Registration Dossier

Administrative data

Endpoint:
one-generation reproductive toxicity
Remarks:
based on generations indicated in Effect levels (migrated information)
Type of information:
experimental study
Adequacy of study:
key study
Study period:
not known
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: The study was carried out in accordance with an appropriate OECD test guideline and in compliance with GLP.

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:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Qualifier:
according to
Guideline:
other: USEPA OPPTS 870.3650
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
3-(triethoxysilyl)propiononitrile (CAS # 919-31-3); purity was >97.8 %
Lot 4A-4363-BS
Colorless to clear liquid
expiration 18-APR-2005

Test animals

Species:
rat
Strain:
other: HanBrl:WIST (SPF)
Sex:
male/female
Details on test animals 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 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:
oral: gavage
Vehicle:
corn oil
Details on exposure:
The test item was adminsitered 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.
Details on mating procedure:
Females were paired with males (1:1)  from the same treatment group until evidence of mating was obtained  (vaginal plug or 
sperm-positive vaginal smear).  Length of cohabitation did not exceed 14 days.
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.
Duration of treatment / exposure:
Exposure period: Premating (14 days), mating, gestation, and postpartum days 1-3 for a maximum total of 44 days depending on
duration of mating phase.
Premating exposure period (males): 14 days
Premating exposure period (females): 14 days
Duration of test: up to a maximum of 44 days
Frequency of treatment:
daily
Details on study schedule:
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.
Doses / concentrations
Remarks:
Doses / Concentrations:
100, 500, and 1000 mg/kg bw/day
Basis:

No. of animals per sex per dose:
10/sex/group
Control animals:
yes, concurrent vehicle
Details on study design:
3-(triethoxysilyl)propiononitrile was administered once daily orally (by gavage) to 10 males and 20 female (10 toxicity group and 10 reproductive group females) rats at doses of 100, 500 and 1000 mg/kg bw/day. A concurrent vehicle control group (dried corn oil) was also included. Males and toxicity group females were sacrificed after they had been treated for at least 28 days; reproductive group females were dosed throughout the
preparing (14 day), pairing and gestation periods until day 3 of lactation up to a maximum of 44 days; reproductive group females and
pups were sacrificed on day 4 of lactation.

Details on mating: After a pre-paring 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 occured 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.

Examinations

Parental animals: Observations and examinations:
Parameters assessed during study (maternal and fetal): 
Maternal body  weight, food consumption, and clinical observations. 
Clinical observations performed and frequency: General clinical observations were made twice daily to assess external condition, behavior and 
mortality/morbidity.  Detailed clinical observations were conducted weekly and were performed after the exposure period.  Examinations
included assessment of external condition, behavior, autonomic activity, gait and posture. Additionally, the females were observed for 
signs of difficult or prolonged parturition. The dams were observed daily for  survival and behavioral abnormalities in nesting.
Litter observations:
Live birth,  stillbirth, any gross abnormalities and weight, litter weight gain, and  macroscopic observations were noted.
Postmortem examinations (parental animals):
Organs examined at necropsy (macroscopic and microscopic): The number  of implantation sites and corpora lutea were determined 
at necropsy.  
Postmortem examinations (offspring):
Live birth,  stillbirth, any gross abnormalities and weight, litter weight gain, and  macroscopic observations were noted.
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. Statistically significant probabilities are 
reported at either the p<0.05 or p<0.01 levels.
Reproductive indices:
Gonadal function, mating behavior, conception, development of the conceptus and parturition

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
no effects observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Organ weight findings including organ / body weight ratios:
not examined
Histopathological findings: non-neoplastic:
not examined

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed

Details on results (P0)

No treatment-related effects were observed in any of the reproductive  parameters evaluated. No effects were observed in mean absolute or 
mean weight gains in any of the treated groups. Mean food consumption was similar in all groups and not affected from treatment. No 
abnormal findings were noted in any treated groups during 4 days  post-partum. No treatment-related effects were observed in any of the  
reproductive parameters evaluated. All females produced litters that were similar in all respects  to control litters.
"        Mortality and day of death:         None.
"        Number pregnant per dose level:  10, 10, 10 and  9 for 0,100, 500 and 1000 mg/kg bw/day
"        Number aborting:  0 "        
" Number of resorptions, early/late if available:  Not reported.
"        Number of implantations: Group Mean (standard deviation): Control:  13.7 (1.34); 100 mg/kg: 13.5 (3.10); 500 mg/kg: 14.2 (2.15); 1000 mg/kg: 13.6 (2.51) 
"        Pre and post implantation loss, if available: Post implantation loss: Control: 1.4 (1.43); 100 mg/kg: 1.4 (1.58); 500mg/kg: 0.7 (1.06); 1000 mg/kg: 1.7 (1.58)
"        Number of corpora lutea: Group Mean (standard deviation): Control: 24.1 (5.0); 100 mg/kg: 23.5 (4.4); 500 mg/kg: 23.5(3.1); 1000 mg/kg: 24.7 (3.8)
"        Duration of Pregnancy:  Group Mean (standard deviation): Control: 21.6 (0.52); 100 mg/kg: 21.6 (0.52); 500 mg/kg: 21.7 (0.48); 1000 mg/kg: 21.7 (0.50)
"        Body weight:  No statistically significant differences in treatment group maternal body weight relative to control group animals.
"        Food/water consumption:  No statistically significant differences in treatment group maternal food consumption relative to control 
group animals.
"        Description, severity, time of onset and duration of clinical signs: 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.
"        Gross pathology incidence and severity:  Gross pathology of the reproductive/developmental group animals was not an endpoint 
for this study.
"        Organ weight changes, particularly effects on total uterine weight:  Organ weight was not assessed in the reproductive/developmental 
group animals.
"        Histopathology incidence and severity: Histopathology was not assessed  in the reproductive/developmental group animals.

Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Sex:
male/female

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Histopathological findings:
not examined

Details on results (F1)

No abnormal findings were noted for pups at first litter check or during the first four days post-partum. Sex ratios were unaffected by treatment at first litter check and during the first four days post-partum. Mean pup weights at day 0 and day 1 post-partum were unaffected by treatment with the test item. Mean pup weight development was unaffected by treatment with the test item. No macroscopic findings were noted during necropsy of the pups.

Effect levels (F1)

Dose descriptor:
NOAEL
Generation:
F1
Effect level:
1 000 mg/kg bw/day
Sex:
male/female

Overall reproductive toxicity

Reproductive effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
No treatment-related effects were observed in any of the reproductive parameters evaluated. Based on the results of this screening study,
the NOAEL for maternal and reproductive toxicity of 3-(triethoxysilyl)propiononitrile in the rat via oral dosing was determined to be 1000
mg/kg bw/day.