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Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 1 (2004)

Chapter: Appendix 8: N-Phenyl-beta-naphthylamine

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Suggested Citation:"Appendix 8: N-Phenyl-beta-naphthylamine." National Research Council. 2004. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/10942.
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Suggested Citation:"Appendix 8: N-Phenyl-beta-naphthylamine." National Research Council. 2004. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/10942.
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Suggested Citation:"Appendix 8: N-Phenyl-beta-naphthylamine." National Research Council. 2004. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/10942.
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Suggested Citation:"Appendix 8: N-Phenyl-beta-naphthylamine." National Research Council. 2004. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/10942.
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Suggested Citation:"Appendix 8: N-Phenyl-beta-naphthylamine." National Research Council. 2004. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/10942.
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Suggested Citation:"Appendix 8: N-Phenyl-beta-naphthylamine." National Research Council. 2004. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/10942.
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Suggested Citation:"Appendix 8: N-Phenyl-beta-naphthylamine." National Research Council. 2004. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/10942.
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Suggested Citation:"Appendix 8: N-Phenyl-beta-naphthylamine." National Research Council. 2004. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/10942.
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Suggested Citation:"Appendix 8: N-Phenyl-beta-naphthylamine." National Research Council. 2004. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/10942.
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Suggested Citation:"Appendix 8: N-Phenyl-beta-naphthylamine." National Research Council. 2004. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/10942.
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Suggested Citation:"Appendix 8: N-Phenyl-beta-naphthylamine." National Research Council. 2004. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/10942.
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Suggested Citation:"Appendix 8: N-Phenyl-beta-naphthylamine." National Research Council. 2004. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/10942.
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Suggested Citation:"Appendix 8: N-Phenyl-beta-naphthylamine." National Research Council. 2004. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/10942.
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Suggested Citation:"Appendix 8: N-Phenyl-beta-naphthylamine." National Research Council. 2004. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/10942.
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Suggested Citation:"Appendix 8: N-Phenyl-beta-naphthylamine." National Research Council. 2004. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/10942.
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Suggested Citation:"Appendix 8: N-Phenyl-beta-naphthylamine." National Research Council. 2004. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/10942.
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Suggested Citation:"Appendix 8: N-Phenyl-beta-naphthylamine." National Research Council. 2004. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/10942.
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Suggested Citation:"Appendix 8: N-Phenyl-beta-naphthylamine." National Research Council. 2004. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/10942.
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Suggested Citation:"Appendix 8: N-Phenyl-beta-naphthylamine." National Research Council. 2004. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/10942.
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Suggested Citation:"Appendix 8: N-Phenyl-beta-naphthylamine." National Research Council. 2004. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/10942.
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Suggested Citation:"Appendix 8: N-Phenyl-beta-naphthylamine." National Research Council. 2004. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/10942.
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Suggested Citation:"Appendix 8: N-Phenyl-beta-naphthylamine." National Research Council. 2004. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/10942.
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Suggested Citation:"Appendix 8: N-Phenyl-beta-naphthylamine." National Research Council. 2004. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/10942.
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Suggested Citation:"Appendix 8: N-Phenyl-beta-naphthylamine." National Research Council. 2004. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/10942.
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Suggested Citation:"Appendix 8: N-Phenyl-beta-naphthylamine." National Research Council. 2004. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/10942.
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Suggested Citation:"Appendix 8: N-Phenyl-beta-naphthylamine." National Research Council. 2004. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/10942.
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Suggested Citation:"Appendix 8: N-Phenyl-beta-naphthylamine." National Research Council. 2004. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/10942.
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Suggested Citation:"Appendix 8: N-Phenyl-beta-naphthylamine." National Research Council. 2004. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/10942.
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Suggested Citation:"Appendix 8: N-Phenyl-beta-naphthylamine." National Research Council. 2004. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/10942.
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Suggested Citation:"Appendix 8: N-Phenyl-beta-naphthylamine." National Research Council. 2004. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/10942.
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Suggested Citation:"Appendix 8: N-Phenyl-beta-naphthylamine." National Research Council. 2004. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/10942.
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Suggested Citation:"Appendix 8: N-Phenyl-beta-naphthylamine." National Research Council. 2004. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/10942.
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Suggested Citation:"Appendix 8: N-Phenyl-beta-naphthylamine." National Research Council. 2004. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 1. Washington, DC: The National Academies Press. doi: 10.17226/10942.
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8 N-Phenyl-beta-naphthylamine Jean' M: Hampton', Ph.D. NASA Acimirlistrator's Fellowship Program Johrlsorl Space Center Houston, Texas PHYSICAL AND CHEMICAL PROPERTIES N-phenyl-beta-naphthylamine (PBNA) is a light tan or gray compound produced as flakes or powder. (See Table 8-1 for summary of physical and chemical properties.) OCCURRENCE AND USE Background PBNA is manufactured from beta-naphthol and aniline (Scott 1962, pp. 73-74~. PBNA has been used in rubber industries as an antioxidant to in- crease resistance to heat and cracking in natural and synthetic rubbers and in latexes (ACGIH 1991, pp.1211-1213~. It has also been used as an anti- oxidant in various greases and lubricating or transformer oils. PBNA has been employed as a stabilizer in industrial applications such as silicone enamels (Kehe and Kouris 1965), as a catalyst, as a polymerization inhibi- tor, and as a vulcanization accelerator. PBNA has been used in the produc- tion of dyes and as a component of rocket fuels since the mid-1950s (Mossberg 1976~. It has also been used in surgical plasters (Brzezicka-Bak 290

N-Phenyl-beta-naphthylamine TABLE X-1 Physical and Chemical Properties 291 Formula COHEN Synonyms PNA, N-phenyl-2-naphthylamine, 2-napthalen- amine, N-phenyl, N-~2-naphthyl) aniline, 2- H a n i 1 i n 0 n a p h t h a 1 i n e , b e t a - n a p h t h y 1 p h e n y 1 a m i n e , / \ Agerite powder, Neozone-D, Antioxidant 1 16 CA 135-88-6 S registry no. Specific gravity 1.24 Molecular weight 219.29 Melting point 108°C Boiling point 395.5°C Solubility Insoluble in water (as pure powder); soluble in alco- hol, ether; soluble in water at parts per million level (Vine et al. 1984) Vapor pressure 8.3 x 10-6 mmHg (at 25°C) 1973) and in tin-electroplating baths. Commercial grade PBNA in the United States has been reported to contain, as a contaminant, 20-30 milli- grams per kilogram (mg/kg) of the human bladder carcinogen beta- naphthylamine (BNA) (IARC 1974~. In Japan, commercial grade PBNA contains aniline, 2-naphthol, and BNA. Levels of BNA contamination in commercial PBNA in the United Kingdom are reportedly reduced to less than 1 mg/kg in at least one commercial product (Veys 1996~. In 1976, PBNA was nominated and selected for toxicology and carcinogenesis stud- ies by the National Toxicology Program (NTP) because of its large annual production, widespread human exposure, and structural andpossible invivo metabolic similarity to the known human urinary bladder carcinogen BNA (NTP 1988~. Domestic production of PBNA in the early 1970s was 1.4 to 2.2 million kg per year (y) (ACGIH 1991, pp. 1211 - 1213~. PBNA is no longer used in the United States. Detection in Spacecraft PBNA has been detected in multiple humidity-condensate and regener-

