3-(triethoxysilyl)propiononitrile

Endpoint summary

Description of key information

In a key combined repeated dose oral toxicity study with the reproduction/developmental toxicity screening test with the registered substance 3-(triethoxysilyl)propiononitrile, conducted according to OECD Test Guideline 422 and in compliance with GLP, a NOAEL for systemic effects was concluded to be 100 mg/kg bw/day (nominal) based on increased organ weights and kidney effects at the 500 mg/kg bw/day (nominal) dose (RCC Ltd, 2005)

 

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2004-09-06 to 2004-10-25

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

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

Version / remarks:

1996

Deviations:

no

Qualifier:

according to guideline

Guideline:

other: USEPA OPPTS 870.3650

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

Wistar

Details on species / strain selection:

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.

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 (dried corn oil)

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

Dose / conc.:

0 mg/kg bw/day (actual dose received)

Remarks:

Group 1

Dose / conc.:

100 mg/kg bw/day (actual dose received)

Remarks:

Group 2

Dose / conc.:

500 mg/kg bw/day (actual dose received)

Remarks:

Group 3

Dose / conc.:

1 000 mg/kg bw/day (actual dose received)

Remarks:

Group 4

No. of animals per sex per dose:

10 males/20 females/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 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.

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 groups were then compared to the controgroups using Dunnett test. Statistically significant probabilities are reported at either the p<0.05 or p<0.01 levels.

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

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

no effects observed

Ophthalmological findings:

not examined

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

Slightly reduced levels in the erythrocyte count, hemoglobin concentration and hematocrit was observed in both sexes at 1000 mg/kg bw/day.

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

Behaviour (functional findings):

no effects observed

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

In males, increased absolute and/or relative organ weight were noted for the following organs: heart (500 and 1000 mg/kg bw/day), liver (100, 500 and 1000 mg/kg bw/day), kidneys (500 and 1000 mg/kg bw/day) and spleen (1000 mg/kg bw/day)
In females, at 1000 mg/kg bw/day, increased absolute and/or relative organs weight were noted for the following organs: kidneys and spleen
These findings correlated with the findings at histopathological examination, where severe renal changes were noted. The change in mean spleen weight was considered to be secondary to these changes.

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

At 1000 mg/kg bw/day, macroscopic renal changes were noted for three males and thickened liver was noted for one male. At 1000 mg/kg bw/day, macroscopic renal changes were noted for three toxicity group females. These findings were considered to be test-item related since they correlated with histopathological findings.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

At 1000 and 500 mg/kg bw/day, chronic tubular lesions of minimal to moderate severity was observed in animals of either sex, correlating with macroscopic renal discoloration and foci and increased kidney weights recorded at necropsy. Males were more severely affected than females. Hyperplasia of transitional cell epithelium of the renal pelvis was seen at 500 and 1000 mg/kg bw/day in either sex, mostly in conjunction with chronic tubular lesions. Further, renal pyelonephritis and increased incidence of splenic extramedullary hematopoiesis (males only) were present in treated animals and were considered secondary to the primary renal tubular lesion.
No test item-related histopathological findings were noted in the reproductive organs of either sex. In particular, the assessment of the integrity of the spermatogenetic cycle did not reveal any evidence of impaired spermatogenesis.

Histopathological findings: neoplastic:

no effects observed

Other effects:

not specified

Details on results:

Oral administration of 3-(triethoxysilyl)propiononitrile 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 Functional Observational Battery (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 minimal to slight hyperplasia of the renal pelvis epithelium [related to tubular damage] 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 with minimal to slight hyperplasia of the renal pelvis epithelium (isolated) 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 correlation 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)propiononitrile was considered to be 100 mg/kg bw/day.

Dose descriptor:

NOAEL

Effect level:

100 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

histopathology: non-neoplastic

organ weights and organ / body weight ratios

Critical effects observed:

yes

Lowest effective dose / conc.:

500 mg/kg bw/day (actual dose received)

System:

urinary

Organ:

kidney

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

not specified

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

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

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

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

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

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

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

Conclusions:

In a repeated dose oral toxicity test with the reproduction/developmental toxicity screening test with the registered substance 3-(triethoxysilyl)propiononitrile, conducted according to OECD Test Guideline 422 and in compliance with GLP, a NOAEL for systemic effects was concluded to be 100 mg/kg bw/day (nominal) based on increased organ weights and kidney effects at the 500 mg/kg bw/day (nominal) dose.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

100 mg/kg bw/day

Study duration:

subacute

Species:

rat

System:

urinary

Organ:

kidney

Additional information

In a 7-day dose range-finding study which was not conducted according to a guideline or GLP, 4 male and 4 female rats were administered daily oral (gavage) doses of 0, 100, 500 and 1000 mg/kg bw/day 3-(triethoxysilyl)propiononitrile in corn oil for up to 7 days. Statistically significant increased absolute and relative kidney weights in males were noted and considered to be test-item related. Based on these data dose levels of  0, 100, 500 and 1000 mg/kg bw/day were considered appropriate for the main combined repeated dose toxicity study with the reproduction/developmental toxicity screening test in the rat (RCC Ltd, 2004).

In the key combined repeated dose oral toxicity study with thereproduction/developmental toxicity screening test conducted according to OECD Test Guideline 422 and in compliance with GLP, 3-(triethoxysilyl)propiononitrile was administered orally by gavage to rats at dosages of 0, 100, 500 and 1000 mg/kg bw/day. Males and females of the toxicity group were treated for 28 days, females of the reproductive groups were treated for two weeks prior to pairing, duringgestation and until day 3 of the lactation period.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 minimal to slight hyperplasia of the renal pelvis epithelium [related to tubular damage] 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 with minimal to slight hyperplasia of the renal pelvis epithelium (isolated) 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 repeated dose toxicity of 3-(triethoxysilyl)propiononitrile was considered to be 100 mg/kg bw/day (RCC Ltd, 2005).

Justification for classification or non-classification

The available data suggests that 3-(triethoxysilyl)propiononitrile should not be classified for specific target organ toxicity following repeated oral exposure according to Regulation (EC) No. 1272/2008