6
Caprolactam

Raghupathy Ramanathan, Ph.D. NASA-Johnson Space Center Houston, Texas

PHYSICAL AND CHEMICAL PROPERTIES

Use and Occurrence

Caprolactam is a cyclic amide, derived from epsilon-aminocaproic acid, from which nylon 6 is polymerized (see Table 6-1). Caprolactam is a monomer primarily used in the manufacture of the synthetic polymer nylon 6, fibers and resins, synthetic leather, and as a polyurethane cross linker. Nylon 6 (polycaprolactam) is used in the production of tire cords, carpeting, plastics, and food-packaging materials. Caprolactam has been

TABLE 6-1 Physical and Chemical Propertiesa

Formula

C6H11 NO

Chemical name

Caprolactam

Synonyms

Hexahydro-2-H-azepin-2-one, 6-Aminocaproiclactam, epsilon caprolactam, 2-Oxohexamethyleneimine, 6-Hexanelactam

CAS registry no.

105-60-2

Molecular weight

113.2

Vapor pressure

6.0 mm Hg @ 120 ­°C (800 Pa at 120 ­°C [ACGIH 1991]) 0.0021 mm Hg at 25 ­°C

Saturated vapor concentration

13 mg/m3

Boiling point

180 ­°C at 50 mm Hg

Solubility

Very soluble in water, benzene, diethylether, and ethanol

Conversion factor

mg/m3 = 4.6 × ppm

aData from HSDB 2006 and Merck Index 1989.



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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 6 Caprolactam Raghupathy Ramanathan, Ph.D. NASA-Johnson Space Center Houston, Texas PHYSICAL AND CHEMICAL PROPERTIES Use and Occurrence Caprolactam is a cyclic amide, derived from epsilon-aminocaproic acid, from which nylon 6 is polymerized (see Table 6-1). Caprolactam is a monomer primarily used in the manufacture of the synthetic polymer nylon 6, fibers and resins, synthetic leather, and as a polyurethane cross linker. Nylon 6 (polycaprolactam) is used in the production of tire cords, carpeting, plastics, and food-packaging materials. Caprolactam has been TABLE 6-1 Physical and Chemical Propertiesa Formula C6H11 NO Chemical name Caprolactam Synonyms Hexahydro-2-H-azepin-2-one, 6-Aminocaproiclactam, epsilon caprolactam, 2-Oxohexamethyleneimine, 6-Hexanelactam CAS registry no. 105-60-2 Molecular weight 113.2 Vapor pressure 6.0 mm Hg @ 120 ­°C (800 Pa at 120 ­°C [ACGIH 1991]) 0.0021 mm Hg at 25 ­°C Saturated vapor concentration 13 mg/m3 Boiling point 180 ­°C at 50 mm Hg Solubility Very soluble in water, benzene, diethylether, and ethanol Conversion factor mg/m3 = 4.6 × ppm aData from HSDB 2006 and Merck Index 1989.

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 approved by the U.S. Food and Drug Administration (FDA) for use in food contact films. Occupational exposure to caprolactam occurs primarily from the manufacture of nylon 6 fibers and resins. Highly soluble in water, caprolactam leaches from clothing made from polyamide fibers when the clothing is soaked in simulated perspiration (Statsek and Ivanova 1978). It has been found in groundwater, surface waters, and finished water (IARC 1986; EPA 1988). Water produced in the Shuttle from fuel cells is iodinated, collected in large containers called contingency water containers (CWCs), and transferred to the International Space Station (ISS) for use by the crew. These CWC bags are used to store drinking water containing silver used as a biocide, and for collection and storage of humidity condensate that will be processed to potable water. The bags are lined with a material called Combitherm. When the Crew and Thermal Systems Division of the National Aeronautics and Space Administration (NASA) was performing material compatibility testing to see if CWC-stored water undergoes quality degradation, it was found that the total organic carbon (TOC) concentration increased. It was determined that caprolactam was the only contributor to this increased TOC. It was also found that the Combitherm material leaches caprolactam during storage, and irrespective of the biocide used (iodine or silver), the leaching continued. A concentration of 16 milligrams per liter (mg/L) of caprolactam was found at the end of 24 weeks (wk). Thus, NASA was prompted to evaluate caprolactam for potential health hazards at this concentration and to recommend a spacecraft water exposure guideline (SWEG). PHARMACOKINETICS AND METABOLISM Absorption, Disposition, and Elimination No human data are available on the absorption of caprolactam from an oral dose. However, from an animal study of disposition pharmacokinetics described below (Unger et al. 1981), it appears that caprolactam is almost completely absorbed from the gastrointestinal (GI) tract, because within 24 hours (h), more than 80% of the administered dose (14C-caprolactam) was recovered in urine, feces, and expired air. Two sets of studies were carried out by Unger et al. (1981) on the disposition kinetics of caprolactam when dosed via the oral route. In the first set of experiments, a single oral bolus of 14C-caprolactam in water

