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5 2-Mercaptobenzothiazole Hector D. Garcia, Ph.D. NASA-Johnson Space Center Toxicology Group Habitability ancI Environmental Factors Branch Houston, Texas PHYSICAL AND CHEMICAL PROPERTIES 2-Mercaptobenzothiazole (MBT) forms pale yellow monoclinic needles or leaflets and has a disagreeable odor (see Table 5-1) (Dieter 1988~. OCCURRENCE AND USE MBT is used commercially as an accelerator in the rubber vulcanization process and as a preservative for textile or cordage materials (Dieter 1988~. The sodium salt is used as a corrosion inhibitor in petroleum products (Di- eter 1988~. MBT can also be found in some antifreezes (Kiec-Swierczynska et al. 1999~; as a corrosion inhibitor in cutting oils (Fregert and Skog 1962~; at 1% in an oil used to release plaster molds from epoxy casts (Wilkinson et al. 1990~; in heavy-duty greases, black tire paints, special detergents, and photographic film emulsion (Ru~zki et al. 1981~; and in fungicides and veterinary medications (Kiec-Swierczynska et al. 1999~. MBT has been reported as a contaminant in some injectable solutions of various drugs (digoxin, sodium pentobarbital, epinephrine, lidocaine hydrochloride, mepivacaine hydrochloride, pilocarpine hydrochloride, and dexamethasone 169

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170 Spacecraft Water Exposure Guidelines TABLE 5-1 Physical and Chemical Properties of MBT Formula Chemical name Synonyms ~ S ~ N C7H5NS2 2-Mercaptobenzothiazole (MBT) Captax, dermacid, mertax, thiotax, 2- benzothiazolethione, 2-benzothiazolyl mercaptan CAS registry no. 149-30-4 Molecular weight 167.25 Melting point 180.2-181.7C Specific gravity 1.42 g/cc Solubility Insoluble in water; soluble in alcohol, acetone, ben- zene, and chloroform sodium phosphate) at concentrations of up to 1 1.6 micrograms per milliliter (~g/mL) (Reepmeyer and Juh! 1983; Salmona et al. 1984~. The MBT con- taminate originated from the rubber closures of the single-dose delivery syringe or syringe cartridge, and the amount extracted might be dependent on the level of MBT in the rubber but appeared not to depend on the com- position of the solvent for the drug (40/0 propylene glycol, 10% alcohol, 50% water for digoxin) (Reepmeyer and Juh! 1983~. The 2-hydroxyethy! derivative of MBT was found to contaminate blood that came in contact with rubber plunger seals of syringes sterilized with ethylene oxide (Peter- son et al. 1981~. MBT was found in aqueous extracts of rubber baby bottle nipples (Blosczykan4Doemling 1982; Schweisfurth 1995) end was identi- fied as one of the allergens responsible for tennis shoe dermatitis (Jung et al. 1988~. MBT may enter spacecraft as a component of rubber materials and thus may leach into spacecraft drinking water. Drinking water on the Interna- tional Space Station (ISS) will be generated from recycled hygiene water, urine, and humidity condensate, and supplemented by water from the shut- tle or the Russian spacecraft Progress. Because the octanol-to-water parti- tion coefficient for MBT is high (Iog Kow = 2.41) (Hansch and Leo 1979) and the solubility of MBT in pure water is very low, one would expect that only traces of MBT, if any, would be found in the ISS drinking water under

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2-Mercaptobenzothiazo1/te 171 normal conditions. However, experience on Russia's Mir space station shows that MBT was detected in five of 27 samples of recycled water and six of 28 samples of humidity condensate collected from U.S. missions Mir- 1 ~ through Mir-25 at levels of up to 155.7 fig per liter (L) (see Table 5-2~. For ISS, none of the water samples for the first three expeditions has contained MBT at levels above the detection limit (approximately 40 vigil). PHARMACOKINETICS AND METABOLISM No data were found in the scientific literature on human or animal uptake, metabolism, or elimination of MBT ingested in drinking water, probably because MBT is essentially insoluble in pure water. The data described below are predominantly for ~4C-labeled MBT ingested in corn oil and, as such, do not distinguish between the parent compound, metabo- lites, and ~4C that has entered the cellular carbon pool. Absorption In rats dosed by gavage with ~4C-labeled MBT in corn oil, nearly all the radioactivity administered was rapidly excreted in the urine, indicating nearly complete absorption of MBT from the gut (el Dareer et al. 1989~. Studies of radiolabeled MBT in guinea pigs showed that it was absorbed through the skin and that abrasion (by tearing off tape stuck on the skin) increased the rate of absorption (Nagamatsu et al. 1979~. At 24 and 48 hours (h) after application of TIC- labeled MBT at 5.1 Hi per 3 milligrams (mg) per 0.1 mL in a solution of sodium carbonate (pH = 9) to an area 4 x 4 centimeters (cm) square, 6.14% and S.39/0 were excreted in the urine of animals not subject to abrasion and 27.42% and 34.58/0 were excreted in the urine of animals whose skin was abraded (Nagamatsu et al. 1979~. Distribution Radiolabeled MBT applied to the shaved skin of guinea pigs was taken up mainly at the application site (15.1%), although small amounts were distributed to the blood (0.063%) andinternal organs (0.023%) (Nagamatsu et al. 1979~. Among the internal organs, the most radioactivity was found in the thyroid gland. Trace amounts were found in the lungs, kidneys, liver,

