regulations: a. Air: EPA OAQPS Hazardous Air Pollutant Yes Public Law 101-549 Section 112 High-risk Pollutant (proposed) Yes EPA 1991c List of Regulated Substances and 5,000 pounds EPA 1993 Threshold for Accidental Release Prevention - Proposed OSHA PEL TWA 0.1 ppm OSHA 1989 (0.1 mg/m’), (29 CFR skin 1910.1000) b. Food: FDA Boiler water additive-limits for 0 21 CFR 173.310 steam that will contact food c. Other: EPA OERR Reportable quantity 1 pound EPA 1989 (40 CFR 302.4) Extremely Hazardous Substance TPQ 1,000 pounds EPA 1987 (40 CFR 355) EPA OSW Hazardous Waste Constituent Yes EPA 1980 (Appendix VIII) (40 CFR 261) Land Disposal Restrictions Yes EPA 1990b, 1991a (40 CFR 268) Burning of Hazardous Waste in 1x10 mg/kg EPA 1991b Boilers and Industrial Furnaces- Residue Concentration Limit EPA OTS Toxic Chemical Release Reporting Rule Yes EPA 1988b (40 CFR 372) Priority Testing List (Section 4E) Yes EPA 1991d Guidelines: a. Air ACGIH TLV TWA Suspected human ACGIH 1992 Proposed TLV TWA carcinogen, 0.1 ppm (0.13 mg/m>), skin 0.01 ppm *** DRAFT FOR PUBLIC COMMENT *** 111 7. REGULATIONS AND ADVISORIES TABLE 7-1. Regulations and Guidelines Applicable to Hydrazine (continued) Agency Description Information References NIOSH REL Ceiling (120 minutes) Potential NIOSH 1992 occupational carcinogen 0.03 ppm (0.04 mg/m’) b. Other: EPA Carcinogenic Classification Group B2° IRIS 1993 Cancer slope factor (q,*) q,* (oral) 3.0 (mg/kg-day)™! q,* (inhalation) 1.7x10" (mg/kg-day)! STATE Regulations and Guidelines: a. Air: Acceptable ambient air concentrations NATICH 1991 Connecticut 1.0 pg/m* (8 hour) Kansas 2.04x 10% pg/m’ (1 year) Massachusetts 7.0x 107 pg/m’ (24 hour) 2.0x 107 pg/m’ (anuual) Nevada 2.0x 103 mg/m’ (8 hour) New York 3.3x 10 pg/m’ (1 year) North Carolina 6.0x 10% mg/m? (24 hour) North Dakota 0 (best available control technology) Oklahoma 3.93x 107! pg/m® (24 hour) Rhode Island 3.0x 10 pg/m* (annual) South Carolina 5.0x 107! pg/m> (24 hour) Texas 1.3x 10" pg/m® (30 minute) 1.3x 107 pg/m? (annual) Virginia 1.3 pg/m® (24 hour) 2 Group 2B: Possible human carcinogen b Due to a Federal court decision, not enforceable as of March 22, 1993 (Hanson 1993). © Group B2: Probable human carcinogen ACGIH = American Conference of Governmental Industrial Hygienists; EPA = Environmental Protection Agency; FDA = Food and Drug Administration; IARC = International Agency for Research on Cancer; NIOSH = National Institute for Occupational Safety and Health; OAQPS = Office of Air Quality Planning and Standards; OERR = Office of Emergency and Remedial Response; OSHA = Occupational Safety and Health Administration; OSW = Office of Solid Waste; OTS = Office of Toxic Substances; PEL = Permissible Exposure Limit; REL = Recommended Exposure Limit; TLV = Threshold Limit Value; TPQ = Threshold Planning Quantity; TWA = Time-Weighted Average *** DRAFT FOR PUBLIC COMMENT *** 112 7. REGULATIONS AND ADVISORIES TABLE 7-2. Regulations and Guidelines Applicable to 1,1-Dimethylhydrazine Agency Description Information References INTERNATIONAL IARC Carcinogenic classification Group 2B? IARC 1987 NATIONAL Regulations: a. Air EPA OAQPS Hazardous Air Pollutant Yes Public Law 101-549 List of Regulated Substances and 5,000 pounds EPA 1993 Threshold for Accidental Release Prevention - Proposed NESHAP for Source Categories: Yes EPA 1992a Organic HAPs from Synthetic Organic Chemical Manufacturing Industry - Proposed Section 112 OSHA PEL TWA 0.5 ppm OSHA 1989 (0.1 mg/m’), (29 CFR skin” 1910.1000) b. Other: EPA OERR Reportable quantity 10 pounds EPA 1989 (40 CFR 302.4) Extremely Hazardous Substance TPQ 1,000 pounds EPA 1987 (40 CFR 355) EPA OSW Hazardous Waste Constituent Yes EPA 1980 (Appendix VIII) (40 CFR 261) Land Disposal Restrictions Yes EPA 1990b EPA 1991a EPA 1992b (40 CFR 268) EPA OTS Toxic Chemical Release Reporting Rule Yes EPA 1988b (40 CFR 372) Priority Testing List (Section 4E) Yes EPA 1991d Guidelines: a. Air ACGIH TLV TWA Suspected human ACGIH 1992 Proposed TLV TWA carcinogen, 0.5 ppm (1.2 mg/m’), skin 0.01 ppm *** DRAFT FOR PUBLIC COMMENT *** 113 7. REGULATIONS AND ADVISORIES TABLE 7-2. Regulations and Guidelines Applicable to 1,1-Dimethylhydrazine (continued) Agency Description Information References NIOSH REL Ceiling (120 minutes) Potential NIOSH 1992 occupational carcinogen 0.06 ppm (0.15 mg/m?) b. Other: EPA Carcinogenic Classification Group B2¢ HEAST 1992 Cancer slope factor (q,*) q,* (oral) 2.6 (mg/kg-day)’! q* (inhalation) 35 (mg/kg-day)! South Carolina Texas Virginia STATE Regulations and Guidelines: a. Air: Acceptable ambient air concentrations NATICH 1991 Connecticut 11 pg/m’ (8 hour) Nevada 2.4x 102 mg/m (8 hour) New York 3.3pug/m’ (1 year) North Dakota 0 (best available control technology) Oklahoma 1.5 ug/m> (24 hour) 5.0 ug/m> (24 hour) 2.5% 10"! pg/m® (30 minute) 2.5x 107 pg/m’ (annual) 12 pg/m’ (24 hour) * Group 2B: Possible human carcinogen Y Due to a Federal court decision, not enforceable as of March 22, 1993 (Hanson 1993). © Group B2: Probable human carcinogen ACGIH = American Conference of Governmental Industrial Hygienists; EPA = Environmental Protection Agency; HAP = Hazardous Air Pollutants; IARC = International Agency for Research on Cancer; NESHAP = National Emission Standards for Hazardous Air Pollutants; NIOSH = National Institute for Occupational Safety and Health; OAQPS = Office of Air Quality Planning and Standards; OERR = Office of Emergency and Remedial Response; OSHA = Occupational Safety and Health Administration; OSW = Office of Solid Waste; OTS = Office of Toxic Substances; PEL = Permissible Exposure Limit; REL = Recommended Exposure Limit; TLV = Threshold Limit Value; TPQ = Threshold Planning Quantity; TWA = Time-Weighted Average. *** DRAFT FOR PUBLIC COMMENT *** 114 7. REGULATIONS AND ADVISORIES TABLE 7-3. Regulations and Guidelines Applicable to 1,2-Dimethylhydrazine Agency Description Information References INTERNATIONAL IARC Carcinogenic classification Group 2B? IARC 1987 NATIONAL Regulations: a. Other: EPA OERR Reportable quantity 1 pound EPA 1989 (40 CFR 302.4) EPA OSW Hazardous Waste Constituent Yes EPA 1980 (Appendix VIII) (40 CFR 261) Land Disposal Restrictions Yes EPA 1990b EPA 1991a (40 CFR 268) EPA OTS Toxic Chemical Release Reporting Yes EPA 1992d Rule - Proposed (40 CFR 372) Guidelines: a. Other: EPA Carcinogenic Classification Group B2° HEAST 1992 Cancer slope factor (q,*) q,* (oral) 3.7x 10' (mg/kg-day)’! q,* (inhalation) 3.7x 10' (mg/kg-day)’! STATE Regulations and Guidelines: a. Air Acceptable ambient air concentrations NATICH 1991 South Carolina 5.0 ug/m> (24 hour) ? 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Liver function studies on Rhesus monkeys (macaca mulatta) following the administration of hydrazine sulfate. Vet Hum Toxicol 26:295-299. *Watanabe M, Koga T, Sugano M. 1985. Influence of dietary cis- and trans-fat on 1,2-dimethylhydrazine- induced colon tumors and fecal steroid excretion in Fischer 344 rats. Am J Clin Nutr 42:475-484. *** DRAFT FOR PUBLIC COMMENT *** 138 8. REFERENCES *Wattenberg LW. 1975. Brief communication: inhibition of dimethylhydazine-induced neoplasia of the large intestine by disulfiram. Journal of the National Cancer Institute 54:1005-1006. Wheeler CE, Penn SR, Cawley EP. 1965. Dermatitis from hydrazine hydrobromide solder flux. Arch Dermat 91:235-239. *WHO. 1987. Environmental health criteria 68: hydrazine. World Health Organization, Geneva, Switzerland, 1-89. *Williams GM, Weisburger JH. 1991. In: Casarett and Doull’s Toxicology, the basic science of poisons. Amdur, MO, Doull J, Klaasen CD, eds. Elmsford, NY: Pergamon Press, Inc. 180-181. *Wilpart M, Mainguet P, Maskens A, et al. 1983. Mutagenicity of 1,2-dimethylhydrazine towards Salmonella typhimurium, co-mutagenic effect of secondary biliary acids. Carcinogenesis 1:45-48. *Wilson RB. 1976. Species variation in response to dimethylhydrazine. Toxicol Appl Pharmacol 38:647-650. *Winton DJ, Gooderham NJ, Boobis AR, et al. 1990. Mutagenesis of mouse intestine in vivo using the DIb-1 specific locus test: studies with 1,2-dimethylhydrazine, dimethylnitrosamine, and the dietary mutagen 2-amino- 3,8-dimethylimidazo[4,5-f]quinoxaline. Cancer Res 50:7992-7996. *Wolter S, Schmahl D, Frank N. 1984. Influence of diet on 1,2-dimethylhydrazine metabolism in rat liver. Nutr Cancer 6:181-186. *Wrangsjo K, Martensson