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 was given to male Fischer rats at a concentration of 0.18 mg per kilogram (kg). Groups of animals were killed after 0.5, 1, 2, 3, 4, 6, 15, or 24 h following dosing; urine was also collected. In addition, exhaled 14C (as carbon dioxide [CO2]) was quantified. Twenty-four hours after a single oral bolus dose of 14C-caprolactam at 0.18 mg/kg, about 77% of radioactivity was excreted in the urine, 3.5% in the feces, and 1.5% in the expired air. Elimination of radioactivity was most rapid in the urine during the initial 6 h following the dose. Analysis of urine indicated that 24 h after dosing, only 2.3% of the radioactivity was in the form of the parent compound. There were two major unidentified metabolites, one comprising 79% and the other 17.7%. After dosing, the peak concentrations of radioactivity in the tissues (nanogram [ng] equivalents of caprolactam per gram of tissue) were similar to that found in the blood (for example, it was about 128 ng/g in blood, 151 ng/g in liver, and about 140 ng/g in spleen), except for stomach (1,907 ± 286 ng/g, including contents), kidney (247 ± 19 ng/g), and bladder (1,240 ± 223 ng/g)—the tissues associated with ingestion and excretion (Unger and Friedman 1980; Unger et al. 1981). In the second experiment, rats were orally treated with caprolactam at 1.5 g/kg for 7 days (d) and 24 h after the last dose; radioactive caprolactam was administered at the same dose. Animals were killed 6 h after receiving the radioactive dose, and their blood, tissues, urine, feces, and expired air were collected. Another set of animals was administered caprolactam containing 14C at 1.5 g/kg, and 24-h urine samples were collected and analyzed for metabolites. When a single dose of 14C-caprolactam at 1.5 g/kg was administered and studied after 6 h, the pattern of distribution was the same as that observed at the low dose except that 40% of the radioactivity was still in the stomach,, whereas in the previous experiment, only 6% of the radioactivity was in the stomach after 6 h. Additionally, at 6 h, 14% was excreted in the urine in the high-dose group, and 39% was excreted in the urine in the low-dose group. The authors did not specify how much was in the stomach tissue or in the contents. In the 7-d study, when radioactive caprolactam was given after 7 d of pretreatment, the tissue distribution was similar to that from a single bolus dose. However, at 6 h, there was a fivefold increase in the excretion of radioactive CO2 in the expired air (about 0.25% of the administered dose). The results of this study indicated that caprolactam is very

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 rapidly and almost completely absorbed at low doses and also rapidly eliminated. From the distribution of radioactivity in the GI tract, it appears that caprolactam is predominantly and directly absorbed from the stomach rather than from the intestine. The fact that liver does not show a very high percentage of the radioactivity may suggest that caprolactam either undergoes extensive biotransformation or is rapidly eliminated from the liver and finally excreted in the urine. In the high-dose group, an appreciable quantity of parent compound was excreted in the urine,, which suggests that biotransformation in liver may not be required for the elimination of caprolactam in urine. This also suggests that the metabolic pathway in liver probably becomes saturated at high doses. Kirk et al. (1987) reported that rats fed a diet containing 3% caprolactam for 2 or 3 wk excreted approximately 16% of the caprolactam ingested as the 4-hydroxy metabolite and a small amount as the nonhydroxylated acid, 6-aminohexanoic acid. The 4-hydroxy metabolite rearranges spontaneously in acidic aqueous medium to an equilibrium mixture in which 6-amino-gamma-caprolactone is the major component and 6-amino-4-hydroxyhexanoic acid is a minor component. The distribution of 14C-caprolactam was also studied by wholebody autoradiography in male, female, and pregnant mice on day 14.5 of gestation which were given an average of 14C-caprolactam at 6.6 mg/kg by oral intubation in water (Waddell et al. 1984). Pregnant mice were frozen 20 minutes (min) and 1, 3, 9, and 24 h after oral administration of the compound. From the pattern of intensity of radioactivity as measured by autoradiography, one can understand the distribution and elimination. The nonpregnant mouse was frozen 3 h after oral dosing, and two male mice were frozen 20 min and 9 h after intravenous (iv) administration. Autoradiography data indicated that radioactivity was rapidly absorbed from the stomach and distributed throughout the entire animal, including the fetuses. There was efficient elimination by the kidney and liver, as evidenced by the shift in density in autoradiograph from the stomach to these organs. Material secreted by the liver into bile and intestinal contents appeared not to be reabsorbed via the enterohepatic circulation. The kinetics of distribution and elimination appeared to be the same in male, female, and pregnant animals. The distribution into and removal from the fetuses was typical of molecules that diffuse freely across the placenta. There was no retention of radioactivity in any fetal tissue, and there was no localized concentration of caprolactam in any specific tissue.

