This report contains the collective views of an international group of experts and does not necessarily represent the decisions or the stated policy of the United Nations Environment Programme, the International Labour Organisation, or the World Health Organization.

Concise International Chemical Assessment Document 19

PHENYLHYDRAZINE

First draft prepared by Mr R. Cary, Health and Safety Executive, Liverpool, United Kingdom, Dr S. Dobson, Institute of Terrestrial Ecology, Huntingdon, United Kingdom, and Dr I. Brooke, Health and Safety Executive, Liverpool, United Kingdom

Please note that the layout and pagination of this pdf file are not identical to the printed CICAD

Published under the joint sponsorship of the United Nations Environment Programme, the International Labour Organisation, and the World Health Organization, and produced within the framework of the Inter-Organization Programme for the Sound Management of Chemicals.

World Health Organization Geneva, 2000 The International Programme on Chemical Safety (IPCS), established in 1980, is a joint venture of the United Nations Environment Programme (UNEP), the International Labour Organisation (ILO), and the World Health Organization (WHO). The overall objectives of the IPCS are to establish the scientific basis for assessment of the risk to human health and the environment from exposure to chemicals, through international peer review processes, as a prerequisite for the promotion of chemical safety, and to provide technical assistance in strengthening national capacities for the sound management of chemicals. The Inter-Organization Programme for the Sound Management of Chemicals (IOMC) was established in 1995 by UNEP, ILO, the Food and Agriculture Organization of the United Nations, WHO, the United Nations Industrial Development Organization, the United Nations Institute for Training and Research, and the Organisation for Economic Co-operation and Development (Participating Organizations), following recommendations made by the 1992 UN Conference on Environment and Development to strengthen cooperation and increase coordination in the field of chemical safety. The purpose of the IOMC is to promote coordination of the policies and activities pursued by the Participating Organizations, jointly or separately, to achieve the sound management of chemicals in relation to human health and the environment.

WHO Library Cataloguing-in-Publication Data

Phenylhydrazine.

(Concise international chemical assessment document ; 19)

1.Phenylhydrazines - toxicology 2.No-observed-adverse-effect level 3.Risk assessment 4.Environmental exposure I.International Programme on Chemical Safety II.Series

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Printed by Wissenschaftliche Verlagsgesellschaft mbH, D-70009 Stuttgart 10 TABLE OF CONTENTS

FOREWORD ...... 1

1. EXECUTIVE SUMMARY ...... 4

2. IDENTITY AND PHYSICAL/CHEMICAL PROPERTIES ...... 5

3. ANALYTICAL METHODS ...... 5

4. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE ...... 5

5. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION ...... 6

6. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE ...... 6

6.1 Environmental levels ...... 6 6.2 Human exposure ...... 6

7. COMPARATIVE KINETICS AND METABOLISM IN LABORATORY ANIMALS AND HUMANS ...... 7

8. EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS ...... 7

8.1 Single exposure ...... 7 8.2 Irritation and sensitization ...... 8 8.3 Short-term exposure ...... 8 8.4 Long-term exposure ...... 9 8.4.1 Subchronic exposure ...... 9 8.4.2 Chronic exposure and carcinogenicity ...... 9 8.5 Genotoxicity and related end-points ...... 10 8.6 Reproductive and developmental toxicity ...... 11 8.7 Immunological and neurological effects ...... 11

9. EFFECTS ON HUMANS ...... 11

10. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD ...... 12

10.1 Aquatic environment ...... 12 10.2 Terrestrial environment ...... 12

11. EFFECTS EVALUATION ...... 13

11.1 Evaluation of health effects ...... 13 11.1.1 Hazard identification and dose–response assessment ...... 13 11.1.2 Criteria for setting guidance values for phenylhydrazine ...... 13 11.1.3 Sample risk characterization ...... 14 11.2 Evaluation of environmental effects ...... 14

12. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES ...... 15

13. HUMAN HEALTH PROTECTION AND EMERGENCY ACTION ...... 15

13.1 Human health hazards ...... 15 13.2 Advice to physicians ...... 15 13.3 Health surveillance advice ...... 15

iii Concise International Chemical Assessment Document 19

14. CURRENT REGULATIONS, GUIDELINES, AND STANDARDS ...... 16

INTERNATIONAL CHEMICAL SAFETY CARD ...... 17

REFERENCES ...... 19

APPENDIX 1 — SOURCE DOCUMENTS ...... 22

APPENDIX 2 — CICAD PEER REVIEW ...... 22

APPENDIX 3 — CICAD FINAL REVIEW BOARD ...... 23

RÉSUMÉ D’ORIENTATION ...... 24

RESUMEN DE ORIENTACIÓN ...... 26

iv Phenylhydrazine

FOREWORD While every effort is made to ensure that CICADs represent the current status of knowledge, new Concise International Chemical Assessment information is being developed constantly. Unless Documents (CICADs) are the latest in a family of otherwise stated, CICADs are based on a search of the publications from the International Programme on scientific literature to the date shown in the executive Chemical Safety (IPCS) — a cooperative programme of summary. In the event that a reader becomes aware of the World Health Organization (WHO), the International new information that would change the conclusions Labour Organisation (ILO), and the United Nations drawn in a CICAD, the reader is requested to contact Environment Programme (UNEP). CICADs join the IPCS to inform it of the new information. Environmental Health Criteria documents (EHCs) as authoritative documents on the risk assessment of Procedures chemicals. The flow chart shows the procedures followed to CICADs are concise documents that provide produce a CICAD. These procedures are designed to summaries of the relevant scientific information take advantage of the expertise that exists around the concerning the potential effects of chemicals upon world — expertise that is required to produce the high- human health and/or the environment. They are based quality evaluations of toxicological, exposure, and other on selected national or regional evaluation documents or data that are necessary for assessing risks to human on existing EHCs. Before acceptance for publication as health and/or the environment. CICADs by IPCS, these documents undergo extensive peer review by internationally selected experts to ensure The first draft is based on an existing national, their completeness, accuracy in the way in which the regional, or international review. Authors of the first original data are represented, and the validity of the draft are usually, but not necessarily, from the institution conclusions drawn. that developed the original review. A standard outline has been developed to encourage consistency in form. The primary objective of CICADs is The first draft undergoes primary review by IPCS to characterization of hazard and dose–response from ensure that it meets the specified criteria for CICADs. exposure to a chemical. CICADs are not a summary of all available data on a particular chemical; rather, they The second stage involves international peer include only that information considered critical for review by scientists known for their particular expertise characterization of the risk posed by the chemical. The and by scientists selected from an international roster critical studies are, however, presented in sufficient compiled by IPCS through recommendations from IPCS detail to support the conclusions drawn. For additional national Contact Points and from IPCS Participating information, the reader should consult the identified Institutions. Adequate time is allowed for the selected source documents upon which the CICAD has been experts to undertake a thorough review. Authors are based. required to take reviewers’ comments into account and revise their draft, if necessary. The resulting second draft Risks to human health and the environment will is submitted to a Final Review Board together with the vary considerably depending upon the type and extent reviewers’ comments. of exposure. Responsible authorities are strongly encouraged to characterize risk on the basis of locally The CICAD Final Review Board has several measured or predicted exposure scenarios. To assist the important functions: reader, examples of exposure estimation and risk characterization are provided in CICADs, whenever – to ensure that each CICAD has been subjected to possible. These examples cannot be considered as an appropriate and thorough peer review; representing all possible exposure situations, but are – to verify that the peer reviewers’ comments have provided as guidance only. The reader is referred to EHC been addressed appropriately; 1701 for advice on the derivation of health-based – to provide guidance to those responsible for the guidance values. preparation of CICADs on how to resolve any remaining issues if, in the opinion of the Board, the author has not adequately addressed all comments of the reviewers; and – to approve CICADs as international assessments. 1 International Programme on Chemical Safety (1994) Assessing human health risks of chemicals: derivation Board members serve in their personal capacity, not as of guidance values for health-based exposure limits. representatives of any organization, government, or Geneva, World Health Organization (Environmental Health industry. They are selected because of their expertise in Criteria 170). human and environmental toxicology or because of their

1 Concise International Chemical Assessment Document 19

CICAD PREPARATION FLOW CHART

SELECTION OF PRIORITY CHEMICAL

SELECTION OF HIGH QUALITY NATIONAL/REGIONAL ASSESSMENT DOCUMENT(S)

FIRST DRAFT PREPARED

PRIMARY REVIEW BY IPCS ( REVISIONS AS NECESSARY)

REVIEW BY IPCS CONTACT POINTS/ SPECIALIZED EXPERTS

REVIEW OF COMMENTS (PRODUCER/RESPONSIBLE OFFICER), PREPARATION OF SECOND DRAFT 1

FINAL REVIEW BOARD 2

FINAL DRAFT 3

EDITING

APPROVAL BY DIRECTOR, IPCS

PUBLICATION

1 Taking into account the comments from reviewers. 2 The second draft of documents is submitted to the Final Review Board together with the reviewers’ comments. 3 Includes any revisions requested by the Final Review Board.

2 Phenylhydrazine

experience in the regulation of chemicals. Boards are chosen according to the range of expertise required for a meeting and the need for balanced geographic representation.

Board members, authors, reviewers, consultants, and advisers who participate in the preparation of a CICAD are required to declare any real or potential conflict of interest in relation to the subjects under discussion at any stage of the process. Representatives of nongovernmental organizations may be invited to observe the proceedings of the Final Review Board. Observers may participate in Board discussions only at the invitation of the Chairperson, and they may not participate in the final decision-making process.