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172 Spacecraft Water Exposure Guidelines TABLE 5-2 Concentrations of MBT in Water Samples from Mir- 18 through Mir-25a Number of Detection Concentration Concentration Source Samples Frequency Range (vigil) Mean(~g/L) Recycled 27 5 ND-41.8 4.2 water Humidity 28 6 ND-155.7 10.2 condensate aSamples collected by U.S. astronauts onMir were analyzed byNASA's Water and Food Analysis Laboratory. Sample collection and storage devices were all Teflon and contained no rubber. Abbreviations: ND, not detected. spleen, and adrenal glands when examined at both 24 hours (h) and 48 h after application (Nagamatsu et al. 1979~. Similar results were reported by el Dareer et al. (1989) for MBT administered orally to rats. At ~ h after a dose of ~4C-labeled MBT at 0.50 mg per kilogram (kg) in corn oil following daily doses at 0.51 mg/kg for 14 days Air, the tissues with the highest concentrations of radioactivity were the kidneys, thyroid, liver, plasma, and whole blood (el Dareer et al. 1989~. At 96 h after the dose, a small portion of the administered radioactivity (1.20-1.69%) remained associated with erythrocytes, and most of that was bound to membranes. A time-course study of the levels of radioactivity in the blood showed nearly constant levels in whole blood but rapidly decreas- ing levels in plasma between ~ h and 48 h after dosing. At 96 h, tissue concentrations were generally low the highest concentrations were in whole blood and thyroid. Metabolism and Excretion Metabolism studies in F-344 rats indicated that the half-life for MBT after administration by gavage was less than ~ h and possibly as short as 4-6 h (CMA 1986~. Nearly all (90.7-101%) the radioactivity administered orally to rats as ~4C-labeled MBT is rapidly excreted in the urine, and 5.22-9.99% is excreted in feces (el Dareer et al. 1989~. Only 0.001% ofthe administered dose of 14C-labeled MBT was retained at 48, 72, and 96 h. The radioactivity appeared to be covalently bound to erythrocyte mem-

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2-Mercaptobenzothiazo1/te 173 branes. Of the radioactivity excreted in the urine within ~ h following oral administration, none was present as the administered compound (MBT). Only two metabolites were found in rat urine. Initial testing suggested that these polar compounds were probably athioglucuronide conjugate of MBT (on the basis of acid and enzymatic hydrolysis ofthe major metabolite) and a sulfonic acid derivative of MBT (on the basis of elusion characteristics, UV spectrum, acid and enzyme stability, and facile methylation). No fur- ther testing to identify these metabolites was reported. Nagamatsu et al. (1979) reported finding similar metabolites in the urine of guinea pigs; however, they reported a sulfate derivative of MBT, for which el Dareer et al. could find no evidence. At 1 h and 6 h after subcutaneous injection of ~4C-labeled MBT into guinea pigs, 66% and 92% of the dose was excreted in the urine (Nagamatsu et al. 1979~. In contrast to the ~4C-labeled MBT metabolites, the urinary metabolites of t35S-mercaptoj2-mercaptobenzothiazole in rats exposed by intraperi- toneal injection were found to consist of conjugates of glutathione (GSH) as well as glucuronic acid and inorganic sulfate (Colucci and Buyske 1965~. MBT also is found as a metabolite after exposure to related substances. MBT is the main urinary metabolite in humans and rats exposed to 2-(thiocyanomethy~thio~benzothiazole, a wood preservative and an indus- trial chemical (Manninen et al. 1996~. In rats, MBT, its three conjugates (mercapturate, glucuronide, and sulfate), and its dimer, 2,2'-dibenzothiazyl disulfide (BTDS), were found in the urine after oral administration of N-oxydiethylene-2-benzothiazyl sulfenamide or N-cyclohexyI-2-benzo- thiazyl sulfenamide (Fukuoka et al. 1995~. The S-glucuronide and S-sulfate conjugates were predominantly excreted into the bile. BTDS was also found as a fecal metabolite. When 2-methy~thiobenzothiazole and 35S-labeled GSH were incubated with ret river homogenates, 35S-labeled S-~2-benzothiazolyI)glutathione and 2-mercaptobenzothiazole were isolated from the reaction mixtures (Larsen et al. 1988~. Glutathione-S-transferase appears to be involved in the S-~2-benzothiazolyI)glutathione (GBZ) formation. The evidence indicates that 2-methy~thiobenzothiazole is oxidized to its corresponding methyI- suIphoxide and/or methylsuIphone, which become substrates for GSH con- jugation. Degradation products identified from the methy~thio group were formaldehyde and suIphate. Although sulfur is exchanged in this pathway, which involves oxidation ofthe methy~thio group and GSH conjugation, the net result is an apparent S-demethylation of the methy~thio group. Another S-demethylation pathway that does not involve GSH conjugation also func- tioned in vitro.

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174 Spacecraft Water Exposure Guidelines TOXICITY SUMMARY Although the oral toxicity of MBT generally is low, MBT is a moder- ately potent contact allergen in humans. At high doses, it can cause central nervous system (CNS) depression and, after a lifetime of exposure, possibly kidney toxicity and cancer. However, except for some rare individuals who are exquisitely allergic to MBT, the toxicity of drinking water saturated with MBT is expected to be low because of the low solubility of MBT in pure water. Acute Toxicity (1 d) Very few data were found in the literature on adverse effects other than contact dermatitis associated with acute exposures to MBT. The only ef- fects described after acute oral exposures were in animals and included transient, marked CNS depression at high doses and death at very high doses. Lethality The oral LD50 (lethal dose in 50/O of subjects) of MBT in rats was reported to be 3,800 mg/kg (Monsanto Company, unpublished material, as cited in el Dareer et al. 1989~. In rabbits dosed dermally, the LD50 of MBT was greater than 7,940 mg/kg (Monsanto Company, unpublished material, as cited in el Dareer et al. 1989~. An LD50 of 1,558 mg/kg was reported in male mice gavage dosed with MBT in a 5/O gum arable aqueous suspen- sion; 1,490 mg/kg was reported in similarly treated female mice; and 3,148 mg/kg was reported in male mice gavage dosed with MBT in corn oil (Ogawa et al. 1989~. A review in a National Toxicology Program (NTP) report on MBT stated that reported oral LD50 values in mice and rats ranged between 2,000 mg/kg and 3,000 mg/kg, and intraperitoneal LD50s ranged between 100 mg/kg and 400 mg/kg in mice (Dieter 1988~. CNS Depression MBT appears to produce marked but transient CNS depression (2-4 h duration) in rodents given large oral doses. Mice receiving daily gavage doses of MBT suspended in corn oil at 750 mg/kg or 1,500 mg/kg for 13

