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Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Dose descriptor:
NOAEL
25 mg/kg bw/day
Additional information

Although the only study available is a screening study, this study is considered to be well conducted. It showed clear signs of adverse effects on reproductive toxicity for males and females.


Short description of key information:
In an oral OECD 422 study in rats (WIL Research, 2005), the mean gestation body weight gains and food consumption were reduced in the 250 mg/kg/day group females throughout gestation (gestation day 20 was 22.1% lower than the control group). Effects on body weight late in gestation were attributed to the increased number (five of nine) of entirely resorbed litters in the 250 mg/kg/day group. Evaluation of lactation body weight and food consumption in the 250 mg/kg/day group was precluded by reduced fertility, embryonic death and total litter loss. There were no such effects in the 25 and 75 mg/kg/day group reproductive phase females. In the reproductive phase, one female in the 75 mg/kg/day group was euthanized in extremis on gestation day 22. The cause of moribundity for this female was considered to be dystocia. In addition, one female in the 250 mg/kg/day group had total litter loss on lactation day 0 and one female in the 75 mg/kg/day group had total litter loss on lactation day 2. All other reproductive phase females survived to the scheduled necropsy. There were no test article-related clinical findings in the reproductive phase females.

Test substance-related effects on reproductive performance (fertility indices) were observed in the 250 mg/kg/day group males and reproductive phase females. Male and female fertility indices were 60.0% in this group compared to 90.0% in the control group. The mean number of days between pairing and coitus was increased in the 250 mg/kg/day group. Mean gestation length was increased in the 75 mg/kg/day group and in the single female in the 250 mg/kg/day group that delivered.

Of the nine reproductive phase females in the 250 mg/kg/day group with evidence of mating, three were nongravid and five had entirely resorbed litters. Only one female in this group delivered, but all pups were found dead on postnatal day (PND) 0, precluding evaluation of pup body weights.

NOAEL parents: 25 mg/kg bw/d
NOAEL offspring: 75 mg/kg bw/d

Effects on developmental toxicity

Description of key information
There are no full developmental toxicity tests available for tris(2-methoxyethoxy)vinylsilane.
In an OECD 422 study by the oral route, the NOAEL for developmental effects was 75 mg/kg bw based on effects at the highest dose leve, 250 mg/kg bw. Further details are given in the discussion below.
Effect on developmental toxicity: via oral route
Dose descriptor:
NOAEL
75 mg/kg bw/day
Additional information

There are no full developmental toxicity tests available for tris(2-methoxyethoxy) vinylsilane. Information on the potential for adverse developmental effects is assumed from the OECD 422 study.

Four groups of male and female rats (10/sex/group) were administered tris(2-methoxyethoxy)vinylsilane daily by oral gavage for up to 46 days; the males were treated 14 days prior to mating and continuing throughout mating. The females were mated with the treated males and were also administered the test article by oral gavage daily for a minimum of 14 days prior to mating, throughout mating and gestation and continuing through lactation day 3. Dose levels were 0, 25, 75 and 250 mg/kg/day. All animals were observed twice daily for appearance and behavior. Clinical observations, body weights and food consumption were recorded at appropriate intervals. All reproductive phase females were allowed to deliver and rear their offspring to lactation day 4; surviving dams and pups were euthanized and examined on lactation day 4. Of the nine reproductive phase females in the 250 mg/kg/day group with evidence of mating, three were non-gravid and five had entirely resorbed litters. Only one female in this group delivered, but all pups were found dead on postnatal day (PND) 0, precluding evaluation of pup body weights. In the 75 mg/kg/day group, the mean numbers of implantation sites, pups born and live litter size on PND 0 were reduced while the number of unaccounted for implantation sites was increased. These effects were considered test article-related; however, only the live litter size on PND 0 was statistically significantly different (p<0.01) from the control group. Postnatal survival in the 75 mg/kg/day group was reduced throughout the lactation period (days 14), primarily due to one female with total litter loss on lactation day 2; the differences from the control group were not statistically significant but were considered test article-related. A slight increase was observed in the number of pups found dead or missing and presumed cannibalized in the 75 mg/kg/day group. The general physical condition and mean body weights and body weight gains of pups in the 25 and 75 mg/kg/day groups were unaffected by maternal test article administration. Clinical or macroscopic examinations of the offspring did not reveal any findings attributable to maternal test article administration in the 25 and 75 mg/kg/day groups. No internal findings in the pups found dead or at the scheduled necropsy were attributed to maternal test article administration. The NOAEL for fetotoxicity/developmental toxicity is 75 mg/kg/day. A role for developmental toxicity in the reduced postnatal survival at this dose cannot be excluded. Teratogenic effects were not observed.

Based on the results of the OECD TG 422 there is sufficient evidence to classify tris(2-methoxyethoxy)vinylsilane for developmental endpoints (Category 1B) without additional testing; once a viable foetus is formed, any subsequent loss (either late in gestation or post-natal) would be regarded as a developmental effect. This conclusion that pup mortality is a major manifestation of developmental toxicity is in agreement with the Classification and Labelling Regulation:

3.7.1.4. Adverse effects on development of the offspring: Developmental toxicity includes, in its widest sense, any effect which interferes with normal development of the conceptus, either before or after birth, and resulting from exposure of either parent prior to conception, or exposure of the developing offspring during prenatal development, or postnatally, to the time of sexual maturation. However, it is considered that classification under the heading of developmental toxicity is primarily intended to provide a hazard warning for pregnant women, and for men and women of reproductive capacity. Therefore, for pragmatic purposes of classification, developmental toxicity essentially means adverse effects induced during pregnancy, or as a result of parental exposure. These effects can be manifested at any point in the life span of the organism. The major manifestations of developmental toxicity include (1) death of the developing organism, (2) structural abnormality, (3) altered growth, and (4) functional deficiency.

The study demonstrates that there are reproductive effects that occur below the systemic toxicity level. Although each individual reproductive effect taken alone may or may not be sufficient to classify the substance as a Category 1B reproductive hazard, the totality of the reproductive effects from the OECD 422 study, taking all of the findings into consideration that occurred at a dose that was not maternally toxic, might suggest that the substance has reached the threshold for classification as a Category 1B.

Justification for classification or non-classification

Based on a LOAEL of 75 mg/kg/day for reproductive parameters in an OECD 422 study, it is proposed to classify tris(2-methoxyethoxy)vinylsilane as Repr. Cat. 2 according to Regulation 1272/2008/EC (Repr. Cat. 3 (R62) according to EU Directive 67/548/EEC).

Based on the effects observed at the LOAEL of 250 mg/kg bw on developmental parameters in an OECD 422 study, tris(2-methoxyethoxy)vinylsilane is classified as Repro. Cat 1B. The study demonstrates that there are reproductive effects that occur below the systemic toxicity level. Although each individual reproductive effect taken alone may or may not be sufficient to classify the substance as a Category 1B reproductive hazard, the totality of the reproductive effects from the OECD 422 study, taking all of the findings into consideration that occurred at a dose that was not maternally toxic, suggests that the substance has reached the threshold for classification as a Category 1B.

The appropriate hazard statement is H360Df “May damage the unborn child. Suspected of damaging fertility.”.

The hydrolysis product, 2-methoxyethanol, is officially classified in Annex VI of Regulation 1272/2008 as Repr. Cat. 1B (R60 -R61).