A. 1986. Hydrazine contact dermatitis from gold plating. Contact Dermatitis 244-245. *Wright D. 1987. Pesticide and industrial chemical residues. New method for the determination of 1,1-dimethylhydrazine residues in apples and peaches. J Assoc Off Anal Chem 70:718-720. *Wryobek AJ, London SA. 1973. Effect of hydrazines on mouse sperm cells. AMRL-TR-73-125. Yamada K, Yoshitake K, Sato M, et al. 1992. Proliferating cell nuclear antigen expression in normal, preneoplastic, and neoplastic colonic epithelium of the rat. Gastroenterology 103:160-167. *Yamamoto K, Kawanish S. 1991. Site-specific DNA damage induced by hydrazine in the presence of manganese and copper ions. J Biol Chem 256:1509-1515. *Yamamoto RS, Weisburger JH. 1970. Failure to arginine glutamate to inhibit lung tumor formation by isoniazid and hydrazine in mice. Life Sci 9:285-289. *Zeilmaker MJ, Horsfall MJ, van Helten JB, et al. 1991. Mutational specificities of environmental carcinogens in the lacl gene of escherichia coli H.V: DNA sequence analysis of mutations in bacteria recovered from the liver of Swiss mice exposed to 1,2-dimethylhydrazine, azoxymethane, and methylazoxymethanolacetate. Mol Carcinog 4:180-188. *Zijlstra JA, Vogel EW. 1988. Influence of inhibition of the metabolic activation on the mutagenicity of some nitrosamines, triazenes, hydrazines and seniciphyliine in drosophila melanogaster. Mutat Res 202:251-267. Zusman I, Madar Z, Nyska A. 1992a. Individual variability of pathological parameters in chemically induced rat colon tumors. Acta Anat 145:106-111. *** DRAFT FOR PUBLIC COMMENT *** 139 8. REFERENCES Zusman I, Zimber A, Madar Z, et al. 1992b. Morphological, histochemical and immunohistochemical differences between tumorous and adjacent tissues in chemically induced colon cancer in rats. Acta Anat 145:29-34. *** DRAFT FOR PUBLIC COMMENT *** 141 9. GLOSSARY Acute Exposure — Exposure to a chemical for a duration of 14 days or less, as specified in the Toxicological Profiles. Adsorption Coefficient (K,) — 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. Genotoxic - Capable of damaging deoxyribonucleic acid (DNA). 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. 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. *** DRAFT FOR PUBLIC COMMENT *** 142 9. GLOSSARY In Vivo — Occurring within the living organism. Lethal Concentration, (LC,,) — The lowest concentration of a chemical in air which has been reported to have caused death in humans or animals. Lethal Concentration, (LCs) — 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, (LD,,) — 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 Dose, (LDs) — The dose of a chemical which has been calculated to cause death in 50% of a defined experimental animal population. Lethal Time, (LT) — 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 (NOAEL) — 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 (K,,) — 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. ¢,* — The upper-bound estimate of the low-dose slope of the dose-response curve as determined by the multistage procedure. The q,* 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/m’ for air). Reference Dose (RfD) — 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 RfD 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 RfDs and an additional modifying factor, which is based on a professional judgment of the entire database on the chemical. The RfDs are not applicable to nonthreshold effects such as cancer. *** DRAFT FOR PUBLIC COMMENT *** 143 9. GLOSSARY 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. 311 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 (TDy) — 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 MRL 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. *** DRAFT FOR PUBLIC COMMENT *** A-1 APPENDIX A USER’S GUIDE Chapter 1 Public Health Statement This chapter of the profile is a health effects summary written in nontechnical language. Its intended audience is the general public especially people living in the vicinity of a hazardous waste site or substance 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 substance. The major headings in the Public Health Statement are useful to find specific topics of concem. 