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Diss Factsheets

Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2004-09-06 to 2004-10-25
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2005
Report date:
2005

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
other: USEPA OPPTS 870.3650
Qualifier:
according to guideline
Guideline:
other: OECD 422
Version / remarks:
1996
Deviations:
no
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
3-(triethoxysilyl)propiononitrile
EC Number:
213-050-5
EC Name:
3-(triethoxysilyl)propiononitrile
Cas Number:
919-31-3
Molecular formula:
C9H19NO3Si
IUPAC Name:
3-(triethoxysilyl)propanenitrile

Test animals

Species:
rat
Strain:
Wistar
Remarks:
HanBrl:WIST (SPF)
Details on test animals or test system and environmental conditions:
Rats were obtained from RCC Ltd Laboratory Animal Services, Fullinsdorf, Switzerland.
Animals were a minimum of 8 weeks of age at delivery. Males were 227-271 grams and females were 165-216 grams. Animals were acclimated for 7 days prior to pairing, under test conditions with an evaluation of the health status. Animals rooms were air conditioned with 10-15 air changes per hour; the environment was monitored continuously with recordings of temperature and relative humidity, 12 hours artificial fluorescent light/12 hours dark with background music played at a centrally defined low volume for at least 8 hours during the light period. Animals were housed in Makrolon (R) cages with wire mesh tops and standard granulated softwood bedding. Pelleted standard rat/mouse maintenance diet was available ad libitum. Tap water from Fullinsdorf in bottles was available ad libitum.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
The test item was administered once daily, by gavage. All animals received a dose volume of 2 mL/kg body weight with a daily adjustment of the individual volume to the actual body weight. Control animals were dosed with the vehicle alone (dried corn oil)
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Samples for determination of actual test item concentrations, stability (7 day) and homogeneity in the prepared mixtures were taken on the first day of preparation. Samples for determination of actual test item concentrations and homogeneity were also taken on one occasion during the gestation period. Analysis were performed using a Gas Chromatographic method.
Details on mating procedure:
After a pre-pairing period of 14 days, males and females in the Reproductive groups were paired overnight, in the ratio of 1 male to 1 female. The female was placed with the same male until mating occurred or two weeks had elapsed. The day on which spermatozoa was observed was designated day 0 post coitum. After mating was ascertained, the animals were separated and housed individually. The females were allowed to litter and rear their progeny to day 4 of lactation.
Duration of treatment / exposure:
Pre-mating (14 days), mating, gestation, and postpartum days 1-3 for a maximum total of 44 days depending on duration of mating phase.
Frequency of treatment:
daily
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (actual dose received)
Remarks:
Group 1
Dose / conc.:
100 mg/kg bw/day (actual dose received)
Remarks:
Group 2
Dose / conc.:
500 mg/kg bw/day (actual dose received)
Remarks:
Group 3
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
Remarks:
Group 4
No. of animals per sex per dose:
10/sex/dose
Control animals:
yes, concurrent vehicle
Details on study design:
Sex: male/female
Duration of test: up a maximum total of 44 days
Animals of both sexes received test article for 14 days prior to pairing and during pairing period. Daily dosing of the females was continued throughout pregnancy and up to day 3 of lactation. Males were dosed for a minimum of 28 days.

Examinations

Maternal examinations:
The dams and pups were observed daily for survival and behavioural abnormalities in nursing. No tissues were collected from the dams or pups for microscopic examination.
Ovaries and uterine content:
Organs examined at necropsy (macroscopic and microscopic): The number of implantation sites and corpora lutea were determined at necropsy.
Fetal examinations:
Pup litter size,  any gross abnormalities and weight, sex ratios, pup viability, litter  weight gain, and macroscopic observations. The dams and pups were observed daily for survival and behavioural abnormalities in nursing. Macroscopic examination was performed at necropsy for the pups.  No tissues were collected from the dams or pups for microscopic examination.
Statistics:
Statistical methods: Mean and standard deviations of data of various parameters were calculated. Univariate one-way analysis of variance was used to assess the significance of intergroup differences. Dunnett t-test, based on a pooled variance estimate, was used for intergroup comparisons. The Steel test (rank test) was applied when the data could not be assumed to follow a normal distribution. Fisher's Exact test for 2x2 tables was applied if the variables could be dichotomized without loss of information. For pup data, the litter is the appropriate unit for statistical comparison. Statistically significant probabilities are reported at either the p<0.05 or p<0.01 levels.
Indices:
Gonadal function, mating behaviour, conception, development of the conceptus and parturition

