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 9
N-PHENYL-1-NAPHTHYLAMINE
First draft prepared by Dr G. Koennecker, Dr I. Mangelsdorf, and Dr A. Wibbertmann, Fraunhofer Institute for Toxicology and Aerosol Research, Hanover, Germany
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, 1998
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 N-phenyl-1-naphthylamine.
(Concise international chemical assessment document ; 9) First draft prepared by G. Koennecker, I. Mangelsdorf and A. Wibbertmann.
1.1-Naphthylamine – adverse effects 2.1-Naphthylamine – toxicity 3.Environmental exposure I.Koennecker, G. II.Series ISBN 92 4 153009 X (NLM Classification: QD 305.A8) ISSN 1020-6167
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The Federal Ministry for the Environment, Nature Conservation and Nuclear Safety, Germany, provided financial support for the printing of this publication.
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iii
FOREWORD . . . 1
1. EXECUTIVE SUMMARY . . . 4
2. IDENTITY AND PHYSICAL/CHEMICAL PROPERTIES . . . 5
3. ANALYTICAL METHODS . . . 5
4. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE . . . 6
5. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION . . . 6
6. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE . . . 7
6.1 Environmental levels . . . 7
6.2 Human exposure . . . 8
7. COMPARATIVE KINETICS AND METABOLISM IN LABORATORY ANIMALS AND HUMANS . . . 8
8. EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS . . . 8
8.1 Single exposure . . . 9
8.2 Irritation and sensitization . . . 9
8.3 Short-term exposure . . . 9
8.4 Long-term exposure . . . 10
8.4.1 Subchronic exposure . . . 10
8.4.2 Chronic exposure and carcinogenicity . . . 10
8.5 Genotoxicity and related end-points . . . 11
8.6 Reproductive and developmental toxicity . . . 11
8.7 Immunological and neurological effects . . . 11
9. EFFECTS ON HUMANS . . . 11
9.1 Case reports . . . 11
9.2 Epidemiological studies . . . 13
10. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD . . . 13
10.1 Aquatic environment . . . 13
10.2 Terrestrial environment . . . 13
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 N-phenyl-1-naphthyl- amine . . . 14
11.1.3 Sample risk characterization . . . 14
11.2 Evaluation of environmental effects . . . 14
12. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES . . . 15
iv
13. HUMAN HEALTH PROTECTION AND EMERGENCY ACTION . . . 15
13.1 Human health hazards . . . 15
13.2 Advice to physicians . . . 15
13.3 Spillage . . . 15
14. CURRENT REGULATIONS, GUIDELINES, AND STANDARDS . . . 15
INTERNATIONAL CHEMICAL SAFETY CARD . . . 16
REFERENCES . . . 18
APPENDIX 1 — SOURCE DOCUMENT . . . 20
APPENDIX 2 — CICAD PEER REVIEW . . . 20
APPENDIX 3 — CICAD FINAL REVIEW BOARD . . . 21
RÉSUMÉ D’ORIENTATION . . . 22
RESUMEN DE ORIENTACIÓN . . . 24
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1. EXECUTIVE SUMMARY amount of N-phenyl-1-naphthylamine released into the This CICAD on N-phenyl-1-naphthylamine was
based principally on a review prepared by the Laboratory studies yielded half-lives for the Fraunhofer Institute for Toxicology and Aerosol photochemical degradation of N-phenyl-1-
Research, Hanover, Germany, for the German Advisory naphthylamine in water of 8.4 and 5.7 min. Photolysis Committee on Existing Chemicals of Environmental may lead to the preliminary breakdown of N-phenyl-1- Relevance (BUA, 1993). This review assesses the naphthylamine under favourable environmental potential effects of N-phenyl-1-naphthylamine on the conditions, but further degradation is unlikely. The environment and on human health. Data identified up to substance is stable to hydrolysis under environmental 1992 were considered in the BUA report. A conditions, and removal by biodegradation in water and comprehensive literature search of several on-line soil is slow. Owing to its moderate to high potential for databases was conducted in 1997 to identify any sorption to organic soil constituents and its limited relevant references published subsequent to those mineralization in soil, N-phenyl-1-naphthylamine is incorporated in the BUA report. Information on the presumed to have geoaccumulation potential. The preparation and peer review of the source document is probability of infiltration into groundwater is low. Based presented in Appendix 1. Information on the peer review upon studies with Daphnia and fish and its measured of this CICAD is presented in Appendix 2. This CICAD log K of 4.2, N-phenyl-1-naphthylamine is expected to was approved as an international assessment at a have a moderate potential for bioaccumulation.
meeting of the Final Review Board, held in Berlin, Nevertheless, secondary poisoning of higher trophic Germany, on 26-28 November 1997. Participants at the levels via the aquatic food-chain seems unlikely in view Final Review Board meeting are listed in Appendix 3. of the chemical's metabolism and extensive excretion.
The International Chemical Safety Card (ICSC 1113) for The acute toxicity of N-phenyl-1-naphthylamine in fish N-phenyl-1-naphthylamine, produced by the and Daphnia is high, with lowest reported no-observed- International Programme on Chemical Safety (IPCS, effect concentrations (NOECs) of 0.11 mg/litre (192 h) 1993), has also been reproduced in this document. and 0.02 mg/litre (21 days), respectively. Despite limited
N-Phenyl-1-naphthylamine (CAS no. 90-30-2) is a this chemical in water is expected to be considerably lipophilic crystalline solid that is used as an antioxidant reduced by sorption and photochemical degradation.
in various lubrication oils and as a protective agent and
antioxidant in rubber and rubber mixtures for various Identified data on concentrations of N-phenyl-1- products, including tyres. Between 1986 and 1990, the naphthylamine in environmental media were limited to estimated worldwide production capacity of N-phenyl-1- older studies from the USA, in which the chemical was naphthylamine was 3000 tonnes per year. One German detected in river water (2-7 µg/litre) and sediment (1-5 company is the sole producer of N-phenyl-1- mg/kg) near a small speciality chemicals manufacturing naphthylamine within the European Union. plant. Available data were inadequate to allow the
Based upon its physical/chemical properties, the concentrations using fugacity modelling.
distribution of N-phenyl-1-naphthylamine in the
environment, predicted on the basis of a Level II Based upon studies conducted with laboratory fugacity model, was approximately 36% to soil, 34% to animals, N-phenyl-1-naphthylamine is well absorbed and sediment, 29% to water, and less than 1% each to air, extensively excreted after ingestion. Following ingestion suspended sediment, and biota. Quantitative data on by rats, 60% of the administered dose was excreted in releases of N-phenyl-1-naphthylamine into the the faeces and 35% in the urine within 72 h. Several environment from production, processing, and use are unidentified metabolites of N-phenyl-1-naphthylamine not available. Indirect discharges to soil and surface have been detected in the urine of exposed rats. On the waters from the leakage of lubrication oils or leaching basis of in vitro studies, metabolism likely occurs from decaying tyres and rubber products may occur; primarily via hydroxylation.
