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EC number: 423-270-5 | CAS number: -
Based on a combined chronic toxicity / carcinogenicity study in Wistar rats (GLP & OECD Guideline 453) the NOAEL was determined to be 262.2 mg/kg bw/day (male) and 333.9 mg/kg bw/day (female) (BASF, 82S0059/95121, 2006).
To assess toxicity of the test item upon chronic oral exposure, Wistar rats of both sexes were administered with 0, 1000, 5000 and 19200 ppm (54 -1317 mg/kg bw) test substance by dietary uptake for 24 month in a GLP and OECD guideline study. In parallel, a satellite group comprising all dose groups was sacrificed and examined after 12 month exposure (BASF, 82S0059/95121, 2006). Adverse effects were exclusively seen in the high dose group. Clinical findings include a red urine, increased water consumption and a decreased body weight. Parameters of clinical chemistry revealed a treatment related increase of total protein, globulins, prothrombin times and urinary erythrocytes in male rats. Increased kidney weights correlated with cysts and pelvic dilation in males. Histopathology revealed chronic nephropathy with highest gradings, focal tubular hyperplasia and cytoplasmic vacuolisation. Importantly, males seem to be more susceptible to test item induced renal toxicity, as most of the toxicological effects are more severe in male rats. Overall, the test item displayed renal toxicity exclusively in the highest dose group. Thus, under the chosen test conditions the NOAEL is 262.2 mg/kg bw/day.
The observations of the key study are supported by two further studies:
To assess toxicity of the test item upon sub-chronic oral exposure, Wistar rats of both sexes were administered with 4 dose levels between 170 -2097 mg/kg bw/d test substance by dietary uptake in a GLP and OECD guideline study (BASF, 50S0059/95106, 1998). Adverse effects included reduced body weight, increased haemoglobin in the urine specimen, decreased magnesium and creatinine concentration, focal tubular hyperplasia and vacuolization. Under the chosen test conditions, the NOAEL was 2400 ppm (170 mg/kg bw/d for males and 204 mg/kg bw/d for females).
In a GLP and OECD 407 guideline study, Wistar rats of both sex were administered with 3 dose levels between 76 - 1504 mg/kg bw/d test substance by drinking water (BASF AG, 39C0059/95008, 1995). Adverse effects included decreased food consumption, decreased body weight, decreased magnesium concentrations in the sera, focal tubular vacuolization and calcification. All toxic effects were completely reversible during a 14 days recovery period. Under the chosen test conditions, the NOAEL was 750 ppm (76 mg/kg bw/d for males and 88 mg/kg bw/d for females).
Toxicity of the test item seems to be independent of the duration of treatment and restricted to higher dose levels. The severity of nephrotoxic symptoms was similar in all studies ranging from 28 days to 24 month (BASF AG, 39C0059/95008, 1995; 50S0059/95106, 1998; 82S0059/95121, 2006). Moreover, their NOAELs are within a comparable range. Individual differences can be explained by the selection and spacing of the different dose levels in the particular studies. In conclusion, the overall NOAEL is 262.2 mg/kg bw/day.
Classification, Labelling, and Packaging Regulation (EC) No 1272/2008 The available experimental test data are reliable and suitable for classification purposes under Regulation (EC) No 1272/2008. The NOAEL for repeated dose toxicity was determined to be 262.2 mg/kg bw/d. As a result the substance is not considered to be classified for specific target organ toxicity under Regulation (EC) No 1272/2008, as amended for the eighth time in Regulation (EU) No 2016/218.
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