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2-Mercaptobenzothiazo1/te 175 weeks (wk) exhibited clonic convulsions and, at 1,500 mg/kg, >50% mor- tality (Dieter 1988~. At 375 mg/kg/d, the mice did not convulse, but exhib- ited post-gavage lethargy. In a 2-y study, post-gavage lethargy and prostra- tion occurred frequently in rats and mice receiving MBT in corn oil at both 375 mg/kg and 750 mg/kg (Dieter 1988~. In another study, no CNS effects were reported in mice consuming MBT in the diet for 20 months (mo) at concentrations up to 1,920 ppm (doses up to 289 mglkg/~) (Ogawa et al. 1989~. Convulsions were seen, however, in mice given single oral doses of MBT at approximately 1,500 mg/kg in 5% gum arable solution or 3,148 mg/kg in corn oil (Ogawa et al. 1989~. MBT has been shown to biochemically inhibit dopamine beta-hydroxy- lase in vitro (72% inhibition at 10-5 M). This in vitro activity correlated with in vivo studies in which MBT injected intraperitoneally at 300 mg/kg (in 0.25% aqueous methy~cellulose) in male CF-1 mice lowered brain noradrenaline levels 60% after 1 h and 2 h while raising brain dopamine levels 24% at 2 h (Johnson et al. 1970~. Both noradrenaline and dopamine returned to control levels at 4 h after dosing. Overtly, the activity levels of the treated mice were extremely depressed shortly after dosing and for at least 2 h. After 4 h, the mice appeared normal. Short-Term Toxicity (2-10 d) Contact Dermatitis Allergic contact dermatitis is a syndrome involving immunologic der- mal responses (e.g., erythema, eczema) to specific environmental materials. It occurs in two stages: sensitization of naive individuals (usually requiring moderate to high doses to induce an initial allergic response) and challenge of sensitized individuals (often inducing allergic responses at doses that can be orders of magnitude lower than the sensitizing dose). Allergic contact dermatitis to MBT and its dimer, dibenzothiazy! disulfide, is common and has been reported for exposure to tennis shoes (Jung et al. 1988; Lear and English 1996), releasing-fluid for pottery molds (Wilkinson et al. 1990), antifreeze (Kiec-Swierczynska et al. 1999), and other materials containing MBT. Although MBT has been characterized as a very strong contact allergen in guinea pigs (Maurer et al. 1979), it has been judged a moderate contact sensitizer in humans (Goodwin et al. 1981~. Contact allergens such as MBT are capable of eliciting dermatitis at very low concentrations in sensitized individuals. Although no similar studies were found involving MBT, several studies demonstrated that inges-

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176 Spacecraft Water Exposure Guidelines tion of another contact allergen (nickel) by sensitive individuals could result in flare-ups of dermatitis (Christensen and Moller 1975; Kaaber et al. 1978; Cronin et al. 1980; Gawkrodger et al. 1986; Veien et al. 1987; Burrows 1992~. Nevertheless, none of these reports suggests that oral exposure to contact allergens leads to sensitization of individuals who are not already sensitive (Nielsen et al. 1990~. In contrast, there have been some reports (Jordan and King 1979; Santucci et al. 1994) that suggest that long-term ingestion of a contact allergen (nickel) by sensitive individuals can result in desensitization, but those results remain controversial. Because MBT was detected in recycled water and humidity condensate on Mir, it is pru- dent for NASA to establish exposure limits for MBT in drinking water on ISS to protect any crew members that may be sensitive to MBT. Lynde et al. (1982) reported the results of patch testing of patients (not further described, but most likely presenting with a suspected allergic der- matitis to an undetermined allergen) with MBT and/or one of two formula- tions of "mercapto-mix." The purpose of the study was to compare the efficacy of different formulations of screens for the detection of allergies to mercapto compounds. The "old" mix consisted of MBT, N-cyclohexy~ben- zothiazylsuiphenamide, dibenzothiazyIdisuiphide, and morpholinyI-mer- captobenzothiazole, each at 0.25% in petroleum jelly; the "new" mix elim- inated MBT but contained cyclohexylbenzothiazylsuiphenamide, diben- zothiazyl-disulphide, and morpholinyl-mercaptobenzothiazole, each at 0.33% in petroleum jelly. Using the old mix, 1 55 of 5,732 patients (2.7%) were positive to either MBT and/or the mix. Using MBT and the new mix separately, 39 of 2,297 patients (1.7%) were positive to both MBT and the new mix, and 26 of 2,297 (1.1%) were positive to MBT and negative to the new mix. Screens of allergens (about 50), including MBT, have been used by members of the North American Contact Dermatitis Group for diagnostic patch testing of large numbers of patients presenting with suspected allergic contact dermatitis. The frequency of positive reactions to MBT for 3,440 patients tested between 1996 and 1998 is shown in Table 5-3 along with the results from previous years (Marks et al. 2000~. The frequency of MBT- sensitive individuals in the general population presumably is lower, but no data for the general population were found. Emmett et al. (1994) tested the skin elicitation threshold of MBT for inducing contact dermatitis in a group of 12 MBT-sensitive volunteers. Patches containing 22.7 ~ 1.9 mg of petrolatum with MBT at weight con- centrations of 1%,0.316%,0.1%,0.0316%,0.01%, and 0.0032% were applied to the subjects' backs and left covered for 4 d, after which standard

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2-Mercaptobenzothiazo1/te TABLE 5-3 Patch Test Results for MBT 177 Study Years /0 MBT-Positive 1996-1998 1994-1996 1992-1994 1985-1989/1989-1990 1.8 2.1 1.8 2.5 graded readings were recorded by an examiner who was blind to the patch test identities. Patches covered an area of 50 square millimeters (mm' of skin, thus MBT at 0.0032% corresponded to a concentration of 1.45 ~g/cm2, or 0.73 fig total. The lowest concentrations producing a definite eczematous positive reaction or provocation threshold were 0.01% (in one subject), 0.032% (in one subject), and 0.1% (in five subjects). The potency of MBT relative to nickel, another common contact allergen, can be esti- mated by comparing these results to those of a previous very similar study of nickel sulfate (Emmett et al. 1988~. In a group of 12 nickel-sensitive subjects, the provocation threshold was 0.47 fig (0.01%) when tested in petrolatum. Thus, the potencies of MBT and nickel (in petrolatum) appear to be similar. The provocation threshold for nickel sulfate in aqueous solu- tions was higher than that for nickel in petrolatum (Emmett et al. 1988~. Wang and Suskind applied preparations of MBT at 0.5%,2%,5%, and 10% in petrolatum to the shaved flanks of naive Hartley albino guinea pigs (350-420 g, 5-6 wk old) under gauze pads for 24 h and examined the sites at 1, 24, and 48 h after removal of the test materials (Wang and Suskind 1988~. They reported irritant reactions for MBT at 5% and 10%. The intensity of the 5% reaction was much weaker than that of the 10%. No reactions were seen for the 2% and 0.5% concentrations. In guinea pigs sensitized by pretreatment with MBT at 5% (24 h application, three applica- tions per week, 2 wk) and then challenged with lower concentrations of MBT for 24 h, seven of 10 animals showed mild effects at 2%, two of 10 at 0.5%, and zero of 10 at 0.1% (Wang and Suskind 1988~. Although the concentrations required to induce irritation in sensitized guinea pigs were greater than those reported in MBT-sensitive humans, the challenge expo- sure duration in guinea pigs was only one-fourth (1 d) that in the humans volunteers (4 d). Wang and Suskind also tested three other rubber accelera- tors and curing agents: morpholine, 4,4-dithiodimorpholine (DTDM), and morpholinyI-mercaptobenzothiazole (MMBT). Of the four compounds