however, quantitative data are not available. Although
data were not identified, N-phenyl-1-naphthylamine may The acute oral toxicity of N-phenyl-1-naphthylamine be emitted to the atmosphere in exhaust gases during its in laboratory animals is low. In standard tests with production and processing and during the vulcanization rabbits, N-phenyl-1-naphthylamine was reported to be of rubber mixtures. The use of N-phenyl-1- neither a skin irritant nor an eye irritant. However, the naphthylamine-containing lubrication oils should not skin sensitizing properties of N-phenyl-1-naphthylamine result in the introduction of this substance into the were revealed in the guinea-pig maximization test as well atmosphere, as these oils are applied in closed systems. as in humans exposed to greases or rubber materials Overall, owing to its limited production capacity and the containing this chemical.
application of emission reduction techniques, the
environment is expected to be low.
ow
hydrolytic or biotic degradation, the bioavailability of
assessment of human exposure or the prediction of
NH
5
Limited data indicate that the kidneys and liver are International Chemical Safety Card reproduced in this the main target organs following ingestion. Adequate document. N-Phenyl-1-naphthylamine decomposes studies with which to derive putative effect levels were upon heating or burning, producing irritating or toxic not identified. The potential carcinogenicity of N- fumes or gases (nitrogen oxides). The conversion for N- phenyl-1-naphthylamine could not be fully evaluated, as phenyl-1-naphthylamine is 1 ppm = 9.114 mg/m (at 101.3 none of the available studies was performed according kPa and 20°C). The structural formula for N-phenyl-1- to currently accepted standard protocols. naphthylamine is:
N-Phenyl-1-naphthylamine was not mutagenic in bacterial cells, nor were the frequencies of gene mutation (mouse lymphoma assay) or chromosomal aberrations (in vitro metaphase analysis in Chinese hamster ovary cells or Chinese hamster lung cells) increased in these cell types exposed in vitro. A marginally positive result in a sister chromatid exchange assay conducted with Chinese hamster ovary cells in the presence of metabolic activation has been reported. Unscheduled DNA synthesis was increased in exposed human lung (WI-38) cells; however, the effects were not clearly
concentration dependent. N-Phenyl-1-naphthylamine was negative in a dominant lethal test conducted in mice. Based upon the available data, N-phenyl-1- naphthylamine does not appear to be genotoxic. Data on the reproductive/developmental toxicity and on immunological or neurological effects of N-phenyl-1- naphthylamine were not identified.
An increased rate of cancer was observed in one epidemiological study of N-phenyl-1-naphthylamine- exposed workers; however, owing to the small number of excess deaths and concomitant exposure to other
substances, it is not possible to attribute this effect solely to N-phenyl-1-naphthylamine. Although data are inadequate to allow a more detailed characterization of the potential health risks of N-phenyl-1-naphthylamine, dermal contact with the chemical should be avoided because of its sensitizing properties.
2. IDENTITY AND PHYSICAL/CHEMICAL PROPERTIES
N-Phenyl-1-naphthylamine (CAS no. 90-30-2;
C H N; 1-anilinonaphthaline; phenyl-[naphthyl-(1)]16 13
amine; phenyl-"-naphthylamine) in its pure form crystallizes into lemon yellow prisms or needles (melting point 62-63°C). The chemical is marketed in the form of brown to dark violet crystals or light brown to light violet granules. The vapour pressure (1.06 × 10 kPa)-6 and the water solubility of N-phenyl-1-naphthylamine at 20°C (3.0 mg/litre) are quite low. With a measured n- octanol/water partition coefficient (log Kow) of 4.2, N- phenyl-1-naphthylamine is characterized as a lipophilic substance. Additional properties are presented in the
3
The commercial product has a typical purity of >99%.
Named impurities from three manufacturers are 1- naphthylamine (<100-500 mg/kg), 2-naphthylamine (<3- 50 mg/kg), aniline (<100-2500 mg/kg), 1-naphthol (<5000 mg/kg), 1,1-dinaphthylamine (<1000 mg/kg), and N- phenyl-2-naphthylamine (500-<5000 mg/kg) (BUA, 1993;
Union Carbide, 1996).
3. ANALYTICAL METHODS
N-Phenyl-1-naphthylamine is quantified in
environmental media either by high-performance liquid chromatography in combination with ultraviolet absorption or by gas chromatography combined with thermionic or mass spectrometric detection, flame ionization detection, or electron capture detection. A method for the determination of secondary amines in air is suitable for the detection of N-phenyl-1-
naphthylamine.
The following enrichment techniques are used for various types of samples: solid-phase adsorption (silica gel, silica gel/glass fibre) with liquid extraction (ethanol, acetic acid/2-propanol) for samples of air (NIOSH, 1984a,b); liquid/liquid extraction (acetonitrile, diethyl ether), stripping with helium, and solid adsorption (Tenax GC) or alkaline extraction (dichloromethane) for samples of water (Jungclaus et al., 1978; Lopez-Avila &
Hites, 1980; Sikka et al., 1981; Rosenberg, 1983); liquid extraction (isopropanol) for sediment (Jungclaus et al., 1978; Lopez-Avila & Hites, 1980); and liquid extraction (methanol) for fish, tissue, and serum (Sikka et al., 1981).
Detection limits range from 0.1 to 1 µg/litre for water and from 50 to 100 µg/kg for sediment; detection limits for biological materials were not identified.
6
4. SOURCES OF HUMAN AND emission reduction techniques are applied, and releases ENVIRONMENTAL EXPOSURE of N-phenyl-1-naphthylamine are therefore presumed to
There are no known natural sources of N-phenyl-1- naphthylamine. Other than the information derived from the national source document, additional data on the production, use patterns, and release of this chemical were not identified.
Within the European Union, one German company is the sole producer of N-phenyl-1-naphthylamine.
Between 1986 and 1990, the estimated worldwide production capacity of N-phenyl-1-naphthylamine was 3000 tonnes per year. Over the same period, estimated production capacities in Western Europe, the People's Republic of China, the USA, and Japan were
approximately 1000-1500 tonnes per year, 1000 tonnes per year, 500 tonnes per year, and 300 tonnes per year, respectively. Between 1986 and 1990, the consumption of N-phenyl-1-naphthylamine in Germany was estimated to be approximately 300-450 tonnes per year, although its use is now declining. Approximately 50-100 tonnes were covered by imports; exports amounted to
approximately 750-1150 tonnes per year (BUA, 1993).
N-Phenyl-1-naphthylamine is used as an antioxidant DISTRIBUTION, AND TRANSFORMATION in gear, hydraulic, lubrication, and bearing oils and as a
protective agent and antioxidant in rubbers and rubber mixtures. In Germany, N-phenyl-1-naphthylamine consumption is divided equally among these two uses.
