Registration Dossier

Diss Factsheets

Toxicological information

Developmental toxicity / teratogenicity

Currently viewing:

Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
supporting study
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 guideline
Qualifier:
according to guideline
Guideline:
other: OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
GLP compliance:
yes
Limit test:
no

Test material

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
Rats were obtained from Charles River Deutschland GmbH
Animals were a minimum of 8 weeks of age at delivery. Males were 309-377 grams and females were 204-248 grams. Animals were acclimated for 7 days prior to treatment, 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 continously 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:
inhalation
Type of inhalation exposure (if applicable):
whole body
Vehicle:
unchanged (no vehicle)
Details on exposure:
(3-Chloropropyl)trimethoxysilane was administered for 6 hours daily by whole-body vapour inhalation to male rats for 28 days and to female rats throughout the 14-day pre-pairing, pairing and gestation period until the individual day 19 post coitum. 
Analytical verification of doses or concentrations:
no
Details on analytical verification of doses or concentrations:
The nominal atmosphere concentration was determined once daily by weighing the test item container before and after each exposure. The weight of the test item used was divided by the total air flow volume to give the nominal concentration. The test atmosphere concentration in each chamber was determined daily, 5 times per hour per chamber during each hour of exposure.
Details on mating procedure:
During the pairing period, rats were housed overnight with one male and one female in Makrolon pairing cages. The female was placed with the same male until mating occurred or two weeks elapsed.

Duration of treatment / exposure:
Exposure period: 28 days
Premating exposure period (males): 14 days
Premating exposure period (females): 14 days
Duration of test: until day 19 post coitum

(3-Chloropropyl)trimethoxysilane was administered for 6 hours daily by whole-body vapour inhalation to male rats for 28 days and to female rats throughout the 14-day pre-pairing, pairing and gestation period until day 19 post coitum.
Frequency of treatment:
daily
Doses / concentrationsopen allclose all
Dose / conc.:
0 ppm
Remarks:
air control
Dose / conc.:
5 ppm
Dose / conc.:
25 ppm
Dose / conc.:
100 ppm
No. of animals per sex per dose:
10/sex/dose
Control animals:
yes, concurrent no treatment
Details on study design:
Control animals were exposed to air only under the same conditions as animals exposed to the test item.
P generation males were sacrificed after they had been treated for 28 days, P generation females and pups were sacrificed on day 4 post partum.

Examinations

Maternal examinations:
Animals were observed twice daily for mortalities and clinical signs. Detailed clinical observations were performed once per week. A Functional Observational battery (modified Irwin screen test) was performed once during the test (on day 3 post-partum). Body weights and food consumption was recorded.
Ovaries and uterine content:
For pregnant females, the number of corpora lutea and the number of implantation sites were recorded, mated females that did not deliver were sacrificed on gestation day 24-27. Histological exam of ovaries and uterus was carried out on any females that did not give birth.
Fetal examinations:
Pups were sacrificed on day 4 post partum.The litters were examined for litter size, live birth, stillbirth and any gross anomalies.
Statistics:
Statistical Methods: Mean and standard deviation of data were calculated. Univariate one-way analysis of variance was used to assess the significance of intergroup differences. If the variables were assumed to follow a normal distribution, the 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.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
One male animal had eyes with crust during all detailed weekly clinical observations, one female had a mass i the right hip/flank region from day 6 of the pre-pairing period until day 4 of lactation.
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, non-treatment-related
Description (incidence):
One animal was found dead, however, in the histopathological examination, this dead depended on myeloid leukaemia.
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
effects observed, non-treatment-related
Description (incidence and severity):
A tendency towards slightly higher food consumption in the groups exposed to the test item. This higher food consumption was considered to be incidental and of no toxicological relevance.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
no effects observed
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Description (incidence and severity):
A marginally, however, statistically significant lower absolute heart weight was noted. Nevertheless, this was not statistically significantly decreased and not considered of toxicological relevance. Mean uterus weight was marginally, however, statistically significantly lower in groups 2 and 4 than in the vehicle control.
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
Enlarged liver, renal pelvic dilation, testes and epididymides reduced in size, spleen enlarged and discoloured mediastinal lymph node(s). However, this was not related to the test-item.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Other effects:
not examined

Maternal developmental toxicity

Number of abortions:
not specified
Pre- and post-implantation loss:
effects observed, non-treatment-related
Description (incidence and severity):
In one of the dose groups, an incidentally although statistically significant lower incidence of post-implantation loss was noted.
Total litter losses by resorption:
effects observed, non-treatment-related
Description (incidence and severity):
Due to the incidentally lower incidence of post-implantation loss the mean number of live pups per litter was statistically significantly higher in group 2 than in the vehicle control.
Early or late resorptions:
not specified
Dead fetuses:
not specified
Changes in pregnancy duration:
not specified
Changes in number of pregnant:
not specified
Other effects:
not examined
Details on maternal toxic effects:
Maternal toxic effects:no effects

Details on maternal toxic effects:
The fertility rate was high resulting in at least 9 litters per group for evaluation of reproduction data. At all concentrations, there were
no treatment-related effects on precoital time, fertility indices, mean duration of gestation, number of implantations, post-implantation
loss through to scheduled sacrifice on day 4 post partum. The mean number of corpora lutea per dam (determined at necropsy) was
similar in all groups and gave no indication of a test item-related effect. There were no findings, which distinguished test item-treated
animals from controls.

Effect levels (maternal animals)

Key result
Dose descriptor:
NOAEC
Effect level:
>= 100 ppm (nominal)
Based on:
test mat.
Basis for effect level:
other: No adverse effects observed

Maternal abnormalities

Abnormalities:
no effects observed

Results (fetuses)

Fetal body weight changes:
no effects observed
Description (incidence and severity):
Mean pup weights on day 0 and day 1 post partum were unaffected by treatment with the test item. Mean pup weight development during the first 4 days post partum lactation was unaffected by treatment with the test item. 
Reduction in number of live offspring:
not specified
Changes in sex ratio:
no effects observed
Description (incidence and severity):
Sex ratios at first litter check and on day 4 post partum were unaffected by treatment with the test item.
Changes in litter size and weights:
no effects observed
Description (incidence and severity):
Mean pup weights on day 0 and day 1 post partum were unaffected by treatment with the test item. Mean pup weight development during the first 4 days post partum lactation was unaffected by treatment with the test item. 
Changes in postnatal survival:
not specified
External malformations:
no effects observed
Description (incidence and severity):
No abnormal findings were noted for pups at first litter check or during the first 4 days post partum. No test item-related findings were noted at macroscopical examination of pups.
Skeletal malformations:
no effects observed
Description (incidence and severity):
No abnormal findings were noted for pups at first litter check or during the first 4 days post partum. No test item-related findings were noted at macroscopical examination of pups.
Visceral malformations:
no effects observed
Description (incidence and severity):
No abnormal findings were noted for pups at first litter check or during the first 4 days post partum. No test item-related findings were noted at macroscopical examination of pups.
Other effects:
not examined

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEC
Effect level:
>= 100 ppm (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects observed

Fetal abnormalities

Abnormalities:
no effects observed

Overall developmental toxicity

Developmental effects observed:
no

Applicant's summary and conclusion

Conclusions:
Exposure to (3-chloropropyl)trimethoxysilane up to and including the high concentration of 100 ppm did not result in any signs of general or reproductive toxicity of the test item. Based on these results the NOEC (no observed effect concentration) was established as >=100 ppm.