Methanesulfonic acid, 1,1'-(1,6-hexanediyldiimino)bis[1-oxo-, sodium salt (1:2)

Endpoint summary

Description of key information

In a comprehensive sub-chronic oral gavage toxicity study in rats conducted according to OECD TG 408 and GLP the NOAEL was reported to be 278 mg/kg. 

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Dose descriptor:

NOAEL

278 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Additional information

Wistar rats of both sexes were orally gavaged with dose levels of 0, 93, 278 and 927 mg/kg body weight/day in a comprehensive sub-chronic oral toxicity study according to OECD TG 408 and GLP. The groups comprised 10 animals per sex which were sacrificed after 91/92 days of treatment. Clinical signs, outside cage observation, food consumption and body weights were recorded

periodically during pretest and treatment periods. Functional observational battery, locomotor activity and grip strength were performed during week 13. At the end of the dosing period, blood samples were withdrawn for hematology and plasma

chemistry analyses. Urine samples were collected for urinalyses. All animals were killed, necropsied and examined post mortem. Histological examinations were performed on organs and tissues from all control and high dose animals, and all gross lesions from all animals.

Test item related effects were observed on body weight. At 927 mg/kg/day, the mean body weights were significantly (approx. 10%) reduced (p<0.05) in males from days 43 to 71 of treatment. Although the differences noted from days 78 to 91 of treatment no longer attained statistical significance, they remained below those of the control males and were considered to be a test item-related effect. Females at this dose level did not have differences that attained statistical significance but remained below that of the control values (approx. 5%). No test item-related changes of toxicological relevance were noted for any organ weight at any dose level because the observations were not dose dependent, in general slight changes are reported within the historical control values and not correlated to histopathologic findings. Of the rats that survived until scheduled necropsy, there were no macroscopical findings that were test item-related.

In clinical biochemistry test item-related changes were restricted to elevated bile acid levels in males and females at the highest dose level of 927 mg/kg/day. All other differences were within the ranges of the historical control values or were unrelated to dose.

Microscopic Findings were observed in the liver of male animals; centrilobular to diffuse hepatocellular hypertrophy was recorded at minimal to slight severity. Since there is no dose response in the incidence or severity of the observation this observation is not regarded as compound related. Hyaline droplets nephropathy was found in males at 927 mg/kg/day. The nephropathy consisted of clearly incidence mean severity of hyaline droplets along with tubular basophilia. However, the increased severity was statistically not significant. Therefore, the toxicological of the nephropathy is not clear from this study. Since the hyaline droplets in the male rat relate to accumulation of alpha2-micoglobulin, and little or none of this protein is present in man, a nephropathy in man that involves the same mechanism is unlikely to occur with the test item (Ref. 1, Greaves 2000), i.e. this finding is adverse during exposure for the male rat but has limited relevance for other species including man.yaline droplets nephropathy was found in males treated with 927 mg/kg/day. The nephropathy consisted of elevated incidence mean severity of hyaline droplets along with tubular basophilia. However, the increased severity was statistically not significant. Therefore, the toxicological of the nephropathy is not clear from this study. Since the hyaline droplets in the male rat relate to accumulation of alpha-2-microglobulin and little or none of this protein is present in man, a nephropathy in man that involves the same mechanism is unlikely to occur with the test item. Although this finding is adverse during exposure for the male rat it has little or no relevance for other species including man.

Overall, in a comprehensive sub-chronic oral gavage toxicity study in rats conducted according to OECD TG 408 and GLP the NOAEL was reported to be 278 mg/kg.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
A subchronic (90-day) repeated dose toxicity study has been conducted since it's required for the registration of this substance in China.

Justification for classification or non-classification

No classification is required according to the EU classification criteria 67/548/EWG and regulation no. 1272/2008 (GHS).