In these products, the chemical acts as a radical
scavenger in the auto-oxidation of polymers and mineral lubricants. Average concentrations of N-phenyl-1- naphthylamine in the final products are <1% w/w (BUA, 1993). In the rubber industry, approximately 75% of the N-phenyl-1-naphthylamine is used in products such as drums, buffers, conveyor belts, flexible tubes, gaskets, and footwear components. The remaining 25% is used in tyres (sidewalls or carcass, but not treads) (BUA, 1993).
In Germany, N-phenyl-1-naphthylamine-containing distillation residues from production facilities
(approximately 20 tonnes per year), like most gear and hydraulic oil, are disposed of in chemical/physical/
biological treatment plants or hazardous waste
incinerators (BUA, 1993). About 30% of used tyres are disposed of in landfill sites, approximately 37% are used for the production of energy in the cement industry, an estimated 22% are recycled, and approximately 11% are exported (BUA, 1993). Exhaust gases may be emitted during the production and processing of N-phenyl-1- naphthylamine and during the vulcanization of rubber mixtures at elevated temperatures; in Germany, however,
be low (<25 kg per year). Data on levels of N-phenyl-1- naphthylamine in exhaust gases from vulcanization processes are not available. The use of N-phenyl-1- naphthylamine-containing lubrication oils should not result in the introduction of the substance into the atmosphere, as the oils are applied in closed systems (BUA, 1993).
Data on releases of N-phenyl-1-naphthylamine in effluents from production and processing facilities were not identified. Indirect discharges from leaching or the decay of tyres and other rubber products are to be expected in the long term; however, estimation of amounts was not possible (BUA, 1993). The release of N-phenyl-1-naphthylamine into the geosphere from the leakage of lubrication oils and discarded rubber products and tyres in landfill sites may occur; however, estimation of the amounts was not possible with the available data (BUA, 1993). Information on the occurrence of N- phenyl-1-naphthylamine in plants or animals was not identified.
5. ENVIRONMENTAL TRANSPORT,
Based on its physical/chemical properties, the distribution of N-phenyl-1-naphthylamine in the environment was predicted, using a Level II fugacity model (Mackay, 1991), to be 36.3% to soil, 33.9% to sediment, 28.9% to water, 0.8% to air, 0.06% to suspended sediment, and 0.02% to biota. Input data for the Level II fugacity model were as follows: temperature, 298°K; atmospheric volume, 6 x 10 m ; soil density, 1.59 3 g/cm ; density of biota, 1 g/cm ; carbon content of soil,3 3 2%; carbon content of sediment, 4%; water depth, 1000 cm; water portion, 70%; soil depth, 15 cm; sediment depth, 3 cm; suspended sediment portion, 5 ppm; biota portion, 1 ppm; molar mass, 219 g/mol; water solubility, 3 mg/litre; vapour pressure, 1.06 mPa; n-octanol/water partition coefficient, 15 850; soil sorption coefficient, 6510; bioaccumulation factor, 760; half-lives (days) in air (0), water (365), soil (29.2), sediment (29.2), suspended sediment (29.2), and biota (0). Owing to the lack of relevant data, it was not possible to predict the
concentrations of N-phenyl-1-naphthylamine in various media using a Level III fugacity model. Based on its calculated Henry's law constant (7.748 x 10 Pa.m /mol;-2 3 20°C) and other information (Thomas, 1990), the volatility of N-phenyl-1-naphthylamine from aqueous solution is expected to be low.
7
Based on its ultraviolet absorption spectrum, direct reflect reduced bioavailability of the N-phenyl-1- photochemical degradation of N-phenyl-1- naphthylamine (Rosenberg, 1983). Measured soil naphthylamine in air is expected (BUA, 1993). Data sorption coefficients (K ) are not available. Using the concerning the photo-oxidative degradation of N- regression equations of Kenaga (1980) and Kenaga &
phenyl-1-naphthylamine in air are not available. Goring (1980), K values of 2400 and 4600, respectively, Measured half-lives for the photochemical degradation were calculated for N-phenyl-1-naphthylamine. Thus, of the chemical in water have been reported at 8.4 and soil sorption is predicted to be moderate to high. From 5.7 min (Sikka et al., 1981). In this experiment, sealed this expected sorption to organic soil constituents and tubes containing aqueous solutions of N-phenyl-1- its limited mineralization in soil, N-phenyl-1- naphthylamine at approximately 1 mg/litre (water naphthylamine is presumed to have geoaccumulation unspecified but assumed to be distilled) were exposed to potential. The probability of infiltration into sunlight. The experiment was conducted in May and groundwater is low (BUA, 1993).
repeated in June in Syracuse, NY (USA); no information
was provided on light intensity. A further experiment Considering its measured log K of 4.2 (Ozeki &
using a lamp at 300 nm (Rayonette Model RNR-400 mini Tejima, 1979) and data from laboratory tests with photochemical reactor; no information provided on Daphnia and freshwater fish, N-phenyl-1-naphthylamine intensity) demonstrated that the photodegradation is classified as a substance with moderate
product was produced rapidly and was itself bioaccumulation potential (Sikka et al., 1981; CITI, 1992).
photostable. Given the lack of detail in the report, the For Daphnia magna, a mean bioconcentration factor importance of photodegradation in the environment is (related to radioactivity) of 637 was calculated following difficult to assess. There is also insufficient information exposure to [ C] N-phenyl-1-naphthylamine in a static to allow the photodegradation product to be fully test (solubilizer: acetone; steady state after 12 h). About characterized, but the authors suggest that it 50% of the accumulated radioactivity had been
incorporates the basic phenylnaphthylamine skeleton. It eliminated after 53 h in clean water (Sikka et al., 1981).
can therefore be concluded that photolysis may lead to Bioconcentration factors ranging from 432 to 1285 preliminary breakdown of N-phenyl-1-naphthylamine (related to radioactivity) and from 233 to 694 (related to under favourable environmental conditions, but that N-phenyl-1-naphthylamine) were determined in a flow- further degradation is unlikely. From experiments through system (sublethal N-phenyl-1-naphthylamine conducted in aqueous solution, hydrolysis of N-phenyl- concentration) for the bluegill sunfish (Lepomis 1-naphthylamine under environmental conditions is macrochirus) at steady state. Depuration was biphasic, expected to be of limited importance (Sikka et al., 1981). with an elimination of [ C] N-phenyl-1-naphthylamine of
Two standard tests on biodegradation performed 32 days after treatment (Sikka et al., 1981).
according to guideline 301C of the Organisation for Bioconcentration factors for N-phenyl-1-naphthylamine Economic Co-operation and Development (OECD) in common carp (Cyprinus carpio), measured in a flow- (modified MITI-I test) reported no degradation of N- through system after 8 weeks, were on the same order of phenyl-1-naphthylamine (100 mg/litre initial magnitude (427-2730) (CITI, 1992). N-Phenyl-1- concentration) within 14 and 28 days, using non- naphthylamine is metabolized by terrestrial and aquatic adapted activated sludge (Bayer AG, 1990; CITI, 1992). microorganisms and by fish to at least two or three In tests with conditions favouring biodegradation, N- unidentified metabolites (Sikka et al., 1981; Rosenberg, phenyl-1-naphthylamine was degraded with a half-life 1983).