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 by duration of exposure and end point and to illustrate graphically levels of exposure associated with those effects. 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) for Less Serious and Serious health effects, or Cancer Effect Levels (CELs). In addition, these tables and figures illustrate differences in response by species, Minimal Risk Levels (MRLs) to humans for noncancer end points, and EPA’s estimated range associated with an upper-bound individual lifetime cancer risk of 1 in 10,000 to 1 in 10,000,000. The LSE tables and figures can be used 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. The legends presented below demonstrate the application of these tables and figures. A representative example 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 exist, 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. (2). Exposure Duration Three exposure periods: acute (14 days or less); intermediate (15 to 364 days); and chronic (365 days or more) are presented within each route of exposure. In this example, an inhalation study of intermediate duration exposure is reported. *** DRAFT FOR PUBLIC COMMENT *** (3). CF (3). (6). (). (8). (0). (10). (10; (12). A-2 APPENDIX A 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. 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 define a NOAEL and a Less Serious LOAEL (also see the two "18r" data points in Figure 2-1). Species The test species, whether animal or human, are identified in this column. 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 from different studies. In this case (key number 18), rats were exposed to [substance x] via inhalation for 13 weeks, 5 days per week, for 6 hours per day. 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, one systemic effect (respiratory) was investigated in this study. NOAEL A No-Observed-Adverse-Effect Level (NOAEL) 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-Effect Level (LOAEL) is the lowest exposure level used in the study that caused a harmful health effect. LOAELSs 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 end point used to quantify the adverse effect accompanies the LOAEL. The "Less Serious" respiratory effect reported in key number 18 (hyperplasia) occurred at a LOAEL of 10 ppm. 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 epidemiological studies. CELs are always considered serious effects. The LSE tables and figures do not contain NOAELSs for cancer, but the text may report doses which did not cause a measurable increase in cancer. Footnotes 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 LSE 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 levels for particular exposure duration. *** DRAFT FOR PUBLIC COMMENT *** «+ LINIWANOD 0178Nd HOH 14VHA «ue » TABLE 2-1. Levels of Significant Exposure to [Chemical x] - Inhalation Exposure LOAEL (effect) Key to frequency/ NOAEL Less serious Serious figure* Species duration System (ppm) (ppm) (ppm) Reference INTERMEDIATE EXPOSURE Systemic 18 Rat 13 wk Resp 3 10 (hyperplasia) Nitschke et al. 5d/wk 1981 6hr/d CHRONIC EXPOSURE > Cancer > he 38 Rat 18 mo 20 (CEL, multiple Wong et al. 1982 Tz 5d/wk organs) Oo 7hr/d x > 39 Rat 89-104 wk 10 (CEL, lung tumors, NTP 1982 5d/wk nasal tumors) 6hr/d 40 Mouse 79-103 wk 10 (CEL, lung tumors, NTP 1982 Sd/wk hemangiosarcomas) 6hr/d * The number corresponds to entries in Figure 2-1. b Used to derive an intermediate inhalation Minimal Risk Level (MRL) of 5 x 107° ppm; dose adjusted for intermittent exposure and divided by an uncertainty factor of 100 (10 for extrapolation from animal to humans, 10 for human variability). CEL = cancer effect level; d = day(s); hr = hour(s); LOAEL = lowest-observed-adverse-effect level; mo = month(s); NOAEL = no-observed-adverse-effect level; Resp = respiratory; wk = week(s) ev «x» LINGWWNOD 2178Nd HOH 14VHQ vue FIGURE 2-1. Levels of Significant Exposure to [Chemical X] - Inhalation INTERMEDIATE CHRONIC (15-364 Days) (> 365 Days) Systemic Systemic i Vd " & 5 & & # s F&F oa os $F <® ® F * FP FP <® & ~ [35] —= oom 10,000 = 