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Description of key information

In an oral OECD 422 study  in rats (Hashima, 2005), administration of trimethoxy(vinyl)silane at a dose of 62.5 mg/kg bw/day did not lead to organ damage including irreversible morphological effects permanently impairing the function of the organ/tissue (reversibility after recovery period). Also, no other effects such as necrosis or other cell death were reported, which could contribute to the degeneration of the metabolically-functional tissue. The No Observed Adverse Effect Level (NOAEL) was therefore determined to be 62.5 mg/kg bw/day. The Lowest Observed Adverse Effect Level (LOAEL) was set to 250 mg/kg bw/day, based on the histopathological changes in the urinary bladder observed in all animals (males and females) at this dose level.

In a 14-week whole-body inhalation study (BRRC, 1990) in which rats were exposed to concentration of trimethoxy(vinyl)silane up to 400 ppm, minimal to mild alterations in body weight, water consumption, urinalysis, organ weights, and bladder and kidney histopathology were observed at the highest concentration of 400 ppm. At a concentration of 100 ppm there were some body weight gain reductions in females, but they were less than 10% and not always statistically significant, and there were no such finding in males; males had mild effects on urine osmolality and urine volume in week one only and there were no associated organ weight changes, macroscopic or microscopic findings. There were no findings at the end of the recovery period. Therefore, the findings at 100 ppm were concluded not to be adverse and the NOAEC in Fischer 344 rats was therefore 100 ppm (605 mg/m3).

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
62.5 mg/kg bw/day
Study duration:
subacute
Species:
rat
System:
urinary
Organ:
bladder

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEC
605 mg/m³
Study duration:
subchronic
Species:
rat
System:
urinary
Organ:
bladder
kidney

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

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

A reliable combined repeated dose oral toxicity study, with a reproduction/developmental toxicity screening test is available as key study for repeated dose oral toxicity (Hashima, 2005). Trimethoxy(vinyl)silane was administered by gavage at doses of 62.5, 250 or 1000 mg/kg bw/day (in corn oil) for 42 days to Sprague-Dawley rats. Two males and one female from the 1000 mg/kg bw/day group died and the clinical signs noted in the dying animals were: decrease in locomotor activity; reddish urine; hypothermia; perioral smudges; perianal soiling; diarrhoea; bradypnea and/or piloerection. Soiled hair and reddish urine were noted in the surviving males and females of the 1000 and 250 mg/kg bw/day groups.

A decrease in relative thymus weights in females was observed at all doses. Decreased absolute thymus weights and increased relative liver weights in females of the 1000 mg/kg bw/day group were noted. In males a decrease in the absolute thymus weight was observed in the 1000 mg/kg bw/day group only. No reduction in thymus weight was observed at the end of the recovery period in males and females at any dose level. Histopathology revealed no changes in the thymus in the 62.5 and 250 mg/kg bw/day group. In the 1000 mg/kg bw/day group a slight atrophy (cortex and medulla) was observed in 2/6 females after the administration period, but no effects were observed after the recovery period.

In the 1000 mg/kg bw/day dose group the incidence of hyperplasia of the transitional epithelium in the kidney was statistically significantly increased in male and female animals. This finding was still present in male and female animals after the recovery period, although the severity was slightly decreased. No effects on the kidney were observed in the 62.5 and 250 mg/kg bw/day groups.