ranging from 4 to 11 days (inocula: domestic sewage and lake water, respectively). Additional substrates
accelerated degradation (Sikka et al., 1981; Rosenberg, 6. ENVIRONMENTAL LEVELS AND
1983). Laboratory results indicate that N-phenyl-1- HUMAN EXPOSURE
naphthylamine is inherently biodegradable in the aquatic
compartment. 6.1 Environmental levels
Mineralization of N-phenyl-1-naphthylamine In older studies from the USA, N-phenyl-1- (measured by the evolution of [ C]carbon dioxide) was14 naphthylamine was detected in river water (2-7 µg/litre) 17% in soil and 35% in a soil suspension in buffered salt and sediment (1-5 mg/kg) near a small speciality solution. In contrast to the aquatic studies, the addition chemicals manufacturing plant (Jungclaus et al., 1978;
of degradable substrates reduced rather than accelerated Lopez-Avila & Hites, 1980). Additional data on levels of degradation. It was suggested that the organic materials N-phenyl-1-naphthylamine in environmental media were increased sorption of the N-phenyl-1-naphthylamine. not identified. Based upon the use patterns of N- The reported lower degradation in soil may therefore phenyl-1-naphthylamine, the presence of this substance
oc
oc
ow
14
14
>90% after 8 days; radioactivity could still be detected
in soil and sediment in some source-dominated areas within 48 h; 95% was excreted within 72 h (60% in the appears possible; however, quantitative data are not faeces and 35% in the urine). In the ether extract of the
available. urine, at least five radioactive metabolites were detected
6.2 Human exposure
Owing to its low vapour pressure and use patterns, the ingestion or inhalation of N-phenyl-1-
naphthylamine is expected to be minor. Dermal contact with oils and rubber articles containing N-phenyl-1- naphthylamine may occur in the workplace. Data on occupational exposure were not available from industries in Germany involved in the manufacture or use of N- phenyl-1-naphthylamine. Dermal contact may also be a2 source of exposure for the general population, although this should be of minor importance because of the small quantities of N-phenyl-1-naphthylamine produced and present in various products. Data on concentrations of N-phenyl-1-naphthylamine in media relevant to assessing exposure of the general population were not identified. Moreover, available data were insufficient to allow an estimation of human exposure based upon concentrations predicted from fugacity modelling.
7. COMPARATIVE KINETICS AND METABOLISM IN LABORATORY ANIMALS
AND HUMANS
Studies providing quantitative information on the absorption or distribution of N-phenyl-1-naphthylamine in humans were not identified. From the limited information available from studies conducted with laboratory animals, it can be concluded that N-phenyl-1- naphthylamine is well absorbed after ingestion and is readily excreted. In vitro studies have demonstrated that the metabolism of N-phenyl-1-naphthylamine occurs primarily via hydroxylation.
In male Sprague-Dawley rats administered a single oral dose of 160 mg [ C] N-phenyl-1-naphthylamine/kg14 body weight, the chemical was well absorbed,
metabolized almost completely, and excreted primarily in the faeces. Radioactivity was detected in plasma within 60 min, with the maximum concentration measured after 4 h. After 24 h, 20% of the radioactivity was found in the gastrointestinal tract (including contents), 2.4% in fatty tissue, 0.4% in the liver, and 0.1% in the kidneys. Ninety per cent of the administered radioactivity was excreted
but not identified. The elimination half-lives were reported as 1.68 h for the fast elimination and 33 h for the slow elimination (Sikka et al., 1981).
In a study in which male rats were administered N- phenyl-1-naphthylamine orally, only small quantities of unchanged N-phenyl-1-naphthylamine were excreted in the faeces and urine (0.4 and 0.01% of the applied dose, respectively). Large amounts of glucuronide and sulfate conjugates, which were not identified further, were detected in the urine. Small quantities of N-phenyl-1- naphthylamine were distributed in fatty tissue after single or multiple (6 day) oral administration, whereas the distribution of unchanged N-phenyl-1-naphthylamine in liver, kidneys, spleen, heart, and lung was extremely low (Miyazaki et al., 1987).
Mono- and dihydroxy-derivatives of N-phenyl-1- naphthylamine have been identified in in vitro metabolic studies conducted with rat liver microsomes (Sikka et al., 1981; Xuanxian & Wolff, 1992). Sikka et al. (1981) suggested that the hydroxyl group in the mono-hydroxy derivative is in the naphthalene moiety at a para-position to the amino group, whereas at least one hydroxyl group in the dihydroxy-derivative is at the available para- position in the naphthyl ring. Pretreatment of male rats with phenobarbital or 3-methylcholanthrene increased the rate of microsomal metabolism, indicating that more than one P-450 enzyme is involved in the metabolism of N-phenyl-1-naphthylamine (Xuanxian & Wolff, 1992).
In studies conducted with human volunteers or laboratory animals, the isomer N-phenyl-2- naphthylamine (CAS no. 135-88-6) was partially metabolized to the known human carcinogen 2-
naphthylamine following ingestion or inhalation (NIOSH, 1976). Although data concerning the formation of this metabolite are not available for N-phenyl-1-
naphthylamine, it should be noted that, based on its chemical structure, it is unlikely that N-phenyl-1- naphthylamine is metabolized to 2-naphthylamine.
8. EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS
In most of the toxicity studies, information on the purity of N-phenyl-1-naphthylamine was not provided.
As discussed in section 2, N-phenyl-1-naphthylamine with a typical purity of >99% contains numerous contaminants, and therefore the observed effects may not be solely attributable to N-phenyl-1-naphthylamine.
Owing to the limited available toxicity data on Personal communications concerning 1) BUA report on
2
N-phenyl-1-naphthylamine, Heidelberg,
Berufsgenossenschaft der chemischen Industrie (BG Chemie), 27 August 1992; and 2) exposure data for N- phenyl-1-naphthylamine, Bundesanstalt für
Arbeitsschutz, Dortmund, 1992.