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 TOXICITY SUMMARY Human Exposure There are several Russian reports indicating that industrial exposures of factory workers to caprolactam resulted in various serious adverse effects on neurologic (headaches to seizures), gynecologic, obstetric, GI (nausea and vomiting), cardiovascular, dermatologic, and hepatic systems. Because these factory workers were also exposed to several organic solvents and other compounds, it is very difficult to associate these effects with caprolactam alone. Because of difficulties involved in getting full translations of these Russian articles for evaluation, these studies have not been included in this document. Caprolactam is suspected to cause contact dermatitis (allergic skin reaction) in an occupational environmental setting. NASA Taste Tests of Caprolactam-Containing Water The Crew and Thermal Systems Division of NASA conducted a fluid compatibility study on water stored in CWCs, the bladders of which were made of a material called Combitherm-140. Earlier results had indicated that a chemical material was leaching out of the bags, increasing the TOC in water and was traced entirely to the increased concentrations of caprolactam, one of the ingredients of the water bags. The water was of the exact composition as that of water available to crew on the ISS, water with silver biocides and minerals. The water contained silver, fluoride, calcium, and magnesium at concentrations of 0.5, 0.55, 29.4, and 4.91 mg/L, respectively. Taste tests were done at 12, 48, and 64 wk after storing ISS-quality water in CWCs using 10-12 panelists who participated in the sensory panel. The caprolactam concentrations were 4.7, 11.5, and 12.6 mg/L, respectively. The sensory panel consisted of odor, flavor, and overall acceptability. The scores were compared with the concentrations of caprolactam in the water. Water from the Johnson Space Center (JSC) drinking water and Ozarka commercial bottled water served as controls for this blinded study. Based on the results, it was concluded that at the maximum concentration of 13 mg/L of caprolactam, the water was declared acceptable for drinking. It must be stressed that the subjects tasted the water only one time and not every day over duration.

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 Animal Exposure Target organs for acute and chronic toxicities from inhalation exposures were suspected to be eye, skin, the respiratory system, neurologic system, and the GI tract (nausea and vomiting). Most of the reports on toxicity are from Russian studies using inhalation exposures on animals. In animals injected with caprolactam via iv or intraperitoneally (ip), observed effects have included reproductive/teratogenic effects, cardiovascular system effects such as hypertension and hypotension depending on the dose, anemia, and degeneration of the renal tubular epithelium (see Gross 1984). Acute Exposures (1 d) The National Toxicology Program (NTP) conducted a carcinogenesis bioassay of caprolactam in F344 rats and B6C3F1 mice in 1982. In the survival determination studies, rats and mice were given single gavage doses of caprolactam at 681, 1,000, 1,470, 2,150, and 3,160 mg/kg for male and female rats and 1,000, 1,470, 2,150, 3,160 and 4,640 mg/kg for male and female mice. The doses were delivered in corn oil. Deaths occurred in rats receiving more than 1,470 mg/kg (males) and 1,000 mg/kg (females). Estimated LD50 (the dose causing death in 50% of test subjects) values are shown in Table 6-2. In a comparative oral toxicity study in different species of animals, a single dose of caprolactam at 1,000 mg/kg resulted in 70% lethality in mice, 60% in rabbits, 30% in guinea pigs, and 30% in rats. In all animal species, death resulted from violent epileptic convulsions, salivation, bleeding from the nostrils, respiratory arrest, tremors, and low body temperature (Savelova 1960, cited in Gross 1984). Six hours after oral administration of a single bolus of caprolactam at 1.5 g/kg to male F344 rats, there were marked inductions of tyrosine amino transferase (TAT, L-tyrosine:2-oxoglutarate aminotransferase) and tryptophan oxygenase (TPO) (Friedman and Salerno 1980). The two enzymes are involved in the first steps of tyrosine and tryptophan catabolism, respectively. Induced activities were seen at 3 h after dosing with a maximum effect occurring at 6 h. Even 24 h postdosing, the induction of enzymes was significantly higher than in untreated controls. A dose-response study of the induction of these two enzymes after single

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 TABLE 6-2 LD50 Values For Rats And Mice Administered Caprolactam by Oral Routea Species LD50 (g/kg) Reference Mouse (strain and sex not known) 1.20 (LD100) Hohenesee 1951 Mouse (B6C3F1 male) 2.07 NTP 1982 Mouse (B6C3F1 female) 2.49 NTP 1982 Rat (strain and sex not known) 1.6 Hohenesee 1951 Rat (F344 male) 1.65 NTP 1982 Rat (F344 female) 1.21 NTP 1982 aFor comparison, the LD50 dose for the mouse by ip was 0.58 g/kg and subcutaneously was 0.75 g/kg (Hohenesee 1951). oral doses of 300, 600, 900, 1,200 and 1,500 mg/kg was conducted. Both enzymes, when measured 5 h after dosing, increased linearly with the dose up to the maximum dose tested, but TAT was induced only at doses higher than 300 mg/kg and increased by 100% at 600 mg/kg. In the case of TPO, a 100% increase was observed even at 300 mg/kg, and the activity continued to increase with doses up to 1,500 mg/kg, the maximum dose used in the studies. In a biochemical study, 90-d-old adult female Sprague-Dawley rats (CD strain) were treated by gavage with two doses of caprolactam at 425 mg/kg (Kitchin and Brown 1989) to give a total dose in 24 h of 850 mg—one dose within 21 h of sacrifice and one 4 h before sacrifice (n = 13). Caprolactam was administered as a saline solution. Serum ornithine decarboxylase, alanine amino transferase (ALT, also called serum glutamic pyruvic transaminase, SGPT), hepatic glutathione content, hepatic cytochrome P-450 concentrations, and DNA damage (as measured by the alkaline elution of DNA) were measured. There was a statistically significant increase in the activity of SGPT (marker enzyme for abnormal liver function). Single- and double-stranded breaks in liver DNA were also measured in the study and were not different from controls. No other parameters were found to be altered. Short-Term Exposures (2-10 d) In another study (Friedman and Salerno 1980), caprolactam was fed to rats for 7 d as 1% and 5% of their diet. The animals were pair fed, and

