3-trimethoxysilylpropyl methacrylate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

No reproductive toxicity studies are available for 3-trimethoxysilylpropyl methacrylate (CAS 2530-85-0, EC No. 219-785-8).

An Extended One-Generation Reproductive Toxicity (EOGRT) test conducted according to OECD Guideline 443 and in compliance with GLP is ongoing, as requested by ECHA. The information herein will be updated accordingly when the final study report becomes available.

Effect on fertility: via oral route

Endpoint conclusion:

no study available (further information necessary)

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

No reproductive toxicity studies are available for the registered substance. An Extended One-Generation Reproductive Toxicity (EOGRT) study is ongoing (according to OECD Test Guideline 443), as requested by ECHA. The information herein will be updated accordingly when the study report becomes available.

Effects on developmental toxicity

Description of key information

The key developmental toxicity study (BRRC, 1994, Reliability Score 1) for 3-trimethoxysilylpropyl methacrylate (CAS 2530-85-0, EC No. 219-785-8) was conducted according to OECD Test Guideline 414 and in compliance with GLP. A NOAEL for maternal toxicity was determined to be 0.5 ml/kg bw/day (equivalent to 520 mg/kg bw/day) and a NOAEL for developmental toxicity was determined to be at least 5 ml/kg bw/day (equivalent to 5200 mg/kg bw/day). Effects in foetuses were only observed at maternally toxic doses, which were in excess of the limit dose for this type of toxicity study. Therefore, there were no relevant developmental toxicity findings.

Link to relevant study records

Reference

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1994

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Qualifier:

according to guideline

Guideline:

EPA OTS 798.4900 (Prenatal Developmental Toxicity Study)

Principles of method if other than guideline:

The objective of this study was to evaluate the potential of 3-trimethoxysilylpropyl methacrylate to produce developmental toxicity (including teratogenicity) when administered by gavage during organogenesis to pregnant CD rats.

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

other: CD

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Labs, Portage, MI, USA
- Age at study initiation: 55 days
- Weight at study initiation: 176-200 g (non-pregnant)
- Housing: 1/stainless steel wire mesh cage (after mating)
- Diet: standard diet ad libitum
- Water: drinking water ad libitum
- Acclimation period: 2 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 66-77 deg F (18.9-25 °C)
- Humidity (%): 40-70%
- Photoperiod (hrs dark / hrs light): 12 hours dark / 12 hours light
TREATMENT DATES: range 11-28 August 1993

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on exposure:

Timed-pregnant CD rats were administered 3-(trimethoxysilyl)propyl methacrylate (gamma-methacryloxypropyI-trimethoxysilane; CAS No. 2530-85-0) by gavage on gestational days (gd) 6 through 15. 25 copulation plug-positive females/group were dosed with undiluted 3-(trimethoxysilyl)propyl methacrylate at dose volumes of 0.5, 2.0, or 5.0 ml/kg/day. An additional group of 25 timed-pregnant females received Milli-Q® (filtered) water (CAS No. 7732-18-5) at a dose volume equivalent to that used in the high dose group and served as the control group.

PREPARATION OF DOSING SOLUTIONS:
Given neat. Controls received distilled water at maximum dosed volume (5 mg/kg bw/day).

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Analytical verification, no further details (details were given in Appendix 1, not seen by this reviewer)

Details on mating procedure:

- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1:1
- Length of cohabitation: up to 2 wk
- Proof of pregnancy: vaginal plug referred to as day 0 of pregnancy

Duration of treatment / exposure:

gestation days 6-15

Frequency of treatment:

daily

Duration of test:

up to gestation day 21

Dose / conc.:

0 other: ml/kg/day

Remarks:

Control group (distilled water)

Dose / conc.:

0.5 other: ml/kg/day

Remarks:

equivalent to 520 mg/kg bw/day

Dose / conc.:

2 other: ml/kg/day

Remarks:

equivalent to 2080 mg/kg bw/day

Dose / conc.:

5 other: ml/kg/day

Remarks:

equivalent to 5200 mg/kg bw/day

Dose / conc.:

5 other: ml/kg/day

Remarks:

ess

No. of animals per sex per dose:

25 females

Control animals:

other: control group given 5 ml distilled water/kg bw/day

Details on study design:

- Dose selection rationale: range finding study (93U1231); 0.5, 1, 2, 5, 10 ml/kg bw/day

Maternal examinations:

Clinical observations were made daily (twice daily during dosing), and maternal body weights were measured on gd 0, 6, 9, 12, 15, 18, and 21. Maternal food consumption was measured at 3-day intervals throughout gestation, gd 0-21. Dams were necropsied on gd 21 and evaluated for body weight, liver weight, kidney weight, gravid uterine weight, and pregnancy status. Maternal liver and kidneys were retained in 10% neutral buffered formalin.

Ovaries and uterine content:

Examination of uteri and unterine contents.

Fetal examinations:

All fetuses were dissected from the uterus, counted, weighed, examined for external malformations (including cleft palate) and variations and for determination of gender. Approximately one-half of the live fetuses in each litter were examined for visceral and craniofacial malformations and variations. The remaining fetuses in each litter were examined for skeletal malformations and variations after staining with alizarin red S.

Statistics:

Levine's test for equality of variances, analysis of variance (anova), T-tests: intercomparison of 3 treatment and 1 control groups.
Kruskal-Wallis test, Mann-Whitney U test: nonparamentric data from laparohysterectomy.
Fisher Exact test: incidence data.

Indices:

None given.

Historical control data:

None given.

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Pertinent clinical signs in the high dose group included incoordination and abnormal gait (in 2 dams, 1 of which died), unkempt appearance, urine stains/urogenital area wetness, and red vaginal discharge. Unkempt appearance, urine stains/urogenital area wetness, and red vaginal discharge were also observed in animals from the 2.0 ml/kg bw/day group. Audible respiration at >=2 mg/kg bw/day. Perioral encrustation and salivation in all treated groups.

Dermal irritation (if dermal study):

not examined

Mortality:

mortality observed, treatment-related

Description (incidence):

In the 5.0 ml/kg bw/day group, 2 dams died after completion of dosing, on gd 16 and 19, respectively.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Gestational body weights were reduced in the 5.0 ml/kg bw/day group throughout the treatment period and subsequent to treatment, on gd 18. Substantial reductions in body weight gain were noted in the high dose group for Days 6 to 12 and consequently, for the entire treatment period. Reductions in weight gain was also noted in the 2.0 ml/kg bw/day group for the first 3 days of the treatment period.

Food consumption and compound intake (if feeding study):

effects observed, non-treatment-related

Description (incidence and severity):

Effects on food consumption correlated well with effects on body weight as food consumption was reduced in the high dose group throughout the treatment period. Reductions in food consumption was also noted in the 2.0 ml/kg bw/day group for the first 3 days of the treatment period.

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Endocrine findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

not specified

Description (incidence and severity):

Absolute liver and kidney weights appeared to be slightly increased in the 2.0 ml/kg bw/day group as well (not statistically significant). Gravid uterine weight appeared to be slightly (but not statistically significantly) reduced in the 5.0 ml/kg bw/day group. Absolute and relative liver and kidney weights were increased in dams from the 5.0 ml/kg bw/day group.

Gross pathological findings:

no effects observed

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Other effects:

no effects observed

Description (incidence and severity):

Two pregnant females from the high dose group bore litters with only non-viable implants at scheduled sacrifice. However, there were no effects of treatment on the number of ovarian corpora lutea.

Pre- and post-implantation loss:

no effects observed

Details on maternal toxic effects:

There were no apparent effects of treatment on dams given 0.5 ml/kg bw/day.

Dose descriptor:

NOAEL

Effect level:

0.5 other: ml/kg bw/day

Basis for effect level:

other: maternal toxicity

Dose descriptor:

LOAEL

Effect level:

2 other: ml/kg bw/day

Basis for effect level:

other: maternal toxicity

Fetal body weight changes:

effects observed, treatment-related

Description (incidence and severity):

Fetal body weights/litter (for males, females and all fetuses) were reduced in the 5.0 ml/kg bw/day group.