N-phenyl-1-naphthylamine, information on the isomer N-phenyl-1-naphthylamine to be an eye irritant. The N-phenyl-2-naphthylamine (a known contaminant of observed effects in some animals (slight conjunctivitis or commercially available N-phenyl-1-naphthylamine) has swelling of the eyelid) were reversible within a maximum been included to aid in the identification of potential of 10 days (van Beek, 1977; Ciba-Geigy Corp., 1987a).
target organs. There is limited evidence to suggest that
the kidneys and liver are the main target organs In a guinea-pig maximization test (Magnusson &
following ingestion of N-phenyl-1-naphthylamine; this Kligman, 1970) and in a test performed according to has also been demonstrated for the isomer N-phenyl-2- OECD guideline 406, N-phenyl-1-naphthylamine was
naphthylamine. shown to be a strong sensitizer (positive reaction in
8.1 Single exposure
The acute oral toxicity of N-phenyl-1-naphthylamine is low. Studies performed according to standard
protocols yielded LD s in male and female Wistar rats of50
>5000 mg/kg body weight (Bayer AG, 1978a,b). LD s50
for male CFE rats and male CF-1 mice are >1625 mg/kg body weight (MacEwen & Vernot, 1974; Vernot et al.,
1977) and 1231 mg/kg body weight (MacEwen & Vernot, In five female Sprague-Dawley rats (two untreated 1974), respectively. No specific signs of toxicity were controls), no adverse clinical signs or effects on body
reported. weight gain were noted after daily oral (gavage)
Slight fatty degeneration in the liver of rabbits was body weight, 5 days per week for 2 weeks. Data observed 3 months after a single subcutaneous injection concerning the purity of the test substance or the of 200 mg N-phenyl-1-naphthylamine/kg body weight formulation administered were not provided. Gross (Bayer AG, 1931). Like other aromatic amines, N- morphological observations (no histopathological phenyl-1-naphthylamine induces the formation of examination) made at necropsy revealed no evidence of methaemoglobin. In mice, a slightly increased exposure-related effects (Mobil Oil Corp., 1989).
methaemoglobin level (4.1% versus 0.4% in controls)
was noted within 10 min of a single intraperitoneal Older studies (Bayer AG, 1931) performed with small administration; the increase was still detectable up to 24 numbers of rabbits, although inadequate to serve as a h later (Nomura, 1977). Mice are less sensitive than basis for the determination of putative effect levels, may humans to methaemoglobin induction, and this small provide some useful information on toxicity and target increase in methaemoglobin level may be of importance organs. The oral administration of 200 mg N-phenyl-1- to human health. Data on effects related to acute naphthylamine/kg body weight per day, 5 days per week exposure to N-phenyl-1-naphthylamine via the for 6 weeks, resulted in diarrhoea, proteinuria, slight inhalation route were not identified. irritation of the kidneys, and a fatty degeneration of the 8.2 Irritation and sensitization
Three studies assessed skin irritation by N-phenyl-1- naphthylamine using the Draize method in rabbits. In one study, no effects were observed within 72 h of application (no further information was reported) (MacEwen & Vernot, 1974). In a study performed according to US Food and Drug Administration (FDA) standards, N-phenyl-1-naphthylamine was classified as a very slight skin irritant (3/6 animals with intact skin and 2/6 animals with abraded skin showed a slight positive reaction) (van Beek, 1977). In a test conducted according to OECD guideline 404, N-phenyl-1- naphthylamine was not considered to be a skin irritant.
Slight erythema and oedema reactions in 1/3 rabbits were observed 1 h after removal of the test substance,
whereas no effects were noted after 24 or 72 h (Ciba- Geigy Corp., 1987b). Studies conducted according to US FDA standards or OECD guideline 405 did not consider
15/20 and 18/20 animals, respectively) (Boman et al., 1980; Ciba-Geigy Corp., 1987c). In the modified Landsteiner's guinea-pig sensitization test (no further information available), which is not a standard method, N-phenyl-1-naphthylamine did not exhibit sensitizing potential (MacEwen & Vernot, 1974).
8.3 Short-term exposure
administration of 2000 mg N-phenyl-1-naphthylamine/kg
liver. After the subcutaneous administration (42 times in 7 weeks) of 50 or 200 mg N-phenyl-1-naphthylamine/kg body weight per day, a fatty degeneration of the liver and single proliferation of connective tissue were noted 3 months after the cessation of exposure. Dermal application of a 5% solution of N-phenyl-1- naphthylamine to the ear (28 times within 5 weeks) produced slight skin erythema, proteinuria, and anorexia.
Death occurred 5 days after the 27th application, and necropsy revealed fatty degeneration of the liver (Bayer AG, 1931).
In mice (sex and number not specified), the intraperitoneal administration of 219 mg N-phenyl-1- naphthylamine/kg body weight for 3 days resulted in increased methaemoglobin levels (1.6% versus 0.4% in controls) 48 h after treatment; methaemoglobin concentrations were not elevated after intraperitoneal administration of 109 mg/kg body weight for 9 days (Nomura, 1977).
8.4 Long-term exposure significant (p < 0.05) increase in the incidence of kidney 8.4.1 Subchronic exposure
There are no studies available concerning
subchronic exposure to N-phenyl-1-naphthylamine. In an oral 13-week study with the isomer N-phenyl-2- naphthylamine (approximately 98% pure, containing <1 mg 2-naphthylamine/kg), relative liver weight in F344/N rats and B6C3F mice increased in a dose-dependent1
fashion. A chemical-related nephropathy was observed in rats, characterized by renal tubular epithelial degeneration and hyperplasia (NTP, 1988).
8.4.2 Chronic exposure and carcinogenicity Long-term toxicity or carcinogenicity studies performed according to currently accepted standard protocols using physiologically relevant routes of exposure were not identified. The inhalation exposure of four rabbits (number of controls not provided,
approximate dose 100 mg/day) for several months (no additional information provided) resulted in progressive anaemia, leucopenia, lymphocytosis, pneumonia, nephritis, nephrosis, formation of lung abscesses, fatty degeneration of the liver after 3-5 months, and death within 6-24 months (Schär, 1930). This study is characterized by the limited number of animals, methodological deficiencies, and insufficient documentation of results.
Bladder tumours were not observed in a long-term study in which three dogs were orally administered 290 mg N-phenyl-1-naphthylamine 5 days per week for up to 3.5 years (DuPont, 1945; Gehrmann et al., 1948; Haskell Laboratory, 1971). Owing to the limited number of animals and the examination for tumours only in the bladder, this study is inadequate for evaluation of the carcinogenic potential of N-phenyl-1-naphthylamine following oral administration.
Wang et al. (1984) observed an increased incidence of malignant tumours in male ICR and TA-1 mice following repeated subcutaneous administration of N- phenyl-1-naphthylamine (technical grade or pure; no additional data provided). In ICR mice, there was a statistically significant increase (p < 0.05) in the
incidence of lung carcinoma (5/30 versus 0/24 in controls administered vehicle alone) after the administration of 16 mg technical-grade N-phenyl-1-naphthylamine per animal 27 times over 9 weeks (total dose 432 mg per animal). The incidence of kidney haemangiosarcomas was 1/30 and 0/24 in the exposed and control groups, respectively; however, the combined incidence of liver, kidney, and lung haemangiosarcomas was significantly (p < 0.05) increased in the exposed animals (5/30 versus 0/24 in unexposed controls). The same dosing regimen using purified N-phenyl-1-naphthylamine produced a
haemangiosarcomas (4/23 versus 0/24 in controls); the numbers of animals with lung carcinoma were 3/23 and 0/24 in the exposed and control groups, respectively.
