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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

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

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1994
Report Date:
1994

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Qualifier:
according to
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

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
other: CD
Details on test animals 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

Administration / exposure

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
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

Examinations

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:
No given.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

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

Maternal developmental toxicity

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.

Effect levels (maternal animals)

open allclose all
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

Results (fetuses)

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.
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.
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

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
5 other: ml/kg bw/day
Basis for effect level:
other: teratogenicity

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

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.

Applicant's summary and conclusion

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 increase soft tissue malformations was said to be unclear. No treatment related adverse effects were reported in either the maternal generation of foetuses at 0.5 ml/kg bw/day and this value was given as the maternal and foetal NOAEL.