292 Spacecraft Water Exposure Guidelines ated-water samples of the Mir space station. Its origin is unknown. The Mir-18 and Mir-19 missions demonstrated PBNA concentrations ranging from 0.3 micrograms per liter (vigil) to 13.1 ~g/L in four samples of regen- erated water (Pierre et al. 1996~. PBNA was detected at concentrations ranging from 0.3 ~g/L to 0.5 ~g/L in humidity-condensate samples col- lected in a series of water tanks during the Mir-20 mission. A concentration of 75 ~g/L was detected in humidity condensate via use of the Russian atmospheric-condensate sampler during that same mission (Pierre et al. 1996~. There was no PBNA detected in ground supply water used in the Mir- 1 ~ or Mir-20 missions. PBNA was detected in four regenerated water samples from the Mir-21 mission at concentrations ranging from 0.2 ~g/L to 11.7 ~g/L (Pierre et al. 1997~. It was also detected in four humidity- condensate samples at concentrations ranging from 4.8 ~g/L to 55.5 vigil. It was not detected in stored (launched from the ground) water samples from that mission. It is noted that BNA was detected at 0.5 ~g/L in one of three hot regenerated water samples collected from Mir- 19 (Pierre et al. 1996~. BNA was not found when evaluated in other spacecraft water sam- ples. PHARMACOKINETICS AND METABOLISM In Vivo PBNA Conversion to BNA It has been reported that PBNA is dephenylated to the bladder carcino- gen BNA in rats, dogs, and humans by an undefined metabolic process. Several studies have been conducted to support that theory, and they are summarized in Table S-2. Kummer and Tordoir (1975) conducted a study in which 19 volunteers orally ingested PBNA containing an impurity of BNA at 0.S parts per million (ppm), which was equated to ~ nanograms (ng) (0.008 Age per 10 mg dose of PBNA. Based on the BNA contamination of ingested PBNA, and the amounts of BNA found in the urine samples ofthe volunteers, PBNA was determined to be at least partially metabolized to BNA in humans. Seven of 19 human subjects, six of whom were nonsmok- ers (BNA is a component oftobacco smoke), demonstrated otherwise unex- plainable amounts of BNA in their urine following PBNA ingestion. Dogs given a single dose of a commercial grade of PBNA at 5 mg/kg were found to have BNA in 24-hour (h) urine samples at 3-4 fig (Batten and Hathway 1977~. Laham and Potvin (1983) described experimental results indicating the metabolism of PBNA to BNA in Sprague-Dawley rats. A study con- ducted at the Southern Research Institute (SoRI) in 1986 for the National

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N-Phenyl-beta-naphthylamine 295 Institute of Environmental Health Sciences determined that BNA detected in the urine of male F-344 rats only indicated an impurity in the 99°/0 pure PBNA test compound. Following acid hydrolysis for improved sensitivity, urine samples were observed to contain 2.~- 10 fig of BNA. From the above studies it appears that humans, dogs, and some rat species metabolize orally ingested PBNA to BNA. The SoRI (1986) and Laham and Potvin (1983) studies demonstrate that better measurements of BNA are obtained using techniques that minimize degradation of the amine in urine samples, such as the collection of urine under dry ice or the use of liquid nitrogen for immediate freezing of the collected sample. Both Batten and Hathway (1977) and Laham and Potvin (1983) utilized heptafluoro derivatives of PBNA and BNA to optimize detection of the amines by gas chromatogra- phy. The purity oftested PBNA, and especially the amount of BNA contami- nation, can effect experimental results relative to the demonstration of BNA excretion in an animal species. The Kummer and Tudoir (1975), Moore (1977), Laham and Potvin (1983), and SoRI (1986) studies provide state- ments regarding the purity and/or BNA contamination ofthe tested PBNA. Batten and Hathway ~ 1977) offer no assertion regarding the amount of BNA contaminant in tested PBNA, but indicate that a commercial (nonpurif~ed) grade of PBNA was used. Laham and Potvin (1983) state that tested PBNA in their study was purified (percentage not given) through treatment with ethanol and charcoal; however, BNA contamination is not addressed. In the absence of verifiable BNA contamination levels (Laham and Potvin 1 983; Batten and Hathway 1977), it may be suggested, but not confirmed, that BNA observed in the urine oftested species originated as an impurity in the tested PBNA rather than as an in vivo metabolite. BNA is excreted in the feces and urine of both rats and dogs (Boyland and Mason 1966) following subchronic dietary administration. Previous investigations have shown that it is the metabolites of BNA that are respon- sible for its carcinogenicity. Primary BNA carcinogenic metabolites 2- naphthy~hydroxylamine (BNHA) and 2-amino-naphthylsulfate were not detected (detection limit of 50 ng) in the urine samples of dogs fed a single dose of PBNA at 5 mg/kg or in the urine of dogs fed multiple doses at 27 mg/kg for 4 weeks (wk) (Batten and Hathway 1977~. Neither BNA nor its carcinogenic metabolite BNHA were detected (detection limits not given) in mammalian hepatic microsomal preparations incubated with 0.5 millimolar (mM) PBNA (Anderson et al. 1982~. Batten and Hathway ~ 1977) applied the Druckrey and Kupfmuller equa- tion c'7 x t x n = k (c! is the daily dose in mg/kg, t is the time between treat- ment initiation and tumor formation in months, and n is a small positive

296 Spacecraft Water Exposure Guidelines integer), which describes the dose-effect and time relationships in animals subjected to daily dosing with a chemical. Assuming that this equation can be employed when BNA is produced as a metabolite of PBNA ingestion, Batten and Hathway calculated that the time that would have to elapse for tumors to be formed when 1,500 ng of BNA (average amount of BNA found in all PBNA-treated animals) was the daily exposure dose would be 31 y, thus exceeding the lifespan ofthe species. They concluded that BNA generated from metabolism of PBNA is at such low levels that any alleged dephenylation of PBNA in viva does not produce carcinogenic risk. Absorption No data on the absorption of PBNA have been found. Laham and Potvin (1983) suggest that PBNA is absorbed through the gastrointestinal tract as demonstrated by slow excretion over several days as either un- changed PBNA or as BNA in both the feces and urine of orally dosed Sprague- Dawley rats administered a single dose (50 mg per rat) of PBNA (Table 8-3~. Distribution There are no data on the distribution of orally ingested PBNA. Laham and Potvin (1983) suggest that PBNA is stored in rat tissues during repeated administration; however, no data have been found to support that sugges- tion. Excretion PBNA is apparently excreted as a free amine, as the dephenylated me- tabolite BNA, as free and conjugated hydroxylated metabolites of either PBNA or BNA, or as epoxides (Laham and Potvin 1983~. The primary route of excretion is the fecal route. Dogs dosed intragastrically with a single dose of ~4C-labeled PBNA at 5 mg/kg demonstrated excretion of >90°/O of the radioactivity from the body within 3 days (~) (Batten and Hathway 1977~. Excretion occurred principally via the biliary/ fecal route (amount not given). PBNA was excreted in the urine for 3 ~ following a single dose (50 ma) by oral administration to male Sprague-Dawley rats (Table 8-3) (Laham and Potvin 1983~. No PBNA was detected after 72 h.