Reduction in number of live offspring:

no effects observed

Changes in sex ratio:

no effects observed

Changes in litter size and weights:

no effects observed

Anogenital distance of all rodent fetuses:

not specified

Changes in postnatal survival:

not specified

External malformations:

no effects observed

Skeletal malformations:

effects observed, treatment-related

Description (incidence and severity):

Increases in the incidence of total malformations in the 5.0 ml/kg bw/day group were partially due to skeletal alterations noted in 3 litters. These skeletal alterations included missing lumbar centra and arches, missing sacral centra and arches, rudimentary ribs (#1 - #12), and extra cervical ribs (at arch #7). Increased incidences of several skeletal variations, including the presence of rudimentary ribs or bone islands on cervical arch #7 and increased incidences of unossified anterior arch of the atlas, poorly ossified squamosal, some poorly ossified or unossified metacarpals, some unossified metatarsals, poorly ossified sternebra #6 and unossified sternebra #6, were also noted at 5.0 ml/kg bw/day. In addition, a slight (but not statistically significant) increase in the incidence of dilated lateral ventricle(s) in the 5.0 ml/kg bw/day group was consistent with a general profile of delayed development.

Visceral malformations:

effects observed, treatment-related

Description (incidence and severity):

Collectively, increases in the incidences of soft tissue malformations by category and of total malformations attained statistical significance in the high and mid dose groups. Due to the low frequency of occurrence of individual anomalies (in particular, malformations involving the circulatory system and palate closure), the toxicologic significance of the increase in soft tissue malformations is unknown.

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects: yes

Dose descriptor:

NOAEL

Effect level:

5 other: ml/kg bw/day

Basis for effect level:

other: teratogenicity

Abnormalities:

not specified

Developmental effects observed:

not specified

The adverse foetal effects reported at >=2 ml/kg bw/day occurred at maternally toxic doses and therefore, have less relevance than similar effects produced at doses without adverse effects on the dams. The foetal effects may be indirect and secondary to the adverse effects in the dams.

Conclusions:

A well reported prenatal developmental toxicity study, conducted according to OECD 414 and in compliance with GLP, found that gavage administration of 2 and 5 ml/kg bw/day to rats on gestation days 6-15 was maternally toxic and produced evidence of delayed development in foetuses at 5 ml/kg bw/day. The incidence of total and soft tissue malformations was increased 2 and 5 ml/kg bw/day. The toxicological significance of increased soft tissue malformations was said to be unclear. No treatment related adverse effects were reported in either the maternal generation or foetuses at 0.5 ml/kg bw/day and this value was given as the maternal and foetal NOAEL.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

5 200 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

The key developmental toxicity study conducted according to OECD Test Guideline 414 and in compliance with GLP (BRRC, 1994, Reliability Score 1) found that gavage administration of 2 and 5 ml/kg bw/day (equivalent to 2080 and 5200 mg/kg bw/day, respectively) to CD rats on gestation days 6-15 was maternally toxic and produced evidence of delayed development in foetuses at 5 ml/kg bw/day. The incidence of total and soft tissue malformations was increased at 2 and 5 ml/kg bw/day. No treatment related adverse effects were reported in either the maternal generation or foetuses at 0.5 ml/kg bw/day (equivalent to 520 mg/kg bw/day) and this value was given as the maternal and foetal NOAEL. Effects in foetuses were only observed at maternally toxic doses, which were in excess of the limit dose for this type of toxicity study. Therefore, there were no relevant developmental toxicity findings.

A developmental toxicity study in rabbits is being conducted according to OECD Test Guideline 414 and in compliance with GLP, as requested by ECHA.

Justification for classification or non-classification

Based on the available data, 3-trimethoxysilylpropyl methacrylate does not require classification for reproductive or developmental toxicity according to Regulation (EC) No 1272/2008.