3-chloropropyltrimethoxysilane

Toxicity to reproduction

Administrative data

Endpoint:

one-generation reproductive 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:

OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

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:

The vapour 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 vapour 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 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. 

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

0 ppm (nominal)

Doses / concentrations 2

Dose / conc.:

5 ppm (nominal)

Doses / concentrations 3

Dose / conc.:

25 ppm (nominal)

Doses / concentrations 4

Dose / conc.:

100 ppm (nominal)

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

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*, ovaries*,
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 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. 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:

Fertility 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 lactation to weaning
Sex ratios
Pup weights to day 4 post partum

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

no effects observed

Dermal irritation (if dermal study):

not examined

Mortality:

not specified

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

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):

not specified

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

In particular, no treatment-related histopathological  findings were observed in the reproductive organs of either sex from the parental generation. 

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:

no effects observed

Reproductive function: sperm measures:

no effects observed

Description (incidence and severity):

The assessment of the integrity of the  spermatogenetic cycle did not provide any evidence of impaired spermatogenesis.

Reproductive performance:

no effects observed

Description (incidence and severity):

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 (P0)

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.

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 specified

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

Sexual maturation:

not examined

Anogenital distance (AGD):

not specified

Nipple retention in male pups:

not specified

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

no effects observed

Histopathological findings:

not examined

Other effects:

not specified

Developmental neurotoxicity (F1)

Behaviour (functional findings):

not specified

Developmental immunotoxicity (F1)

Developmental immunotoxicity:

not specified

Effect levels (F1)

Key result

Dose descriptor:

NOAEC

Generation:

F1

Effect level:

>= 100 ppm (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No adverse effects observed.

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.

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.