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178 Spacecraft Water Exposure Guidelines tested, morpholine did not induce any dermatitis reaction, DTDM and MMBT induced erythema and swelling, and MBT induced only erythema. The studies of Emmett et al., taken together with those of Wang and Suskind, demonstrate that induction of cell-mediated contact hypersensitiv- ity is dependent on dose and duration of exposure as well as the molecular structure of the test chemical. They also show that when sensitized individ- uals are given a challenge dose of MBT under defined conditions, there are threshold doses below which no reaction will occur, but the magnitude of the threshold dose varies widely between individuals. Subchronic Toxicity (11-100 d) Treatment of male and female F-344/N rats by gavage with MBT sus- pended in corn oil at doses up to 2,500 mg/kg/d for 16 ~ produced no com- pound-related gross pathologic effects other than slightly reduced weight gain (Dieter 1988~. Similarly treated B6C3F~ mice that received up to 1,500 mg/kg/d also displayed no compound-related gross pathologic effects other than post-gavage lethargy after day 1, but four of five females that received 1,500 mg/kg/d died before the end ofthe study, as did four off~ve males and five of five females that received 3,000 mg/kg/d (Dieter 1988~. Post-gavage lethargy and rough coats were reported for rats and mice treated by gavage with MBT in corn oil at 375 mg/kg/d for 13 wk (Dieter 1988~. Five of 10 male mice and seven of 10 female mice that received 1,500 mg/kg/d died before the end of the study, but two of those deaths were related to gavage technique (Dieter 1988~. No compound-related gross pathologic effects were reported, but clonic seizures, lacrimation, and salivation were observed in the 750-mg/kg and 1,500-mg/kg groups (Dieter 1988~. Chronic Toxicity (>101 d) No-Observed-Adverse-Effect Levels (NOAELs) Lehman (1965) reported that rats fed a 2-year (y) diet formulated to contain MBT at 12, 37.9, and 120 parts per million (ppm) and dimethyI- dithiocarbamate at 138, 486, and 1,380 ppm, respectively, and dogs fed the same doses for 1 y, exhibited no significant effects on survival, body-weight

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2-Mercaptobenzothiazo1/te TABLE 5-4 Daily Intake of MBTa 179 Dose (ppm) Male (mg/kg/d) Female (mg/kg/d) 30 3.60 3.61 120 14.69 13.52 480 57.90 58.82 1,920 289.40 247.98 aDoses Tom 20-mo study by Owaga et al. (1989) . gain, hematologic parameters, blood sugar, nonprotein nitrogen values, or histopathology. In SIc:~dY mice fed a diet containing MBT at 480 ppm or 1,920 ppm for 20 mo (see Table 5-4 for daily doses), Ogawa et al. (1989) reported no treatment-related effects on hematologic parameters (red blood cell tRBC] count, hemoglobin, hematocrit, mean cell volume, mean cell hemoglobin, mean cell hemoglobin concentration, platelets, white blood cell counts), blood biochemistry (total protein, albumin, albumin-globulin ratio, blood urea nitrogen, total cholesterol, alkaline phosphatase, aspartate aminotrans- ferase, alanine aminotransferase), or organ histopathology of the lungs, liver, or kidneys, including tumor incidence. They did not report any con- vuisions in mice in the chronic part of their study, whereas convulsions were the primary adverse effect observed during their determination ofthe LD50s for MBT administered by gavage. Nephrotoxicity Ogawa et al. (1989) reported an increased incidence of cell infiltration ofthe interstitium ofthe kidneys in male SIc:~dY mice after 20 mo of a diet containing MBT at 480 ppm or 1,920 ppm, as shown in Table 5-5. In fe- male mice, not only was there no increased incidence at either 12 or 20 mo, but the incidence for the zero-dose controls was higher than that for the high-dose males. This may be due, in part, to the small number (5-10) of mice per interim-sacrif~ce group, although there were 30 mice total per treatment group and 60 per contro! group. In a 2-y gavage study forNTP, Dieter (1988) reported an increase in the severity of nephropathy in male F-344/N rats dosed at 375 mg/kg or 750 mg/kg in corn oil for 5 d/wk compared with controls (Dieter 1988):