3 Concise International Chemical Assessment Document 19

1. EXECUTIVE SUMMARY and there is evidence that it has skin-sensitizing proper- ties in humans. Exposure to phenylhydrazine may cause damage to red blood cells, potentially resulting in This CICAD on phenylhydrazine was based on a anaemia and consequential secondary involvement of review of human health concerns (primarily occupation- other tissues, such as the spleen and liver. Phenylhydra- al) prepared by the United Kingdom’s Health and Safety zine is mutagenic in vitro, and there is some evidence to Executive (Brooke et al., 1997) and a report prepared for indicate that it may express genotoxic activity in vivo. the German Advisory Committee on Existing Chemicals The substance is clearly carcinogenic in mice following of Environmental Relevance (BUA, 1995). Hence, this oral dosing, inducing tumours of the vascular system. document focuses on exposures via routes relevant to The mechanism for tumour formation is unclear, but a occupational settings but also contains environmental genotoxic component cannot be excluded. Hence, it is information. Data identified as of December 1993 and not considered possible to reliably identify a level of December 1994, respectively, were covered. A further exposure at which there will be no risk of carcinogenic or literature search was performed up to January 1998 to genotoxic effects. identify any extra information published since these reviews were completed. Information on the nature of the There are no adequate data available regarding peer review and availability of the source documents is reproductive or developmental effects; hence, it is not presented in Appendix 1. Information on the peer review possible to evaluate the risk to human health for these of this CICAD is presented in Appendix 2. This CICAD end-points. was approved as an international assessment at a meeting of the Final Review Board, held in Washington, The level of risk in occupational settings is uncer- DC, USA, on 8–11 December 1998. Participants at the tain; as a result, there is a continuing requirement to Final Review Board meeting are listed in Appendix 3. The reduce exposure levels as much as is reasonably prac- International Chemical Safety Card (ICSC 0938) for phe- ticable with the technology that is currently available. nylhydrazine, produced by the International Programme on Chemical Safety (IPCS, 1993), has also been The lack of available data to serve as a basis for reproduced in this document. estimation of indirect exposure of individuals to phenyl- hydrazine from the general environment precludes the Phenylhydrazine (CAS No. 100-63-0) exists as characterization of potential cancer risks for the general yellow to pale brown crystals or as a yellowish oily population. liquid. It is sparingly soluble in water and is miscible with other organic solvents. No atmospheric effects are expected given the release of phenylhydrazine predominantly to water, its Phenylhydrazine is used worldwide mainly as a extremely low volatilization from water to the atmos- chemical intermediate in the pharmaceutical, agrochemi- phere, and its rapid calculated atmospheric half-life cal, and chemical industries. following reaction with hydroxyl radicals.

The number of persons potentially exposed to Phenylhydrazine is degraded photochemically and phenylhydrazine or its hydrochloride salt is not known, autoxidizes in water. It is readily biodegradable, and this but it is expected to be small. No personal exposure data is expected to be the major route of breakdown in the were available, although the Estimation and Assessment environment. There is minimal sorption to particulates. of Substance Exposure (EASE) model predicted exposure (8-h time-weighted average) to be around 2.3 mg/m3 (0.5 Phenylhydrazine is toxic to aquatic organisms, with ppm). In practice, the 8-h time-weighted average the lowest reported no-observed-effect concentration exposure will be less than this figure. (NOEC) in standard acute fish tests at 0.01 mg/litre; fish are generally more sensitive than either daphnids or The limited data on toxicokinetics indicate that bacteria. A NOEC of 0.49 :g/litre has been reported for phenylhydrazine is well absorbed by inhalation, oral, and embryo-larval stages of the zebra fish (Brachydanio dermal routes and binds readily to haemoglobin in red rerio). blood cells. Metabolism seems to occur via ring hydroxylation and conjugation, probably with gluc- The risk to aquatic organisms is expected to be uronic acid. Excretion is primarily via the urine. low, based on very conservative assumptions.

Phenylhydrazine is toxic by single exposure via the oral route (LD50 80–188 mg/kg body weight) and is expected to be toxic by the inhalation and dermal routes (data from these routes of exposure are less clear). Phenylhydrazine has potential for skin and eye irritation,

4 Phenylhydrazine

2. IDENTITY AND PHYSICAL/CHEMICAL 4. SOURCES OF HUMAN AND PROPERTIES ENVIRONMENTAL EXPOSURE

Phenylhydrazine (C6H8N2; molecular weight 108; There are a few reports of the natural occurrence of CAS No. 100-63-0; see structural diagram below) exists phenylhydrazine in plants (BUA, 1995). Phenylhydrazine as yellow to pale brown crystals or as a yellowish oily is produced commercially by the diazotization of aniline liquid, with a freezing point of 19.6 °C, a boiling point of followed by reduction of the azo compound. 243.4 °C, and a vapour pressure of 133 Pa at 72 °C. It is soluble in water (values ranging from 145 to 837 g/litre at Production figures for 1990–1992 in Germany were 24 °C have been reported) and is miscible with alcohol, about 3000–4000 t/year; use figures for Western Europe ether, chloroform, benzene, and acetone. The conversion in 1988 totalled 6650 t (BUA, 1995). Use patterns for factor for phenylhydrazine is 1 ppm = 4.5 mg/m3 (at 20 °C, Western Europe in 1988 and for Germany in 1990–1992 101 kPa). Additional physical/chemical properties of phe- are shown in Table 1. nylhydrazine are presented in the International Chemical Safety Card reproduced in this document. Table 1: Phenylhydrazine use patterns in Western Europe and Germany.

Phenylhydrazine use (%) NH NH2 Western Europe, Germany, Industry 1988 1990–1992

Pharmaceuticals 37.6 70.2

Agrochemicals 42.9 7.2 Dyes 15 21.8 3. ANALYTICAL METHODS Others 4.5 0.8

From production and processing of phenylhydra- For measurement of phenylhydrazine in water, zine in Germany during 1990–1992, an estimated 50 kg reduction of Cu(II) to Cu(I) by phenylhydrazine has been and <13 t were emitted to the atmosphere and the hydro- used as the basis for spectrometric analytical methods sphere, respectively, each year. Less than 50 t of phenyl- measuring coloured complexes (Besada, 1988; Hasan, hydrazinium chloride were released to water each year in 1988). The methods are not specific and react to other the same period (BUA, 1995). reducing substances. A detection limit of 10 :g/litre is given for one method (Hasan, 1988). There are now no manufacturers of phenylhydra- zine or the phenylhydrazine hydrochloride salt in the In a method published by NIOSH (1994) for mea- United Kingdom (Brooke et al., 1997). Two firms are surement of phenylhydrazine in workplace air, the air is known to import phenylhydrazine into the United King- sampled into a midget bubbler containing hydrochloric dom, one from its manufacturing site in Germany and the acid. Phosphomolybdic acid is added to the resulting other from Japan. The total market for phenylhydrazine solution, and the reaction with phenylhydrazine causes in the United Kingdom is thought to be about 20 t/year, the formation of a bluish-green complex that can be whereas the market for phenylhydrazine hydrochloride is measured at 730 nm with a spectrophotometer. This not known. The market for phenylhydrazine has been method has a detection limit of about 5 mg/m3 (about static for several years. 1 ppm), based on a 100-litre sample. Potential interfer- ences are listed as other hydrazine derivatives, alde- Phenylhydrazine is used worldwide mainly as a hydes, and ketones. chemical intermediate in the pharmaceutical, agrochemi- cal, and chemical industries. The United Kingdom’s Both the MIRAN 1B and the Bruel and Kjaer 1302 pattern of use appears representative. One company Multigas Monitor may be used to measure phenylhydra- uses phenylhydrazine to produce a chemical zine in air, with a detection limit of around 13.5 mg/m3 (3 intermediate for use in the photographic industry. ppm) (Brooke et al., 1997). Any other substance having Another manufacturer uses the chemical in the synthesis similar infrared absorbances can be expected to interfere of organic chemicals. Phenylhydrazine is also used as a with the measurement. chemical intermediate in the pharmaceutical and agrochemical industries in the United Kingdom. In There are no published biological monitoring addition, there is some laboratory-scale use of this methods available for phenylhydrazine. chemical.

5 Concise International Chemical Assessment Document 19

There are no known consumer uses of phenylhy- In a modified OECD ready biodegradability screen- drazine or its hydrochloride salt in the United Kingdom ing test (OECD 301E), phenylhydrazine was “readily or Germany. No information is available regarding the biodegradable”; elimination was 77% after 10 days and potential for consumer exposure in other countries. 97% after 28 days using non-adapted inoculum. Elimination through abiotic processes in controls was 11% after both 10 and 28 days (BASF, 1993). In the Zahn-Wellens test for inherent biodegradability (OECD 5. ENVIRONMENTAL TRANSPORT, 302B), 20–30% elimination occurred over 3 h (sorption), DISTRIBUTION, AND TRANSFORMATION with 80% chemical oxygen demand achieved over 15 days using non-acclimatized industrial activated sludge. Using acclimatized activated sludge, 85% elimination Most emissions of phenylhydrazine into the was seen after 10 days (Hoechst, 1980, 1992). A similar environment are into the hydrosphere. At acidic pH, value of 85% elimination in 9–13 days was reported in phenylhydrazine occurs as the salt (BUA, 1995). the same test by Wellens (1990).

