Registration Dossier

Administrative data

Description of key information

There is currently an ongoing 90-day inhalation repeated dose toxicity study, conducted according to OECD Test Guideline 413 and in compliance with GLP. Based on the study schedule animal arrival is on 8 October 2020, treatment start is on 19th October and the draft report is expected by mid-April 2021. Therefore, the substance will be updated by the end of July 2021.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Data for the final hydrolysis product, dimethylsilanediol (DMSD), have been included in the dossier to allow risk characterisation for exposure of humans via the environment.

In the combined repeated dose toxicity study with the reproduction / developmental toxicity screening test with dimethylsilanediol, conducted according to OECD Test Guideline 422 and in compliance with GLP, dimethylsilanediol was administered by oral gavage in corn oil for 28 (toxicity group females) or 29 (males) days to 10 rats/sex/group (exception, female 50 mg/kg group where N=9) at 0, 50, 250 or 500 mg/kg bw/day (Dow Corning Corporation, 2009).  A single group of males was used for both the toxicity and reproductive phases of the study.  Reproductive group females were treated (10 rats/dose group) for 14 days prior to the mating period, during the mating period and through post-partum day 3. Clinical observations were performed daily immediately following exposure.  Body weight measurements were performed weekly.  All animals received a detailed physical examination once before the first dose (to allow for within-subject comparisons), and weekly thereafter. Additional body weights on reproductive females were obtained on gestational days (GD) 0, 7, 14, and 20, within 24 hours of parturition, and on post-partum day four. Individual food consumption was recorded at least weekly, except during the cohabitation period. Functional observational battery (FOB) and motor activity evaluations were performed on males and toxicity group females once prior to initiation of exposures and during the 4th week of exposure.  Blood samples for haematology and serum chemistry evaluations were collected at the scheduled necropsy from males and toxicity group females. Complete necropsies were performed on the males and the toxicity group females and selected organs were weighed. Microscopic examination was performed on protocol specified tissues on all toxicity group animals from the control and 500 mg/kg bw/day dose groups. Target tissues examined from the low- and mid-dose levels included liver, lung, prostate gland and thyroid gland from male rats and liver and lung from female rats.  

Mating was initiated after the first two weeks of exposure by pairing reproductive group females with males of the same treatment group until positive evidence of mating was obtained. Reproductive and developmental parameters evaluated included evidence of mating, pregnancy, duration of gestation, mean litter size, mean live litter size, mean litter weight, and mean ratio of live births/litter size. Dams and pups were euthanized on post-partum day 4 and examined for external gross lesions. The number of corpora lutea, and the number of uterine implantation sites were determined for all reproductive group females.

Oral gavage administration of dimethylsilanediol to male and female Sprague-Dawley rats at concentrations of up to 500 mg/kg bw/day for 28 (toxicity females) or 29 (males) consecutive days was generally well tolerated. For the toxicity group males at 250 and 500 mg/kg bw/day significant soiling was observed (abdominal region and urogenital soiling).  Soiling of the muzzle was a significant abnormal observation in the toxicity group females at 500 mg/kg bw/day. Both abdominal soiling and urogenital soiling were significant abnormal observations in the reproductive group females at 500 mg/kg bw/day.  

There were no statistically significant differences across exposure groups in the mean body weights on any day for toxicity group females and reproductive toxicity group females. In the male group there was a significant difference across treatment groups in week 2, however, there was not a significant difference between control and any of the treatment groups for that week. With respect to body weight gain, male group 4 animals had a significant decrease in body weight gain during week 4 and in total gain from day 1 to 29. For toxicology females there was significant decrease in body weight gain during week 3. There were no statistically significant differences in body weight gain for the reproductive females in any of the treatment groups during any of the measured intervals. There were no differences in the average daily food consumption between control and treatment groups for the reproductive females group or the toxicity male and female groups for any of the measured time periods. There were no significant differences of toxicological significance between the control and treatment groups in either sex for the FOB ranked tests. There were no significant differences between either male or female treatment groups and their respective controls for the FOB continuous test and motor activity. There were no treatment-related changes associated administration on rat neurobiological function as evaluated with FOB and motor activity parameters. The significant changes that were noted in haematological parameters and prothrombin times for toxicity group males and females were within or slightly below historical control values. The significant changes that were noted in clinical chemistry parameters for toxicity group males and females were within or slightly below historical control values. The increased liver weights in toxicity males and females at 250 and 500 mg/kg bw/day correlated with the histopathologic finding of centrilobular hypertrophy. There were no other treatment-related differences in organ weights, absolute and relative for toxicity group males and females.  

There were three primary effects of the test article observed in the liver, including centrilobular hypertrophy in both sexes, periportal hepatocellular vacuolation (microvascular lipidosis, females only), and brown pigment accumulation (males only) which was accompanied by chronic inflammation and bile duct hyperplasia. Centrilobular hypertrophy is considered an adaptive change. Hepatic lipidosis, unless severe, is generally considered non-adverse. Hepatic brown pigment is considered an adverse effect. Follicular cell hypertrophy was observed in the thyroid gland of mid- and high-dose male rats. This may reflect an adaptive secondary effect and adverse in the rat, but the mechanism is generally not applicable to species with significant levels of thyroid binding globulin (Capen, et al., 2002). Lung (males and females) and prostate gland were considered possible target tissues; however, further examination and inclusion of animals from the mid- and low-dose groups did not support this interpretation. There were no treatment-related effects apparent for any of the reproductive endpoints:  gestation length, litter size, litter weight, ratio live births/litter size, litter sex ratio, number of implantation sites, number of corpora lutea, mating and fertility indices.  

Based on the results of this study, the systemic toxicity NOAEL (No-Observed-Adverse-Effect-Level) for dimethylsilanediol in rats via oral administration in corn oil is considered to be 250 mg/kg bw/day based on hepatic brown pigment accumulation in and around the bile ducts, with associated bile duct hyperplasia and chronic inflammation at 500 mg/kg bw/day. In the absence of adverse effects on reproductive or developmental parameters in this study, a NOAEL of ≥500 mg/kg bw/day is assigned for reproductive and developmental toxicity.

Justification for classification or non-classification

In the absence of data, the substance is not classified for specific target organ toxicity following repeated exposures according to Regulation (EC) No 1272/2008.