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192 Spacecraft Water Exposure Guidelines Hardin et al. (1981) reported finding no fetal toxicity or teratogenesis in groups of 10-15 inseminated Sprague-Dawley rats (250-300 g) adminis- tered the maximum tolerated dose (200 mg/kg/~) of MBT in corn oil by intraperitoneal injection on days 1-15 of gestation. Hardin et al. examined uterine contents on day 21 of gestation. The individual fetuses were weighed, measured for crown-rump length, sexed, and examined for exter- nally visible malformation. One-half to two-thirds of each litter was pre- served in Bouin's fluid for internal examination by the Wilson method of free-hand razor-blade sectioning, and the balance of each litter was pre- served in ethanol for clearing and skeletal staining with alizarin red. No teratogenic effects were suggested for MBT and no treatment-related histo- pathologic changes were observed in maternal tissues. RATIONALE Acceptable concentration (AC) values were determined following the guidelines ofthe National Research Council (NRC 2000~. ACs were calcu- lated assuming consumption of 2.8 L of water per day. This includes an average of 800 me/d of water used to prepare and reconstitute food and 2.0 L/d for drinking. For each exposure duration, the spacecraft water expo- sure guideline (SWEG) (Table 5-9) was set based on the lowest value among the ACs for all the significant adverse effects at that exposure dura- tion. Drinking water standards set by other organizations are listed in Table 5-10. Carcinogenicity No compelling arguments for or against the carcinogenicity of MBT can be made from the available data. The available data from human epide- miological studies show no increased risk of mortality from cancer due to exposure to MBT, but the confounding effect of concomitant exposures to known carcinogen 4-aminobiphenyl does not permit one to rule out a weak contribution by MBT to the observed rate of carcinogenesis. An NTP study of MBT administered by gavage yielded some evidence of carcinogenicity in male and female rats and equivocal evidence of carcinogenicity in female mice. No carcinogenicity was reported in rats, mice, or dogs in the studies of Innes et al. (1969), Lehman (1965), and Ogawa et al. (1989~. That could be attributed either to the fact that in those studies MBT was administered

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2-Mercaptobenzothiazo1/te TABLE 5-9 Spacecraft Water Exposure Guidelines for MBT 193 Duration Concentration(mg/L) Target Toxicity 1 d 200 CNS depression 10 d 30 Nephrotoxicity 100 d 30 Nephrotoxicity 1,000 d 30 Nephrotoxicity, carcinogenicity in the feed rather than by gavage (as in the NTP study) or to the use of doses lower than those used in the NTP study. Assuming that MBT may be weakly carcinogenic, AC values for carcinogenicity were calculated as follows. The data for the five types of tumors reported in the NTP study were reviewed to determine whether benchmark dose (BMD) methodology could be applied to estimate a NOAEL. Ofthe five, the data for mononuclear cell leukemia in male rats and for pancreatic acinar cell adenomas in male rats could not be used because, although the low-dose response was more than double the zero-dose response, the high-dose response was less than the zero-dose response. Of the remaining tumor types (adrenal gland pheo- chromocytomas in male rats, adrenal gland pheochromocytomas in female rats, and pituitary gland adenomas in female rats), the only tumors common to males and females in either species were adrenal pheochromocytomas in rats. Because the low dose for female rats was lower than that for males, the pheochromocytomas incidence data for female rats were used as input for EPA's BMD software, version 1.3.1, to calculate a BMD (BMDLo~. The value of the BADLY (the lower limit of the dose of MBT that would produce a 1% lifetime tumor incidence in female rats),17 mg/kg/d, was used as a point of departure to calculate an AC for carcinogenicity. The rats in the NTP study were treated 5 d/wk, so the effective weekly dose, divided over 7 4, is 17 mg/kg/d x 5/7 = 12 mg/kg/~. For a 70-kg astronaut consuming 2.S L of water, the MBT concentration needed to achieve a dose of 12 mg/kg/d is 12 mg/kg x 70 kg 2.S L = 303 mg/L. No species extrapolation factor was used because the epidemiological

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194 Spacecraft Water Exposure Guidelines data indicate that MBT is, at most, a weak human carcinogen (i.e., humans are probably not more sensitive than rodents to potential MBT carcinoge- nicity). Thus, the following equation, based on Crump and Howe's 1984 multistage model, with only the first stage dose-related, was used to calcu- late the exposure concentrations, D, that would yield a tumor risk of 10-4 for exposure durations of 10, 100, and 1,000 d: d (25,600)k- . D- risk (25,600- 365 agents - t(25,600- 365 age)- tat ' where c'7= the concentration during a lifetime exposure (303 mg/L in this case); 25,600 = the number of days in a 70-y human lifetime; k= the number of stages in the model (1 in this case); 10-4 = the acceptable risk level; age = the minimum age of an astronaut, in years (30 in this case); t= the exposure duration, in days (10, 100, or 1,000~; and risk= the risk oftumor for lifetime exposure to c'7~10-2 in this case). This equation yields values of Do 000 = (303 mg/L)~25,600~1E-2~/1000), Do 000 = (5.0835E13 / 6.0090E11), Do 000 = 80 mg/L; Duo = 800 mg/L; and Do = 8,000 mg/L. Dividing the calculated dose values, D, by a factor of 3 to partially protect against the known allergenicity of MBT yields ACs (for carcinoge- nicity) of 1,000-d AC = 30 mg/L (rounded); 100-d AC = 300 mg/L (rounded); and 10-d AC = 3000 mg/L (rounded). The available data support the conclusion that if MBT is a carcinogen, it is a weak one. Thus, the risk of tumorigenesis due to ingestion of MBT in drinking water is believed to be negligible on the basis oftwo arguments.

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2-Mercaptobenzothiazo1/te 195 First, the intermittent exposure by drinking water more closely approxi- mates the exposure pattern in the diet (for which no animal carcinogenesis has been reported) than the bolus exposure by gavage in corn oil (for which some evidence of carcinogenicity has been reported). Second, MBT has very poor solubility in pure water, making it unlikely that sufficient MBT could be ingested in drinking water to result in tumorigenesis. Allergic Dermatitis MBT is a known sensitizer for allergic contact dermatitis. However, no data were found in the scientific literature on the effects of exposure to MBT by ingestion in sensitized individuals. Data were found that indicated that ingested nickel, another contact sensitizer with potency similar to MBT (Emmett et al. 1988, 1994), could induce dermatitis in nickel-sensitive patients (Santucci et al. 1988~. In another study, orally administered nickel consistently induced dermatitis (pompholyx) in nickel-sensitive subjects only when given in high bolus doses (5.6 mg as NiSO4.7H2O) (Gawkrodger et al. 1986~. Emmett et al. (1994) showed that in a small population (n = 12) of MBT-sensitive individuals, the lowest concentration of MBT inpetrolatum that would induce an observable dermatitis reaction when applied to the skin for 48 h in an occlusive patch was 0.01% (0.1 ppt; 100 ppm). For the conditions ofthe patch test (22.7 mg of petrolatum-based MBT preparation applied to an area 50 mm2), that corresponds to 4.5 ~g/cm2. The highest concentration of MBT to which no reaction occurred in any of the 12 indi- viduals was 0.0032% (0.032 ppt; 32 ppm; 32 mg/L), which corresponds to 1.45 ~g/cm2. We must assume that it is possible that a small proportion of astronauts will be already sensitized to MBT before flight. A large range has been reported in the degree of sensitivity of individuals to contact allergens- with a small number of people being extremely sensitive, it is not possible to set an exposure level that will protect all individuals against allergic dermatitis. Thus, to provide at least partial protection against allergic der- matitis, ACs for other toxic end points will be decreased by an arbitrary factor of 3. A larger factor is not warranted because the effect (dermatitis) is not usually severe and can be minimized by pharmacological treatments (e.g., allergy medications, cortisone ointments) that are available in the medical kits on U.S. spacecraft.