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 the authors estimated the doses as 1.1 g/kg/d and 1.8 g/kg/d, respectively. Liver protein synthesis was studied using incorporation of 3H-leucine. Although food restriction (pair feeding) alone increased this activity by 60%, the inclusion of caprolactam blocked this increase in protein synthesis. Also, the authors reported that food-conversion efficiency (gain in weight per gram of diet consumed), was reduced by 1.8 g/kg/d. While induction of TAT was also observed in this 7-d study compared to pairfed controls, TAT activity was lower than corresponding pair-fed controls (although, the difference was not statistically significant) (Friedman and Salerno 1980). This induction did not appear to require RNA synthesis, because RNA synthesis inhibitors did not prevent the observed induction of TAT and TPO. It must be pointed out that with a single oral bolus dose, the increased activities of TPO and TAT were several-fold higher than were observed in the week-long pair-feeding study in which the caprolactam was administered via the diet. Thus, the data will be used for the 10-d acceptable concentration (AC), which is based on the effect of caprolactam on increased amino acid catabolism, which is also reflected on the effect of protein synthesis. Subchronic Exposures (10-100 d) In a three-generation reproduction study by Serota et al. (1988), F344 albino rats (10 males and 20 females) were fed diets containing caprolactam at 0, 50, 250, or 500 mg/kg/d for 10 wk. Body weights of the parental generations and their offspring (in the 250 and 500 mg/kg/d groups) were significantly reduced. In this study, the authors noted that on microscopic evaluation of the kidney sections and gross lesions, there was also a slight increase in the severity of spontaneous nephropathy accompanied by the presence of granular casts in some animals of the 500mg/kg/d group. According to the authors, this was related to the administration of caprolactam. A lowest-observed-adverse-effect level (LOAEL) of 500 mg/kg/d and a no-observed-adverse-effect-level (NOAEL) of 250 mg/kg/d were identified. Powers et al. (1984) administered caprolactam in the feed to F344, Sprague-Dawley, and Wistar rats for 90 d at 0, 0.01, 0.05, 0.1, and 0.5% (or 0, 5, 25, 50, and 250 mg/kg/d). The authors measured glomerular filtration rates (by 3H-inulin clearance) and other renal parameters (urine volume, sodium, potassium, chloride, osmolality, protein, creatinine, glucose [a proximal tubular damage marker], and alkaline phosphatase [a

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 marker for kidney brush border membrane damage]). Blood samples were analyzed for blood urea nitrogen (BUN), protein, creatinine, hematocrit, sodium, potassium, and chloride. There were no significant differences in the urine parameters in any of the three strains of rats. However, a dose-related increase in BUN was observed in male F344 and Sprague-Dawley rats in the 0.1% (not statistically significant) and 0.5% caprolactam groups. If the compound is a suspect nephrotoxin, BUN is used as a marker for glomerular filtration rate (GFR); BUN rises when GFR slows. A LOAEL and a NOAEL for the increased BUN are identified as 250 mg and 50 mg/kg/d, respectively. Although there was an increase of about 15% in the ratio of kidney weight to body weight in 0.1%- and 0.5%-dose groups of male rats, this effect was not seen in female rats. Renal histopathology data showed that although eosinophilic hyaline droplets were present in the tubules of all groups including controls, they were found at a higher concentration in higher-dosage groups. In the 0.5% group, there was also an increase in the number of tubules with basophilic and hyperplasic epithelial cells. The authors suggested that a slight nephrosis might be present because of 0.5% caprolactam. Furthermore, in the 0.5% group, the frequency and degree of chronic inflammation and interstitial lymphoid cells were the highest. This occurred without any change in chronic inflammation or nephropathy. These effects were seen only in male rats of all strains, and any effect seen in females was not consistent with the dose. Rabbits given caprolactam at 500 mg/kg/d for 6 months (mo) exhibited cellular changes in the gastric and intestinal mucosa along with lower hemoglobin values. The details of how the caprolactam was administered are not available (Savelova 1960, cited by Gross 1984). NTP (1982) conducted a 14-d repeated-dose study in which groups of five F344 male and female rats and groups of five B6C3F1 male and female mice were fed a diet containing caprolactam at 0, 5,000, 10,000, 15,000, 20,000, or 30,000 ppm (estimated dose range of 0-4,500 mg/kg/d for rats and mice). There was no mortality in any of the species or sexes of these animals. However, NTP reported pale, mottled kidneys in all treated groups of dosed male rats in incidences of 60-100%. No histopathology was carried out to identify any specific lesions that coincide with the mottled kidneys. No such changes were seen in mice. In both the acute and 14-d studies, NTP did not look at any serum or urine clinical chemistry. Several studies have reported decreased weight gain and thus reduced body weight in animals administered caprolactam by various