1,000 | > Oo 100 | @10r ®17r P24g B25m O21r M24g P21r O22h ma o [ Oszem Par Paar Paar Paar - 5 19r 38r : 2 5: § Oz5m Par @ 3m Osx Pasm Bose Q3ar Osar Oar O34 Parr Pom ser : = Q1erOtor > 1 pF ) 1 1 E 1 0.1 ' 104 1 0.01 [+ y 10-5 { Estimated Upper- <=— |: ' Bound Human - 0.001 f~ ' Cancer Risk ~~ 106 4 | evels 0.0001 |= Key 10-7 r Rat @ LOAEL for serious effects (animals) * ) 9.00004 I~ m Mouse @ LOAEL for less serious effects (animals) ): Minimal ekiavel 15 h Rabbit QO NOAEL (animals) I effects other than cancer 9 Guinea pig @ CEL - Cancer Effect Level (animals) ~r h Monkey The number next to each point corresponds to entries in Table 2-1. * Doses represent the lowest dose tested per study that produced a tumorigenic response and do notimply the existence of a threshold for the cancer end point. 139017-1 vv (13). (14). (15). (16). am. (18). (19). A-5 APPENDIX A Exposure Duration 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. Health Effect These are the categories of health effects for which reliable quantitative data exist. The same health effects appear in the LSE table. Levels of Exposure Exposure levels for each health effect in the LSE tables are graphically displayed in the LSE figures. Exposure levels are reported on the log scale "y" axis. Inhalation exposure is reported in mg/m* or ppm and oral exposure is reported in mg/kg/day. NOAEL In this example, 18r NOAEL is the critical end point for which an intermediate inhalation exposure MRL is based. As you can see from the LSE figure key, the open-circle symbol indicates 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). CEL Key number 38r is one of three studies for which Cancer Effect Levels (CELs) were derived. The diamond symbol refers to a CEL for the test species (rat). The number 38 corresponds to the entry in the LSE table. Estimated Upper-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 EPA’s Human Health Assessment Group’s upper-bound estimates of the slope of the cancer dose response curve at low dose levels @)). Key to LSE Figure The Key explains the abbreviations and symbols used in the figure. Chapter 2 (Section 2.4) Relevance to Public Health The Relevance to Public Health section provides a health effects summary based on evaluations of existing toxicological, epidemiological, and toxicokinetic information. This summary is designed to present interpretive, weight-of-evidence discussions for human health end points by addressing the following questions. 1. 2. 3. What effects are known to occur in humans? What effects observed in animals are likely to be of concern to humans? What exposure conditions are likely to be of concern to humans, especially around hazardous waste sites? The section discusses health effects by end point. Human data are presented first, then animal data. Both are organized by route of exposure (inhalation, oral, and dermal) and by duration (acute, intermediate, and 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. *** DRAFT FOR PUBLIC COMMENT *** A-6 APPENDIX A 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. MRLs for noncancer end points if derived, and the end points from which they were derived are indicated and discussed in the appropriate section(s). Limitations to existing scientific literature that prevent a satisfactory evaluation of the relevance to public health are identified in the Identification of Data Needs section. Interpretation of Minimal Risk Levels Where sufficient toxicologic information was available, MRLs were derived. MRLs are specific for route (inhalation or oral) and duration (acute, intermediate, or chronic) of exposure. Ideally, MRLs can be derived from all six exposure scenarios (e.g., Inhalation - acute, -intermediate, -chronic; Oral - acute, -intermediate, - 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 substance emission, given the concentration of a contaminant in air or the estimated daily dose received via food or water. MRLs are based largely on toxicological studies in animals and on reports of human occupational exposure. MRL users should be familiar with the toxicological information on which the number is based. Section 2.4, "Relevance to