In the atmosphere, phenylhydrazine would exist solely in the vapour phase (HSDB, 1998). Calculated half-lives of 3.1 h (BUA, 1995) and 9 h (Meylan & 6. ENVIRONMENTAL LEVELS AND Howard, 1993) have been reported for phenylhydrazine HUMAN EXPOSURE following reaction with hydroxyl radicals in the atmosphere. 6.1 Environmental levels Phenylhydrazine strongly absorbs ultraviolet light in the environmentally significant range, suggesting that Phenylhydrazine was not detected (detection limit it may photolyse in sunlight (HSDB, 1998); slow photo- 0.002 :g/ml with high-performance liquid chromatog- decomposition in diffuse daylight in the absence of raphy) in 30 samples of surface water in the 1986 oxygen is deduced in BUA (1995). In the presence of monitoring of the general environment by the Japan oxygen, phenylhydrazine is subject to autoxidation, the Environment Agency (1987). It was also not detected in reaction being accelerated by light and heat; the sub- 30 samples of sediment (detection limit 0.2 :g/kg with stance becomes reddish brown on exposure to air as a high-performance liquid chromatography). result of this autoxidation (Ullmann, 1977). Monitoring of wastewater at the Hoechst produc- No hydrolysis is expected to occur (BUA, 1995). tion plant in Germany failed to detect the compound in either inflow or outflow wastewater (detection limit The Henry’s law constant for phenylhydrazine has 500 :g/litre) (BUA, 1995). been calculated at 9.69 × 10–3 Pa@m3/mol (BUA, 1995). This is equivalent to a dimensionless Henry’s law 6.2 Human exposure constant (air/water partition coefficient) of 3.92 × 10–6. These values indicate that phenylhydrazine is The number of persons potentially exposed to phe- essentially non-volatile from water surfaces. nylhydrazine or its hydrochloride salt is not known, but it is expected to be small (Brooke et al., 1997). Industry in Reported log octanol/water partition coefficients the United Kingdom has not been able to provide any

(log Kow) range from 1.25 to 1.90 (BUA, 1995); an personal exposure data, although it has been indicated estimated bioconcentration factor of 5 was based on the that exposure to airborne phenylhydrazine between 1993 lower value (HSDB, 1998), indicating a low capacity for and 1994 was controlled by process enclosure, the provi- bioaccumulation. However, sorption based on chemical sion of local exhaust ventilation, and personal protective binding is possible, which could lead to some bioaccu- equipment. mulation (BUA, 1995). The sorption coefficient (Koc) can be calculated to range between 7.3 (Organisation for As there are no measured data available, the Economic Co-operation and Development [OECD] sections below describe the use of computer-modelled Technical Guidance Manual) and 11 (Karickhoff et al., exposure data from the EASE model. This is a general- 1979), indicating little sorption to particulates and a purpose predictive model for workplace exposure capacity for mobility in soil. However, the regression assessments, which is used when measured exposure equations on which these estimates are based derive data are limited or not available. In its present form, the from hydrophobic compounds and may not adequately model is in widespread use across the European Union reflect the likely sorption of the hydrophilic phenylhy- for the occupational exposure assessment of new and drazine. existing substances.

6 Phenylhydrazine

Following descriptions of precautions taken during tion, resulting in the generation of destructive free use, the most appropriate parameters for the use of the radicals, which are responsible for subsequent haemol- EASE model are non-dispersive use with local exhaust ysis (e.g., Itano et al., 1975; Valenzuela et al., 1977, 1981; ventilation in place. Exposure between 25 and 40 °C with Goldberg et al., 1979; Jain & Hochstein, 1979; Jonen et these assumptions is predicted to be within the range al., 1982; Hill, 1985; Marks, 1985; Di Cola et al., 1988, 2.3–13.5 mg/m3 (0.5–3 ppm) (8-h time-weighted average). 1989; Maples et al., 1988). Further, as only small quantities are involved, and as extensive containment is provided by the combination of There is little information available on tissue a vessel open only at the bung hole and transfer being distribution. achieved by vacuum transfer, exposure will be at the low end of this range (i.e., 2.3 mg/m3 [0.5 ppm] 8-h time- There is only one study available that investigates weighted average). In practice, the 8-h time-weighted the metabolism and excretion of phenylhydrazine, average exposure will be less than this figure, as the following oral dosing in rabbits (McIsaac et al., 1958). activities involving exposure to phenylhydrazine will This study shows that phenylhydrazine is extensively take place for only part of the shift. metabolized following oral administration, although the complete metabolic pathway has not been characterized. These predicted exposures would be even lower The main reactions identified in this study were hydrox- for work carried out in fume cupboards and would be ylation of the aromatic ring to p-hydroxyphenylhydra- extensively mitigated at the operator by use of respira- zine, followed by conjugation, probably with glucuronic tory protective equipment; air-fed suits would effectively acid, and production of phenylhydrazones, by reaction reduce exposures of these magnitudes to zero. with natural keto acids.

For direct handling and non-dispersive use with a This study also indicated that the major route of contact level assumed to be incidental from the process excretion is via the urine. A significant proportion of a descriptions, EASE predicts dermal exposures to range single dose was excreted relatively slowly; 50% of the from 0 to 0.1 mg/cm2 per day. If direct handling is dose was excreted within 4 days of dosing. There are eliminated, dermal exposure is very low. Again, these insufficient data to determine whether there is any exposures would effectively be reduced to zero by accumulation of phenylhydrazine in body tissues on adoption of high-quality personal protective equipment repeated exposure. and distancing procedures described in this assessment.

8. EFFECTS ON LABORATORY 7. COMPARATIVE KINETICS AND MAMMALS AND IN VITRO TEST SYSTEMS METABOLISM IN LABORATORY ANIMALS AND HUMANS Many of the studies reported for phenylhydrazine have been conducted using phenylhydrazine hydro- Phenylhydrazine reacts readily with the carbonyl chloride. This salt is a weak, complex-forming compound, group, –C=O, which is common among biological and either the salt or the free base will form depending molecules. It is therefore expected that direct binding to on the physiological medium, regardless of the form in biological molecules would occur. which the phenylhydrazine is administered (NIOSH, 1978). The toxicological properties of the salt can There is only limited information available on the therefore be considered to be at least equivalent to those toxicokinetics of phenylhydrazine. Evidence from toxi- of free phenylhydrazine. Differences in toxicity may arise cokinetic and toxicity studies and from human experience when properties such as pH or solubility contribute to indicates that phenylhydrazine is well absorbed by the the expression of toxicity. All dose values quoted inhalation, oral, and dermal routes in animals and throughout this document refer to free phenylhydrazine. humans. 8.1 Single exposure Once absorbed, some phenylhydrazine appears to be rapidly taken up by red blood cells, where destructive In relation to inhalation exposure, there is only intracellular reactions may occur. one very poorly reported study, which reports LC50 values for an unstated exposure period of 2745 mg/m3 Evidence from a number of studies in vitro and (610 ppm) in the rat and 2093 mg/m3 (465 ppm) in the in vivo suggests that phenylhydrazine interacts with mouse (Pham, 1979). However, it is expected that the haemoglobin and cytochrome P-450 in an oxidation reac- marked toxicity seen following oral and dermal exposure

7 Concise International Chemical Assessment Document 19 would also be expressed following inhalation. Phenylhy- consistently seen. This response to 10% phenylhydra- drazine is toxic by oral administration, and oral LD50 zine was more severe than that described in animals that values in the range 80–188 mg/kg body weight have had not been pretreated. been reported for the rat, mouse, guinea-pig, and rabbit (Ekshtat, 1965; Pham, 1979). Clinical signs reported were No information is available in relation to respira- motor excitation and tonic/clonic spasms. In rabbits, tory tract sensitization. dermal exposure to 380 mg phenylhydrazine/kg body weight for 24 h resulted in 20–30% mortality, although 8.3 Short-term exposure no deaths occurred in rats at this dose (Derelanko et al., 1987). The toxic effects are characterized by destruction There are only very limited, poor-quality data of red blood cells, causing a reduction in erythrocyte available in relation to short-term repeated-dose toxicity. count, increased reticulocyte count, methaemoglobin The effects seen are similar to those seen following formation, and the formation of Heinz bodies, and a single exposure — in particular, destruction of circu- cyanotic external appearance may develop. Enlargement lating red blood cells. Toxicity to the spleen, liver, and and dark coloration of the spleen are also reported, kidney has also been observed in animal studies, possi- effects that are considered to be secondary to the bly secondary to haemolysis. erythrocyte damage. Kelly et al. (1969) administered phenylhydrazine 8.2 Irritation and sensitization hydrochloride to 21 mice by oral gavage once weekly for 8 weeks, at an estimated dose of 85 mg/kg body weight In the single-dose dermal toxicity study in rabbits per week. There were 10 saline-treated controls. The and rats reported in the previous section, phenylhydra- study report described only tumour-related findings. zine hydrochloride was applied to the skin as a solid There was 30% mortality in treated mice compared with moistened with distilled water, under either an occlusive none in controls. or semi-occlusive dressing, for 24 h (Derelanko et al., 1987). Skin irritation was seen in all rabbits, with some Haematological changes were reported in four necrosis at the treated site at 24 h post-application and dogs administered 60 mg phenylhydrazine/kg body sloughing of the skin reported in some animals. Skin weight, either as a single dose or as 2, 3, or 10 equal irritation, which appeared within 24 h and persisted for doses on consecutive days (Giffin & Allen, 1928). There up to 7 days post-exposure, was seen in a high propor- was a marked reduction in erythrocyte count that was tion of rats. Necrosis developed in a small number of comparable in magnitude in all dogs at the end of rats. 10 days, but that occurred at a faster rate after a single high dose compared with repeated lower doses. The quality of skin irritation data from other studies is limited; overall, however, the results support In another dog study, 60 mg phenylhydrazine/kg the conclusion reached by Derelanko et al. (1987) — that body weight was administered daily to three dogs for phenylhydrazine should be considered a skin irritant 5 days (Allen & Giffin, 1928). One animal was moribund (Jadassohn, 1930; von Oettingen & Deichmann-Gruebler, at sacrifice on the fifth day and one animal died on the 1936; Roudabush et al., 1965; Schuckmann, 1969; fifth day, although it is not specified that death was Derelanko et al., 1987). Further details of these studies treatment related. Full necropsy was performed on only can be obtained in the source document (Brooke et al., one animal, in which it was found that the blood was 1997). brown and did not coagulate readily. Several organs, including the liver and kidneys, were darkly coloured, The only available information on the eye irritation and several organs contained capillaries engorged with potential of phenylhydrazine in animals comes from a blood. Blood pigment and partially destroyed erythro- poorly described study in which application of a 50% cytes were found in the spleen. Hepatic cell atrophy was solution of phenylhydrazine to the eyes of rabbits was noted, and there was an increase in the iron content of reported to cause severe suppurative conjunctivitis the liver. Similar liver effects were seen in the two other (Pham, 1979). dogs.