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 routes. When caprolactam was given in drinking water to rats (670 mg/kg/d, duration not known), weight loss was observed, and it was determined that it was due in part to decreased water intake (Goldblatt et al. 1954). Because of the lack of detailed data, this study cannot be used for AC derivations. NTP also conducted a 13-wk subchronic feeding study (NTP 1982) in which groups of male and female F244 rats were fed diets containing caprolactam at 0, 625, 1,250, 2,500, 5,000, or 7,500 ppm (estimated dose range of 0-1,125 mg/kg for male and female rats). Male and female mice were fed diets containing caprolactam at 0, 5,000, 10,000, 15,000, 20,000, or 30,000 ppm (estimated dose range of 0-6,000 mg/kg). There were weight gain depressions and a reduction in food intake in all caprolactam-treated groups of rats. In the highest-dose group of rats, food consumption was decreased by 23% in males and by 19% in females. No compound-related adverse histopathology was noted. In mice, there were two deaths at the high dose, and as in rats, depressions in weight gain and reduced food consumption were noted. In the early 1970s, the Central Institute of Nutrition and Food Research conducted dose-range finding and subchronic toxicity studies on caprolactam in the feed using two strains of males and females of Wistarderived (CIVO strain) and Sprague-Dawley rats at two different concentration ranges. In the 28-d study, with caprolactam constituting 5% of the diet (about 3.8 g/kg), renal damage consisting of hyaline droplet degeneration in the epithelium of the proximal convoluted tubules was reported in both sexes of CIVO Wistar-derived rats, with minimal changes (only in males) at 1% (850 mg/kg). In the 90-d study, females of both strains of rats seemed to be less sensitive to these effects. The above mentioned effects were seen at doses greater than 0.05% in Sprague-Dawley male rats and greater than 0.3% in the Wistar-derived male rats (Wijnands and Fern 1969; de Knecht-van Eekelen and van der Meulen 1970, cited in Gross 1984). Increased kidney weights were seen only in male rats of both strains. No proteinuria could be demonstrated. The nephrotoxicity of caprolactam could be supported by the degeneration in the epithelium of the convoluted tubules of rats receiving caprolactam by ip at 50 mg/kg or 100 mg/kg for 6 mo (see Gross 1984). Because these data were presented only as an abstract and details of the data were not available for review, this data cannot be used for AC derivation. However, this study indicated that caprolactam might be a nephrotoxin.

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 Chronic Exposures (>100 d) NTP (1982) conducted a chronic feed study in which male and female F344 rats and male and female B6C3F1 mice were given caprolactam in their diet at 0, 3,750, or 7,500 ppm (estimated doses for rats of 0, 560, and 1,120 mg/kg/d) or 0, 7,500, and 15,000 ppm (estimated doses for mice of 0, 1,500, or 3,000 mg/kg/d) for a period of 103 wk. Evaluations were made of grossly visible lesions and histopathology of all organs of animals surviving at the end of 105 wk (103 wk plus 2 wk on a normal diet). Necropsies were performed. Only periodic data on body weight and food consumption were collected, and no serum or urine clinical chemistry measurements were done. From the dose-related decrement in mean body weight gain and feed consumption, it appears that the LOAEL is 1,120 mg/kg/d for the rat, and 3,000 mg/kg/d for mice (NTP 1982). The various types of neoplasms occurring in dosed animals did not appear to be related to caprolactam ingestion. The degenerative and inflammatory lesions of the type and frequency seen in dosed rats are usually observed as a function of age in Fischer rats. Caprolactam and Allergic Contact Dermatitis Epsilon-aminocaproic acid, from which caprolactam is derived, has been known to cause allergic contact dermatitis (Shono 1989). Tanaka et al. (1993) presented a case report from Japan in which a 43-year (y)-old woman with a history of wearing nylon body stockings developed scaly erythema on her trunk. The lesions were resolved after she stopped wearing the body stocking. She also developed the same lesions around her waist from wearing nylon panty hose. When a patch test was done using the monomer, epsilon-aminocaproic acid 3% and 5% in petrolatum, positive reactions were obtained for both concentrations. Other cases of dermatitis have been reported in Russian factory workers involved in nylon synthesis (Kelman 1986). In one case history, a 62-y-old man who had worked in a textile factory (in the nylon drawing factory) for 29 y, presented with an 18-mo history of itchy erythematous scaly patches of eczema involving the neck, chest, and extensor limbs, although the back and flexor limbs were also involved to a lesser degree (Aguirre et al. 1995). This individual had positive reaction in the open test and patch test when caprolactam 5% aqueous patches were used. Fifteen healthy