N-Phenyl-beta-naphthylamine TABLE X-3 Urinary Excretion of PBNA and BNA in Male Sprague-Dawley Rats Following a Single Oral Dose of PBNAa 297 Time Interval After Dose (h) PBNA (fig) BNA (fig) 0-24 15.96 0.37 24-48 3.93 0~40 48-72 Trace 0.35 72-96 Not detected 0.28 a50 mg per rat (200 mg/kg assuming a 0.25-kg rat); detection limit was 0.5 ~g/mL. Source: Laham and Potvin 1983. Following multiple-dose administration ( 100 mg/kg/d), PBNA was detected in rat feces in substantial amounts 5 d after the last administration. Increas- ing urinary concentrations of PBNA and BNA at 0-96 h after the first dose are presented in Table 8-4 (Laham and Potvin 1983~. Metabolism Anderson et al. ( 1982) conducted an in vitro study on the hepatic micro- somal metabolism of and macromolecular binding to PBNA in seven mam- malian species, including male Sprague-Dawley rats, male B6C3F~ mice, a male rhesus monkey, male Syrian Golden hamsters, a human, a male beagle, and a female pig. The relative abilities of the tested species to me- tabolize PBNA decreased in the order of hamster, mouse, rat, monkey, dog, human, pig (Table 8-5~. Rates of metabolism were determined by colori- metric assay indicating formation of hydroxylated species. Hydroxyaryl- amine concentrations were calculated on the basis of changes in absorption at 535 nm. Anderson suggests that metabolism of PBNA may occur via oxidation by cytochrome P-450 mixed function oxidase systems to various hydroxyl- ated metabolites. Two metabolites formed by all seven animal species were 6-hydroxy-N-phenyl-2-naphthylamine (6-OH-PBNA) and 4'-hydroxy-N- phenyl-2-naphthylamine (4'-OH-PBNA). These (and other) metabolites were identified by high performance liquid chromatography (HPLC) and mass spectral analysis, with nuclear magnetic resosance (NMR) confirma- tion. The ratio of 6-OH-PBNA to 4'-OH-PBNA formation varied between species: In mouse, rat, and monkey, the ratio was 0.4; in man and dog, the ratio was 1.0; and in hamster, the ratio was 1.5. Induction of cytochrome

298 Spacecraft Water Exposure Guidelines TABLE X-4 Urinary Excretion of PBNA and BNA in Male Sprague-Dawley Rats After 4 ~ of Oral Administrationa Time Interval After First Dose (h) PBNA hogs BNA begs 0-24 20.92 2.62 24-48 110.64 7.28 48-72 277.91 5.36 72-96 415.37 18.48 alOO mg per rat per day (400 mg/kg/d assuming a 0.25-kg rat); detection limit was 0.5 ~g/mL. Source: Laham and Potvin 1983. P-450 in rats by pretreatment with phenobarbital or 3-methy~chol-anthrene caused an increase in the rate of formation of hydroxylated species (Table S-6~. Rat liver microsomes incubated with PBNA in the presence of cytochrome P-450 inhibitors resulted in reduced production of the hy- droxylated metabolites by approximately 50%. The ratio of 6-OH-PBNA and 4'-OH-PBNA formation varied with species, with cytochrome P-450 induction by 3-methy~cholanthrene, and with cytochrome P-450 inhibition by DPEA (Table S-7~. This infers that epoxidation of PBNA occurs through distinct cytochrome P-450 systems. There is no information avail- able on the specific cytochromes responsible for PBNA metabolism. TABLE 8-5 Relative Rates of Microsomal Metabolism of PBNA by Various Speciesa Species Pig Human Dog Monkey Rat Rate (nmol/min per mg protein) ~ SD 0.4~0.2 Mouse Hamster aRates were determined by calorimetric assay. Abbreviations: nmol, nanomoles; SD, standard deviation. Source: Anderson et al. 1982. 0.6 0.9~0.2 1.2~0.4 1.3~0.1 1.9~0.1 3.5 ~ 0.5

N-Phenyl-beta-naphthylamine 299 TABLE X-6 Induction of PBNA Metabolism in Rat Hepatic Microsomesa Pretreatment Rate (NO of control) ~ SD 100 ~ 13 300+ 13 Control 3 -Methylcholanthrene Phenobarbitol 150~8 aRates were determined by calorimetric assay. Abbreviation: SD, standard deviation. Source: Anderson et al. 1982. Figure 8-1 illustrates the conjectured avenues of metabolic degradation of PBNA. Anderson et al. (1982) hypothesize that epoxidation of the naphthy! or the phony! group of PBNA occurs via cytochrome P-450 oxida- tion, followed by isomerization to yield the respective 6-OH-PBNA and 4'-OH-PBNA metabolites. Alternatively, N-hydroxylation of PBNA could occur, followed by acid-catalyzed decomposition to produce a delocalized nitrenium-carbonium ion, which would then solvolyse, leading to the for- mation of the same hydroxylated metabolites. However, the N-hydroxyI- ation pathway is unlikely. For either argument, Anderson et al. suggest that 4'-OH-PBNA can undergo oxidation to form benzoquinone and BNA. An- derson et al. (1982) demonstrated oxidative dephenylation of 4'-OH-PBNA to produce BNA and 1,4-benzoquinone (Figure 8-1) by treating the hydroxyarylamine with an excess of hydrogen peroxide in sodium phos- phate. These avenues of PBNA metabolism are purely conjectural, as many of the proposed metabolic species (bracketed in Figure 8-1) were not iso- TABLE X-7 Ratio of Principal Metabolites of PBNA Formed in Microsomal Incubations When Pretreated with DPEAa Ratio (6-OH-PBNA/4'-OH-PBNA) Rat Microsomes Control MC-treatedb Human Microsomes 0 0.30 0.25 0.35 0.1 0.43 0.80 0.82 0.5 0.62 1.09 1.04 aPretreated for 3 min. bRat microsomes subjected to the cytochrome P-450 inducer 3-methylcholanthrene. Source: Anderson et al. 1982.

