3-(trichlorosilyl)propiononitrile

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

not known

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: The study was conducted in accordance with an appropriate OECD test guideline and in compliance with GLP, using a related test substance.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2005

Report date:

2005

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

other: OECD TG 422

Test guideline 2

Qualifier:

according to guideline

Guideline:

other: USEPA OPPTS 870.3650

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

3-(triethoxysilyl)propiononitrile

EC Number:

213-050-5

EC Name:

3-(triethoxysilyl)propiononitrile

Cas Number:

919-31-3

IUPAC Name:

3-(triethoxysilyl)propanenitrile

Details on test material:

3-(triethoxysilyl)propanenitrile (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 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 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 oral 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.

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:

Males and toxicity group females: at least 28 days; Reproductive group females: throughout the pre-pairing (14 day), pairing and gestation periods until day 3 of lactation

Frequency of treatment:

daily

Doses / concentrations

Remarks:

Doses / Concentrations:
100, 500, and 1000 mg/kg bw/day
Basis:

No. of animals per sex per dose:

10 males/20 females/group

Control animals:

yes, concurrent vehicle

Details on study design:

The test substance 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 
prepairing (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.

Examinations

Observations and examinations performed and frequency:

All animals were observed at least twice daily to assess external condition, behavior and mortality/morbidity.  Detailed clinical observations 
were conducted outside the home cage once prior to the first test item administration and weekly thereafter. The FOB evaluation was 
performed on all adult males and all toxicity group females prior to the start of dosing and during the last week of dosing. Body weights and 
food consumption were recorded weekly. From all males and all toxicity group females, blood samples were obtained on the day of scheduled 
necropsy for hematology and clinical  chemistry parameters evaluations.  

Sacrifice and pathology:

Organs examined at necropsy (macroscopic and microscopic):   Animals were subjected to a complete gross necropsy that included 
examination of the cranial, thoracic, and abdominal cavities and  their contents.  Tissues and organs were collected for histological  
examination.  The following organs were collected for males and females  and weighed: adrenals, brain, heart, kidneys, liver, lungs, 
spleen,  thymus, uterus, ovaries, testes, prostate, seminal vesicles, and  epididymides.

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. 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. Quantitative data were used by a one-way analysis of
variance (ANOVA) when the variance were considered homogeneous according to Bartlett. Alternatively, if the variances were considered 
to be heterogeneous, a non-parametric  Kruskal-Wallis was used. Treated group were then compared to the control groups using Dunnett 
test. Statistically significant probabilities are reported at either the p<0.05 or p<0.01 levels.

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Haematological findings:

effects observed, treatment-related

Behaviour (functional findings):

no effects observed

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Details on results:

Oral administration of 3-(triethoxysilyl)propanenitrile to male and  toxicity group female rats at concentrations of 1000 mg/kg/day for 28  
consecutive days was generally well tolerated. No effects were observed  in the body weight and food consumption. None of the parameters 
under  investigation during the FOB gave any indication of treatment-related  effects. Increased organ weights (kidneys, spleen, heart and liver 
in  males; kidneys and spleen in toxicity group females), slight reduction in  red cell count (not statistically significant), hemoglobin 
concentration  and hematocrit in males and toxicity group females and histopathological  changes in kidneys (chronic tubular lesions of minimal 
to moderate  severity with hyperplasia of the renal pelvis epithelium and renal  pyelonephritis) were noted in males and toxicity group females 
dosed at  1000 mg/kg bw/day.
Administration of 500 mg/kg bw/day resulted in increased organ weights  (kidneys, heart and liver in males only) and histopathological changes in  
kidneys including chronic tubular lesions, hyperplasia of the renal  pelvis epithelium and renal pyelonephritis (males and toxicity group  females) 
and spleen including extramedullary hematopoiesis (males only).
Administration of 100 mg/kg bw/day resulted in increased liver weight in  males. In the absence of a histopathologic correlate the increased liver  
weight was considered most probably of adaptive nature and therefore of  no adverse character.   
Based on these data, the No Observed Adverse Effect Level (NOAEL) for  toxicity of 3-(triethoxysilyl)propanenitrile was considered to be 100  
mg/kg bw/day.

Effect levels

1

Dose descriptor:

NOAEL

Effect level:

100 mg/kg bw/day (nominal)

Sex:

male/female

2

Dose descriptor:

LOAEL

Effect level:

500 mg/kg bw/day (nominal)

Sex:

male/female

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

ABSOLUTE MEAN LIVER WEIGHT in grams (St. Dev.):
Males:
0 mg/kg: 9.40 (0.52)
100 mg/kg: 10.25 (0.93)
500 mg/kg: 10.33* (0.73)
1000 mg/kg: 10.26 (1.03)

Toxicity group females:
0 mg/kg: 6.31 (0.48)
100 mg/kg: 6.05 (0.51)
500 mg/kg: 6.26 (0.46)
1000 mg/kg: 6.76 (0.50)

RELATIVE MEAN LIVER/BODY WEIGHT in grams (St. Dev.):
Males:
0 mg/kg: 2.66 (0.12)
100 mg/kg: 2.86 (0.19)
500 mg/kg: 2.98** (0.13)
1000 mg/kg: 2.95** (0.23)

Toxicity group females:
0 mg/kg: 2.91 (0.27)
100 mg/kg: 2.80 (0.23)
500 mg/kg: 2.89 (0.20)
1000 mg/kg: 3.13 (0.14)

RELATIVE MEAN LIVER/BRAIN WEIGHT in grams (St. Dev.):
Males:
0 mg/kg: 464.83 (31.38)
100 mg/kg: 510.76* (43.28)
500 mg/kg: 519.72* (32.61)
1000 mg/kg: 507.52 (52.15)

Toxicity group females:
0 mg/kg: 334.47 (18.01)
100 mg/kg: 329.74 (35.48)
500 mg/kg: 339.49 (20.97)
1000 mg/kg: 358.50 (22.19)

Where:
*/**: Dunnett-test based on pooled variance sig. at 5% or 1% level,  respectively.

Applicant's summary and conclusion

Conclusions:

Based on the results of this study, the NOAEL for 3-(triethoxysilyl)propanenitrile in the rat via the oral route was determined to be 100
mg/kg bw/day.