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 Thus, an RfD of 0.5 mg/kg/d or 35 mg/d for a 70 kg human was derived. If we were to extend the calculations for use by NASA, an AC for more than 1,000 d would be as follows: It should be noted that EPA did not use any time factor even though the three-generation exposure in this study consisted of a total of 30 wk, or 210 d, and not a lifetime for rats or mice. 1-d AC The data on sensory threshold values measured for caprolactam cannot be used. The olfactory threshold was found to be 0.3 mg per cubic meter (m3). Caprolactam is not expected to vaporize out of water because of its low vapor pressure at room temperature. Therefore, an odor threshold value is not calculated. NASA taste tests indicated that at least up to a concentration of 13 mg/L, water containing caprolactam will not be objectionable to drink. It may be overly conservative to use this value as a 1-d AC because such data for higher concentrations are not available. TAT and TPO are two enzymes that are involved in the first steps of tyrosine and tryptophan metabolism. After oral administration of a bolus of caprolactam at 1.5 g/kg to male F344 rats, there were marked inductions of TAT and TPO activities at 3 h with maximum inductions at 6 h (Friedman and Salerno 1980). Although these data pertain to the induction of two important amino acid metabolizing enzymes by caprolactam, whether it can be considered an adverse effect in this acute exposure is questionable. Thus, the data were not used for deriving a 1-d AC. A second study that was considered for the 1-d AC was that of Kitchin and Brown (1989). Oral ingestion of caprolactam at 425 mg/kg (twice) by gavage resulted in a significant increase in the activity of ALT (30%) over controls. Clinically, an increase in this enzyme indicates hepatocyte necrosis or damage. While 850 mg/kg appears to be a LOAEL, a NOAEL was not identified, because there were no dose-response data. However, with the changes in the liver protein metabolism enzymes, TAT and TPO, reported by Friedman and Salerno (1980), in conjunction with these changes reported by Kitchin and Brown (1989), it can be concluded that caprolactam resulted in adverse effects on liver. Because the investigators administered one dose at 21 h and one more dose 4 h before sacrifice, the effect may have been from the combined dose of 850 mg/kg. Therefore, this dose will be used in deriving an AC.

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 The 1-d AC was calculated based on hepatotoxicity as follows: where 850 mg/kg = LOAEL; 70 kg = nominal body weight; 10 = LOAEL to NOAEL; 10 = species extrapolation factor; and 2.8 L/d = nominal water consumption. 10-d AC for Ingestion Data from Friedman and Salerno (1980), in which rats fed caprolactam in their diet for 7 d at doses of 1.1 and 1.8 g/kg (calculated by the authors), showed inhibition of liver protein synthesis and also induction of liver TPO measured at the end of the treatment period. Diet restriction increased protein synthesis by at least 63%, but a dose of 1.8 g/kg blocked this increase. Also, TPO activity was found to be increased at the 1.1 g/kg dose. Therefore, 1.1 g/kg is used as the LOAEL for the induction of this enzyme. Although we considered that the change in activity of the enzyme may be an adaptive response to a single dose, the change in conjunction with an inhibition of protein synthesis allows us to use these data to derive a 10-day AC after applying a time extrapolation factor. 10-d AC for adverse effect on amino acid metabolism is calculated as follows: where 1,100 mg /kg = LOAEL; 70 kg = nominal body weight; 10 = LOAEL to NOAEL; 10 = species extrapolation factor; 2.8 L/d = nominal water consumption; and 10 d/7 d = time extrapolation factor.

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 100-d AC for Ingestion Powers et al. (1984) studied three strains of male rats fed diets containing caprolactam at doses of 0, 0.01, 0.05, 0.1, 0.5, and 2.5% (or 0, 1, 10, 50, and 250 mg/kg/d) for 90 d. A dose-related increase in BUN was observed in male F344 and Sprague-Dawley rats at 0.1% and 0.5% dose groups but was statistically significant only in the 0.5% dose group. If the compound is a suspected nephrotoxin, BUN is used as a marker for GFR; BUN rises when GFR slows. A LOAEL and NOAEL for increased BUN are identified as 250 and 50 mg/kg/d, respectively. Although there was an increase of about 15% in the kidney weight to body weight ratio in the 0.1% and 0.5% dose groups of male rats, this effect was not seen in female rats. The increase in the ratio is because of an absolute increase in kidney weight, probably indicating hypertrophy of the kidney. Renal histopathology data revealed that, although eosinophilic hyaline droplets were present in the tubules of all groups including controls, this was found at a higher concentration in higher-dosage groups. Although the numbers were minimal, the number of rats affected increased with the dose of caprolactam. These effects were seen only in male rats of all strains, and any effect seen in females was not consistent with the dose. Thus, a 100-d AC for renal toxicity can be derived as follows: where 50 mg/kg/d = NOAEL for BUN; 70 kg = nominal body weight; 10 = species extrapolation factor; 2.8 L/d = nominal water consumption; and 100 d/90 d = time extrapolation factor. Another study that was considered for calculating a 100-d AC was Serota et al. (1988), a three-generation reproductive study in which rats were fed diets containing caprolactam at 0, 50, 250, or 500 mg/kg/d. In this study, the authors noted that there was a slight increase in the severity of nephropathy on histologic examination of the male rats of the 500 mg/kg/d group. The duration of each generation was 10 wk (70 d). Body weights of the parental generations and their offspring (of the 250 and 500 mg/kg/d dose groups) were significantly reduced. The reported slight increase in severity in spontaneous nephropathy in exposed groups, ac-