The administration of 5.3 mg purified N-phenyl-1- naphthylamine per animal, 27 times over 9 weeks (total dose 143 mg per animal), produced a significant (p <
0.05) increase in the number of animals with lung carcinomas (6/25 versus 0/24 in controls). The incidence of kidney haemangiosarcomas was not elevated (1/25 and 0/24 in the exposed and control groups,
respectively); however, there was a significant increase (p < 0.05) in the combined incidence of kidney and lung haemangiosarcomas (4/25 versus 0/24 in the controls).
All animals in the study were sacrificed after 10 months.
In TA-1 mice administered a total dose of 328 mg technical-grade N-phenyl-1-naphthylamine per animal subcutaneously over a period of 12 weeks (48 mg peranimal over 3 weeks, followed by 280 mg per animal over 9 weeks), there was a significant increase (p < 0.05) in the incidence of kidney haemangiosarcomas (7/19 compared with 0/18 in unexposed controls). The incidence of renal tumours was also significantly (p <
0.05) elevated in unilaterally nephrectomized TA-1 mice (one kidney was removed 1 week prior to treatment) subcutaneously administered a total dose of 328 mg of either purified or technical-grade N-phenyl-1-
naphthylamine per animal over a period of 12 weeks (48 mg per animal over 3 weeks, followed by 280 mg per animal over 9 weeks). The incidence of kidney haemangiosarcomas in controls and the unilaterally nephrectomized animals administered either the pure or technical-grade material was 0/18, 12/16, and 13/13, respectively (Wang et al., 1984). Evaluation of this report is difficult owing to the number of individual experiments. These studies are characterized by the use of small numbers of animals of a single sex, limited dose groups, the absence of data on mortality and morbidity, use of a non-physiologically relevant route of exposure, and insufficient characterization of the substance tested.
N-Phenyl-2-naphthylamine, which had effects comparable to those of N-phenyl-1-naphthylamine in the above-mentioned study by Wang et al. (1984), has been tested in a 2-year carcinogenicity bioassay (NTP, 1988). There was no evidence of carcinogenic activity in male or female F344/N rats administered diets containing 2500 or 5000 ppm (mg/kg) N-phenyl-2-naphthylamine (estimated daily intakes of 100 and 225 mg/kg body weight for males and 120 and 260 mg/kg body weight for females, respectively). The lack of carcinogenicity in rats may be related to an inability to metabolize N- phenyl-2-naphthylamine to the known animal and human carcinogen 2-naphthylamine (NTP, 1988). There was no evidence of carcinogenic activity in male B6C3F mice1 administered diets containing 2500 or 5000 ppm (mg/kg) N-phenyl-2-naphthylamine (estimated daily intakes of
500 or 1000 mg/kg body weight, respectively). However, mg N-phenyl-1-naphthylamine/kg body weight per day in female mice receiving these diets (estimated daily for 5 consecutive days followed by 2 days without intakes of 450 or 900 mg/kg body weight, respectively), exposure. Each male was then caged with two virgin there was equivocal evidence of carcinogenic activity, females 5 days per week, and the sequence was repeated based upon the occurrence of rare kidney neoplasms in weekly with two new females each week for 8 weeks.
two high-dose animals (one tubular cell adenoma and Examination of females 14 days from the mid-week in one tubular cell adenocarcinoma). For non-neoplastic which they were caged with the males yielded negative effects, the kidney was the principal target organ. results (Brusick & Matheson, 1976, 1977).
Mineralization, necrosis of the renal papilla, epithelial hyperplasia, calculi of the kidney pelvis,
hydronephrosis, atrophy, fibrosis, and chronic focal inflammation of the kidney were observed in the high- dose female rats. In male rats of both dose groups and in the high-dose female rats, cysts and acute
suppurative inflammation of the kidney were also noted.
Nuclear enlargement of renal tubular epithelial cells and nephropathy were observed in the high-dose female mice (NTP, 1988).
In a dermal carcinogenicity study, approximately 0.75 mg N-phenyl-1-naphthylamine/kg body weight
(dissolved in 50 µl toluene) was applied to the skin of 50 male C3H mice twice per week for 80 weeks. Data concerning the purity of the test substance or the formulation applied were not provided. No adverse effects on survival or increased incidence of skin tumours were observed; however, pigmentation, fibrosis, scar formation, acanthosis, and hyperkeratosis were noted. Histopathological examinations of organs other than the skin were not performed (Mobil Oil Corp., 1985).
8.5 Genotoxicity and related end-points The results of experiments on the genotoxicity of N- phenyl-1-naphthylamine are summarized in Table 1. N- Phenyl-1-naphthylamine was not mutagenic in bacterial tests conducted in the presence or absence of metabolic activation. In mammalian cells, neither gene mutations (mouse lymphoma assay) nor chromosomal aberrations (in vitro metaphase analysis in Chinese hamster ovary cells or Chinese hamster lung cells) were induced by N- phenyl-1-naphthylamine. A sister chromatid exchange assay in Chinese hamster ovary cells was marginally positive in the presence of metabolic activation. An unscheduled DNA synthesis assay with human lung (WI-38) cells yielded positive results, although the effects were not clearly concentration dependent. A number of non-validated short-term tests yielded conflicting results on the transforming potential of N- phenyl-1-naphthylamine (BUA, 1993). Based upon the weight of evidence from in vitro studies, N-phenyl-1- naphthylamine does not appear to be genotoxic.
No in vivo somatic cell mutation tests were identified. In a dominant lethal test, 10 male ICR mice were intraperitoneally administered 0, 50, 166, or 500
8.6 Reproductive and developmental toxicity Data on the reproductive and developmental toxicity of N-phenyl-1-naphthylamine were not identified.
8.7 Immunological and neurological effects Data on immunological and neurological effects of N- phenyl-1-naphthylamine in laboratory animals were not identified.
9. EFFECTS ON HUMANS
9.1 Case reports
N-Phenyl-1-naphthylamine, mixed with oil (Bayer AG, 1931) or water (Haskell Laboratory, 1971), was not irritating when applied to the skin of volunteers (no data on concentrations available). Skin eczema in workers has been attributed to repeated exposure to high levels of N-phenyl-1-naphthylamine, possibly in combination with other substances. Reportedly, the content of N- phenyl-1-naphthylamine in a special antirust oil had to be lowered from 2% to 0.5% because of skin problems.
Workers, who did not wear gloves, were exposed during the packaging of bearing rings covered with antirust-oil containing N-phenyl-1-naphthylamine (Järvholm &
Lavenius, 1981).
N-Phenyl-1-naphthylamine was also reported to have sensitizing properties in humans. Case-studies on patients with contact dermatitis, potentially associated with occupational exposure to N-phenyl-1-
naphthylamine in greases or oils, have been identified.