There are no good-quality studies available in Bolton (1935) briefly reported the effect of repeated animals that investigate the skin sensitization potential oral administration of 14 mg phenylhydrazine hydro- of phenylhydrazine. Only one poorly described study in chloride/kg body weight to one dog on 4 consecutive guinea-pigs is available (Jadassohn, 1930). When a 10% days. There was a reduction in erythrocyte count and solution of phenylhydrazine in alcohol was painted on a haemoglobin concentration, whereas white cell count skin site that had been pretreated 2–3 weeks previously gradually increased. These parameters had returned with undiluted phenylhydrazine, very intense erythema towards pretreatment values 12 days after the last dose. and swelling, followed by scaling and encrustation, were

8 Phenylhydrazine

Pathological findings were reported to be non- & Giffin, 1928). Three dogs were administered phenylhy- conclusive, but no details were given. drazine in 146 daily doses over a period of 8 months, to give a total dose of 950 mg/kg body weight; the dosing Overall, the frequency, duration, and level of regimen included a period of about 60 days of exposure often varied throughout the studies reported uninterrupted administration of a single dose level or of above, so that interpretation of results is very difficult. two dose levels (6–12 mg/kg body weight per day). In all studies, phenylhydrazine as phenylhydrazine Again, the route of administration was unclear. Kidney hydrochloride was administered either by stomach tube function and hepatic function were unaffected by treat- or by subcutaneous injection. The authors report that ment. Erythrocyte count was reduced by treatment but similar findings were obtained regardless of route. There recovered after cessation of treatment, at a rate that was were no control animals. None of the treated animals unrelated to the duration of exposure, thus indicating showed clinical signs of toxicity, and there was no that the administered dose had no effect on erythropoi- excessive weight loss or gain reported. etic function. Pathological examination was conducted on two of these dogs at 12 or 13 months. There was There have been a number of studies that investi- evidence of spleen toxicity, liver congestion, and kidney gate the effect of short-term repeated parenteral admin- damage. istration of phenylhydrazine (Bodansky, 1923; von Oettingen & Deichmann-Gruebler, 1936; Säterborg, 1974; In a very briefly reported study, phenylhydrazine Ades & Cascarano, 1979; Jain & Hochstein, 1979; was administered to 25 female Swiss mice by oral Goldstein et al., 1980; Nishida et al., 1982; Dornfest et al., gavage, 5 days/week for 40 weeks, at an estimated daily 1986). These studies confirm the ability of phenylhydra- dose of 17–33 mg/kg body weight (Roe et al., 1967). zine to damage red blood cells but otherwise do not There were 85 untreated controls. Marked anaemia provide any other information in relation to the toxicity necessitated a reduction in the dose during the sixth of phenylhydrazine administered by occupationally week of treatment. No other toxic effects were observed. relevant routes of exposure. 8.4.2 Chronic exposure and carcinogenicity 8.4 Long-term exposure Phenylhydrazine hydrochloride was administered 8.4.1 Subchronic exposure daily by stomach tube for 42 weeks to 30 BALB/c mice, at an estimated dose level of 25 mg phenylhydrazine/kg In a very poorly reported study from which limited body weight (Clayson et al., 1966). Thirty control animals conclusions can be drawn, rats, mice, guinea-pigs, and were included in the study, but a control animal was rabbits were exposed to phenylhydrazine vapour at 0, killed whenever a treated animal died, to match survival 0.1, 15.8, 22.5, or 225 mg/m3 (0, 0.03, 3.5, 5, or 50 ppm) rates. There was a statistically significant increase in the (Pham, 1979). Group sizes, duration of exposure, and incidence of animals with lung tumours in the treated exposure regime were not given, although it can be group (53%) compared with controls (13%). There was inferred that some animals were exposed for at least 6 also a slight increase in the average number of tumours months. Deaths were reported to occur in animals per mouse, and the majority of treated mice had multiple exposed to 225 mg phenylhydrazine/m3 (species not pulmonary tumours. Adenomas accounted for 83% of specified). Severe weight loss and unspecified haemato- pulmonary tumours in the treated group, half of which logical changes and changes in central nervous system were judged to be becoming malignant, and 17% of function were reported to precede death, and there was tumours were carcinomas. evidence of haemolysis and dystrophic changes in the liver, spleen, and cerebrum. Animals exposed to 15.8 and Phenylhydrazine hydrochloride was administered 22.5 mg/m3 were reported to have a reduction in in drinking-water to 100 Swiss mice for their lifetime, at erythrocyte count and haemoglobin concentration, an an estimated daily dose of 22 mg/kg body weight (Toth increase in reticulocytes, and methaemoglobinaemia; & Shimizu, 1976). There were 200 control mice. Complete these changes were reversible at 15.8 mg/m3. Haemolysis necropsy was performed on all animals. All organs were and dystrophic changes in the liver and other unspeci- examined macroscopically, and histological analysis was fied organs were also reported for animals exposed to performed on a wide range of tissues as well as on any 22.5 mg/m3. No further information is available on organ showing gross pathology. Phenylhydrazine was pathological changes at 0.1 mg/m3. It is not clear if there reported to decrease survival in comparison with were lung effects at any of the exposure concentrations. controls, and many of the treated decedents showed splenomegaly, although numbers were not given. There It is not possible to draw firm conclusions from a was a statistically significant increased incidence of poorly reported study in three dogs in which the effect blood vessel tumours (mainly angiosarcomas and of phenylhydrazine administration on renal and hepatic angiomas) in the liver of treated animals (21%) compared function and on erythropoiesis was investigated (Allen with controls (0%).

9 Concise International Chemical Assessment Document 19

8.5 Genotoxicity and related end-points the presence and absence of metabolic activation. A total of 1500 polychromatic erythrocytes (PCEs) per Phenylhydrazine and phenylhydrazine hydro- concentration was scored for the presence of chloride have been investigated in a number of Ames micronuclei. There was no measure of cytotoxicity. tests, in a variety of strains, and in the presence and absence of exogenous metabolic activation using up to The percentage of micronucleated PCEs was 1000 :g phenylhydrazine or phenylhydrazine hydro- statistically significantly increased, in the presence of S9 chloride per plate (Shimizu et al., 1978; Tosk et al., 1979; only, at phenylhydrazine concentrations of 5 :g/ml and De Flora, 1981; Parodi et al., 1981; Levin et al., 1982; greater in a concentration-related manner. Malca-Mor & Stark, 1982; Rogan et al., 1982; De Flora et al., 1984a,b; Wilcox et al., 1990; Muller et al., 1993). The BALB/c mice were administered a single intra- quality of these studies is generally high, and the peritoneal injection of phenylhydrazine, and the inci- studies were apparently conducted according to dence of micronucleated PCEs in the bone marrow was standard methodology, although detailed reporting of measured at 24 and 48 h (Suzuki, 1985). Phenylhydrazine the results is not always available. was reported to be positive in this test, but no details of the results or of the test were given. In view of the poor There is some variability in the findings, although reporting, no firm conclusions can be drawn from this positive results have been obtained in Salmonella study. typhimurium strains TA97, TA100, TA102, TA1537, and TA1538 in the absence of exogenous metabolic Groups of 11–12 female BALB/c mice were given a activation. In addition, positive results were obtained in single intraperitoneal injection of 50 mg phenylhydra- the presence of metabolic activation in TA98 and zine/kg body weight in saline (Steinheider et al., 1985). TA1535. Some investigators have reported that the Blood smears of tail vein blood were prepared at 24-h mutagenic action is slightly decreased by the presence intervals for 7 or 11 days, and reticulocytes and micro- of exogenous metabolic activation (Parodi et al., 1981; nuclei in normochromatic erythrocytes (NCEs) and PCEs Malca-Mor & Stark, 1982; De Flora et al., 1984a,b). were counted. It is not stated how many cells were However, one study reports an increase in mutagenic counted per mouse. There was no reporting of toxicity. activity in the presence of metabolic activation (Rogan et al., 1982). Phenylhydrazine caused a statistically significant increase in the reticulocyte count on days 2–4 post- Phenylhydrazine has also given positive results in injection and in PCEs on day 3. There was a statistically a number of other, less well validated bacterial assays significant increase in the incidence of micronucleated (using S. typhimurium strains such as TA2638, TP138, PCEs at 24 h post-injection (from 1 to 4.7 per 1000) and in BA9, and BA13), in the presence and absence of micronucleated NCEs at 48 h post-injection (from 0.7 to exogenous metabolic activation (De Flora et al., 1984b; 2.3 per 1000). Ulitzur et al., 1984; Ruiz-Rubio et al., 1985; Levi et al., 1986; Muller et al., 1993). However, similar increases in micronucleated NCEs were also seen following bleeding of the animals and Phenylhydrazine has not been tested in an in vitro splenectomy. The authors suggest that the increase in chromosomal aberration assay. In a brief abstract of a micronuclei seen following phenylhydrazine treatment mammalian cell gene mutation assay in V79 cells, with was due at least partly to stimulation of erythropoiesis and without metabolic activation, a positive result was because of the haemolysis induced by phenylhydrazine, reported for phenylhydrazine (Kuszynski et al., 1981). thus leading to more errors of nuclear expulsion; hence, However, no firm conclusions can be drawn from this the results do not necessarily indicate a direct genotoxic report because of deficiencies in the reporting. action of phenylhydrazine.

