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Key value for chemical safety assessment

Effects on fertility

Description of key information

Only one study (DCC, 2005) examining toxicity to reproduction was included in the dataset for D6. This study was a rat oral combined repeated dose toxicity study with the reproduction/developmental toxicity screening test, conducted according to the current guideline (OECD 422) and in accordance with GLP. This screening study identified an NOAEL for reproductive toxicity of 1000 mg/kg bw/day, the highest dose tested, for the parental and foetal generations.

An increase in non-gravid sperm-positive females at the top dose was said to not be statistically significant. The one generation reproductive toxicity test (OECD 415) requires groups of 20 pregnant females, whereas this combined, screening test, calls for 10 females; a larger group size might have provided better evidence of the significance of this effect. The Registrants intend to carry out a study for extended one-generation reproductive toxicity (EOGRTS) in accordance with an ECHA draft decision; the ECHA final decision is awaited.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

The key reproductive study is the only available study for this endpoint (Dow Corning Corporation, 2005). The test was carried out in accordance with an appropriate OECD test guideline and in compliance with GLP, and was therefore assigned Reliability 1.


Effects on developmental toxicity

Description of key information

In the key developmental toxicity study (OECD 414) with D6 and Wistar Han rats (Charles River Report Amendment 2, 2017), no maternal or developmental toxicity was observed in this study with treatment up to 1000 mg/kg bw/day. The maternal and developmental NOAEL for D6 were established as being at least 1000 mg/kg bw/day. 

In the key developmental toxicity study (OECD 414) with D6 and NZW rabbits (The Dow Chemical Company, 2018), no maternal or developmental toxicity was observed in this study with treatment up to 1000 mg/kg bw/day. The maternal and developmental NOAELs for D6 were established as being at least 1000 mg/kg bw/day. 

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

In the key OECD 414 developmental toxicity study (Charles River Report Amendment 2, 2017), D6 was administered to pregnant female Wistar Han rats at doses of 0, 100, 330 or 1000 mg/kg/day by oral gavage daily from Days 6 to 20 of pregnancy. At 1000 mg/kg/day maternal animals had higher absolute and relative liver weights with the difference from controls being slight but statistically significant. There were no test item-related microscopic findings observed during the histopathological evaluation so the increases in liver weights were considered not to be toxicologically relevant. No maternal toxicity was observed in any of the other maternal parameters examined in this study. Therefore the maternal no-observed-adverse-effect-level was considered to be 1000 mg/kg/day.

In the initial observation, effects on skeletal morphology were observed at 1000 mg/kg/day. A higher incidence of the skeletal malformations of (severe) malaligned and fused sternebra(e) were seen with four fetuses, one from each of four litters, affected. Of these, two fetuses had both severely malaligned and fused sternebra(e) while one fetus had only fused sternebra(e) and one had only severely malaligned sternebra(e). Based on these initial findings,  an external expert peer review (Charles River Report Amendment 2, 2017, Appendix 7) was performed which concluded that fused and malaligned sternebrae are variations rather than malformationsand therefore, there were no toxicologically relevant effects on skeletal morphology following treatment up to 1000 mg/kg bw/day. Skeletal malformations only occurred in two fetuses of this study. At 1000 mg/kg bw/day, 1 fetus had a short rib and since this occurred singly and was seen previously in historical control fetuses, it was considered to be a chance finding. The other malformation was noted in a control fetus with polydactyly (not detected externally) and as such was not considered related to treatment. There was no significant impact on skeletal variations proportion/litter (i.e.changes other than malformations) at 1000 mg/kg nor on fetal skeletal morphology at 100 or 330 mg/kg/day and no effects on fetal external or visceral morphology were seen with treatment up to 1000 mg/kg/day. The fetal NOAEL was therefore considered to be 1000 mg/kg/day.

A DRF probe study was performed prior to the pre-natal developmental toxicity study (OECD 414) in rabbits ( Dow Chemical Company, 2017). Groups of five time-mated female NZW rabbits were administered neat D6 via oral gavage at dose levels of 0, 50, 150, 450, 750, or 1000 mg/kg/day on gestation day (GD) 7-27. No maternal toxicity and no indication of embryo/fetal toxicity were reported. On the basis of this probe study, 0, 100, 300 and 1000 mg/kg bw/day dose levels were selected for the key pre-natal developmental toxicity (OECD 414) study (Dow Chemical Company, 2018a), D6 was evaluated for the maternal and developmental toxicity in NZW rabbits following repeated oral gavage administration. Groups of 24 time-mated female rabbits were administered 0, 100, 300, or 1000 mg/kg/day on gestation day (GD) 7-27. No analyses of concentration verification, homogeneity, or stability were conducted because the test material was administered neat (undiluted). In-life parameters evaluated for all groups included: clinical observations, body weight, body weight gain, and feed consumption. On GD 28 all surviving rabbits were euthanized and examined for gross pathologic alterations. Liver, kidneys, and gravid uterine weights were recorded, along with the number ofcorpora lutea, uterine implantations, resorptions, and live/dead fetuses. All fetuses were weighed, sexed, and examined for external and visceral alterations. The heads were examined for craniofacial alterations by serial sectioning in approximately one half of the fetuses in each litter, and skeletal examinations were performed on all fetuses.Gavage administration ofD6, up to and including the limit dose of 1000 mg/kg/day,resulted in no treatment-related maternal toxicity and no indication of embryo/fetal toxicity or teratogenicity.Therefore, under the conditions of this study, NOAEL for maternal toxicity and developmental toxicity was the limit dose of 1000 mg/kg/day.

In a preceding OECD 422 reproductive and developmetnal screening study (Dow Corning Corporation, 2005), there were no remarkable findings at oral gavage doses of up to 1000 mg/kg/day. The maternal and fetal NOAEL were therefore considered to be 1000 mg/kg/day.

Justification for classification or non-classification

Based on the available data dodecamethylcyclohexasiloxane does not require classification for reproductive or developmental toxicity according to Regulation (EC) No 1272/2008.

Additional information