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Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

In a well conducted reproductive and developmental toxicity screening study conducted to OECD 421 and to GLP (Harlan Laboratories Ltd., 2010) tri(isopropyl)silyl acrylate was administered at doses of 30, 150 or 750 mg/kg bw/day to male and female Wistar rats for 15 days prior to mating, throughout mating, and through to postnatal day 5 for offspring and females. Males were treated for a total of 43 days. Clinical observations and effects on body weight were not considered to be toxicologically relevant, and the NOAEL for general parental systemic toxicity was at least 750 mg/kg bw/day. There were no effects on fertility, so the NOAEL for reproduction was at least 750 mg/kg bw/day.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
750 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

tri(isopropyl)silyl acrylate has been tested for its potential to cause adverse effects on reproductive parameters in an OECD 421 screening study. In this study there were no adverse effects on fertility or other reproductive parameters, and therefore the NOAEL was at least 750 mg/kg bw/day for reproductive toxicity.


Effects on developmental toxicity

Description of key information

In the key pre-natal developmental toxicity study for tri(isopropyl)silyl acrylate was conducted according to OECD TG 414 and in compliance with GLP. The reported NOAEL for maternal and foetal toxicity was 150 mg/kg bw/day was based on statistically significantly reduced body weight, body weight gain and food consumption during the treatment period in high dose group females and a statistically significantly lower mean terminal, adjusted maternal weight and foetal weight in high dose group when compared with the control ( Eurofins / BSL Bioservice, 2018). Furthermore, no treatment related external, visceral and craniofacial findings were observed in high dose group. However, reduced ossification of some bones was observed which was indicative of a generalized delayed ossification associated with foetal growth retardation. Observed foetal effects in the high dose group might be secondary to maternal toxicity.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
150 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 pre-natal developmental toxicity study for tri(isopropyl)silyl acrylate was conducted according to OECD TG 414 and in compliance with GLP. 30, 150, 750 or 450 mg/kg bw/day of tri(isopropyl)silyl acrylate (CAS 157859-20-6) were administered via oral route (gavage) to female rats during gestation days 5 to 19 at the dose volume of 4 ml/kg bw in dried corn oil (Eurofins / BSL Bioservice, 2018). Due to morbidity in the high dose group, the high dose was reduced to 450 mg/kg bw/day during the study.

The 4 groups comprised 24 female Wistar rats each in the control and low dose group, 25 female Wistar rats in mid dose group and 29 in the high dose group. The high dose (HD) group comprised 29 females as 4 additional animals were allocated to this group due to high mortality and morbidity.11 females from the high dose group were treated with 750 mg/kg body weight/day from the start of the study for several treatment days (animal no. 88 from GD 5 to GD 18; animal no. 89 from GD 5 to GD 17; animal no. 90 from GD 5 to GD 16 (Euthanised on GD 16); animal no. 91 from GD 5 to GD 16; animal no. 92 from GD 5 to GD 16; animal no. 93 from GD 5 to GD 15; animal no. 94 from GD 5 to GD 15; animal no. 95 from GD 5 to GD 9; animal no. 96 from GD 5 to GD 9; animal no. 97 from GD 5 to GD 8; animal no. 98 from GD 5 to GD 8). Females no. 76- 87 of the HD group were treated with a dose of 750 mg/kg body weight/day for the whole treatment period or until the animals were euthanised for animal welfare reasons (Female No. 80 euthanised on GD 17, 85 euthanised on GD 19 and 86 euthanised on GD 18). Females no. 99, 100-104 of the HD group were treated with a dose of 450 mg/kg body weight/day for the whole treatment period. The highest dose level was chosen with the aim of inducing toxic effects, but not death or severe suffering. Thereafter, a descending sequence of dose levels was selected with a view to demonstrate any dose-related response and a NOAEL.

During the period of administration, the animals were observed precisely each day for signs of toxicity and mortality. Animals that died during the study were examined macroscopically. All surviving female animals were sacrificed on the respective gestation day 20. Following the gross necropsy, the uteri and ovaries were removed, weighed and examined for number of implantations, resorptions (early and late), and live and dead foetuses. Food consumption of sperm positive females was measured on gestation days 5, 8, 11, 14, 17 and 20.

One half of each litter was examined for soft tissue anomalies. The remaining foetuses were processed and the first 20 litters per group were examined for skeletal alterations. Craniofacial examination of the heads of the foetuses used for the soft tissue examination of at least 20 litters per group was performed for internal structure including the eyes, brain, nasal passage and tongue by razor blade serial sectioning technique.

No mortality occurred in the control or any of the dose groups during the treatment period of this study. However, four females of the high dose group were euthanized in a moribund condition for animal welfare reasons between gestation day 16-19.

None of the females showed signs of abortion prior to the scheduled sacrifice.

There were no clinical signs of toxicological relevance observed in the control, low dose and mid dose groups. In high dose females sacrificed in moribund condition, predominant clinical signs observed were prone position, slight to severe piloerection, reduced spontaneous activity, half eyelid closure, nasal discharge, abnormal breathing and moving the bedding. Piloerection, reduced spontaneous activity, ataxia, hypothermia, prone position, hunched posture, wasp waist, pale skin and dehydration was also noted in few terminally sacrificed females of the high dose group.

