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Repeated oral toxicity: BASF/CIT (2003) reported a combined repeated dose toxicity study with a reproduction/developmental toxicity screening test (OECD guidelines 407 and 422). Male and female rats were given orally doses (gavage) of 15, 50 and 75 mg/kg bw/d (0.192, 0.640 and 0.960 mmol/kg bw/d) over a study period of about 7 weeks. No toxic effects were recorded at 15 mg/kg bw/day in males and females. A slightly higher body weight gain and food consumption was seen in treated females (not significant, also at higher dose levels) whereas in males at > = 50 mg/kg bw/day a significant lower body weight gain (-11 to -24%) compared to controls was detected. Ptyalism was observed in both genders at the mid and high dose levels. Males showed the following effects on the liver: at > = 50 mg/kg bw/day paleness and accentuated lobular pattern of the liver at necropsy, histopathology revealed minimal to marked vacuolated hepatocytes accompanied by lower blood cholesterol (0, 50, 75 mg/kg bw/day: 1.6 vs. 0.9 and 0.6 mmol/l) and triglyceride levels (0.85 vs. 0.39 and 0.23 mmol/l); at 75 mg/kg/day, absolute and relative liver weight (22 and 36%, respectively) were significantly increased, as well as minimal to slight hypertrophy of hepatocytes. In females at the dose levels of 50 and 75 mg/kg bw/day absolute (32 and 36%, respectively) and relative liver weight (28 and 37% respectively) were significantly increased, and paleness of the liver was detected at termination; histopathological examinations showed minimal to slight liver cell hypertrophy, and increased incidence and severity of vacuolated hepatocytes. Incidence and severity of cardiomyopathy was increased in males at 75 mg/kg/day and in females at 50 and 75 mg/kg bw/day. Hematology, seminology and urine analysis did not show any alterations. The NOAEL for male and female rats is 15 mg/kg bw/day (0.192 mmol/kg bw/d).

The observed effects after oral administration of 2-mercaptoethanol were supported by the available data for sodium 2-mercaptoacetate (CAS 367-51-1). From the available in vitro and in vivo data (cf. chapter toxicokinetics), it can be reasonably concluded that 2-mercaptoethanol is metabolized under formation of 2-mercaptoacetate in the mammalian organism. Thus, comparable effects and dose response relationships were observed after repeated oral administration.

The potential toxicity of sodium 2-mercaptoacetate (sodium thioglycolate) was evaluated following daily oral administration (gavage) of 7, 20 and 60 mg/kg bw to rats for 13 weeks according to OECD guideline 408 (ECHA disseminated dossier, 2017-10-02). On completion of the treatment period, designated animals were held for a 4-week treatment-free period in order to evaluate the reversibility of any findings. At 60 mg a.i./kg/day, one female was prematurely sacrificed for humane reasons on day 14 and one male was found dead on day 90. Changes, which were also noted in the animals sacrificed on schedule, were found in the kidneys of the female sacrificed for humane reasons, and the liver and thymus of both these animals. The vacuolation /microvacuolation of kidney and liver was considered to be related to treatment with sodium thioglycolate. The demise and death of these animals were attributed to treatment. In surviving animals, hypersalivation, piloerection and/or areas of thinned hair were transiently observed in some animals. At laboratory investigations, marked panleucopenia was noted in both sexes (all the white blood cell subtypes were affected). High mean red blood cell count, hemoglobin concentration, packed cell volume and mean prothrombin time were observed in males and females. However, the bone marrow cellularity and number of megakaryocytes were similar to the control values. Hypoglycemia was noted in males and females, associated with high urea (males and females) and creatinine (males only) levels and low chloride levels (male and female). High fat acid level was observed in males and females. High aspartate aminotransferase (males only) and alanine aminotransferase (males and females) activities were noted. Low mean ßhydroxybutyrate levels, associated with high lactate concentrations, were reported in males and females. At the end of the treatment-free period, the hematological parameter disturbances were no longer observed in the high-dose group when compared to controls, suggesting total reversibility of the findings. At microscopic examination, periportal hepatocellular vacuolation was noted in the liver of males given 20 mg a.i./kg/day and in males and females given 60 mg a.i./kg/day. This change was not present at the end of the treatment-free period. Microvacuolation in the liver was Oil Red O positive, indicating the presence of neutral lipids and a lipidosis (syn. steatosis) change. Increased Oil Red O positive vacuoles were noted in males treated from 20 mg a.i./kg/day and in females treated at 60 mg a.i./kg/day. Tubular vacuolation was observed in the kidneys from females given 60 mg a.i./kg/day. This correlated with increased urea and creatinine values at clinical examination. In heart of other animals, minimal to slight vacuolation were also observed in control and treated males and in one high-dose female. This lesion was considered not to be related to treatment in view of the low magnitude and its occurrence in one control male. These findings were not seen in male rats at the end of the treatment-free period. Minimal focal degenerative cardiomyopathy was observed in 2/9 females given 60 mg a.i./kg/day but not in controls. Since this change was minimal, focal and with a pattern similar to what is found in untreated males, the relationship of this finding to treatment was considered to be unlikely. Increased absolute and relative liver weights were noted in females treated at 60 mg a.i./kg/day and correlated microscopically with minimal centrilobular hepatocellular hypertrophy noted in the liver of a few females. Other minor treatment-related changes noted in females treated at 60 mg a.i./kg/day were observed in the liver. These changes consisted of minimally increased incidence and severity of extramedullary hematopoiesis in the liver. All these changes were not observed at the end of the treatment-free period. Thioglycolate is known to inhibit the mitochondrial beta-oxidation of fatty acids in liver resulting in a greater conversion of the latter into triglycerides that accumulated in the liver, as a result, ketogenesis was inhibited (Bauché et al., 1977, 1981, 1982 and 1983). The changes observed in the blood chemistry parameters (decreased blood glucose and ß-hydroxybutyrate and increased lactate and fatty acids) and in the liver (microvesicular lipidosis) are consistent with the mode of action of the compound. In the kidney of the female, subtle microvacuolar changes were noted in the proximal convoluted tubules of the kidney, and again this change could correspond to mitochondrial changes. At 20 mg a.i./kg/day, non-adverse minimal periportal microvacuolation corresponding to minimally increased severity of lipidosis (syn. steatosis) was noted in two males. In females, low glucose and ß hydroxybutyrate levels were noted, associated with high urea and fatty acid concentrations. High mean prothrombin time was also noted in females. At this dose level, no signs of adverse toxic effects were noted.

Consequently, under the experimental conditions of this study, based on the adverse effects observed at 60 mg a.i./kg/day, particularly mortality, hematological and significant blood chemistry changes associated with liver microscopic changes and the limited blood chemistry effects without microscopic changes in the liver observed at 20 mg a.i./kg/day, the No Observed Adverse Effect Level (NOAEL) of sodium thioglycolate was 20 mg a.i./kg/day, and the No Observed Effect Level (NOEL) was 7 mg a.i./kg/day given by daily oral administration (gavage) to rats for 13 weeks.

Justification for classification or non-classification

Justification for classification or non classification

Based on the liver and heart effects seen in this study at >50 mg/kg/day and in consideration of the criteria of DSD and CLP (using Haber’s Law for 7-wk exposure), a classification of Xn; R48/22 under DSD and a Category 2 (H373; target organs: liver and heart) under GHS/CLP are warranted. No assessable data/information for repeated dermal toxicity are available. No information about repeated inhalation toxicity is available.