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196 Spacecraft Water Exposure Guidelines Nephropathy The NTP study of Dieter (1988) reported nephropathy at the end of 2 y in 100% of both control and treated male F-344/N rats, in 75/O of the female rats, and in none of the mice. In addition, Dieter reported a treatment-related increase in the severity of nephropathy in male rats. Se- verity was scored as 1 (minimal), 2 (mild), 3 (moderate), and 4 (severe). The data for the severity ratings for individual animals was not reported. The mean severity rating was the same for rats treated at either 375 mg/kg or 750 mg/kg (3.4 "moderate to severe]), but it was higher than for the vehicle-treated controls (2.3 Wild to moderately. Nephropathy is common in old rats, and the biologic relevance of such severity data is uncertain. For setting SWEGs, the treatment time was considered lifetime rather than 2 y, because nephropathy occurred only in old age and was seen even in con- trols. In addition, because there was essentially only a single non-back- ground-effect level, the BMD approach was not used to estimate an AC for this effect. Instead, an AC was calculated by applying uncertainty factors to the lowest tested dose (the LOAEL tiowest-observed-adverse-effect level]) of 375 mg/kg. A factor of 10 was used to estimate the NOAEL from the LOAEL. Other factors include a factor of 3 to partially protect against the known allergenicity of MBT, a weight of 70 kg per crew member, an interspecies extrapolation factor of 10, and a water consumption volume of 2.8 L per crew member per day. Thus, Lifetime AC= (375 mg/kg x 70 kg) (3 x 10 x 10 x 2.~= 30mg/L. Although a standard lifetime is 70 y, and the longest exposure duration for which we currently set SWEG values is 1,000 d, the calculated ACs were not increased by a time factor, because the policy ofthe subcommittee has been to avoid increasing the AC for exposure durations shorter than the duration for which we have data. This is particularly a problem when data indicating time-dependency are not available. In the absence of other rele- vant studies on which to base ACs for nephropathy, a conservative approach is to use the 1,000-d AC as the 10-d and 100-d ACs, because it is not clear that the kidneys were examined histologically in the 16-d or 13-wk studies by Dieter. Thus, the ACs for nephropathy are 1000-d AC = 30 mg/mL; 100-dAC=30mg/mL;and 10-dAC=30mg/mL.

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197 4 =0 o .5 =0 ~ O 8 ~ D O a=> Ct ?~ .O -E e A V an cat cam as an cam ~ v: ~ a, to I O $ rem ~ O O O rem o o o o rem rem ~^ ~ a, ^ ~~ ~-0 { O ~ ;~~ c) a, ~ cd a, O 0 ~ ~ a, ~ ~ = 00 0 ~ ~ ~ O = $-O 0 ~ ~ ~ O rem O rem O rem O ~ r~ ~ ~ oo a, ~ ~ o ~ ca) ~ c~ ~ o ~l :O o o ca) . ~ ~ c) ~ cd ~ a, ~ ~ o o 50 ~ c~ a~ cd a, 0 ~ ~ ~o o 0Q a~ ~ a, a, . - a, .= 5-1 a ~ = ~ ~ - - - ~ cd 50 - E~ a., - 0 :~ - c<$ ~ ~ o ~ Ho.- ~ ~ ~-- ~ ~ a~ a~ a.~ a~ a., ;~4 a, ~ jo ~ :~^ ~ ~ ~o ~ a, ~ ~ ~ = ~ ~ . ~o o . - ~ ~ ~ - <$ -~ Cd 5-1 0 a, a, o C o .~ . o~ o ~ o ~

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198 Spacecraft Water Exposure Guidelines No AC for nephropathy was set for exposure durations of 1 d. CNS Effects Clonic convulsions were reported in mice at single gavage doses near the LD50 (approximately 1,500 mg/kg, suspension in aqueous media; approximately 3,100 mg/kg, suspension in olive oil) (Ogawa et al. 1989) and in rats and mice treated for 13 wk with MET in corn oil at approx- imately 750 mg/kg/d (Dieter 1988~. No convulsions were reported in mice during chronic (20 mo) studies at average MET intakes of up to 289 mg/kg/d in the diet (Ogawa et al. 1989), but post-gavage lethargy at 375 mg/kg was reported by Dieter. An AC was calculated using the highest reported dietary dose as a NOAEL for convulsions or lethargy (Ogawa et al. 1989~. The daily intake for mice was adjusted using a factor of 10 for interspecies differences. Thus, for a 70-kg human consuming 2.8 L of water per day, AC (allergenicity) = (289 mg/kg/d x 70 kg) (10 x 3 x 2.8 Lob; AC (allergenicity) = 241 mg/L (rounded to 200 mg/L). Since recovery from MBT-induced CNS depression has been shown to occur within 4 h in mice, the same AC value is used for all exposure dura- tions. Spaceflight Effects Since CNS effects and allergic dermatitis are not known to be affected by spaceflight, no spaceflight factors were applied in the calculation ofthe ACs. REFERENCES Aleksandrov, S.E. 1982. Effect of vulcanizing accelerants on embryolethality in rats. Biull. Eksp. Biol. Med. 93:87-88. Anderson, B.E., E. Zeiger, M.D. Shelby, M.A. Resnick, D.K. Gulati, J.L. Ivett and K.S. Loveday 1990. Chromosome aberration and sister chromatic exchange test results with 42 chemicals. Environ. Mol. Mutagen.16(Suppl.18~:55-137. Blosczyk, G. and H.J. Doemling 1982. HPLC determination of 2-mercapto-