In an unscheduled DNA synthesis assay in rat and Groups of 7–12 mice were given a single intraperi- mouse primary hepatocytes, concentrations of 0.0144– toneal injection of either 85 or 170 mg phenylhydrazine/ 144 mg phenylhydrazine hydrochloride/litre were kg body weight and killed 1 and 6 h, respectively, after assessed (Mori et al., 1988). Although toxicity was treatment (Parodi et al., 1981). In addition, six mice were measured, no details were given, and quantitative data given a series of five daily intraperitoneal injections of were not reported. A positive result was obtained in 7.6 mg phenylhydrazine/kg body weight and sacrificed 6 both cell types, although the effect was small. h after the last injection. Control animals were injected with saline only. DNA damage was assessed by Phenylhydrazine was tested in a micronucleus measurement of the alkaline elution rate of single-strand assay in vitro using primary mouse bone marrow cells DNA from liver and lung tissue extracts. (Suzuki, 1985). Bone marrow cells from the femur were exposed to 1–50 :g phenylhydrazine/ml for 30 min, in

10 Phenylhydrazine

A statistically significant change in the elution rate hyperbilirubinaemia (resulting from haemolysis) in of liver and lung DNA was seen in all groups of treated fetuses and newborns. animals compared with controls, except in the case of lung tissue DNA from mice given a single dose of 85 mg 8.7 Immunological and neurological phenylhydrazine/kg body weight. Phenylhydrazine is effects considered to give a positive result in this assay for DNA damage. No studies are available that specifically investi- gate the immunological and neurological end-points, and . The formation of DNA adducts (N7-methylguanine there is no relevant information from toxicity studies in and a trace of O6-methylguanine) in the liver was demon- animals. strated in rats receiving 65 mg phenylhydrazine/kg body weight by oral gavage (Mathison et al., 1994). Other tissues were not examined. 9. EFFECTS ON HUMANS 8.6 Reproductive and developmental toxicity In humans, no information is available in relation to Each of three dogs (one dog per dose group) single exposure via the inhalation or oral routes, received 20, 30, or 40 mg phenylhydrazine/kg body although effects similar to those seen following dermal weight in saline by subcutaneous injection on 2 exposure would be expected to occur. Systemic toxicity consecutive days (Witchett, 1975). Two control animals developed in humans after dermal exposure to liquid were not injected. At necropsy, performed on all three phenylhydrazine, despite immediate attempts to reduce animals within a few days of dosing, a “striking” exposure by removal of contaminated clothing and reduction in spermatogenesis was reported, with an washing of skin (Schuckmann, 1969). Toxicity was absence of sperm in the epididymis. The validity of this manifest by damage to red blood cells, in one case result is not clear, given the apparent extreme rapidity of resulting in haemolytic jaundice. No such systemic the effect. effects were reported in two cases of skin contamination with solid phenylhydrazine hydrochloride. Groups of 8–12 pregnant Wistar rats were given an intraperitoneal injection of 7.5 mg phenylhydrazine/kg In relation to skin irritation, information is available body weight as phenylhydrazine hydrochloride on days from worker exposure data. There was no reporting of 17, 18, and 19 of gestation; or 15 mg phenylhydrazine/kg irritancy effects in workers exposed to liquid phenylhy- body weight as phenylhydrazine hydrochloride on days drazine following accidental exposure, although systemic 18 and 19 of gestation (Tamaki et al., 1974). Control effects were seen (Schuckmann, 1969). Skin irritation animals were not treated. There was no reporting of following contact with phenylhydrazine hydrochloride maternal toxicity or of the effect of treatment on powder was reported in two workers following accidental gestation or pup viability. Toxicity of the pups was exposure. Local irritation, superficial erythema, and reported only insofar as there was incidence of jaundice partly bullous-papular changes were noted in one case and/or anaemia among the offspring of treated animals. following spillage of powder on arms; multiple burn Twelve male offspring with severe jaundice and anaemia, marks and small blisters at the site of contact were selected from treated dams, and nine males from control reported in the second case in which phenylhydrazine dams were assessed at 9–22 weeks of age for functional hydrochloride had spilled into the worker’s gloves and and behavioural status. shoes. The author also refers to medical records at the works that describe a number of cases of skin irritation Although the authors reported that experimental of differing severity due to phenylhydrazine hydro- animals showed statistically significant differences from chloride, but no details are given. controls in some tests, these findings are not considered to be reliable because of the small numbers of animals There are no data available on the eye irritation used and the exclusion of a control animal from the potential of phenylhydrazine in humans. analysis. In addition, it is noted that only a brief part of the gestation period was covered by the treatment There are a number of case reports of skin hyper- regime (days 17–19); no explanation is available for this sensitivity reactions to phenylhydrazine and its hydro- choice of dosing regime. chloride salt in humans. Solomons (1946) conducted a patch test in one subject with a phenylhydrazine crystal Yamamura et al. (1973) reported in a brief abstract placed on the forearm under a dressing for an unstated that intraperitoneal injection of pregnant rats with 15 mg exposure period. Marked erythema and some oedema phenylhydrazine/kg body weight as phenylhydrazine developed on the exposure site after 18 h, with the hydrochloride on days 18 and 19 of gestation produced

11 Concise International Chemical Assessment Document 19 formation of vesicles after 30 h and crusting after a of the test tank, and slowed and erratic respiration. No further 24 h. gross lesions were found following dissection, although all viscera showed focal haemorrhaging (Houston et al., Similar hypersensitive skin reactions were reported 1988). following individual exposures to solid or aqueous solutions of phenylhydrazine or phenylhydrazine salts Effects on blood cells and the haematopoietic (Wright & Joyner, 1930; Frost & Hjorth, 1959; Pevny & system, comparable to those found in mammals, were Peter, 1983). seen in fish injected with phenylhydrazine. Chinook salmon (Oncorhynchus tshawytscha) juveniles were There is also evidence that cross-sensitization can injected with 12.5 mg phenylhydrazine/kg body weight. occur between hydrazine compounds, so that subjects Red cell count, haemoglobin, and haematocrit fell to already sensitized to hydrazine, a known skin sensitizer, 1–5% of their normal values within 10 days of treatment; are also sensitized to hydrazine derivatives, including a slight improvement was reported 15 days following phenylhydrazine (Malten, 1962; Van Ketel, 1964; injection, and values had returned to normal 95 days Hovding, 1967; Rothe, 1988). after treatment (Smith et al., 1971).

No data are available on the potential of phenyl- 10.2 Terrestrial environment hydrazine to cause respiratory tract sensitization. Phenylhydrazine at 21.6 mg/litre in a nutrient Earlier this century, phenylhydrazine and phenyl- culture medium had no effect on the growth of various hydrazine hydrochloride were administered orally soil fungi (Zsolnai, 1975). (usually around 100–200 mg/day) for the treatment of blood disorders (e.g., Giffin & Allen, 1933). In some A phenylhydrazine concentration of 50 mg/litre in cases, treatment was effective; in others, however, the a hydroponic culture solution inhibited germination of outcome was fatal (e.g., Giffin & Conner, 1929). The Hordeum seeds for at least 6 days, whereas growth was effects seen (beneficial or otherwise) may have been stimulated in Lepidium. At 100 mg/litre, seedling growth related to the disease process and cannot be attributed was stimulated in Hordeum but not in Lepidium. At entirely to phenylhydrazine. 500 mg/litre, phenylhydrazine inhibited growth in seedlings of both species, although the seedlings were still apparently “healthy” (Bokorny, 1933).

10. EFFECTS ON OTHER ORGANISMS IN Exposure of soil nematodes Caenorhabditis THE LABORATORY AND FIELD briggsae in culture to phenylhydrazine at 50 mg/litre of medium resulted in reduced growth of all four larval stages (the effect was most marked on the last larval 10.1 Aquatic environment instar) and therefore delayed development to adults. However, the adults formed were capable of reproduc- Results of acute toxicity tests on aquatic tion, although the number of progeny was reduced. A organisms are summarized in Table 2. All concentrations concentration of 15 mg/litre also delayed development, are nominal. although to a lesser degree compared with the higher concentration (Kampfe et al., 1986a,b). A 6-day EC50 of 12 In the early life stage test summarized in Table 2 mg/litre was reported for production of progeny in (Xiu et al., 1992), newly fertilized eggs of the zebra fish culture for the same nematode (Kreil, 1982). were exposed to concentrations of phenylhydrazine through hatch and into the larval stage (total exposure No dietary or oral toxicity studies have been time was 16 days). A NOEC (survival) was established performed on birds. However, injection studies have for eggs at 5 days post-fertilization at 0.0039 mg/litre, shown haemolytic anaemia and reduced white cell with a lowest-observed-effect concentration (LOEC) at counts in birds. In contrast to mammals, cell division in 0.0078 mg/litre. At the end of the test (16 days), the erythropoietic tissue is unaffected by phenylhydrazine NOEC for larvae was 0.000 49 mg/litre, and the LOEC was (Williams, 1972; Clark et al., 1988; Datta et al., 1989, 1990). 0.000 98 mg/litre. The study was conducted according to a Swedish standard protocol (ss 028193).

In a study on the goldfish (Carassius auratus), 40% of fish died when exposed to phenylhydrazine at a nominal concentration of 1 mg/litre for 48 h. Signs of toxicity included erratic swimming, sinking to the bottom

12 Phenylhydrazine

Table 2: Acute toxicity of phenylhydrazine to aquatic organisms.

Organism End-point Concentration (mg/litre) Reference Bacteria

Photobacterium phosphoreum 30-min EC50 (luminescence) 66.9 Kaiser et al. (1987)

Facultative anaerobes 24-h toxic threshold 60 Hoechst (1980) (mixed culture) Escherichia coli minimum inhibitory concentration 109.3 Romero & Canada (1991)

Escherichia coli, Micrococcus minimum inhibitory concentration >3000 Zemek et al. (1978) luteus, Bacillus licheniformis

Invertebrates

water flea LC50 (immobilization) 2–5 Hoechst (1980) (Daphnia magna) Fish

zebra fish 96-h LC50 0.16–0.25 Hoechst (1982) (Brachydanio rerio) 96-h NOEC 0.1

zebra fish 5-day NOEC (eggs) 0.0039 Xiu et al. (1992) (Brachydanio rerio) 16-day NOEC (larvae) 0.000 49

Japanese killifish 48-h LC50 15.7 Tonogai et al. (1982) (Oryzias latipes)

a common carp 24-h LC100 1.0 Menzie (1979) (Cyprinus carpio) 96-h NOEC 0.1

a bluegill 48-h LC50 0.1 Menzie (1979) (Lepomis macrochirus) 96-h NOEC 0.01 a Menzie C (1979) Value taken from the DIMDI/ECDIN database. Test performed by the United States Fish and Wildlife Service, Bureau of Sports, Fisheries and Wildlife, Department of the Interior, Washington, DC [cited in BUA, 1995].

