2,11-Dioxa-3,10-disiladodecane, 3,3,10,10-tetramethoxy-

Endpoint summary

Description of key information

Three reliable repeated dose oral toxicity studies are available for 1,6-bis(trimethoxysilyl)hexane. The key study (Hita Research Laboratories, 1996) was selected on the basis of a worst-case NOAEL of 8 mg/kg bw/day. All studies reported effects in the kidneys and the urinary bladder, and in the liver and stomach.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

8 mg/kg bw/day

Study duration:

subacute

Species:

rat

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

In a key 28-day oral gavage study (Hita Research Laboratories, 1996a) conducted according to OECD 407 and in compliance with GLP, rats were given doses of 0, 8, 40, 200 or 1000 mg/kg/day, followed by a 14-day recovery period for a subset of animals. Effects on the urine and kidneys were recorded but there were no changes considered attributable to treatment on any of the other parameters investigated. Turbid urine was noted for animals receiving 40, 200 or 1000 mg/kg/day during the dosing period. At the end of dosing necropsy, whitish regions in the kidney were noted in 1000 mg/kg/day both at the end of dosing and recovery periods. Histopathological examination of the kidney showed interstitial round cell infiltration, fibrosis, pyelitis, tubular basophilia, dilatation, degeneration and necrosis and neutrophil and multinucleate giant cell infiltration. These kidney findings were noted both at the end of dosing and recovery periods at a generally similar incidence and severity. Based on the urine and kidney changes noted at 40 mg/kg/day and above, the No-Observed-Adverse-Effect-Level (NOAEL) was defined as 8 mg/kg/day in this study.

In a supporting 28-day oral study (Dow Corning Corporation, 2010) conducted to OECD 422 and to GLP, oral doses of 30, 300 or 1000 mg/kg/day 1,6-Bis(trimethoxysilyl)hexane resulted in marked effects and identified the kidney, urinary bladder, liver and stomach as target organs. At necropsy discolouration of the kidneys was recorded, mainly at the intermediate and high doses. Microscopically, various renal findings collectively termed as obstructive nephropathy were noted at 1000 mg/kg/day and attributed to precipitation of a globular pale staining material in the tubules of the cortex or medulla, with a markedly higher incidence in males compared to females. In the urinary bladder the epithelium was diffusely hyperplastic in the majority of treated males and most females at 300 or 1000 mg/kg/day. A minimal to mild inflammatory response was generally associated with the urinary bladder hyperplasia and in males there was also increased inflammation in the prostate considered to be associated with the urinary bladder inflammation.

Centrilobular hypertrophy was noted in the liver of 1000 mg/kg/day females (with associated increased liver weight) but not males and dilation of the gastric glands in the stomach with single cell necrosis were noted in both sexes at this dose.

Various other effects, considered to be associated with the kidney and bladder changes were noted, including higher kidney weight, changes in some haematology (including differential white cell counts), clinical chemistry (including BUN and creatinine) and urine (pH) parameters. There were also effects on clinical condition (staining of muzzle and/or repetitive behaviour) and body weight (loss and lower gain) at the intermediate and/or high doses.

Based on the urinary bladder epithelial hyperplasia noted at all doses in males and at 300 and 1000 mg/kg/day in females, a No-Observed-Adverse-Effect-Level (NOAEL) for males was not identified in this study. The NOAEL for females was 30 mg/kg bw/day. The Lowest-Observed-Adverse-Effect-Level (LOAEL) was defined as 30 mg/kg/day for males.

A third oral 28 day repeated dose toxicity study was carried out in 120 rats (60 males, 60 females), with a 14 day treatment free period (WIL, 2015). The rats were assigned to 4 dose groups. Groups 1 and 4 contained 20 males and 20 females and groups 3 and 4 contained 10 males and 10 females. The test item was administered once daily by gavage at the doses of 0, 10, 100 and 1000 mg/kg for at least 28 days. The rats in group 1 received the vehicle (corn oil) alone.

At the end of the treatment period 10 surviving animals of each sex from each group were euthanized and subjected to complete necropsies - these animals are referred to as main groups. The remaining ten male and female animals were necropsied after a 14 day recovery period, and are considered the recovery groups.

Two premature deaths were recorded at 1000 mg/kg bw dose in males. The cause of death was deemed papillary necrosis of the kidney, related to treatment with the test item. Test item related morphological alterations were present in the urinary bladder of both sexes starting at the 100 mg/kg/day group and in the kidneys, prostate gland and ureter of males of the 1000 mg/kg/day group. There was a partial recovery of the findings in the urinary bladder (both sexes) and no recovery for the kidney findings (males) in the 1000 mg/kg/day group after a 14 day treatment free period.

A NOAEL of 10 mg/kg was established for both sexes, based on adverse effect in male animals at 1000 mg/kg, evident as mortality and irreversible histopathological lesions in kidneys, urinary bladder, ureter and prostate. In females at the same dose level effects were restricted to urinary bladder. At 100 mg/kg, a minimal degree of urothelial hyperplasia of the urinary bladder was evident in both sexes. At 10 mg/kg, the only treatment related (non-adverse) effect was lower urinary pH which was noted in females.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
The selected key study is a repeated dose 28-day study (OECD 407) in which a NOAEL dose was clearly identified. A NOAEL for females and a LOAEL for males of 30 mg/kg bw/day has been derived from a supporting study conducted according to OECD 422. A third 28-day oral study reported a NOAEL of 10 mg/kg bw/day. All studies were conducted according to appropriate OECD test guidelines and in compliance with GLP. The study giving the most adverse NOAEL was selected as the key study.

Repeated dose toxicity: via oral route - systemic effects (target organ) digestive: liver; digestive: stomach; urogenital: kidneys; urogenital: urinary bladder

Justification for classification or non-classification

Based on the available oral data 1,6 -bis(trimethoxysilyl)hexane is classified for specific target organ toxicity following repeated exposures, STOT RE, Cat. 1; H372: Causes damage to organs (urinary bladder) through prolonged or repeated exposure, in accordance with Regulation (EC) No 1272/2008.