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Commencing around day 14 of gestation and for the duration of the remaining treatment period, all females of the high dose group showed signs of discomfort after administration of the test article (pushing head through bedding material). 
During this period, stretched forelimbs were noted on single or few days in six females.
For four females, saltatory spasms were noted for up to few days. These clinical signs were considered to be test item-related.
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No effects were observed in mean absolute or mean weight gains in any of the treated groups. 
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
Mean food consumption was similar in all groups and not affected from treatment.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry 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 examined
Gross pathological findings:
no effects observed
Description (incidence and severity):
No macroscopic findings were noted during macroscopic examination.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
not specified

Maternal developmental toxicity

Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
The mean number of implantations per litter and post-implantation loss were unaffected by treatment. The mean numbers of implantations per dam were 13.7, 13.5, 14.2 and 13.6 in order of ascending dose level. The mean incidence of post-implantation loss as a percentage of total implantations was 10.2, 10.4, 4.9 and 12.3% in order of ascending dose level.
Total litter losses by resorption:
no effects observed
Early or late resorptions:
not specified
Dead fetuses:
no effects observed
Description (incidence and severity):
Neonatal mortality was generally low and not affected by treatment with the test item. The total numbers of pup loss during the first four days of life were 1, 2, 3 and 3 in order of ascending dose level, corresponding to 0.8, 1.7, 2.2 and 2.8% of living pups.
Changes in pregnancy duration:
no effects observed
Description (incidence and severity):
The duration of gestation was unaffected by treatment. Mean duration of gestation was 21.6, 21.6, 21.7 and 21.7 days, in order of ascending dose level.
Changes in number of pregnant:
no effects observed
Description (incidence and severity):
Number of pregnant per dose level:  10, 10, 10 and  9 (one female was not pregnant) for 0, 100, 500 and 1000 mg/kg bw/day
Other effects:
not specified

Effect levels (maternal animals)

open allclose all
Key result
Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: no adverse findings related to development in maternal animals
Dose descriptor:
NOAEL
Effect level:
ca. 100 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
histopathology: non-neoplastic
organ weights and organ / body weight ratios

Results (fetuses)

Fetal body weight changes:
no effects observed
Reduction in number of live offspring:
no effects observed
Description (incidence and severity):
Neonatal mortality was generally low and not affected by treatment with the test item. The total numbers of pup loss during the first four days of life were 1, 2, 3 and 3 in order of ascending dose level, corresponding to 0.8, 1.7, 2.2 and 2.8% of living pups.
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
no effects observed

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: based on no adverse developmental effects in pups

Fetal abnormalities

Abnormalities:
no effects observed

Overall developmental toxicity

Developmental effects observed:
no

Any other information on results incl. tables

Reproduction data: Summary of performance

Table 1: F0 animals breeding for F1 Litters

 Group (mg/kg/day)  1 (0) 2 (100)  3 (500)  4 (1000)
 Number of females paired 10 10  10  10 
 Number of females mated 10  10  10  10 
 Number of pregnant females  10 10  10  9 (A) 
 Number of females delivering pups  10 10 10  9
 Number of females with live pups on day 4 post-partum  10 10  10  9

(A) = Female No 79 was not pregnant

Applicant's summary and conclusion

Conclusions:
In a combined repeated dose oral toxicity study with the reproduction/developmental toxicity screening test with the registered substance 3-(triethoxysilyl)propiononitrile, conducted according to OECD Test Guidelines 422 and in compliance with GLP, the NOAEL for developmental toxicity was concluded to be greater than or equal to 1000 mg/kg bw/day based on no treatment-related effects observed in any of the developmental parameters evaluated.