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2-Mercaptobenzothiazo1/te 199 benzothiazole in rubber baby bottle nipples. Lebensmittelchem. Gerichtl. Chem. 36:90 (abstract). Brewster, D.W., K.J. Mirly, A.G. Wilson and J.W. Barnett, Jr. 1989. Lack of in vivo binding of mercaptobenzothiazole to selected tissues ofthe rat. Biochem. Biophys. Res. Commun. 165~1~:342-348. Burrows, D. 1992. Is systemic nickel important? J. Am. Acad. Dermatol. 26~4~: 632-635. Christensen, O.B., and H. Molter. 1975. Nickel allergy and hand eczema. Contact Dermatitis 1: 129-35. CMA (Chemical Manufacturers Association).1986. Disposition of 2-mercaptoben- zothiazole-ring-UL 14C 2-mercaptobenzothiazole disulfide-ring-UL 14C in Fischer 344 male and female rats dosed orally. CMA, Washington, DC. Collins, J.J., M.E. Strauss, and S.G. Riordan. 1999. Mortalities of workers at the Nitro plant with exposure to 2-mercaptobenzothiazole. Occup. Environ. Med. 56~10~:667-671. Colucci, D.F., and D.A. Buyske. 1965. The biotransformation of a sulfonamide to a mercaptan and to mercapturic acid and glucuronide conjugates. Biochem. Pharmacol. 14:457-466. Cronin, E., A. Di Michiel, and S.S. Brown. 1980. Oral nickel challenge in nickel-sensitive women with hand eczema. Pp.149- 152 in Nickel Toxicology. S.S. Brown and F.W.J. Sunderman, eds. New York, NY: Academic Press. Dieter, M.P. 1988. Toxicology and carcinogenesis studies of 2-mercapto- benzothiazole (CAS No.149-30-4) in F344/N rats and B6C3F1 mice (gavage studies). NTP TR 332. National Institutes of Health, National Toxicology Program, Research Triangle Park, NC. el Dareer, S.M., J.R. Kalin, K.F. Tillery, D.L. Hill and J.W. Barnett, Jr. 1989. Disposition of 2-mercaptobenzothiazole and 2-mercaptobenzothiazole disulfide in rats dosed intravenously, orally, and topically and in guinea pigs dosed topically. J. Toxicol. Environ. Health 27~1~:65-84. Emmett, E.A., T.H. Risby, L. Jiang, S.K. Ng and S.E. Feinman. 1988. Allergic contact dermatitis to nickel: Bioavailability from consumer products andprov- ocation threshold. J. Am. Acad. Dermatol. 19~2 Ptl):314-322. Emmett, E.A., T.H. Risby, J. Taylor, C.L. Chen, L. Jiang, and S.E. Feinman.1994. Skin elicitation threshold of ethylbutylthiourea and mercaptobenzothiazole with relative leaching from sensitizing products. Contact Dermatitis (Denmark) 30~2~:85-90. Fregert, S., and E. Skog. 1962. Allergic contact dermatitis from mercaptoben- zothiazole in cutting oil. Acta Derm. Venereol. 42:235. Fukuoka, M., M. Satoh and A. Tanaka.1995. Metabolism of 2-thiobenzothiazoles in the rat. Urinary, fecal and biliary metabolites of 2-benzothiazyl sulfena- mides. Arch. Toxicol. 70~1~:1-9. Gawkrodger, D.J., S.W. Cook, G.S. Fell and J.A. Hunter.1986. Nickel dermatitis: The reaction to oral nickel challenge. Br. J. Dermatol. 115~1~:33-38. Goodwin, B.F., R.W. Crevel, and A.W. Johnson. 1981. A comparison of three

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200 Spacecraft Water Exposure Guidelines guinea-pig sensitization procedures for the detection of 19 reported human contact sensitizers. Contact Dermatitis 7:248-258. Hansch, C., and A. Leo. 1979. Substituent Constants for Correlation Analysis in Chemistry and Biology. New York: John Wiley and Sons, Inc. Hardin, B.D., G.P. Bond, M.R. Sikov, F.D. Andrew, R.P. Beliles, and R.W. Niemeir.1981. Testing of selected workplace chemicals for teratogenic poten- tial. Scand. J. Work Environ. Health 7(suppl.4~:66-75. Innes, J.R.M., B.M. Ulland, M.G. Valerio, L. Petrucelli, L. Fishbein, E.R. Hart, A.J. Pallotta, R.R. Bates, J.L. Falk, J.J. Gart, M. Klein, I. Mitchell, and J. Peters.1969. Bioassay of pesticides and industrial chemicals for tumorigenicity in mice: A preliminary note. J. Natl. Cancer Inst. 42:1101-1114. Johnson, G.A., S.J. Boukma, and P.A. Platz. 1970. 2-Mercaptobenzothiazole, an inhibitor ofdopaminebeta-hydroxylase. J. Pharm. Pharmacol.22~9~:710-702. Jordan, W.P.J., and S.E. King. 1979. Nickel feeding in nickel-sensitive patients with hand eczema. J. Am. Acad. Dermatol. 1 :506-508. Jung, J.H., J.L. McLaughlin, J. Stannard, and J.D. Guin.1988. Isolation, via activ- ity-directed fractionation, of mercaptobenzothiazole and dibenzothiazyl di- sulfide as 2 allergens responsible for tennis shoe dermatitis. Contact Dermatitis (Denmark) 19~4~:254-259. Kaaber, K., N.K. Veien, and J.C. Tjell. 1978. Low nickel diet in the treatment of patients with chronic nickel dermatitis. Br. J. Dermatol. 98:197-201. Kiec-Swierczynska, M., B. Krecisz, and B. Szul 1999. An unusual case of contact allergy to mercaptobenzothiazole in antifreeze. Contact Dermatitis (Denmark) 41~5~:303-304. Larsen, G.L., J.E. Bakke, V.J. Feil, and J.K. Huwe. 1988. In vitro metabolism of the methylthio group of 2-methylthiobenzothiazole by rat liver. Xenobiotica 18~3~:313-322. Lear, J.T., and J.S. English.1996. Hand involvement in allergic contact dermatitis from mercaptobenzothiazole in shoes. Contact Dermatitis (Denmark) 34~6~: 432. Lehman, A.J.1965. Mercaptobenzothiazole. Pp.90-91 in Summaries of Pesticide Toxicity. York, PA: Association of Food and Drug Officials. Lynde, C.W., J.C. Mitchell, R.M. Adams, H.I. Maibach, W.J. Schorr, F.J. Storrs, and J. Taylor. 1982. Patch testing with mercaptobenzothiazole and mercapto- mixes. Contact Dermatitis 8~4~:273-274. Manninen, A., S. Auriola, M. Vartiainen, J. Liesivuori, T. Turunen, and M. Pasanen. 1996. Determination of urinary 2-mercaptobenzothiazole (2-MBT), the main metabolite of 2-(thiocyanomethylthio~benzothiazole (TCMTB) in humans and rats. Arch. Toxicol. 70~9~:579-584. Marks, J.G.J., D.V. Belsito, V.A. DeLeo, J.F. Fowler, A.F. Fransway, H.I. Maibach, C.G.T. Mathias, M.D. Pratt, R.L. Rietschel, E.F. Sherertz, F.J. Storrs, and J.S. Taylor. 2000. North American Contact Dermatitis Group patch-test results, 1996-1998. Arch. Dermatol. 136:272-273. Maurer, T., P. Thomann, E.G. Weirich, and R. Hess. 1979. Predictive evaluation