Public Health," contains basic information known about the substance. Other sections such as 2.6, "Interactions with Other Chemicals" and 2.7, "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 used by the Environmental Protection Agency (EPA) (Bames and Dourson 1988; EPA 1989a) to derive reference doses (RfDs) for lifetime exposure. To derive an MRL, ATSDR generally selects the end point 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 poten- tial effects (e.g., systemic, neurological, and developmental). In order to compare NOAELSs and LOAELSs for specific end points, all inhalation exposure levels are adjusted for 24hr exposures and all intermittent exposures for inhalation and oral routes of intermediate and chronic duration are adjusted for continuous exposure (i.e., 7 days/week). If the information and reliable quantitative data on the chosen end point are available, ATSDR derives an MRL using the most sensitive species (when infor- mation from multiple species is available) with the highest NOAEL that does not exceed any adverse effect levels. The NOAEL is the most suitable end point for deriving an MRL. When a NOAEL is not available, a Less Serious LOAEL can be used to derive an MRL, and an uncertainty factor of (1, 3, or 10) is employed. MRLs are not derived from Serious LOAELs. Additional uncertainty factors of (1, 3, or 10) are used for human variability to protect sensitive subpopulations (people who are most susceptible to the health effects caused by the substance) and (1, 3, or 10) are used for inter- species variability (extrapolation from animals to humans). In deriving an MRL, these individual uncertainty factors are multiplied together. Generally an uncertainty factor of 10 is used; however, the MRL workgroup reserves the right to use uncertainty factors of (1, 3, or 10) based on scientific judgement. The product is then divided into the adjusted 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. *** DRAFT FOR PUBLIC COMMENT *** 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 FIFRA fpm ft FR g GC gen HPLC hr IDLH IARC ILO B-1 APPENDIX B 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 octanol-water partition coefficient liter liquid chromatography lethal concentration, low lethal concentration, 50% kill *** DRAFT FOR PUBLIC COMMENT *** LD,, LD;, LOAEL LSE m mg min mL mm mmHg mmol mo mppcf MRL MS NIEHS NIOSH NIOSHTIC ng nm NHANES nmol NOAEL NOES NOHS NPL NRC NTIS NTP OSHA PEL pg pmol PHS PMR ppb ppm ppt REL RfD RTECS sec SCE SIC SMR STEL STORET TLV TSCA TRI TWA U.S. UF B-2 APPENDIX B 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 standard mortality ratio short term exposure limit STORAGE and RETRIEVAL threshold limit value Toxic Substances Control Act Toxics Release Inventory time-weighted average United States uncertainty factor *** DRAFT FOR PUBLIC COMMENT *** FX =r RIAA NV V = oe B-3 APPENDIX B 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 micron microgram *** DRAFT FOR PUBLIC COMMENT *** 0 - L - c i - n B n ol - a, EK . . - = *® Ls nL - i . - HCH . - - kh u- ot. } E - - § . 5 - . ing * oH - on , . . a : - L. 3 a n . Ih - [I in) B oo ol mE "a. B n - } - \ - we - - } . - - i: - - ® - - er In . r 1: bl EN B . - i nn a in = 5 Co. - Lh - a - a. . = wr 8 N # l l = B - = A n - = " w & oa Ho i oe H = I fn a =i i ht 1s CN gL Eh] » nl | =e oy RA a 1 i i Es 1 . & a i i » di I | a i. I * b “ I - i wo C-1 APPENDIX C PEER REVIEW A peer review panel was assembled for hydrazine. The panel consisted of the following members: Dr. Emerich Fiala, Chief, Division of Biochemical Pharmacology, American Health Foundation, Valhalla, NY; Dr. Maryce Jacobs, Vice President for Research, the American Institute for Cancer Research, McLean, VA; Dr. Raghubir Sharma, Professor, Utah State University, Center for Environmental Toxicology, Department of Veterinary Sciences, Logan, UT. These experts collectively have knowledge of hydrazine’s physical and chemical properties, toxicokinetics, 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. *** DRAFT FOR PUBLIC COMMENT *** # U.S. GOVERNMENT PRINTING OFFICE:1994-537-974 U. C. 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