300 Spacecraft Water Exposure Guidelines PBhlA OH 7~ MAT/ :2 At/ 45 11 1 1 11 1 Am\ 4~ ~3 21~ ~4' N-Hydroxylation ~,6-Ep Will atio I OH I'm! o 07 H H | OH I OH 3'14'-E po xi~l~ion H H2O 1 /~ ~ OH ¢~ O 5 Jet'. s~.T j~\ H2~/ ~20 I H H 6-OH-PONA 4P-OH -Pa NA OH 1 [o] ~ —\ o +H~ J ~ ~ A 0 1 ' - =eoqu~e FIGURE 8-1 Conjectured metabolism of PBNA by microsomal enzymes via cytochrome P-450. Bracketed species were not isolated. Source: Anderson et al. 1982. lated in the experiment. Also, the BNA was produced only by artificial (nonphysiologic) means. 3H-PBNA microsomal incubations were examined by HPLC for detec- tion of BNA and its primary hydroxylation product, 2-amino-1-naphthol

N-Phenyl-beta-naphthylamine i 301 (detection limit not giver). However, neither BNA nor2-amino-1-naphtho! was detected in microsomal incubations. Anderson et al. (1982) also demonstrated a time-related linear increase In protein binding occurring parallel to the formation of the above metabo- lites by microsomal metabolism of PBNA. This finding suggests that me- tabolites of PBNA, perhaps epoxides, are involved in macromolecular bind- ing. TOXICITY SUMMARY There are no studies that address toxicity resulting from ingestion of PBNA in drinking water for humans or nonhumans. Toxicity studies have been conducted for orally administered PBNA by means of intragastric or dietary ingestion. Loss of body weight and increased liver-to-body weight ratios were seen in short-term, subchronic, and chronic rodent toxicity studies (NTP 1988~. The kidney is the primary target organ for adverse effects of orally ingested PBNA. Nephropathic lesions were observed in both F-344N rats and B6C3F~ mice. Other adverse effects include gastroin- testinal disturbances, evidence of immunotoxicity end reproductive toxicity, and hematopoietic irregularities. A primary concern of PBNA exposure is that it is converted in viva to the bladder carcinogen BNA, and can hence initiate cancerous lesions. Epidemiological studies of workers in rubber tire factories presented no evidence that occupational exposure to atmospheric PBNA increased incidence of bladder tumors, although inhalation of PBNA mixed with other chemicals was associated with increased incidences of other cancers among workers. No studies have been conducted to determine carcinogenicity of PBNA to humans exposed via oral ingestion. Acute Toxicity (1-5 d) r An oral LD50 (dose lethal to 50°/O of subjects) of 8,730 mg/kg has been established for rats administered PBNA orally in a vegetable oil suspension (Kelman 1964~. Unspecified vascular changes in the liver, lungs, and brain occurred as a result of venous congestion in rats administered this dose. Kelman also established an oral LD50 of 1,450 mg/kg for mice given PBNA in an oil suspension. Evidence of central nervous system (CNS) depression was observed and disturbance of liver function was indicated by depressed concentrations of hippuric acid. The strain and gender of the animals and

302 Spacecraft Water Exposure Guidelines the purity of the PBNA were not specified in either study. There are no human studies that address acute toxicity from PBNA administered orally. Short-Term Toxicity (6-30 d) The NTP electedto evaluate PBNA for its toxicologic and carcinogenic potential as an industrial chemical. Groups of five female and five male F- 344N rats and B6C3F~ mice were used in a 14-d study (NTP 1988~. Rats were fed 98°/O pure PBNA via ad libitum diet at doses of 330, 660, 1,400, 3,250, and 7,900 mg/kg (males) and 380, 820, 1,680, 4,120, and 7,800 mg/kg (females). Mortality rates were significant for both male and female rats at the higher doses three of five males and four of five females that received the highest doses died prior to the end ofthe study. Arched backs, rough coats, and diarrhea were observed in males that received PBNA at 1,400 mg/kg or higher and in females that received 4,100 mg/kg or higher. B6C3F~ mice received PBNA at 380, 740, 1,480, 2,960, and 6,150 mg/kg (males) and 450, 1,000, 1,900, 4,000, and 7,620 mg/kg (females). No compound-related clinical signs oftoxicity were observed in this trial. Rats apparently were more susceptible to adverse effects of oral ingestion of PBNA than were mice. It is noted that mice in the 14-dNTP (1988) study received PBNA at up to 7,620 mg/kg via ad libitum diet and demonstrated no evidence of clinical toxicity, whereas Kelman (1964) established an LD50 for mice ingesting PBNA at 1,450 mg/kg via oil suspension. These differing responses may be attributed to the strains of mice used in the experiments (the strain of mice in Kelman's study is not stated), the vehicle used for ingestion of PBNA, the purity of the PBNA (purity of PBNA was not given in the Kelman study), or the animal or laboratory husbandry employed in the studies. Subchronic Toxicity (30-lXO d) In 13-wk feed studies, groups of 10 male and 10 female F-344N rats were fed 98°/O pure PBNA via ad libitum diet at 200, 400, 800,1,800, and 6,800 mg/kg (males) and 300, 600, 1,200, 2,800, and 8,300 mg/kg (fe- males) (NTP 1988~. Rough coats were observed in rats that received 1,800 mg/kg. Liver-to-body weight ratios in dosed animals were observed to be substantially higher than those in control animals. The final mean body

N-Phenyl-beta-naphthylamine 303 weights of rats that received the highest doses were 60% lower than those of controls in males and 44°/O lower than those of controls in females. B6C3F~ mice fed 800,1,400,3,300,5,200, and 13,000 mg/kg (males) and 1,000,1,900,4,300,6,400, and 17,000 mg/kg (females) were also observed to have substantially higher liver-to-body weight ratios compared with control groups. Renal injury was the primary toxic response to PBNA in male and female rats and mice. Increased incidences of nephrotoxic lesions were observed in both species at higher dose levels. Four of 10 male rats died at peak dosage (6,800 mg/kg) 4 wk into the study. Nine of 10 female rats died at a peak dosage (S,300 mg/kg) 4 wk into the study. Two of 10 male mice died at peak dosage (13,300 mg/kg) and seven of 10 female mice died at peak dosage (17,000 mg/kg) at varying times prior to the completion of the study. Hematologic Effects In the 13-wkNTP (1988) oral feed study, hematopoietic hypoplasia or atrophy of the femoral bone marrow was seen in 7 of 10 male rats and in ~ of 10 female rats at the maximum doses of PBNA, 6,800 mg/kg and 8,300 mg/kg, respectively (NTP 1988~. Two of 10 females also demonstrated these hematological effects at a dose of 2,800 mg/kg. Evidence that these lesions caused specific hematopoietic deficiencies such as erythropenia was not presented, nor was a quantifiable description of the hematopoietic ef- fects offered in the study. For these reasons, hematologic effects were not used in establishing an acceptable concentration (AC) for PBNA ingestion. Gastrointestinal Effects In a study conducted to examine the induction of bladder cancer by aromatic amines, Syrian Golden hamsters were dosed twice per week via gavage with technical-grade PBNA in arachadis oil at 75 mg/kg for approx- imately 10 wk (Green et al.1979~. Hamsters exhibited hemorrhagic enteri- tis, diarrhea, and stomach ulcers. The majority (exact number not given) of the animals perished within a 10-wk period. Green et al. attributed the high mortality to the inability of the hamsters to tolerate this dose. Other possi- ble explanations include the use of a technical grade of PBNA as the test chemical or the quality of animal care.