11. EFFECTS EVALUATION daily doses of the order of 1.5–4 mg/kg body weight per day have caused a reduction in the numbers of red blood cells; given the health status of the individuals con- 11.1 Evaluation of health effects cerned, however, these data are of limited use. Phenylhy- drazine is mutagenic in vitro, and, although not 11.1.1 Hazard identification and dose–response conclusive, there is some evidence to indicate that it may assessment express genotoxic activity in vivo. The substance is clearly carcinogenic in mice following oral dosing, Phenylhydrazine is toxic by single exposure via the inducing tumours of the vascular system. The mecha- oral route (LD50 80–188 mg/kg body weight) and is nism for tumour formation is unclear, and, given the expected to be toxic by the inhalation and dermal routes genotoxic profile of phenylhydrazine, a genotoxic (data from these routes of exposure are less clear). Phe- component cannot be excluded. Carcinogenic potential nylhydrazine solution was severely irritating to rabbit in humans cannot be excluded given the profile of eyes; hence, it is reasonable to predict that it would have genotoxicity and animal carcinogenicity, particularly as significant eye irritation potential in humans. other expressions of phenylhydrazine toxicity are common to a number of species, including humans. Phenylhydrazine also has skin irritation potential, and there is evidence from human case reports that it has No conclusions can be drawn from the available skin sensitizing properties. Exposure to phenylhydrazine information on fertility or development. may cause damage to red blood cells, potentially result- ing in anaemia and consequential secondary involve- 11.1.2 Criteria for setting guidance values for ment of other tissues, such as the spleen and liver. The phenylhydrazine dose (exposure)–response characteristics for the induc- tion of damage to the red blood cells are poorly defined, There are no adequate data available regarding and a no-effect level has not been identified. Where phe- reproductive or developmental effects; hence, it is not nylhydrazine has been used therapeutically in humans, possible to evaluate the risk to human health for these via the oral route, for the treatment of blood disorders, end-points.

13 Concise International Chemical Assessment Document 19

The use pattern and physical/chemical characteris- Phenylhydrazine also possesses skin and eye tics of the compound suggest that exposure of the gen- irritant properties and possibly skin sensitizing potential. eral population would be negligible. The information available indicates that local exposure of these tissues is unlikely; if it did occur, however, then Using United Kingdom workplace conditions as an there would be risk of irritation to the eyes and the example (section 6.2), exposure to phenylhydrazine development of irritant and/or allergic dermatitis. vapour during most occupational processes would result in a body burden of up to 0.33 mg/kg body weight per 11.2 Evaluation of environmental effects day, assuming a 70-kg worker breathes 10 m3 of air in a working day and that 100% phenylhydrazine is No atmospheric effects are expected given the absorbed. There are no data available from which to release of phenylhydrazine predominantly to water, its estimate the contribution to body burden from dermal extremely low volatilization from water to the atmos- uptake, although this is expected to be negligible. A phere, and its rapid calculated atmospheric half-life threshold for the induction of red blood cell damage following reaction with hydroxyl radicals. probably exists but has not been identified, although daily oral doses calculated at about 1.5 mg/kg body Few toxicity studies are available for terrestrial weight per day and above are associated with such organisms, and little emission to land is expected; on this effects. Overall, at these levels of predicted inhalation basis, no quantitative risk assessment can be attempted exposure, the risk of developing damage to the red blood for the terrestrial environment. cells is considered to be low; if the levels were exceeded (e.g., of the order of a few ppm, approximately 15–20 Phenylhydrazine is degraded photochemically and mg/m3), however, then this would be cause for some autoxidizes in water. It is readily biodegradable, and this concern. is expected to be the major route of breakdown in the environment. There is minimal sorption to particulates. On the basis that the carcinogenicity of phenylhy- drazine may involve a genotoxic mechanism, it is not Phenylhydrazine is toxic to aquatic organisms, with possible to reliably identify a threshold below which the lowest reported NOEC in acute fish tests at occupational exposure to phenylhydrazine would not 0.01 mg/litre; fish are generally more sensitive than either result in some risk to human health. daphnids or bacteria. A NOEC for embryo-larval stages following 16 days of exposure from fertilization has been 11.1.3 Sample risk characterization reported at 0.000 49 mg/litre for the zebra fish.

The scenario chosen as an example is occupational There are no reported measurements of phenylhy- exposure in the United Kingdom. drazine in environmental media. Monitoring studies of both inflow and outflow to the wastewater treatment The main health concerns associated with expo- plant of the Hoechst Hochst production plant in Ger- sure to phenylhydrazine are damage to the red blood many showed no detectable phenylhydrazine (detection cells, deleterious effects on genetic material, and the limit 500 :g/litre) in weekly samples. Maximum emission development of cancer. to wastewater was estimated at 13 t/year, and this will be used as a worst-case example. It is recognized that there are a number of different approaches to assessing the risks to human health for Based on this emission rate, and using mainly genotoxic and carcinogenic substances and in the default values from the OECD Technical Guidance subsequent risk management steps that may be taken. In Manual, the initial predicted environmental concentra- addition, although not used in the United Kingdom, tion of phenylhydrazine in river water (PEClocal (water), in there are models for characterizing potency that may be g/litre) would be as follows: of some benefit in priority-setting schemes. In the United Ceffluent Kingdom occupational setting, a Maximum Exposure PEClocal (water) = Limit or MEL (which is not a health-based standard) has (1 + K × C ) × D p(susp) susp been proposed at 0.9 mg/m3 (0.2 ppm), 8-h time-weighted average. The numerical value for the MEL was based on where: a level of control that was deemed (by tripartite agreement) to be reasonably practicable under United # Ceffluent is the concentration of phenylhydrazine in Kingdom workplace conditions, and in the United the wastewater treatment plant effluent (g/litre),

Kingdom there is a continuing requirement to reduce calculated as Ceffluent = W × (100 ! P)/(100 × Q), exposure levels as far as reasonably practicable with the where: technology that is currently available. W = emission rate (35.6 kg/day)

14 Phenylhydrazine

P = percent removal in the wastewater treatment plant (based on the “ready biodegradability” of the compound, 91%) Q = volume of wastewater in m3/day (default 200 litre/day per capita for a population of 10 000 inhabitants; wastewater volume for the production plant is unknown)

# Kp(susp) is the suspended matter/water adsorption

coefficient, calculated as Kp(susp) = Koc × foc(susp), where:

Koc = organic carbon/water partition coefficient (7.3)

foc(susp) = fraction of organic carbon in suspended matter (default 0.1)

# Csusp is the concentration of suspended matter in the river water (in kg/litre; default 15 mg/litre) 12. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES # D is the dilution factor for river flow (flow rate for the River Main averages 188 m3/s compared with the estimated flow rate of the wastewater at Previous evaluations by other international bodies 3 0.02 m /s; dilution factor approximately 10 000) were not identified. Information on international hazard classification and labelling is included in the Interna- Under these very conservative conditions, PEClocal (water) tional Chemical Safety Card (ICSC 0938) reproduced in = 0.16 :g/litre. this document.

Of the reported acute toxicity test results for organisms in the environment, those for the majority of fish tested are substantially lower than those for other 13. HUMAN HEALTH PROTECTION AND organisms tested. The predicted no-effect concentration EMERGENCY ACTION (PNEC) will therefore be based on the fish results.

No long-term test results are available. Applying Human health hazards, together with preventive an uncertainty factor of 1000 to the lowest reported and protective measures and first aid recommendations, standard acute LC value of 0.1 mg/litre for the bluegill 50 are presented in the International Chemical Safety Card (Lepomis macrochirus) would give a PNEC of (ICSC 0938) reproduced in this document. 0.1 :g/litre. This is a factor of 100 lower than the lowest reported NOEC for the same species. Alternatively, 13.1 Human health hazards applying an uncertainty factor of 10 to the NOEC for the early life stage test on the zebra fish larvae gives a PNEC Phenylhydrazine induces damage to red blood of 0.049 :g/litre. The more conservative value will be cells. Repeated or prolonged contact with the substance used in estimating risk. causes skin sensitization, and there is cause for concern for carcinogenicity. The low PEC of 0.16 :g/litre would not have been detected in the monitoring at the site. Assuming that this 13.2 Advice to physicians value is the worst case, a PEC/PNEC ratio of 3.2 is generated. This indicates that the risk to aquatic organ- Phenylhydrazine is a haemolytic agent. There is no isms is low, based on very conservative assumptions. specific antidote, but treatment should be supportive. The distribution of reported toxicity test results against the worst-case PEC is plotted in Figure 1, illustrating the 13.3 Health surveillance advice safety margin. Periodic medical examination of the area of the skin exposed to phenylhydrazine and annual blood count should be included in the health surveillance programme.

15 Concise International Chemical Assessment Document 19

14. CURRENT REGULATIONS, GUIDELINES, AND STANDARDS

Information on national regulations, guidelines, and standards may be obtained from UNEP Chemicals (IRPTC), Geneva.

The reader should be aware that regulatory deci- sions about chemicals taken in a certain country can be fully understood only in the framework of the legislation of that country. The regulations and guidelines of all countries are subject to change and should always be verified with appropriate regulatory authorities before application.

16 PHENYLHYDRAZINE 0938 November 1998 CAS No: 100-63-0 Hydrazinobenzene RTECS No: MV8925000 Monophenylhydrazine

UN No: 2572 C6H8N2 / C6H5NHNH2 EC No: 612-023-00-9 Molecular mass: 108.1

TYPES OF HAZARD/ ACUTE HAZARDS/SYMPTOMS PREVENTION FIRST AID/FIRE FIGHTING EXPOSURE

FIRE Combustible. Gives off irritating or NO open flames. Water spray, alcohol-resistant toxic fumes (or gases) in a fire. foam, powder, carbon dioxide.

EXPLOSION Above 88
C explosive vapour/air Above 88
C use a closed system, In case of fire: keep drums, etc., mixtures may be formed. ventilation. cool by spraying with water.

EXPOSURE STRICT HYGIENE!

Inhalation Cough. Laboured breathing. Sore Local exhaust or breathing Fresh air, rest. Refer for medical throat. Cyanosis. protection. attention.

Skin MAY BE ABSORBED! Dry skin. Protective gloves. Protective Remove contaminated clothes. Redness. Pain. clothing. Rinse skin with plenty of water or shower. Refer for medical attention.

Eyes Redness. Pain. Blurred vision. Face shield, or eye protection in First rinse with plenty of water for combination with breathing several minutes (remove contact protection. lenses if easily possible), then take to a doctor.

Ingestion Abdominal pain. Diarrhoea. Do not eat, drink, or smoke during Rest. Refer for medical attention. Nausea. Vomiting. Weakness. work. Vertigo.

