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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2004-2005
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Cross-reference
Reason / purpose:
reference to same study

Data source

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

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
Obtained from ABCR GmbH & Co. KG, Karlsruhe, Germany
99.0% pure (3-chloropropyl) trimethoxysilane
Product code SIC2410.0
Lot number KH03851-FS
Clear colorless liquid

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland GmbH
- Age at study initiation: min. 8 week
- Weight at study initiation: 309-377 g (males) and 204-248 g (females)
- Housing: in Makrolon (R) cages with wire mesh tops and standard granulated softwood bedding
- Diet: pelleted standard rat/mouse maintenance diet, ad libitum
- Water: tap water from Fullinsdorf in bottles, ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12
Background music was played at a centrally defined low volume for at least 8 hours during the light period.

Administration / exposure

Route of administration:
inhalation
Type of inhalation exposure (if applicable):
whole body
Vehicle:
unchanged (no vehicle)
Details on exposure:
The vapor generation system consisted of a round bottomed flask that was placed in a heating device set at 30 °C. Compressed air was supplied into the glass flasks and allowed the liquid test item to equilibrate with the temperature of the walls of the container. The vapor produced passed through a pipe and was then mixed and diluted with filtered air and conveyed to the inlet of the whole-body exposure chamber. After set-up of the definitive generation system the chamber concentration and stability of CPTMO over the duration of 6 hours was determined on two occasions prior to the start of the animal exposures.
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.
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.
Duration of treatment / exposure:
Exposure period: 28 days Premating exposure period (males): 14 days Premating exposure period (females): 14 days Duration of test: until the individual 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 the  individual day 19 post coitum. 
Frequency of treatment:
daily
Details on study schedule:
Premating exposure period (males): 14 days
Premating exposure period (females): 14 days
Duration of test: until the individual 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 the  individual day 19 post coitum. 
Doses / concentrationsopen allclose all
Dose / conc.:
5 ppm (nominal)
Dose / conc.:
25 ppm (nominal)
Dose / conc.:
100 ppm (nominal)
No. of animals per sex per dose:
10
Control animals:
yes, concurrent no treatment
Details on study design:
The animals were exposed to the following mean test item concentrations:
Group 1: 0 ppm (air control)
Group 2: 5 ppm
Group 3: 25 ppm
Group 4: 100 ppm
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

Parental animals: Observations and 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 (males: shortly before sacrifice; females: on day 3 post-partum). Body weights and food consumption was recorded.
Litter observations:
The litters were examined for litter size, live birth, stillbirth and any gross anomalies. The sex ratio of the pups was recorded. Pups were weighed individually on day 0, 1 and 4 post-partum. The pups were observed daily for survival and behavioural abnormalities in nesting and nursing. Dead pups and pups killed on day 4 post-partum were examined macroscopically.
Postmortem examinations (parental animals):
Parental generation males were sacrificed after they had been treated for  28 days, parental generation females were sacrificed on day 4  post-partum.
A complete gross necropsy was performed on all adult animals.
ORGAN WEIGHTS From all adult males and females the following organs were taken, trimmed and weighed: liver, heart, adrenals*, overies*,
thymus, uterus, kidneys*, testes*, spleen, epididymides*, seminal vesicles, with coagulating glands and their fluids(as one unit), lungs, prostate,
brain * = paired weights
TISSUE PRESERVATION The following tissues were collected from all adult males and females and preserved in neutral phosphate buffered
4% formaldehyde solution (except for testes and epididymides, which were fixed in Bouin's fixative): gross lesions, uterus, heart, brain,
thymus, spinal cord, thyroid, small and large intestines (incl. Peyers Patches), trachea and lungs (preserved by inflation with fixative and then
immersion), stomach, urinary bladder, liver, lymph nodes (mediastinal and mesenteric), kidneys, sciatic nerve, adrenals, bone marrow, spleen,
testes, ovaries, epididymides, uterus, prostate, seminal vesicles with coagulation glands
Full histopathology was carried out on the preserved organs and tissues of the control and high dose group animals.Examinations were extended to lower dose group animals if treatment related changes were seen in the high dose group.
For perganant females, the number of corora lutea and the number of impantation 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 onany females that did not give birth. Microscopic exam of the reproductive organs of all infertile males was made if necessary.
Postmortem examinations (offspring):
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.
Reproductive indices:
- Fertlity and mating performance
- Duration of gestation
- Implantation rate and Post-implantation loss
- Litter size at first litter check
- Postnatal loss day 0 - 4 post partum
Offspring viability indices:
- Abnormal findings at first litter check and during lacatation to weaning
- Sex ratios
- Pup weights to day 4 post partum

Results and discussion

Results: P0 (first parental animals)

General toxicity (P0)

Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed

Details on results (P0)

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. In particular, no treatment-related histopathological findings were observed in the reproductive organs of either sex from the parental generation. The assessment of the integrity of the spermatogenetic cycle did not provide any evidence of impaired spermatogenesis.

Effect levels (P0)

open allclose all
Dose descriptor:
NOAEC
Remarks:
systemic
Effect level:
>= 100 ppm (nominal)
Based on:
test mat.
Remarks:
equivalent to 810.32 mg/m³
Sex:
male/female
Basis for effect level:
other: No adverse effects observed up to the highest dose tested.
Dose descriptor:
NOEC
Remarks:
reproduction
Effect level:
>= 100 ppm (nominal)
Based on:
test mat.
Remarks:
equivalent to 810.32 mg/m³
Sex:
male/female
Basis for effect level:
other: No adverse effects observed up to the highest dose tested.

Target system / organ toxicity (P0)

Critical effects observed:
no

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not examined
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not examined
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
Urinalysis findings:
not examined
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Histopathological findings:
not examined

Developmental neurotoxicity (F1)

Behaviour (functional findings):
not examined

Developmental immunotoxicity (F1)

Developmental immunotoxicity:
not examined

Details on results (F1)

At all concentrations, there were no treatment-related effects on pup survival or litter size from birth through to scheduled sacrifice on day 4 post-partum. No abnormal findings were noted for pups at first litter check or during the first 4 days post-partum. Sex ratios at first litter check and on day 4 post-partum were unaffected by treatment with the test item. 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.

Effect levels (F1)

Dose descriptor:
NOEC
Generation:
F1
Effect level:
>= 100 ppm (nominal)
Based on:
test mat.
Remarks:
equivalent to 810.32 mg/m³
Sex:
male/female
Basis for effect level:
other: No effects observed up to the highest dose tested.

Target system / organ toxicity (F1)

Critical effects observed:
no

Overall reproductive toxicity

Reproductive effects observed:
no

Any other information on results incl. tables

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 (corresponding to 99.7 ppm mean analytical concentration and equivalent to 810.32 mg/m³)

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 (nominal concentration, corresponding to 99.7 ppm mean analytical concentration and equivalent to 810.32 mg/m³).