304 Reproductive Toxicity Spacecraft Water Exposure Guidelines Testicular hypospermatogenesis was demonstrated in two of 10 male F-344N rats that received the maximum dose of PBNA, 6,800 mg/kg, in the 13-wkNTP feed study (NTP 1988~. Immunotoxicity Lymphoid degeneration ofthe thymus occurred in 4 of 10 male F-344N rats and in 7 of 10 females at the maximum doses of 6,800 mg/kg and 8,300 mg/kg, respectively, in the 13-wk toxicity study byNTP (1988~. Lymphoid depletion of the spleen also occurred at the above doses in 2 of 10 males and 6 of 10 females. Nephrotoxicity F-344N rats exposed to PBNA in the NTP (1988) 13-wk feed study were observed to have chemical-related nephropathies characterized by renal tubular epithelial degeneration and hyperplasia, with the occurrence of reddish-brown granulated material and degenerating leukocytes within the dilated tubules. The nephropathic lesions occurred at increased inci- dence and severity in female rats receiving PBNA at 1,200 mg/kg or greater doses. Male rats demonstrated lesions at doses of 1,800 mg/kg (4/10) and 6,800 mg/kg (7/10~. Dose-related nephropathies were also observed in B6C3F, mice that received PBNA at 1,900 mg/kg or greater in the 13-wk NTP feed study. Lesions included cortex dilation, epithelial necrosis, and tubular epithelial regeneration. Chronic Toxicity (0.5-3 y) PBNA was administered in the diet (ad libitum) to F-344N rats and B6C3F~ mice for 2 y (NTP 1988~. Doses given to rats were 103 mg/kg (Iow dose) and 225 mg/kg (high dose) for males and 11 ~ mg/kg (Iow dose) and 261 mg/kg (high dose) for females. Male mice received 500 mg/kg (Iow dose) and 1,000 mg/kg (high dose). Female mice received 450 mg/kg (Iow dose) and 900 mg/kg (high dose). Rats treated at low doses were

N-Phenyl-beta-naphthylamine 305 observed to have mean body weights 12- 15% lower than controls, and rats treated at high doses had mean body weights 16-3 1 % lower than controls. Mean body weights of low-dose mice were comparable to or within 7°/0 of controls, while mean body weights of high-dose mice were 5-13% lower than controls. Survival rates of dosed mice were comparable to those of controls. Dosed male and female rats had greater survival rates than those ofthe control animals; this was attributed to the lower body weight of dosed rats. Nephrotoxicity The kidney was the target organ for toxic effects in the 2-y feed study by NTP (1988), a finding consistent with previous observations that aro- matic amine s have a high potential for producing kidney lesions (NTP 1988~. Male rats received 103 mg/kg as a low dose and 225 mg/kg as a high dose. Female rats received 1 18 mg/kg as a low dose and 261 mg/kg as a high dose. Male mice received 500 mg/kg flow dose) and 1,000 mg/kg (high dose), and female mice received 450 mg/kg flow dose) and 900 mg/kg (high dose). Chemical-related non-neoplastic nephropathic lesions, karyomegaly, and hyperplasia occurred in the kidneys of both rats and mice that received the high doses of PBNA. Chemical-related kidney lesions in male rats consisted primarily of acute suppurative inflammation ofthe renal tubules. Suppurative inflammation ofthe kidneys occurred in 80°/0 (40/50) of the high-dose male rats, in 64% (32/50) of the low-dose male rats, and in 16% (~/50) of the control rats. This inflammation could possibly be attributed to an infectious process among the experimental animals; there- fore, its implications are examined with caution. Kidney lesions were more extensive and severe in female rats than in males. Kidney mineralization and calculi, necrosis of the renal papilla, tubular atrophy, epithelial hyperplasia, hydronephrosis, atrophy, and multifocal fibrosis were observed at increased incidences in high-dose (261 mg/kg) female rats. Nephropathic observations in high-dose (900 mg/kg) female mice in- cluded karyomegaly, occurring primarily in the convoluted tubules of the renal cortex, tubular regeneration, thickened basement membrane, dilated tubules containing granular casts, and mononuclear cell infiltrates. Tubular cell hyperplasia was observed in two high-dose female mice.

306 Carcinogenicity Spacecraft Water Exposure Guidelines Syrian golden hamsters were administered technical-grade PBNA in arachidis oil by gavage at 37.5 mg/kg twice per week for life (approx- imately 1.8 y). No chemical-related neoplastic growths were observed. Tumorigenic results were comparable between dosed and control animals, with tumor incidences of 1 1% for PBNA-treated animals and 14% for con- tro! animals receiving only arachidis oil. Other observed macroscopic and microscopic alterations were comparable to controls used in the experiment (Green et al. 1979~. In NTP's 2-y study, there was no evidence of carcinogenic activity for male or female F-344N rats fed diets containing PBNA at 103 mg/kg (Iow dose) and 225 mg/kg (high dose) for males and 1 18 mg/kg (Iow dose) and 262 mg/kg (high dose) for females (NTP 1988~. The absence of carcinoge- nicity in rats in that study might be related to the limited ability of this species strain to metabolize PBNA to the carcinogen BNA or its carcino- genic metabolites; however, PBNA metabolites were not evaluated in the study (NTP 1988~. Kidney neoplasms observed in both rats and mice were not significantly different from the historical incidence of tumors in NTP studies, with the exception oftwo tubular adenomas found in the high-dose female mice. Other carcinomas found in the study were determined to be unrelated to PBNA administration. Equivocal evidence of carcinogenic activity, indicated by the occurrence oftwo rare kidney neoplasms, a tubu- lar cell adenoma and a tubular cell adenocarcinoma, was seen in high-dose (900 mg/kg) female B6C3F~ mice. Incidences of other neoplasms found in that study were within the historical control range ofthe laboratory in which the studies were conducted (NTP 1988~. Ref~ned PBNA (ref~ned via repeated dissolution in 98% ethyl alcohol end recrystallization) was administered by gavage to male Wistar rats at 160 mg/kg and 320 mg/kg for 12 months (mo) (Wang and Wang 1981~. Twenty- seven of 57 dosedrats developed carcinomas ofthe lungs, kidneys, prostate, and pancreas. (Six of 43 oil-injected control animals developed these predominant tumors.) There was no information given regarding distinction of results on the basis of dose. In contrast to the 1988 NTP chronic (2-y) study in which PBNA was administered via ad libitum diet, rats in the Wang and Wang (1981) study received gavage (intragastric) administration of PBNA. Absorption characteristics differ between dietary and bolus dosage of a chemical and can affect the toxicologic consequences of chemical ingestion.