The mean body weight increased with the progress of the study in the control, the low dose, the mid dose and the high dose group. However, after initiation of treatment, the mean body weight gain was noted to be moderately but statistically significantly lower in the high dose group when compared to controls during gestation days 11-14 (54.4 % of controls), 14-17 (60.1 % of controls), 17-20 (42.3 % of control) and 0-20 (65.2 % of controls). This was based on a loss of body weight of some of the high dose females. Lower body weight gain resulted in statistically significantly lower mean body weight of the high dose group at the end of the treatment period. Mean body weight of the high dose group was slightly lower on gestation day 17 (94 % of controls, p < 0.01) and moderately lower on gestation day 20 (89 % of controls, p < 0.001). Effects on mean body weight and body weight gain in the high dose group were considered to be test item related. In correlation to the body weight and body weight gain, food consumption in the high dose group was noted to be moderately and statistically significantly lower compared to the control group on various gestation days. Test item related, moderately, statistically significantly lower mean terminal body weight was observed in the high dose group when compared to the control group. Furthermore, moderately, statistically significantly lower mean adjusted maternal weight (terminal body weight - gravid uterus weight) was noted in the high dose group. This was considered as an effect of the test item.

No test item related effects of toxicological relevance were noted for gravid uterus weight, number of corpora lutea, implantation sites, early and late resorptions, number of live foetuses, number of male and female foetuses, sex ratio, number of foetuses in each uterine horn and percent pre- and post-implantation loss. No dead foetuses were noted in any of the groups.

No gross pathological changes of toxicological relevance were observed during the macroscopic examination of the females of control, low dose and mid dose group. In high dose euthanised animals due to welfare reasons, macroscopic findings like small spleen, discoloured pale /spotted liver, enlarged adrenal glands, discoloured dark lung, gas filled gastrointestinal tract were observed. In terminally sacrificed females, enlarged adrenal and right atrial auricle enlarged/left atrial auricle rudimentary were observed. These gross pathological changes in high dose group could be considered as test item related.

The mean foetus weight (individual basis) of the high dose group was moderately, statistically significantly lower when compared to the control group. The mean male foetus weight (Individual basis) of the high dose group  was also statistically significantly lower when compared to the control group. The mean female foetus weight (Individual basis) of the high dose group was lower when compared to the control but without achieving statistical significance. Moderately, statistically significantly lower mean foetus weight (litter basis) of the high dose group was observed when compared to the control group. The lower mean foetus weight (individual and litter basis) and male/female foetus weight (individual basis) of the high dose group was considered to be related to the treatment with the test item. There were no external abnormalities considered to be of toxicological relevance in any of the dose groups. Statistical analysis of data revealed no significant differences to the control group. Internal observation of the foetal viscera by free hand microdissection technique revealed a range of visceral findings in all groups including control. All litter incidences of soft tissue findings were statistically insignificant when compared with the control. A statistically significant increase for litter incidences of unossified caudal vertebral centrum was observed in high dose group when compared with the controls. The observed statistically significant reduced ossification or without achieving statistical significance of several bones in the high dose group that normally exhibit rapid ossification in the last days of gestation indicates a generalised skeletal delay in the high dose group. This delayed ossification was considered to be associated with the observed maternal toxicity (lower body weight and food consumption) and reduced foetal body weight of the high dose group. Generally delayed ossification is not regarded to persist postnatally and not associated with long-term consequences on survival, general growth and development and therefore not considered to be adverse.

The reported NOAEL for maternal and foetal toxicity was 150 mg/kg bw/day based on statistically significantly reduced body weight, body weight gain and food consumption during the treatment period in high dose group females and a statistically significantly lower mean terminal, adjusted maternal weight and foetal weight in high dose group when compared with the control (Eurofins / BSL Bioservice, 2018). Furthermore, no treatment related external, visceral and craniofacial findings were observed in high dose group. However, reduced ossification of some bones was observed which was indicative of a generalized delayed ossification associated with foetal growth retardation. Observed foetal effects in high dose group might be secondary to maternal toxicity.

In a supporting reproductive and developmental toxicity screening study conducted in accordance with OECD TG 421 and in compliance with GLP (Harlan Laboratories Ltd., 2010) tri(isopropyl)silyl acrylate was administered at doses of 30, 150 or 750 mg/kg bw/day to male and female Wistar rats for 15 days prior to mating, throughout mating, and through to postnatal day 5 for offspring and females. Males were treated for a total of 43 days. Clinical observations and effects on body weight were not considered to be toxicologically relevant, and the NOAEL for general parental systemic toxicity was at least 750 mg/kg bw/day. There were some adverse effects on developmental parameters. These were smaller litter sizes (compared with control group) at birth and two litter losses at 750 mg/kg bw/day, reduced litter weights at day 4 of lactation were also evident at 750 mg/kg bw/day (compared with controls), and body weight gains of the offspring were lower in the litters from the 750 mg/kg bw/day group compared with controls. The NOAEL was therefore 150 mg/kg bw/day.  


Justification for classification or non-classification

Based on the available data, tri(isopropyl)silyl acrylate is not classified for effects on reproduction and development according to Regulation (EC) No 1272/2008. The observed effects in foetuses are considered to be secondary to maternal toxicity.