[3-(triethoxysilyl)propyl]urea

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

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: The study was conducted according to an appropriate OECD test guideline and in compliance with GLP. Since this study is a read-across from CAS 116912-64-2, the reliability downgraded from RL1 to RL2.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2000

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)

Version / remarks:

adopted 1995

Deviations:

no

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

116912-64-2

Cas Number:

116912-64-2

IUPAC Name:

116912-64-2

Constituent 2

Reference substance name:

-

EC Number:

449-160-7

EC Name:

-

IUPAC Name:

449-160-7

Constituent 3

Reference substance name:

Ureidopropyltrialkoxysilane, mixed methoxy and ethoxy esters

IUPAC Name:

Ureidopropyltrialkoxysilane, mixed methoxy and ethoxy esters

Details on test material:

- Name of test material (as cited in study report): A-1160 (methanol stripped)
- Physical state: clear, colourless liquid
- Substance type: Alkoxysilane
- Storage condition of test material: at room temperature in the dark under nitrogen

Test animals

Species:

rat

Strain:

other: Crl:(WI) BR (outbred, SPF quality)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Deutschland, Germany
- Age at study initiation: approx. 8 weeks
- Weight at study initiation: 282 ± 5 g (males); 209 ± 3 g (females)
- Fasting period before study: no data
- Housing: 5 animals per sex and per cage in stainless steel cages; single housing overnight in Makrolon plastic cages during activity monitoring
- Diet: standard pelleted laboratory animal diet (from Carfil Quality BVBA, Oud-Turnhout, Belgium), ad libitum
- Water: tap-water, ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 (Fluctuations were observed, but were not considered to be relevant)
- Humidity (%): 50 (Fluctuations were observed, but were not considered to be relevant)
- Air changes (per hr): 15
- Photoperiod: 12 hrs dark / 12 hrs light

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

28 days

Frequency of treatment:

once daily, 7 days/week

Doses / concentrations

Remarks:

Doses / Concentrations:
61, 184, 1228 mg/kg bw
Basis:
actual ingested

No. of animals per sex per dose:

5

Control animals:

yes

Details on study design:

- Dose selection rationale: A project pilot study was performed were 3 rats per sex were dosed with 61, 184, 1228 mg/kg bw for 5 days by gavage. No adverse effects were observed up to 1228 mg/kg bw.

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Mortality and viability were checked twice daily. Clinical observations wer performed once daily.


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Before treatment and on days 8, 15, 22, and 28 detailed clinical observations were performed outside the home cage and a grading of effects was performed.

BODY WEIGHT: Yes
- Time schedule for examinations: On days 1, 8, 15, 22, and 28

Food consumption: weekly

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: prior to post mortem examination
- Anaesthetic used for blood collection: Yes (light ether anaesthesia)
- Animals fasted: Yes (maximum of 20 h)
- How many animals: all animals
- Parameters that were examined see table 1

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: prior to post mortem examination
- Animals fasted: Yes (maximum of 20 h)
- How many animals: all animals
- Parameters that were examined see table 1

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: during week 4 of treatment
- Dose groups that were examined: all animals
- Battery of functions tested: hearing ability/ pupillary reflex/ static righting reflex/ grip strength / activity test

Sacrifice and pathology:

GROSS PATHOLOGY: Yes (all animals)
HISTOPATHOLOGY: Yes, slides of all organs and tissues collected from the control and high-dose group and gross lesions of all animals were examined (see table 2). Additionally, spleen (males) and thymus (male, female) were examined in the intermediate dose groups.

Statistics:

Dunnett-test (many-to-one t-test) based on a pooled variance estimate (if normal distribution): comparison of the reated and control groups of each sex. Steel-test (many-to-one rank test; if no normal distribution).
All tests were two-sided and in all cases p<0.05 was accepted as the lowest level of significance.
Group means were calculated for continuous data and medians were calculated for discrete data (scores). Test statistics were calculated on the basis of exact values for means and pooled variances. Individual values, means and standard deviations may have been rounded off before printing.

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

1228 mg/kg bw: salivation (non adverse)

Mortality:

mortality observed, treatment-related

Description (incidence):

1228 mg/kg bw: salivation (non adverse)

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 specified

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

not examined

Behaviour (functional findings):

no effects observed

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Details on results:

CLINICAL SIGNS AND MORTALITY
No mortality occurred. Salivation was observed in the animals of the high dose group but was not considered to be a sign of adverse systemic toxicity.
BODY WEIGHT AND WEIGHT GAIN
Slightly lower body weight gain was observed in the mid and high dose males, but was not statistically significant.

HAEMATOLOGY
Decrease of RBC, HB, relative number of lymphocytes and an increase of relative number of neutrophils in the female mid-dose group were considered to have occurred by chance, as there was no dose-response relationship and the values were within the historical control data.

CLINICAL CHEMISTRY
No treatment-related effects have been observed.

NEUROBEHAVIOUR
In two females of the mid-dose group the total motor activity was increased. Moreover, in one of these females the ratio between upper and lower sensor recordings was reverse to what is expected. These effects were considered to have occurred by chance because no corroborative findings in the animals and no dose-response relationship was observed.

ORGAN WEIGHTS
A decrease in the thymus:body weight ratio of high dose males was not supported by histological examination of the thymus. In view of the very small variation in the thymus weights of the male high dose group and the fact that all thymus weights were within the range of the historical control data, the toxicological significance of this effect was doubted.

GROSS PATHOLOGY and HISTOPATHOLOGY
Thickening of the limiting ridge was observed in the stomach of 2/5 females of the high dose group. Microscopically a minimal squamous hyperplasia was observed. These effects were attributed to an irritative effect of the substance and are also commonly seen in gavage studies.

Effect levels

Dose descriptor:

NOAEL

Effect level:

1 228 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

A 28-day repeated dose toxicity study according to OECD 407 and GLP is available by the oral route for ureidopropyltrialkoxysilane, mixed methoxy and ethoxy esters (CAS: 116912-64-2). Exposure to up to 1228 mg/kg bw test substance did not results in any substance-related adverse effects. Thus, a NOAEL of 1228 mg/kg bw/day is proposed.