N-Phenyl-beta-naphthylamine 307 No bladder tumors were observed in female dogs fed PBNA at 540 ma, 5 d/wk in food, for 4.5 y (Gehrmann et al. 1949~. Male and female mice were given commercial (nonpurified) PBNA at 46 mg/kg by gavage for 3 wk followed by 18 mo of PBNA administration via ad libitum feed at 500 mg/kg (Innes et al. 1969~. Dosed animals had increased tumor incidences in an uncertain range. The results of this study were inconclusive, and the authors cited a need for additional statistical evaluation and/or experimenta- tion for adequate interpretation of the findings. In another study, male and female Sprague-Dawley rats given 600 mg/kg intragastrically twice per week for life demonstrated no neoplastic growths (Ketkar and Mohr 1982~. Tumors observed in treated animals (and not seen in controls) were considered isolated observations or within com- monly occurring spontaneous tumor incidences for a normal population of the animals. Tumor incidence data revealed a 20% tumor incidence for treated male rats and a 3% incidence for treated female rats. Control ani- mals, which received only arachidis oil, were observed to have a tumor incidences of 60% and 75% for male and female rats, respectively. An epidemiological study of workers in Shanghai concluded that an excess incidence of lung cancer in certain workshops of rubber tire factories might have resulted from exposure to PBNA aerosols (Wang et al. 1984~. The average concentrations measured in air samples in the "mixing" areas of one rubber factory ranged from 0.404 mg per cubic meter (m3) to 0.535 mg/m3. Concentrations in a second factory, where there was a lesser inci- dence of cancer among workers, averaged from 0.082 mg/m3 to 0.140 mg/m3. Wang et al. concluded that although experimental results suggest that PBNA might be carcinogenic to the lungs via inhalation, those results are inconsistent with the results of a separate in situ animal study that indi- cated that PBNA was not the sole cause of excess cancer incidences of the lungs or other organs. It is appropriate that Wang et al. also concluded that further epidemiological investigations of other materials in the factories, including other rubber additives, would be valuable. The epidemiological study conducted at a Midlands tire factory in the United Kingdom concluded that exposure to and use of PBNA did not increase the incidence of bladder tumors in the exposed workforce at the factory under normal operating conditions (Veys 1996~. The study, under- taken to assess bladder cancer morbidity, compared the medical follow-up through 1990 of 3,038 male rubber workers employed beginning January 1950 with the 2,577 men employed beginning January 1951 (less the 461 men engaged in 1950~. Antioxidants used in rubber manufacture contained

308 Spacecraft Water Exposure Guidelines BNA at 2,500 ppm; those antioxidants were withdrawn from factory use in 1949. Workers employed beginning January 1950 were exposed to the residuals ofthose antioxidants. Workers employed beginning January 1951 were exposed to PBNA (at 0.34-6.7 mg/m3) and other antioxidants contain- ing trace amounts of BNA (20-50 ppm). Observed bladder tumors in fac- tory workers were compared with national and regional rates of bladder tumor incidence. Based on national and regional incidence rates, a small excess of bladder tumors was observed in the cohort employed beginning January 1950. This excess was considered the result of "spillover risk" from residuals of carcinogenic antioxidants used prior to 1950. There was no excess bladder tumor incidence in factory workers employed starting January 1951, supporting the conclusion that there was effective removal of occupationally hazardous antioxidants from the work environment at the end of 1949. It is noted that Veys (1996) presented his study only in respect to blad- der cancer, whereas Wang et al. (1984) included cancers detected in multi- ple body organs. Wang et al. asserted that other factory aerosols could be responsible for the increased cancer incidences. Reproductive Toxicity No data were found relating to the reproductive toxicity of PBNA in humans. Impaired reproductive function, indicated by desquamation of spermatogenic epithelium, was reported in white male rats fed diets contain- ing industrial-grade PBNA at 100 mg/kg for 18 mo (Shumskaya et al. 1971). Shumskaya et al. observed that when dosed males were mated with healthy females, the resulting embryos perished twice as often as embryos resulting from mating between control males and healthy females. Further quantitative or qualitative descriptions of reproductive toxicity were not presented. In the NTP (1988) 2-y rodent feed study, ovarian and uterine suppurative inflammation and abscesses of other organs were observed in 15 of 50 female mice given the low dose (450 mg/kg) and in 19 of 50 fe- male mice fed PBNA at the high dose (900 mg/kg) (NTP 1988~. However, 10 of 50 control female mice also demonstrated these abscesses. The in- flammations were not specified as chemical-related events, and may have resulted from infection that subsequently compromised both the kidneys and ovaries in the mice. These inflammations are not useful as end points for establishing PBNA ACs because of the uncertainty of their origin.

N-Phenyl-beta-naphthylamine Developmental Toxicity No data were found on the developmental toxicity of PBNA. Genotoxicity 309 PBNA was evaluated as having a structural alert for DNA reactivity (potential genotoxic carcinogenicity) because of its carcinogenic subunit, BNA (Ashby et al. 1989~. Per evaluation of results from a battery of geno- toxicity tests disposed by the NTP, PBNA is ostensibly a rather weak cIastogen and mutagen at elevated concentrations, extended exposure times, and in the presence of metabolic activation (Table A-. Dimethyl sulfoxide (DMSO) was the solvent of choice for those studies, and the purity of the tested PBNA was 99°/O or better. PBNA has been detected in both recIaimed-water and humidity-conden- sate samples from the Mir space station. The data from Mir-21 are repre- sentative of the concentrations that were found at roughly equal intervals over the duration of the mission. Five sequential samples of reclaimed water had concentrations of 0.2, 0.2, 0, 6.3, and 11.7 vigil. Four samples of humidity condensate had concentrations of 15.3, 4.S, 15.3, and 55.5 vigil. The data on PBNA presented in Table S-S show that it is a weak, if not questionable, genotoxic compound at nontoxic concentrations. Levels of PBNA detected in spacecraft regenerated-water or humidity-condensate sample levels did not exceed 55 vigil, or 0.055 fig per milliliter (mL). Because test concentrations are several orders of magnitude above space- craft contaminant levels and yield mainly negative results, there should be minimal risk of PBNA genotoxicity for spacecraft crew members. Health and Occupational Standards The International Agency for Research on Cancer (IARC) has classified PBNA a Group 3 (not classifiable as to its carcinogenicity to humans) chemical (IARC 1987~. IARC has concluded that there is limited evidence that PBNA is a carcinogen to animals. The Occupational Safety and Health Administration (OSHA) has not set a PEL (permissible exposure limit) for PBNA (ACGIH 1991, pp. 121 1-1213~. The National Institute for Occupa-