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2-Mercaptobenzothiazo1/te 201 In animals of the contact allergenic potential of medically important sub- stances. II. Comparison of different methods of cutaneous sensitization with "weak" allergens. Contact Dermatitis 5:1-10. Monahan, P.V., R. Joseph, P. Ramesh, and K. Rathinam. 2000. Assessment of in vivo chromosomal aberrations potency of zinc mercaptobenzothiazole. J. Biomater. Appl. 14~3~:224-228. Nagamatsu, K., Y. Kido, G. Urakubo, Y. Aida, Y. Ikeda, and Y. Suzuki. 1979. Absorption, distribution, excretion end metabolism of2-mercaptobenzothiazole in guinea pig. Eisei Kagaku 25:59-65. Nielsen, G.D., L.V. Jepson and P.J. Jorgensen.1990. Nickel-sensitive patients with vesicular hand eczema: Oral challenge with a diet high in nickel. Br. J. Dermatol. 122:299-308. NRC (National Research Council). 2000. Methods for Developing Spacecraft Water Exposure Guidelines.Washington,DC: NationalAcademy Press. Nyska, A., J.K. Haseman, J.R. Halley, S. Smetana and R.R. Maronpot. 1999. The association between severe nephropathy and pheochromocytoma in the male F344 rat the National Toxicology Program experience. Toxicol. Pathol. 27(4):456-462. Ogawa, Y., E. Kamata, S. Suzuki, K. Kobayashi, K. Naito, T. Kaneko, Y. Kurokawa, and M. Tobe.1989. Toxicity of 2-mercaptobenzothiazole in mice. Eisei Shikenjo Hokoku 107:44-50. Peterson, M.C., J.H. Vine, J.J. Ashley, and R.L. Nation. 1981. Leaching of a con- taminant into the contents of disposable syringes. Aust. N. Z. J. Med. 11: 208-209. Reepmeyer, J.C., and Y.H. Juhl. 1983. Contamination of injectable solutions with 2-mercaptobenzothiazole leached from rubber closures. J. Pharm. Sci.72~11~: 1302-1305. Rudzki, E., T. Napiorkowska, and I. Czerwinska-Dihm. 1981. Dermatitis from 2-mercaptobenzothiazole in photographic films. Contact Dermatitis 7~1~:43. Salmona, G., A. Assaf, A. Gayte-Sorbier, and C.B. Airaudo. 1984. Mass spectral identification of benzothiazole derivatives leached into injections by disposable syringes. Biomed. Mass Spectrom. 11~9~:450-454. Santucci, B., A. Cristaudo, C. Cannistraci, andM. Picardo.1988. Nickel sensitivity: Effects of prolonged oral intake of the element. Contact Dermatitis 19: 202-205. Santucci, B., F. Manna, C. Cannistraci, A. Cristaudo, R. Capparella, A. Bolasco, and M. Picardo. 1994. Serum and urine concentrations in nickel-sensitive patients after prolonged oral administration. Contact Dermatitis 30~97-101~. Schweisfurth, H. 1995. 2-Mercaptobenzothiazole in baby pacifiers. Dtsch. Med. Wochenschr. (Germany) 120~31-32~: 1102-1103. Sorahan, T., L. Hamilton, and J.R. Jackson.2000. A further cohort study of workers employed at a factory manufacturing chemicals for the rubber industry, with special reference to the chemicals 2-mercaptobenzothiazole (MBT), aniline, phenyl-beta-naphthlyamine and o-toluidine. Occup. Environ. Med. 57~2~: 106-115.

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202 Spacecraft Water Exposure Guidelines Sorahan, T., and D. Pope. 1993. Mortality study of workers employed at a plant manufacturing chemicals for the rubber industry: 1955-1986. Br. J. Ind. Med. 50:998-1002. Strauss, M.E., E.D. Barrick, and R.M. Bannister. 1993. Mortality experience of employees exposed to 2-mercaptobenzothiazole at a chemical plant in Nitro, West Virginia. Br. J. Ind. Med. 50~10~:888-893. Veien, N.K., T. Hattel, O. Justesen, and A. Norholm. 1987. Oral challenge with nickel and cobalt in patients with positive patch tests to nickel and/or cobalt. Acta Derm. Venereol. 6:321-325. Wang, X.S., and R.R. Suskind. 1988. Comparative studies of the sensitization potential of morpholine,2-mercaptobenzothiazole and 2 oftheir derivatives in guinea pigs. Contact Dermatitis (Denmark) 1 9( 1 ): 1 1 - 1 5. Wilkinson, S.M., P.H. Cartwright, andJ.S. English.1990. Allergic contactdermati- tis from mercaptobenzothiazole in a releasing fluid. Contact Dermatitis (Den- mark) 23~5~:370. Zeiger, E., J.K. Haseman, M.D. Shelby, B.H. Margolin, and R.W. Tennant. 1990. Chromosome aberration and sister chromatic exchange test results with 42 chemicals. Environ. Mol. Mutagen. 16(Suppl 18~:1-14.