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EC number: 200-890-2 | CAS number: 75-66-1
Repeated-dose toxicity of 2-methylpropane-2-thiol has been investigated a in a 13-week inhalation toxicity study and an oral combined repeated-dose/reproductive/developmental toxicity study in rats. In the 3-month inhalation study, the NOAEC for systemic toxicity was 196 ppm (723 mg/m3)In the oral repeated-dose toxicity study (OECD TG 422), based on decreased body weight reduction in females at 200 mg/kg/day, the NOAEL was considered to be 50 mg/kg/day.
In an OECD TG 422 study (MHLW, 2006; Klimisch score = 2), Sprague-Dawley rats were dosed by oral gavage with 0, 10, 50, or 200 mg/kg 2-methylpropane-2-thiol for 42 to 53 days. A 14-day recovery period was included for the control and the 200 mg/kg dose groups. There was no mortality, effect on urinalysis, clinical signs of toxicity, changes in functional observational battery (FOB) measurements, or motor activity.
One key 90 -day study was available. Additionally, one subchronic inhalation toxicity study on another C2 -C4 alkyl mercaptan (butane-2-thiol) can be used as read across for 2 -methylpropane-2-thiol.
In a key 90 -day inhalation toxicity study (Ulrich, 1982a, 1983, 1984; Klimisch score = 2),male and female Sprague-Dawley rats (15/sex/dose) were exposed (whole body) to 2 -methylpropane-2-thiol at measured concentrations 0, 9, 97, or 196 ppm (0, 33, 357 or 721 mg/m3, respectively) for six hours per day, five days per week. There were no deaths, clinical signs of toxicity or body weight changes observed. Blood urea nitrogen was statistically significantly different from the control group at the 6-week interval only for the 97 ppm exposure group; this change was not considered biologically relevant because it occurred at only one time interval. Statistically significant differences in erythrocyte count were only found in females at 6-week (97 ppm) and 12-week (97 and 196 ppm). The clinical pathology endpoints that differed from concurrent controls remained within the range of historical control values and were not considered to be biologically or toxicologically relevant. No compound-related macroscopic lesions were observed in any of the rats that were sacrificed at the termination of the study or those that died during the course of the study. There was a compound related increase in alveolar macrophages among males and females of the mid dose (97 ppm) and high dose (196 ppm) groups exposed to 2 -methylpropane-2-thiol. At the mid dose level, 5 of 15 males and 3 of 15 females were affected. All lesions were trace in severity. At the high dose level 14 of 15 males and 12 of 15 females were affected. One male and one female were mild and all of the others were trace in severity. This lesion did not occur at the low dose level (9 ppm). Toxicologically significant increases in the mean weights of kidneys occurred in male rats exposed to 97 and 196 ppm. There was a compound and concentration-related increase in chronic nephrosis (varying degrees of multifocal degeneration of the proximal convoluted tubules, tubular regeneration, and inflammatory cell infiltration of the interstitium) in 14 of 15 animals at the high concentration (196 ppm). The lesion was also noted in 13 of 15 at the mid concentration (97 ppm) and 7 of 15 animals at the low concentration (9 ppm). However, findings in the kidneys of males were considered to be rat-specific with no relevance for human risk assessment. The NOAEC for systemic toxicity was determined to be ≥ 196 ppm (721 mg/m3).
In a key 90-day inhalation toxicity study (Kim et al., 2009; Klimisch score = 1), butane-2 -thiol was administered to 10 sprague-dawley rats/sex/concentration by whole body exposure at concentrations of 0, 0.092, 0.367, or 1.488 mg/L (0, 25.1, 99.6, or 403.4 ppm) for 6 hours per day, 5 days/week for a total of 91 days. No treatment-related toxic symptoms or mortality were observed in any of the animals treated with butane-2 -thiol during the experimental period. In males, the amount of food consumed was significantly lower on Days 0 and 7 of treatment in the 1.488 mg/L (403.4 ppm) group (11.7 ± 3.9 and 20.7 ± 1.5 g) than in the control group (22.6 ± 2.4 and 24.3 ± 2.3 g). In females, food consumption of the group exposed to 1.488 mg/L (403.4 ppm) was also decreased significantly on Days 0 and 7 of treatment (9.6 ± 3.5 and 13.6 ± 1.8 g) than in the control group (18.2 ± 2.7 and 18.8 ± 3.3 g). Significant decreases in body weight gain were observed in females in the high concentration group and decreases in RBC, haemoglobin and hematocrit levels were reported in both male and female animals in the 1.488 mg/L (403.4 ppm) group. In males, the relative weights of the liver and kidneys in the 1.488 mg/L (403.4 ppm) group were increased significantly in a dose-dependent manner compared to those of the control group. In females, the relative weights of the kidneys, brain, lung, and heart in the 1.488 mg/L (403.4 ppm) group were also significantly increased in a dose-dependent manner compared to those of the control group. No gross pathological changes were observed at necropsy, however histopathological alterations observed predominantly in the 1.488 mg/L (403.4 ppm) groups, included centrilobular hepatocyte hypertrophy in the liver of males (which corresponded with increased liver weights) and tubular hyaline droplets, granular cast, pyelonephritis, and tubular degeneration/regeneration in the kidneys (severe in male animals), extramedullary haematopoiesis and hemosiderin pigment in the spleen, and eosinophilic inclusions and mineralization in the nasal olfactory epithelium. Based on these findings the target organs of butane-2-thiol were determined to be the erythrocyte, kidneys, liver, and nasal turbinates in rats. The LOAEC is 1.488 mg/L (403.4 ppm or 1488 mg/m3) and the NOAEC is 0.367 mg/L (99.6 ppm or 367 mg/m3).
According to REGULATION (EC) No 1272-2008 and the available data for the repeated dose toxicity:
- Specific target organ toxicity after repeated exposure: Hematological changes seen in the oral and inhalation studies on 2-methylpropane-2-thiol and butane-2 -thiol, respectively, appear to be the result of increased RBC destruction in the spleen, as indicated by the presence of hemosiderin pigment. These effects were slight in nature with no indication of any associated adverse clinical or histopathological effects in either study. It is believed that the centrilobular hepatocellular hypertrophy is an adaptive response which is reversible upon cessation of exposure. Therefore, 2 -methylpropane-2-thiol is not classified for specific target organ toxicity after repeated exposure.
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