The majority of these patients also had a positive reaction to other substances in the test series, such as mercaptobenzothiazole or p-phenylenediamine. Lower incidences were reported in patients with past exposure to rubber materials (Blank & Miller, 1952; Schultheiss, 1959; Nater, 1975; Te Lintum & Nater, 1979; Boman et al., 1980; Järvholm & Lavenius, 1981; Kantoh et al., 1985;
Table 1: In vitro genotoxicity studies on N-phenyl-1-naphthylamine
Cell type Test Result Remarks References
(end-point) concentration (with/ without
a
metabolic activation)
Salmonella typhimurium 0.5-500 µl/plate with and - / - Brusick &
TA98, TA100, TA1535, without metabolic activation Matheseon 1976,
TA1537,TA1538; 1977
Escherichia coli WP2uvrA- (gene mutation)
S. typhimurium TA98, 0.01-1000 µl/plate with and - / - Baden et al., 1978
TA100, TA1535, TA1537; without metabolic activation E. coli WP2
(gene mutation)
S. typhimurium TA97, 0.3-666 µl/plate with and - / - Zeiger et al., 1988
TA98, TA100, TA1535, without metabolic activation TA1537
(gene mutation)
S. typhimurium TA98, 0.2-1000 µl/plate with and - / - JETOC, 1996
TA100, TA1537, TA1538 without metabolic activation (gene mutation)
E. coli WP2uvrA 20-5000 µl/plate with and - / - JETOC, 1996
(gene mutation) without metabolic activation
S. typhimurium TA98, Not provided - / - Rannug et al., 1984
TA100, TA1535, TA1537, TA1538
(gene mutation)
Saccharomyces cerevisiae D4 0.5-500 µl/plate with and - / - Brusick &
(gene mutation) without metabolic activation Matheseon 1976,
1977
Mouse lymphomna 0.005-0.1 µl/plate with - / - Brusick &
(L5178Y) cells metabolic activation Matheseon 1976,
(gene mutation) 0.5-25 µl/plate without 1977
metabolic activation
Human lung (WI-38) cells 5, 10, or 50 µl/ml with - / (+) Weak positive response at Brusick &
(DNA repair[unscheduled metabolic activation 50 µg/ml and toxic at 100 Matheseon 1976,
DNA synthesis]) 10, 50, or 100 µl/ml µg/ml without metabolic 1977
without metabolic activation activation; effects not clearly concentration related
Human lung (WI-38) cells 5, 10, or 50 µl/ml with and (+) / (+) Positive response at 10 Brusick &
(DNA repair[unscheduled without metabolic activation µg/ml and toxic at 100 Matheseon 1976,
DNA synthesis]) µg/ml with metabolic 1977
activation; positive response at 5 and 50 µg/ml without metabolic activation; effects not clearly concentration related
Chinese hamster ovary cells 0.6-19,9 µl/ml with (+) / - Marginally positive with NTP, 1987;
(sister chromatid exchange) metabolic activation metabolic activation Loveday et aö.,
1.8-18,2 µl/ml without 1990
metabolic activation
Chinese hamster ovary cells 1,49-19,9 µl/ml with - / - NTP, 1987;
(chromosomal aberrations) metabolic activation Loveday et al.,
2,99-29,9 µl/ml without 1990
metabolic activation
Chinese hamster lung cells 15,6 µl/ml with metabolic - / - Sofuni et al., 1990
(chromosomal aberrations) activation 30 µl/plate without metabolic activation
a - = negative result; (+) = weak positive result
Kalimo et al., 1989; Carmichael & Foulds, 1990). Because lowest reported NOEC was 0.02 mg/litre (nominal of the chemical's incorporation into the polymer matrix, concentration; solubilizer: ethanol) (Sikka et al., 1981).
exposure to N-phenyl-1-naphthylamine in rubber
materials is assumed to be lower than exposure from Acute toxicity tests in semi-static (daily renewal of
greases or oils. test medium) and flow-through systems yielded 96-h
9.2 Epidemiological studies mykiss) and >0.57-0.82 mg/litre for bluegill sunfish
An increased occurrence of cancers in a small packaging unit in a Swedish engineering company was reported in a cohort study (Järvholm & Lavenius, 1981).
Between 1954 and 1957, a special anticorrosive oil, which contained 0.5% N-phenyl-1-naphthylamine in addition to other chemicals, had been used in this unit. In 12 of 78 women in this unit (group A: 78 women/20 men), cancers were diagnosed between 1964 and 1973 in several organs (predominantly the uterus and ovary).
The staff performing the actual packaging, and thus in contact with the oil, were mainly women. Morbidity and mortality from cancer were 3.1- and 3.5-fold higher, respectively, than expected, based upon age-specific and sex-specific data from the Swedish Cancer Register (the standard cancer rates for the period 1974-1976 were estimated on the basis of the 1973 rate). In the males of group A, no significant differences were established. In another unit (reference group B: 25 women/8 men) where anticorrosive oil without N-phenyl-1-naphthylamine had been used, morbidity and mortality from cancer were not elevated. This was also true for reference group C (8 women/23 men), from units that had been in contact with N-phenyl-1-naphthylamine-containing anticorrosive oil for a short period of time only, because they had demonstrated allergic reactions. The authors concluded that, apart from exposure to N-phenyl-1-naphthylamine, the formation of N-nitroso- N-phenyl-1-naphthylamine from sodium nitrite originating from the packaging paper used may be a possible explanation for the increased frequency of cancer in group A.
10. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD 10.1 Aquatic environment
Valid results from laboratory tests with ciliates, Daphnia, and fish indicate that N-phenyl-1- naphthylamine is highly toxic to aquatic species. An EC (48 h) of 2 mg N-phenyl-1-naphthylamine/litre50
(nominal concentration; static; solubilizer: acetone) was measured for the inhibition of cell proliferation of freshwater ciliates (Tetrahymena pyriformis) (Epstein et al., 1967). Forty-eight-hour LC s from static and semi-50 static acute toxicity tests with young and adult
Daphnia magna were in the range of 0.30-0.68 mg N- phenyl-1-naphthylamine/litre (nominal concentration;
solubilizer: ethanol). The lowest reported 21-day LC50
from long-term semi-static tests was 0.06 mg/litre; the
LC s in the range of 0.44-0.74 mg N-phenyl-1-50
naphthylamine/litre for rainbow trout (Oncorhynchus (solubilizers: ethanol and acetone, respectively; nominal concentrations); the lowest reported NOEC (192 h) was 0.11 mg/litre (Sikka et al., 1981). Sublethal N-phenyl-1- naphthylamine concentrations of approximately 5.2 and 5.6 mg/litre had teratogenic effects on embryos and larvae, respectively, of the clawed frog (Xenopus laevis).
Concentrations above 6.2 mg/litre were lethal (100%
death of larvae within 24 h) for both (Greenhouse, 1976a,b). During neurulation, an EC of 4.57 mg/litre for50 teratogenic effects was established. For larvae, a 48-h LC of 2.3 mg/litre was determined (Greenhouse, 1977). 50
For larvae of the leopard frog (Rana pipiens), a 48-h LC of 5 mg/litre was reported; no effects occurred after100
24 h of exposure (Greenhouse, 1976b).