SPILLAGE DISPOSAL PACKAGING & LABELLING

If the substance is melted: collect leaking and T Symbol Airtight. Do not transport with food spilled liquid in sealable containers as far as N Symbol and feedstuffs. possible. Absorb remaining liquid in sand or inert R: 23/24/25-36-50 absorbent and remove to safe place. Do NOT wash S: (1/2-)28-45-61 away into sewer. If the substance is solid: sweep UN Hazard Class: 6.1 spilled substance into container, carefully collect UN Pack Group: II remainder, then remove to a safe place Do NOT let this chemical enter the environment. (Extra personal protection: complete protective clothing including self-contained breathing apparatus).

EMERGENCY RESPONSE STORAGE

Transport Emergency Card: TEC (R)-61G61b Separated from strong oxidants, food and feedstuffs. Cool. Keep in the NFPA Code: H3; F2; R0; dark.

Prepared in the context of cooperation between the International IPCS Programme on Chemical Safety and the European Commission International © IPCS 1999 Programme on Chemical Safety SEE IMPORTANT INFORMATION ON THE BACK. 0938 PHENYLHYDRAZINE

IMPORTANT DATA

Physical State; Appearance Routes of Exposure COLOURLESS TO YELLOW OILY LIQUID OR CRYSTALS. The substance can be absorbed into the body by inhalation of TURNS BROWN RED ON EXPOSURE TO AIR AND LIGHT. its aerosol, through the skin, by ingestion.

Chemical Dangers Inhalation Risk The substance decomposes on heating and on burning A harmful contamination of the air can be reached rather producing toxic fumes including nitrogen oxides. Reacts with quickly on evaporation of this substance at 20
C. oxidants. Reacts violently with lead dioxide. Effects of Short-term Exposure Occupational Exposure Limits The substance irritates the eyes, the skin, the respiratory tract. TLV: 0.1 ppm; 0.44 mg/m3 A3 (skin) (ACGIH 1998). The substance may cause effects on the blood, resulting in hemolysis, kidney impairment, liver impairment. The effects may be delayed. Medical observation is indicated.

Effects of Long-term or Repeated Exposure Repeated or prolonged contact with skin may cause dermatitis. Repeated or prolonged contact may cause skin sensitization. The substance may have effects on the blood, resulting in anaemia.

PHYSICAL PROPERTIES

Boiling point (decomposes): 243.5
C Relative vapour density (air = 1): 3.7 Melting point: 19.5
C Flash point: 88
C c.c. Relative density (water = 1): 1.09 Auto-ignition temperature: 174
C Solubility in water: poor Octanol/water partition coefficient as log Pow: 1.25 Vapour pressure, Pa at 71.8
C: 133

ENVIRONMENTAL DATA The substance is toxic to aquatic organisms.

NOTES The symptoms of hemolysis do not become manifest until hours have passed.

ADDITIONAL INFORMATION

LEGAL NOTICE Neither the EC nor the IPCS nor any person acting on behalf of the EC or the IPCS is responsible

© IPCS 1999 Phenylhydrazine

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APPENDIX 1 — SOURCE DOCUMENTS APPENDIX 2 — CICAD PEER REVIEW

Brooke I, Cain J, Cocker J, Groves J (1997) The draft CICAD on phenylhydrazine was sent for review Phenylhydrazine. Sudbury, Suffolk, HSE Books to institutions and organizations identified by IPCS after contact with IPCS national Contact Points and Participating Institutions, (Risk Assessment Document EH72/1; ISBN 0 7176 as well as to identified experts. Comments were received from: 1355 0) Department of Health, London, United Kingdom The author’s draft version is initially reviewed internally by a group of approximately 10 Health and Safety Executive Federal Institute for Health Protection of Consumers & experts — mainly toxicologists, but also experts in other relevant Veterinary Medicine, Berlin, Germany disciplines, such as epidemiology and occupational hygiene. The toxicology section of the amended draft is then reviewed by Institut de Recherches en Santé et Sécurité du Travail du toxicologists from the United Kingdom Department of Health. Québec, Montreal, Canada Subsequently, the entire Criteria Document is reviewed by a tripartite advisory committee to the United Kingdom Health and Institute of Occupational Medicine, Chinese Academy of Safety Commission, the Working Group for the Assessment of Preventive Medicine, Ministry of Health, Beijing, People’s Toxic Chemicals (WATCH). This committee is composed of Republic of China experts in toxicology and occupational health and hygiene from industry, trade unions, and academia. National Institute of Health Sciences, Tokyo, Japan

The members of the WATCH committee at the time of the Senatskommission der Deutschen GSF-Forschungszentrum peer review were Mr S.R. Bailey, Independent Consultant; für Umwelt und Gesundheit GmbH, Institut für Professor J. Bridges, University of Surrey; Dr H. Cross, Toxikologie, Oberscheissheim, Germany Trade Unions Congress; Dr A. Fletcher, Trade Unions Congress; Dr I.G. Guest, Chemical Industries Association; Dr A. Hay, Trade United States Department of Health and Human Services Unions Congress; Dr J. Leeser, Chemical Industries Association; (National Institute for Occupational Safety and Health, Dr L. Levy, Institute of Occupational Hygiene, Birmingham; Mr Cincinnati; National Institute of Environmental Health A. Moses, Chemical Industries Association; Dr R. Owen, Trade Sciences, Research Triangle Park; Agency for Toxic Unions Congress; Mr J. Sanderson, Independent Consultant; and Substances and Disease Registry, Atlanta), USA Dr M. Sharratt, University of Surrey. United States Environmental Protection Agency (National Center for Environmental Assessment, Washington, DC; Region VIII), USA BUA (1995) Phenylhydrazine. Beratergremium fur Umweltrelevante Altstoffe (BUA). GDCh Advisory Committee on Existing Chemicals of Environmental Relevance. Stuttgart, S. Hirzel, Wissenschaftliche Verlagsgesellschaft (Report No. 120; ISBN 3-7776-0691-X)

For the BUA review process, the company that is in charge of writing the report (usually the largest producer in Germany) prepares a draft report using literature from an extensive literature search as well as internal company studies. This draft is subject to a peer review during several readings of a working group consisting of representatives from government agencies, the scientific community, and industry.

22 Phenylhydrazine

APPENDIX 3 — CICAD FINAL REVIEW Dr W. Snellings (ICCA representative), Union Carbide BOARD Corporation, Danbury, CN, USA Dr M. Sweeney, Document Development Branch, National Washington, DC, USA, 8–11 December 1998 Institute for Occupational Safety and Health, Cincinnati, OH, USA

Dr K. Ziegler-Skylakakis, GSF-Forschungszentrum für Umwelt und Members Gesundheit GmbH, Institut für Toxikologie, Oberschleissheim, Germany Dr T. Berzins, National Chemicals Inspectorate (KEMI), Solna, Sweden (Vice-Chairperson)

Mr R. Cary, Toxicology Unit, Health Directorate, Health and Secretariat Safety Executive, Bootle, Merseyside, United Kingdom (Rapporteur) Dr M. Baril, Institut de Recherches en Santé et Sécurité du Travail du Québec (IRSST), Montreal, Quebec, Canada Dr S. Dobson, Institute of Terrestrial Ecology, Monks Wood, Abbots Ripton, Huntingdon, Cambridgeshire, United Kingdom Dr H. Galal-Gorchev, Chevy Chase, MD, USA

Dr O. Faroon, Agency for Toxic Substances and Disease Ms M. Godden, Health and Safety Executive, Bootle, Registry, Centers for Disease Control and Prevention, Atlanta, Merseyside, United Kingdom GA, USA Dr R.G. Liteplo, Environmental Health Directorate, Health Dr G. Foureman, National Center for Environmental Assessment, Canada, Ottawa, Ontario, Canada US Environmental Protection Agency, Research Triangle Park, NC, USA Ms L. Regis, Programme for the Promotion of Chemical Safety, World Health Organization, Geneva, Switzerland Dr H. Gibb, National Center for Environmental Assessment, US Environmental Protection Agency, Washington, DC, USA Mr A. Strawson, Health and Safety Executive, London, United (Chairperson) Kingdom

Dr R.F. Hertel, Federal Institute for Health Protection of Dr P. Toft, Programme for the Promotion of Chemical Safety, Consumers & Veterinary Medicine, Berlin, Germany World Health Organization, Geneva, Switzerland

Dr I. Mangelsdorf, Documentation and Assessment of Chemicals, Fraunhofer Institute for Toxicology and Aerosol Research, Hanover, Germany

Dr A. Nishikawa, Division of Pathology, National Institute of Health Sciences, Tokyo, Japan

Dr E.V. Ohanian, Office of Water/Office of Science and Technology, Health and Ecological Criteria Division, US Environmental Protection Agency, Washington, DC, USA

Dr J. Sekizawa, Division of Chem-Bio Informatics, National Institute of Health Sciences, Tokyo, Japan

Professor P. Yao, Institute of Occupational Medicine, Chinese Academy of Preventive Medicine, Ministry of Health, Beijing, People’s Republic of China

Observers

Dr K. Austin, National Center for Environmental Assessment, US Environmental Protection Agency, Washington, DC, USA

Dr I. Daly (ICCA representative), Regulatory and Technical Associates, Lebanon, NJ, USA

Ms K.L. Lang (CEFIC, European Chemical Industry Council, representative), Shell International, London, United Kingdom

Ms K. Roberts (ICCA representative), Chemical Self-funded Technical Advocacy and Research (CHEMSTAR), Chemical Manufacturers Association, Arlington, VA, USA