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 companied by the presence of granular casts in some rats, was used as a toxicologic end point. A NOAEL of 250 mg/kg/d for severity of nephropathy was identified. The developmental effects observed in the study are not the basis for the 100-d AC. Thus, a 100-day AC for nephropathy can be derived as follows: where 250 mg/kg = NOAEL; 70 kg = nominal body weight; 10 = species extrapolation factor; 2.8 L/d = nominal water consumption; and 100 d/70 d = time extrapolation factor. NASA’s Position and Rationale for 10-d and 100-d ACs The SWEG for the 100-d duration will be accepted as the SWEG for 10-d duration, instead of the calculated value of 200 mg/L as 10-d AC. The reasons are outlined below. The 1-d AC was based on hepatotoxic effects derived from a LOAEL of 850 mg/kg. A factor of 10 was used for LOAEL to NOAEL. The 10-d AC was based on adverse effects on amino acid catabolism and protein synthesis (Friedman and Salermo 1980). This data was used to calculate a 10-d AC of caprolactam at 200 mg/L. In this study, hepatotoxic indices were not measured. It is quite possible that 10 d of continuous ingestion of water containing caprolactam at 200 mg/L will lead to hepatoxicity, because it approaches the LOAEL for hepatotoxicity observed in 1 d and will not provide any margin of safety. The rationale for using 100 mg/L as the 10-d AC and for adopting the 100-d AC obtained using the Powers et al. (1984) study is as follows: NTP (1982) conducted a carcinogenesis bioassay of caprolactam in the feed for 103 wk in F344 rats and B6C3F1 mice. The study also included a 1-d gavage and a 14-d feed protocol. In these protocols, the focus was on food and water consumption, body weight gain, and survival rates in addition to general clinical observations and necropsy. NTP reported that at the end of 2 wk, there were no deaths; however, pale, mottled kidneys occurred in all groups of dosed rats in incidences of 60-100%. NTP did not discuss the significance of this observation. The calculated dose rates for male and female rats for the lowest-dose group that showed the pale, mottled kid-

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 neys are about 860 mg/kg/d, and 750 mg/kg/d respectively. Although the biologic significance of mottled kidney is not clear, it appears that the kidney is somewhat affected. This is somewhat in concordant with the observations from the 90-d study of Powers et al. (1984) that showed that the kidney is a target organ. NTP did not conduct any clinical chemistry on blood or urine. Therefore, it was decided to adopt the 100-d AC derived from the Powers et al. (1984) study for 10 d, because it would offer enough margin of safety for kidney effects and for hepatotoxicity. In addition, the 28-d and 90-d rat subchronic caprolactam-feed study conducted by the Central Institute of Nutrition in the Netherlands reported changes in the kidney resulting from caprolactam feeding. However, as details of the study were unavailable as a full report, the data could not be critically evaluated for NASA in the determination of 10-d or 100-d AC. 1,000-d AC for Ingestion The 2-y carcinogenesis bioassay study sponsored by NTP (1982) is the only study that can be considered for 1,000-d AC derivation. In this study, rats and mice were exposed to caprolactam in their diet for 2 y (male and female F344 rats to 0, 3,750, or 7,500 ppm, and male and female B6C3F1 mice to 0, 7,500, or 15,000 ppm). These mean concentrations for males and females corresponded to estimated doses of 0, 560, and 1,120 mg/kg/d for rats and 0, 1,500, and 3,000 mg/kg/d for mice. The feed consumption in the highest-dose groups was only 70-80% of that of controls, and thus, body weights were lower. The NRC committee had recommended in the past that body weight changes should not be used to set ACs when it is known that changes occurred because of reduced food consumption. According to the NTP report (NTP 1982), the frequency of the large number of degenerative, proliferative, and inflammatory lesions encountered in caprolactam-treated rats was not different from that in control rats. However, there were some observations of toxicologic concern. One is that in rats, testicular interstitial cell tumors were observed in increasing proportions as a function of dose, even though they occur historically at 80%. The Cochran-Armitage linear trend analysis was statistically significant. Also, carcinomas of the pituitary were observed in increased proportions in high-dose male rats. The Cochran-Armitage linear trend analysis was statistically significant in the positive direction. However, the committee recommended that NTP data could not be used to set an AC based on non-neoplastic lesions, because

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 NTP concluded that it did not find any evidence of neoplastic or non-neoplastic lesions related to dietary caprolactam. The 100-d AC was adopted as the 1,000-d AC in the absence of sufficient data for long- term ingestion. The use of the 100-d AC without any time factor for 1,000 d was justified by the fact that caprolactam does not accumulate in the body and is excreted efficiently. Furthermore, if one were to use the lowest dose (560 mg/kg/d) used in the NTP 2-y carcinogenicity study for rats, which did not produce any compound-related long-term adverse tissue pathology, and calculate an AC using only the species extrapolation factor, a concentration of 1,400 mg/L would be obtained as the AC. Thus, the use of 100 mg/L as the 1,000-d AC is justified and conservative. See Table 6-7 for a summary of all ACs and final SWEGs for all durations.