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316 Spacecraft Water Exposure Guidelines tional Safety and Health (NIOSH) considers PBNA to be a potential occu- pational carcinogen. NIOSH recommends that all occupational carcinogens be limited to the lowest feasible concentration. There are no set recom- mended exposure limit/immediately dangerous to life or health (REL/ IDLH) levels for PBNA by NIOSH. The American Conference of Govern- mental Industrial Hygienists (ACGIH) has evaluated PBNA as an A4 (not classifiable as a human carcinogen) chemical with no recommended Thresh- old Limit Value (TLV) (ACGIH 1998, p. 55~. There are no further regula- tory agency health or occupational standards for PBNA. RATIONALE There were no toxicity studies in which PBNA was administered in drinking water to human or nonhuman species. Therefore, data used to establish acceptable concentrations (ACs) for PBNA are those involving oral ingestion via ad libitum feed. This lends some uncertainty to the pro- cess of deriving spacecraft water exposure guidelines (SWEGs) for PBNA, because absorption of PBNA administered intragastrically or in the diet can vary from absorption of PBNA ingested in drinking water. ACs were for- mulated for each principal adverse affect, nephrotoxicity and gastrointesti- nal toxicity, observed following exposure of various animal species to PBNA. Calculation of ACs includes the assumption that each crew member will use 2.8 L of water per day and has an average body weight of 70 kg. SWEG values were derived based on the lowest obtained AC for each prin- cipal adverse effect. AC values were determined following guidance set by the National Research Council (NRC 2000~. PBNA is stated to be soluble in water at the parts-per-million level (Vine et al. 1984~. The established guidelines for 1- and 10-d exposures (Table 8-10) clearly exceed PBNA water solubility. These guidelines af- ford crew members protection from gastric irritation. All of the ACs for PBNA are presented in Table 8-1 1. Ingestion for 1 d There are no reported human or nonhuman studies for acute toxicity to PBNA. Short-term toxicity studies conducted by NTP demonstrated a NOAEL (no-observed-adverse-effect level) of 660 mg/kg for gastrointesti- nal effects (diarrhea) observed at 1,400 mg/kg or more in male F-344N rats receiving 98°/O pure PBNA for 14-d in feed (NTP 1988~. A species extra-

N-Phenyl-beta-naphthylamine TABLE X-10 Spacecraft Water Exposure Guidelines for PBNA 317 Exposure Duration 1 d 10 d 100 d 1,000 d Concentration (mg/L) 1,600 1,600 500 260 Target Toxicity Gastrointestinal toxicity Gastrointestinal toxicity Nephropathic lesions Nephropathic lesions polation factor of 10 was applied in addition to the assumption of a 70-kg person ingesting 2.S L of water per day. The AC for 1 d was calculated as follows: 1-d AC = (660 mg/kg x 70 kg) (10 x 2. ~ L/d) = 1,650 mg/L. Ingestion for 10 d The AC for a 10-d exposure period was derived on the basis ofthe 14-d NTP study using the NOAEL of 660 mg/kg for gastrointestinal disturbances in male F344N rats. 10-d AC = (660 mg/kg x 70 kg) (10 x 2.8 L/d) =1,650 mg/L. Ingestion for 100 d Chemical-related nephrotoxicity was demonstrated in NTP's 13-wk studies in F-344N rats and B6C3F~ mice. A dose-related increase in the severity of nephrotoxic response occurred in females of both species (NTP 1988). Nephropathic lesions were observed at 1,900 mg/kg doses in mice. Nephropathic lesions observed at 1,200 mg/kg in female rats were not seen at the next lower dose of 600 mg/kg, hence a NOAEL of 600 mg/kg was designated. A species extrapolation factor of 10 and a time factor of 1.1 (for extrapolation from 91 d to 100 d) were applied to the AC calculation along with the assumption of a 70-kg person ingesting 2.8 L of water per day. The 100-d AC for nephrotoxicity was calculated as follows: 100-d AC = (600 mg/kg x 70 kg) (10 x 2.8 L/d x 1.1); 100-d AC = 1,300 mg/L (rounded).

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320 Spacecraft Water Exposure Guidelines BMD calculations for the 100-d AC were derived using data from the NTP (1988) study in which female F-344N rats were fed doses of PBNA at 300, 600, 1,200, 2,800, and 8,300 mg/kg for 13 wk. (Incidences of nephrotoxicity were 0/10, 0/10, 0/10, 2/10, and 7/10 at those respective doses.) A dose-related increase in the severity of nephropathic lesions was observed in the rats. Nine of 10 rats receiving the highest dose, 8,300 mg/kg, perished; consequently, this dose was not included for derivation of the BMD. The probit-Iog model was selected as the most appropriate model based on the generateUp value of 0.97. BMD calculations at the 95°/O confidence interval and at a benchmark response of 1% resulted in a 500 mg/L AC for nephrotoxicity. (BMD results are presented in Table 8- 12, above.) 100-d AC = (226 mg/kg (BMDLo~ orNOAEL) x 70) (10 x 2.8 L/d x 1.1~; 100-d AC = 500 mg/L (rounded). Ingestion for 1,000 d The 1,000-d AC was calculated on the basis ofthe 2-y NTP (1988) feed studies in which F-344N rats were observed to have non-neoplastic kidney lesions at the maximum doses of PBNA, 225 mg/kg for male rats and 261 mg/kg for female rats. Lesions were not observed at the lowest dose of 103 mg/kg in the male species or 11 ~ mg/kg in the female species. 1,000-d AC = (103 mg/kg x 70 kg) (10 x 2.8 Lab; 1,000-d AC = 260 mg/L (rounded). REFERENCES ACGIH (American Conference of Governmental and Industrial Hygienists). 1991. Documentation of the Threshold Limit Values and Biological Exposure Indi- ces. Cincinnati, OH: ACGIH. ACGIH (American Conference of Governmental and Industrial Hygienists).1998. Threshold Limit Values for Chemical Substances and Physical Agents Biologi- cal Exposure Indices for 1998. Cincinnati, Ohio: ACGIH. Anderson, B.E., et al. l 990. Chromosome aberration and sister chromatic exchange test results with 42 chemicals. Environ. Mol. Mutagen.16(Suppl.18~:55-137. Anderson, M.M., R.K. Mitchum, and F.A. Belum.1982. Hepatic microsomal met- abolism and macromolecular binding of the antioxidant, N-phenyl-2- naphthylamine. Xenobiotica 12~1~:31-43.