23 Concise International Chemical Assessment Document 19

RÉSUMÉ D’ORIENTATION que ce composé est bien absorbé après inhalation, ingestion ou par voie percutanée et qu’il se combine facilement à l’hémoglobine des hématies. Il semble que Ce CICAD relatif à la phénylhydrazine résulte sa métabolisation implique une hydroxylation du cycle d’une étude des risques pour la santé humaine (princi- suivie probablement de la formation d’un glucuro- palement dans un cadre professionnel) rédigée par le conjugué. Il est principalement éliminé par voie urinaire. Health and Safety Executive du Royaume-Uni (Brooke et al., 1997) et d’un rapport préparé par le Comité L’ingestion d’une seule dose peut provoquer une consultatif allemand sur les substances chimiques intoxication (DL50 : 80-188 mg/kg de poids corporel) et la importantes pour l’environnement (BUA, 1995). Il est phénylhydrazine est sans doute également toxique si elle donc consacré aux divers types d’exposition par les est inhalée ou entre en contact avec la peau (les données voies existant sur les lieux de travail, mais contient concernant ces deux voies d’exposition sont moins également des données concernant l’environnement précises). La phénylhydrazine pourrait être irritante pour général. Les données prises en compte dans ces deux la peau et les yeux et on est fondé à penser qu’elle documents de base remontent respectivement à décem- produit une sensibilisation cutanée chez l’homme. bre 1993 et décembre 1994. Une étude bibliographique L’exposition à ce composé peut endommager les complémentaire arrêtée à janvier 1998 a été effectuée à la hématies, d’où un risque d’anémie et d’atteinte recherche de données supplémentaires qui auraient pu secondaire d’autres tissus comme le tissu splénique et le être publiées postérieurement à ces documents. On tissu hépatique. La phénylhydrazine est mutagène in trouvera à l’appendice 1 des indications sur le mode vitro et selon certaines données, elle pourrait également d’examen par des pairs ainsi que sur les sources docu- avoir une activité génotoxique in vivo. Elle est de toute mentaires utilisées. Les renseignements concernant évidence cancérogène pour la souris (administration par l’examen du CICAD par les pairs font l’objet de l’appen- voie orale) et provoque des tumeurs vasculaires. On ne dice 2. Ce CICAD a été approuvé en tant qu’évaluation peut, à la lumière de toutes ces données, indiquer le internationale lors de la réunion du Comité d’évaluation niveau d’exposition en dessous duquel il n’y a pas de finale qui s’est tenue à Washington du 8 au 11 décembre risque d’effets cancérogènes ou génotoxiques. 1998. La liste des participants à cette réunion figure à l’appendice 3. La fiche d’information internationale sur la On ne possède pas de données suffisantes concer- sécurité chimique (ICSC No 0938) relative à la nant les effets sur la reproduction ou le développement; phénylhydrazine, établie par le Programme international il n’est donc pas possible de dire si l’homme court des sur la sécurité chimique (IPCS, 1993), est également risques de cette nature. reproduite dans ce document. Le degré de risque professionnel n’est pas connu La phénylhydrazine (CAS No 100-63-0) se présente avec certitude. Il s’ensuit qu’il est toujours nécessaire de sous la forme de cristaux de couleur jaune à brun pâle ou réduire le niveau d’exposition au minimum raisonnable d’un liquide jaunâtre de consistance huileuse. Il est compte tenu de l’état actuel de la technique. légèrement soluble dans l’eau et miscible aux solvants organiques. Comme on ne dispose pas de données qui puissent servir à estimer l’exposition individuelle à la La phénylhydrazine est utilisée dans le monde phénylhydrazine présente dans l’environnement général, entier comme intermédiaire dans l’industrie chimique, on ne peut pas préciser quel risque de cancer elle pharmaceutique et agrochimique. représente pour la population.

On ignore combien de personnes sont On n’envisage pas d’effets atmosphériques, étant susceptibles d’être exposées à la phénylhydrazine ou à donné que le composé est essentiellement libéré dans son chlorhydrate, mais elles sont vraisemblablement un l’eau et qu’une fois dans ce milieu, il ne s’en évapore petit nombre. On ne dispose d’aucune donnée sur que très faiblement. En outre, le calcul montre que sa l’exposition individuelle, mais le modèle EASE demi-vie atmosphérique est très courte par suite de sa (Estimation and Assessment of Substance Exposure) combinaison avec les radicaux hydroxyles. permet de prédire une exposition d’environ 2,3 mg/m3 (0,5 ppm) en moyenne pondérée par rapport au temps sur 8 h. La phénylhydrazine subit une décomposition En pratique, l’exposition moyenne pondérée par rapport photochimique et s’oxyde dans l’eau. Elle est facilement au temps sur 8 h est inférieure à cette valeur. biodégradable et c’est probablement ainsi qu’elle se décompose dans l’environnement. Sa sorption par les Les données limitées dont on dispose au sujet de matières particulaires est minime. la pharmacocinétique de la phénylhydrazine indiquent

24 Phenylhydrazine

La phénylhydrazine est toxique pour les organ- ismes aquatiques, la concentration sans effet observable (NOEC) la plus faible qui ait été indiquée lors d’épreuves classique de toxicité aiguë sur des poissons étant de 0,01 mg/litre. Les poissons sont habituellement plus sensibles que les daphnies ou les bactéries. On a fait état d’une NOEC de 0,49 :g/litre pour les stades embryo- larvaires d’un poisson, le danio (Brachydanio rerio).

Le risque pour les organismes aquatiques devrait être faible, même dans l’hypothèse la plus prudente.

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RESUMEN DE ORIENTACIÓN en las glóbulos rojos. El metabolismo parece que se produce por hidroxilación del anillo y conjugación, probablemente con el ácido glucurónico. La excreción El presente CICAD sobre la fenilhidrazina se basa tiene lugar fundamentalmente por vía urinaria. en un examen de problemas relativos a la salud humana (fundamentalmente ocupacionales) preparado por el La fenilhidrazina es tóxica en una exposición única

Health and Safety Executive del Reino Unido (Brooke et por vía oral (DL50 80-188 mg/kg de peso corporal) y es de al., 1997) y un informe preparado por el Comité prever que sea tóxica por inhalación y por vía cutánea Consultivo Alemán sobre las Sustancias Químicas (los datos relativos a esas vías de exposición son menos Importantes para el Medio Ambiente (BUA, 1995). Por claros). Puede provocar irritación cutánea y ocular y hay consiguiente, este informe se concentra en la exposición pruebas de que tiene propiedades de sensibilización a través de las vías de interés para los entornos ocupa- cutánea en el ser humano. La exposición a la cionales, pero también contiene información medio- fenilhidrazina puede provocar daños en los glóbulos ambiental. Incluye los datos identificados a partir de rojos, pudiendo producir anemia y en consecuencia diciembre de 1993 y diciembre de 1994, respectivamente. afectar de manera secundaria a otros tejidos, por ejemplo Se realizó una nueva búsqueda en lo publicado hasta los del bazo o del hígado. La fenilhidrazina es enero de 1998 para localizar toda la información mutagénica in vitro y hay algunos indicios de que puede aparecida desde la terminación de estos exámenes. La mostrar actividad genotóxica in vivo. Esta sustancia es información relativa al carácter del examen colegiado y a claramente carcinogénica en ratones tras la administra- la disponibilidad de los documentos originales figura en ción oral, induciendo la formación de tumores en el el apéndice 1. La información sobre el examen colegiado sistema vascular. No está claro el mecanismo de de este CICAD aparece en el apéndice 2. Este CICAD se formación de tumores, pero no se puede descartarr un aprobó como evaluación internacional en una reunión de componente genotóxico. Por consiguiente, no parece la Junta de Evaluación Final celebrada en Washington, que sea posible identificar con seguridad un nivel de DC (Estados Unidos de América), del 8 a 11 de diciembre exposición para el cual no haya riesgo de efectos de 1998. En el apéndice 3 figura la lista de los carcinogénicos o genotóxicos. participantes en esta reunión. La ficha internacional de seguridad química (ICSC No 0938) para la fenilhidrazina, No se dispone de datos adecuados relativos a los preparada por el Programa Internacional de Seguridad de efectos en la reproducción o el desarrollo; no es posible, las Sustancias Químicas (IPCS, 1993), también se pues, evaluar el riesgo para la salud humana de esos reproduce en el presente documento. efectos finales.

La fenilhidrazina (CAS No 100-63-0) se encuentra en El nivel de riesgo en el entorno ocupacional es forma de cristales de un color entre amarillo y marrón incierto; en consecuencia es constante la necesidad de claro o como líquido oleoso amarillento. Es moderada- reducir los niveles de exposición todo lo que sea mente soluble en el agua y es miscible con otros disol- razonablemente posible con la tecnología disponible en ventes orgánicos. la actualidad.

La fenilhidrazina se usa en todo el mundo, princi- La falta de datos disponibles que sirvan como base palmente como intermediario químico en las industrias para la estimación de la exposición indirecta de las farmacéutica, agroquímica y química. personas a la fenilhidrazina a partir del medio ambiente impide determinar los riesgos potenciales de cáncer para No se conoce el número de personas potencial- la población general. mente expuestas a la fenilhidrazina o sus hidrocloruros, pero se supone que es bajo. No hay datos disponibles No son de prever efectos atmosféricos, debido a sobre la exposición personal, aunque el modelo EASE que la fenilhidrazina se libera fundamentalmente en el (Estimation and Assessment of Substance Exposure) agua, a su escasa volatilización del agua a la atmósfera y predecía (como promedio ponderado en función del a su rápida semivida en la atmósfera calculada tras la tiempo durante ocho horas) una exposición de unos reacción con los radicales hidroxilo. 2,3 mg/m3 (0,5 ppm). En la práctica, la exposición promedio ponderada en función del tiempo durante ocho La fenilhidrazina se degrada por vía fotoquímica y horas es inferior a esa cifra. se autooxida en el agua. Es fácilmente biodegradable y se supone que es ésta la principal ruta de descompo- Los limitados datos sobre la toxicocinética indican sición en el medio ambiente. La sorción en partículas es que la fenilhidrazina se absorbe bien por inhalación y por mínima. vía oral y cutánea y se une fácilmente a la hemoglobina

26 Phenylhydrazine

La fenilhidrazina es tóxica para los organismos acuáticos, siendo de 0,01 mg/litro la concentración sin efectos observados (NOEC) más baja notificada en pruebas normalizadas de toxicidad aguda en peces; en general, los peces son más sensibles que los dáfnidos o las bacterias. Se ha notificado una NOEC de 0,49 :g/litro para las fases embriolarvarias del pez Brachydanio rerio.

Se supone que el riesgo para los organismos acuáticos es bajo, a partir de hipótesis muy prudentes.

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