On histopathological examination, hyperplasia of the transitional epithelium in the urinary bladder was noted in males at all doses. The effect seemed to be substance-related and followed a dose-response relationship. The incidence of hyperplasia in the 250 and 1000 mg/kg bw/day groups was statistically significantly increased up to the end of the recovery period, although a slight decrease (mild to slight) in severity was observed from end of administration period to the end of the recovery period. Hyperplasia that was observed in 2/6 male rats of the 62.5 mg/kg bw/day group after the administration period seemed to be treatment-related, as there were no incidences in the control group; hyperplasia was not observed in the urinary bladder of females in the 62.5 mg/kg bw/day goup. In general, hyperplasia in the urinary tract/bladder is not a typical spontaneous lesion, but simple hyperplasia may also occur in untreated animals. Often it is a secondary effect provoked by inflammation or physical damage. The effects observed in males at 62.5 mg/kg bw/day were not evaluated as adverse, as the incidence was not increased statistically significantly and the severity of the effect was stated as "slight". In addition, the effects were fully reversible within the recovery period. Administration of trimethoxy(vinyl)silane at a dose of 62.5 mg/kg bw/day did not lead to organ damage including irreversible morphological effects permanently impairing the function of the organ/tissue (reversibility after recovery period). Also, no other effects such as necrosis or other cell death were reported, which could contribute to the degeneration of the metabolically-functional tissue. The No Observed Adverse Effect Level (NOAEL) was therefore determined to be 62.5 mg/kg bw/day. The Lowest Observed Adverse Effect Level (LOAEL) was set to 250 mg/kg bw/day, based on the histopathological changes in the urinary bladder observed in all animals (males and females) at this dose level.

A fourteen week vapour inhalation study in rats which was conducted according to current guideline and in compliance with GLP, was selected as key study for repeated dose inhalation toxicity (BRRC 1990). Rats repeatedly exposed to 400 ppm of the registered substance for

6 hours per day over 14 weeks had minimal to mild alterations in body weight, water consumption, urinalysis, organ weights, and bladder and kidney histopathology. Clinical signs in the 400 ppm group included urogenital area wetness and alopecia. There were no treatment-related eye lesions. Male and female rats of the 400 ppm group had decreased body weights (11 to 16% below control values). Occasional decreases in body weights of the female rats of the 100 ppm group were also observed. Food consumption was not altered. Water consumption was increased in the male rats of the 400 ppm group at study weeks 1, 5, 8, and 14 and for females during the first week. Urinalysis results indicated that male rats of the 400 ppm group had lower osmolality, lower electrolyte concentrations, and a decrease in estimated creatinine clearance. Female rats of the 400 ppm group had similar changes, but at week 14 only. A decrease in urine osmolality with a concomitant increase in urine volume was observed in male rats of the 100 ppm group at week 1. There were no biologically significant changes in hematology or serum chemistries in rats exposed to the test material. At necropsy, there were no exposure-related lesions, and changes in organ weights in rats of the 400 ppm group were considered to result from body weight depression. Noteworthy microscopic lesions in rats of the 400 ppm group were observed in two tissues, the urinary bladder and the kidney. Minimal cystitis in the bladder submucosa was observed at 14 weeks, and submucosal mastocytosis was observed at 18 weeks. Renal lesions in a few of the 400 ppm-exposed rats included papillary necrosis, interstitial edema, and/or papillary hyperplasia of the transitional epithelium. Electron microscopic examination of the kidneys supported the light microscopic findings. Based on the fact that at 100 ppm (605 mg/m3) there were some body weight gain reductions in females, but they were less than 10% and not always statistically significant, and there were no such finding in males, males had mild effects on urine osmolality and urine volume in week 1 only, and there were no adverse findings from serum chemistry, haematology, organ weight, macro- or microscopy and no findings at all at the end of the recovery period for this group, it is concluded that the effects at 100 ppm are non-adverse and the NOAEC is 100ppm. [study author opinion - NOAEC and an opinion on adversity of the findings were not stated in the test report]

Justification for classification or non-classification

The rats in the oral combined repeated dose oral toxicity study, with a reproduction/developmental toxicity screening test were exposed to the test substance for 42 days. Therefore, the guidance value for classification as STOT RE 2, which are based on a 90 day study, can be adjusted by a factor of 2, to give an equivalent guidance value for the 42 day study of 200 mg/kg bw/day. The LOAEL from the oral OECD 422 trimethoxy(vinyl)silane was 250 mg/kg bw/day. Therefore, based on the available data, trimethoxy(vinyl)silane does not require classification according to Regulation (EC) No 1272/2008.