N-Phenyl-beta-naphthylamine 321 Arutyunyan, R.M., et al. 1987. Study ofthe mutagenic effect of latex polymeriza- tion stabilizer on various systems. Tsitol. Genet. 21~6~:450-454. Ashby, J., et al.1989. Classification according to chemical structure, mutagenicity to salmonella and level of carcinogenicity of a further 42 chemicals tested for carcinogenicityby the U.S.NationalToxicology Program. Mutat. Res.223:73- 103. Batten, P.L., and D.E. Hathway. 1977. Dephenylation of N-phenyl-2-naphthyl- amine in dogs and its possible oncogenic implications. Br. J. Cancer 35:342-346. Bourne, H.G., et al. 1968. The toxicity of rubber additives. Arch. Environ. Health 16:700-705. Boyland, E., and D. Manson. 1966. The biochemistry of aromatic amines. Biochem. J. 101:84-102. Brzezicka-Bak, M. 1973. Evaluation of plasters used in medicine. Farm. Poll 29:865- 872. Case, R.A.M., and M.E. Hosker. 1954. Tumour of the urinary bladder as an occupational disease in the rubber industry in England and Wales. Br. J. Preventat. Soc. Med. 8:39-50. Emmelot, P., and E Kriek, eds. 1979. Environmental Carcinogenesis: Occurrence, Risk Evaluation and Mechanisms. Proceedings ofthe International Conference on Environmental Carcinogenesis, Amsterdam, Netherlands. Fox, A.J., D.C. Lindars, and R. Owen.1974. A survey of occupational cancer in the rubber end cable-making industries: Results offive-yearanalysis, 1967-71. Br. J. Ind. Med. 31: 140-151. Gehrmann, G.H., J.H. Foulger, and A.J. Fleming. 1948. Occupational tumors of the bladder. The Proceedings ofthe Ninth International Congress on Industrial Medicine, London, UK. Green, U., J. Holste, and A.R. Spikermann. 1979. A comparative study of the chronic effects of magenta, paramagenta, end phenyl-naphthylamine in Syrian golden hamsters. J. Cancer Res. Clin. Oncol. 95:51-55. Haseman, J.K., and A.-M. Clark. 1990. Carcinogenicity results for 114 laboratory animal studies used to assess the predictivity of four in vitro genetic toxicity assays for rodent carcinogenicity. Environ. Mol. Mutagen. 16( Suppl. 18~:15- 31. IARC (International Agency for Research on Cancer). 1978. N-Phenyl- 2-naphthylamine - some aromatic amines and related nitro compounds - hair dyes, coloring agents and miscellaneous industrial chemicals. Pp. 325-341 in Monographs on Carcinogenic Risk of Chemicals to Man, Vol. 16. Lyon, France: IARC. IARC (International Agency for Research on Cancer). 1987. Overall Evaluations of Carcinogenicity: An Updating of IARC Monographs, Vols. 1-42. Lyon, France: IARC. Pp. 318-319. Innes, J.R.M., et al. 1969. Bioassay of pesticides and industrial chemicals for tumorigenicityin mice: A preliminary note. J. Natl. CancerInst.42:1101-1114. James, J.T., and D.E. Gardner.1996. Exposure limits for airborne contaminants in

322 Spacecraft Water Exposure Guidelines space atmospheres. Appl. Occup. Environ. Hyg. 11~12~:1424-1431. Kawachi, T., et al. 1980. Cooperative program in short-term assays for carcino- genicity in Japan. Pp. 323-330 in IARC Scientific Publication #27. Lyon, France: International Agency for Research on Cancer (IARC). Kehe, H.J., and C.S. Kouris. 1965. Pp. 40-49 in Encyclopedia of Chemical Tech- nology,2nd Ed., R.E. Kirk and D.F. Othmer, eds. New York, NY: Wiley and Sons. Kelman, G.Y. 1964. A study of toxicity of certain rubber antioxidants and their hygienic assessment. Gig. Sanit. 31 :25-28. Ketkar, M.B., and M.B. Mohr.1982. The chronic effects of magenta, paramagenta, and phenyl -naphthylamine in rats after intragastric administration. Cancer Lett. 16:203-206. Klaassen, C., ed. 1996. Casarett and Doull's Toxicology: The Basic Science of Poisons, 5th Ed. New York, NY: McGraw-Hill. Kummer, R., andW.F. Tordoir.1975. Phenyl-beta-naphthylamine (PBNA), another carcinogenic agent? Tijdschr. Soc. Geneeskd. 53 :415-419. Laham, S., and M. Potvin. 1983 Biological conversion of N-phenyl-2-naphthyl- amine. Drug Chem. Toxicol. 6~3~:295-309. Moore, R.M., et al. 1977. Metabolic precursors of a known human carcinogen. Science 195:344. Mossberg, W.1976. U.S. mulls curb on rocket-fuel chemical due to possible cancer link for workers. New York Times, December 21. Myhr, B., et al. 1990. L5178Y mouse lymphoma cell mutation assay results with 41 compounds. Environ. Mol. Mutagen. 16(Suppl. 18~: 138-167. NIOSH (National Institute for Occupational Safety and Health). 1975-77. Meta- bolic precursors of a known carcinogen, beta-naphthylamine. NIOSH Current Intelligence Bulletin, Vol.1 - 18. National Institute for Occupational Safety and Health, National Institutes of Health, Bethesda, MD. NIOSH (National Institute for Occupational Safety and Health). 1997. NIOSH Pocket Guide to Chemical Hazards. PublicationNo.97-140. Washington, DC: U.S. Government Printing Office. NRC (National Research Council). 1992. Chemical water quality and monitoring requirements of reclaimed water for space station Freedom. Washington, DC: National Academy Press. NTP (National Toxicology Program).1988. Toxicology and Carcinogenesis Studies of N-Phenyl-2-naphthylamine (CAS No. 135-88-6) in F344/NRats and B6C3F1 Mice (Feed Studies). NTP TR 333. National Toxicology Program, U.S. Department of Health and Human Services, Washington, DC. Paxman, D.G., and J.C. Robinson. 1990. Regulation of occupational carcinogen under OSHA's air contaminants standard. Regul. Toxicol. Pharmacol. 12: 296-308. Pierre, L., et al. 1996. Collection and Chemical Analysis of Reclaimed Water and Condensate from the Mir Space Station. SAE-ICES Paper 961569. Warren- dale,PA: Society of Automotive Engineers. Pierre, L., et al. l 997. Chemical Analysis of Potable Water and Humidity Conden-

N-Phenyl-beta-naphthylamine 323 sate Collected During the MIR-21 Mission. SAE-ICES Paper 972462. Warrendale, PA: Society of Automotive Engineers. Sax, N.I. 1984. Dangerous Properties of Industrial Materials, 6th Ed. New York, NY: Van Nostrand Reinhold Company. Scott, T.S. 1962. Carcinogenic and Chronic Toxic Hazards of Aromatic Amines. New York, NY: Elsevier. SoRI (Southern Research Institute). 1986. Metabolism of N-Phenyl-2-naphthyl- amine (PNA) After Feeding to Fischer 344 Rats. Prepared by Southern Re- search Institute, Birmingham, AL, for National Institute of Environmental Health Sciences, Research Triangle Park, NC. Shumskaya, N.V., V.N. Ivanov, andN.S. Toltskaya.1971 Long-term effects ofthe chronic poisoning of white rats with neozone D. Toksikol. Novykh. Prom. Khim. Veshchestv. 12:86-93. Sofuni, T., et al. 1990. A comparison of chromosome aberration induction by 25 compounds tested by two Chinese hamster cell (CHL and CHO) systems in culture. Mutat. Res. 241:175-213. Veys, C.A. 1996. Bladder cancer in rubber workers. Prog. Rubber Plastics Technol. 12:258-273. Vine, J., Watson, T.R., and B. Ford. 1984. Three new contaminants detected in postmortem blood samples. J. Anal. Toxicol. 8:290-292. Wang, H.W., et al. 1984. Investigation of cancer epidemiology and study of carcinogenic agents in the Shangai rubber industry. Cancer Res. 44:3101- 3105. Wang, D., and H.-W. Wang.1981. The carcinogenicity of refined antioxidant D in wistar rats. Tumor 1:1-2. Zieger, E. 1990. Mutagenicity of 42 chemicals in salmonella. Environ. Mol. Muta- gen. 16(Suppl. 18~:32-54.

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To protect space crews from contaminants in potable and hygiene water, NASA requested that the National Research Council (NRC) provide guidance on how to develop water exposure guidelines and subsequently review NASA’s development of exposure guidelines for specific chemicals.

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