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 TABLE 6-7 Acceptable Concentrations (ACs) for Caprolactam in Water Toxicity End Point LOAEL or NOAEL (mg/kg/d) Species Modifying Factors Acceptable Concentrations (mg/L) Reference To NOAEL Species Exposure Time Spaceflight 1 d 10 d 100 d 1,000 d Hepatotoxicity LOAEL = 850 Rat 10 10 1 1 200       Kitchin and Brown (1989) Increased amino acid catabolism LOAEL = 1,100 Rat 10 10 10 d/7 d 1   200     Friedman and Salerno (1980) Renal toxicity: increased BUN; renal histopathology NOAEL = 50 Rat 1 10 100 d/ 90 d 1   100 (adopted 100-d AC) 100   Powers et al. (1984) Increased severity of nephropathy NOAEL = 250 Rat 1 10 100 d/ 70 d 1     438   Serota et al. (1988) No chronic toxicity data                   No suitable data available   SWEGa             200 100 100b 100c   aTabulated values may not protect against water that has a taste to it. The levels are protective against adverse health effects. bBased on evaluation of summary of ACs, the 100-d AC of 100 mg/L will be used for 100 and 1,000 d. cNo suitable data available for deriving 1000-d AC. Note: The rationale for adopting the 100-d SWEG as 10-d SWEG has been discussed at the end of the 100-d AC derivation section in this document. Also, these values will not be protective of individuals who may be allergic to nylon who may show hypersensitivity to caprolactam ingestion. No data is available to determine or justify whether any safety factor would be needed.

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Spacecraft Water Exposure Guidelines: For Selected Contaminants, Volume 2 REFERENCES ACGIH (American Conference of Governmental Industrial Hygienists). 1991. Documentation of Threshold Limit Values and Biological Exposure Indices, 6th Ed. American Conference of Governmental Industrial Hygienists, Cincinnati, OH. Aguirre, A., R. Gonzalez Perez, J. Zubizarreta, N. Landa, C. Sanz de Galdeano, and J.L. Diaz Perez. 1995. Allergic contact dermatitis from epsilon-caprolactam. Contact Dermatitis 32:174-175. Ashby, J., and M.D. Shelby, eds. 1989a. Assessment of Genotoxicity In Vivo of the Rodent Non-Carcinogens Caprolactam (CAP) and Benzoin (ZOIN). Mutat. Res. Ashby, J., and M.D. Shelby. 1989b. Overview of the genetic toxicity of caprolactam and benzoin. Mutat. Res. 224:321-324. Bermudez, E., T. Smith-Oliver, and L.L. Delehanty. 1989. The induction of DNA-strand breaks and unscheduled DNA synthesis in F-344 rat hepatocytes following in vivo administration of caprolactam or benzoin. Mutat. Res. 224(3):361-364. Brady, A.L., H.F. Stack, and M.D. Waters. 1989. The genetic toxicology of benzoin and caprolactam. Mutat. Res. 224:391-403. Carls, N., and R.H. Schiestl. 1994. Evaluation of the yeast DEL assay with 10 compounds selected by the International Program on Chemical Safety for the evaluation of short-term tests for carcinogens. Mutat. Res. 320(4):293-303. de Knecht-van Eekelen, A., and H.C. van der Meulen. 1970. Subchronic (90 day) toxicity study with caprolactam in Sprague-Dawley albino rats. Central Institute for Nutrition and Food Research, Netherlands, page 13. Elison, C., E.J. Lien, A.P. Zinger, M. Hussain, G.L. Tong, and M. Golden. 1971. CNS activities of lactam derivatives. J. Pharm. Sci. 60:1058-1062. EPA (U.S. Environmental Protection Agency). 1988. Health and environmental effects profile for caprolactam. ECAO-CIN-G018. Office of Health and Environmental Assessment, U.S. Environmental Protection Agency, Cincinnati, OH. Fahrig, R. 1989. Possible recombinogenic effect of caprolactam in the mammalian spot test. Mutat. Res. 224:373-375. Foureman, P., J.M. Mason, R. Valencia, and S. Zimmering. 1994a. Chemical mutagenesis testing in drosophila. IX. Results of 50 coded compounds tested for the National Toxicology Program. Environ. Mol. Mutagen. 23:51-63. Foureman, P., J.M. Mason, R. Valencia, and S. Zimmering. 1994b. Chemical mutagenesis testing in Drosophila. X. Results of 70 coded chemicals tested for the National Toxicology Program. Environ. Mol. Mutagen. 23:208-227.

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