Data on chronic effects of N-phenyl-1- naphthylamine in the aquatic environment are not available.
10.2 Terrestrial environment
Data on toxic effects of N-phenyl-1-naphthylamine on terrestrial microorganisms, plants, animals, and ecosystems are not available.
11. EFFECTS EVALUATION
11.1 Evaluation of health effects
11.1.1 Hazard identification and dose–response assessment
N-Phenyl-1-naphthylamine is well absorbed and readily excreted following ingestion; accumulation in the body is not expected. The acute oral toxicity of N- phenyl-1-naphthylamine in laboratory animals is low.
Based on the results of tests performed according to OECD guidelines, the substance is not considered to be a skin or eye irritant. N-Phenyl-1-naphthylamine has been observed to be a skin sensitizer in laboratory animals and humans.
A no-observed-effect level could not be derived from the available toxicological studies. There is limited evidence to suggest that the kidneys and liver are the main target organs following oral exposure to N-phenyl- 1-naphthylamine, a finding comparable to that observed
for its isomer, N-phenyl-2-naphthylamine. As indicated cannot be excluded. Although quantitative information above, useful data on the toxicity of N-phenyl-1- on the leaching of N-phenyl-1-naphthylamine from naphthylamine are limited, and therefore additional data rubber products is not available, the extent of such on its isomer, N-phenyl-2-naphthylamine, have been leaching is expected to be low. Any leached material is included to assist in the identification of potential target expected to be degraded faster than it is leached.
organs. Available carcinogenicity studies on N-phenyl- Indirect exposure of humans to N-phenyl-1-
1-naphthylamine have not been performed according to naphthylamine leached from rubber products into the currently accepted standard protocols, and therefore the soil is unlikely.
potential carcinogenicity of this chemical cannot be fully evaluated. However, in a 2-year carcinogenicity
bioassay conducted with N-phenyl-2-naphthylamine in rats and mice, there was no evidence of carcinogenic activity in male or female rats or male mice and equivocal evidence of carcinogenic activity in female mice.
N-Phenyl-1-naphthylamine was not mutagenic in bacterial test systems. In tests with mammalian cells, some investigations yielded marginally positive or questionably positive results. Based upon the available evidence, N-phenyl-1-naphthylamine does not appear to be genotoxic. It is worth noting, however, that several aromatic amines (the chemical class to which N-phenyl- 1-naphthylamine belongs), while yielding negative or weakly positive results in mutagenicity assays, are carcinogenic.
An increased occurrence of cancers was observed in one limited epidemiological study of occupationally exposed individuals; however, because of the small number of excess deaths and concomitant exposure to other chemicals, it is not possible to attribute this finding solely to N-phenyl-1-naphthylamine.
Information on the reproductive or developmental toxicity of N-phenyl-1-naphthylamine was not available.
11.1.2 Criteria for setting guidance values for Owing to its moderate to high potential for sorption to N-phenyl-1-naphthylamine organic soil constituents and its limited mineralization in Data are inadequate to allow the derivation of a no-
observed-effect level or the performance of a risk estimation for carcinogenicity. Dermal contact with N- phenyl-1-naphthylamine should be avoided because of its sensitizing properties.
11.1.3 Sample risk characterization Owing to the lack of available data with which to derive a suitable guidance value as well as the lack of information on exposure, a sample quantitative risk characterization could not be performed. At the workplace, there is a risk of dermal sensitization from exposure to greases and antirust oils containing N- phenyl-1-naphthylamine. The risk from exposure to rubber materials may be much lower, owing to the low concentrations of N-phenyl-1-naphthylamine in such materials; a risk to the general population from exposure to products containing N-phenyl-1-naphthylamine
11.2 Evaluation of environmental effects
Overall, releases of N-phenyl-1-naphthylamine to the environment from production and processing (e.g.
vulcanization of rubber mixtures) are expected to be small in view of the chemical's low production. Based upon the chemical's physical and chemical properties, it is predicted that soil and sediment will be affected indirectly by the leaching of N-phenyl-1-naphthylamine from decaying tyres and rubber products; however, the amounts of N-phenyl-1-naphthylamine introduced into the environment via this route could not be quantified.
Data on the occurrence of N-phenyl-1-naphthylamine in environmental media were available only from some older studies for highly polluted river water and sediment samples; recent measurements on levels in water, soil, or biota were not identified. Data on geoaccumulation or on the toxic effects of N-phenyl-1- naphthylamine on terrestrial microorganisms, plants, animals, and ecosystems were unavailable.
As data on effect levels for terrestrial organisms or on current concentrations in environmental media were not available, a quantitative risk assessment for the main target compartments, water and soil, could not be carried out; however, some qualitative statements can be made.
soil, N-phenyl-1-naphthylamine released to this environmental compartment is presumed to have geoaccumulation potential. The probability of its infiltration into groundwater is low. In laboratory experiments, the acute toxicity of N-phenyl-1- naphthylamine in fish and Daphnia was high, with lowest reported NOECs of 0.11 mg/litre (192 h) and 0.02 mg/litre (21 days), respectively. Although considerable bioconcentration factors were measured in fish and Daphnia, biomagnification and secondary poisoning of higher trophic levels via the aquatic food-chain seem unlikely in view of the metabolism and extensive excretion of N-phenyl-1-naphthylamine. Biodegradation is expected to be the predominant route of environmental breakdown; in water, it is aided by the presence of other degradable substrates, but it is reduced in soil by sorption. Available N-phenyl-1-naphthylamine is likely to be biodegraded in both compartments with half-lives of days to weeks. Photolysis may lead to initial degradation under favourable conditions but is not
considered important in the mineralization of N-phenyl- 1-naphthylamine. Hydrolysis is of very limited or no importance in the environment.
12. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES
Previous evaluations of N-phenyl-1-naphthylamine by international bodies were not identified. Information on international hazard classification and labelling is included in the International Chemical Safety Card reproduced in this document.
13. HUMAN HEALTH PROTECTION AND EMERGENCY ACTION
Human health hazards, together with preventative and protective measures and first aid recommendations, are presented in the International Chemical Safety Card (ICSC ) reproduced in this document.
13.1 Human health hazards
N-Phenyl-1-naphthylamine has sensitizing properties.
13.2 Advice to physicians
In case of intoxication, the treatment is supportive.
Some chemicals of this class induce methaemoglobinaemia.
13.3 Spillage
Because N-phenyl-1-naphthylamine is classified as a sensitizer, emergency crews need to wear proper equipment to prevent contact with the skin.
14. CURRENT REGULATIONS, GUIDELINES, AND STANDARDS Information on national regulations, guidelines, and standards can be found in the International Register of Potentially Toxic Chemicals (IRPTC), available from UNEP Chemicals (IRPTC), Geneva.
The reader should be aware that regulatory decisions 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.
