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Diss Factsheets

Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
7th April 1994 - 10th November 1994
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Remarks:
The study was conducted according to an older (1981) version of OECD Test Guideline 407, therefore some of the examination parameters in the current guideline were not assessed

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1994
Report date:
1994

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
Version / remarks:
1981
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Limit test:
no

Test material

1
Chemical structure
Reference substance name:
-
EC Number:
419-560-6
EC Name:
-
Cas Number:
4369-14-6
Molecular formula:
C9H18O5Si
IUPAC Name:
3-(trimethoxysilyl)propyl prop-2-enoate

Test animals

Species:
rat
Strain:
Crj: CD(SD)
Details on species / strain selection:
Not specified, noting the rat is the preferred species for OECD Test Guideline 407
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Japan, Inc.
- Females nulliparous and non-pregnant: Yes
- Age at study initiation: 5 weeks old
- Weight at study initiation: Males 124.7-159.6 g, females 117.9-144 g
- Fasting period before study: Not specified
- Housing: Individually
- Diet: MF pelleted diet, ad libitum
- Water : City water supply (chlorinated), ad libitum
- Acclimation period: Yes, but duration not specified

DETAILS OF FOOD AND WATER QUALITY: Contaminants in both the diet and drinking water were regularly analyzed by the laboratory, with the results indicating no effect on this study.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23+/-2
- Humidity (%): 55+/-10
- Air changes (per hr): 10 to 15
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
olive oil
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: For preparation of the substance, it was weighed accurately and dissolved in olive oil by stirring to make the highest formulation of 10 w/v % (0.1 g/mL). This formulation then was diluted with olive oil to make three lower formulations of 0.08, 0.4, 2.0 w/v %. Based on stability testing, the dosing formulations were prepared once a week for dosing.

VEHICLE :
- Justification for use and choice of vehicle: Not specified
- Concentration in vehicle: 0, 0.08, 0.4, 2.0, 10.0 w/v %
- Amount of vehicle (if gavage): 10 mL/kg
- Lot/batch no.: 146RSP or 147RTT
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
The stability test of the substance was confirmed indicating that it was stable enough in the dosing formulations for 7 days, thus the formulations were prepared weekly.
Duration of treatment / exposure:
Treatment period: 28 days
Recovery period: 14 days
Frequency of treatment:
daily
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (nominal)
Remarks:
Control group
Dose / conc.:
8 mg/kg bw/day (nominal)
Remarks:
Low dose (LD)
Dose / conc.:
40 mg/kg bw/day (nominal)
Remarks:
Mid dose (MD) #1
Dose / conc.:
200 mg/kg bw/day (nominal)
Remarks:
Mid dose (MD) #2
Dose / conc.:
1 000 mg/kg bw/day (nominal)
Remarks:
High dose (HD)
No. of animals per sex per dose:
Test group: 6M, 6F
Recovery group: 6M, 6F
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: A preliminary oral toxicity test was conducted by dosing with the substance via oral gavage daily for 14 days at three doses of 50, 250, and 500 mg/kg bw/day. Abnormal changes were noted in hematological examinations, blood chemical examinations and necropsy in the 1000 mg/kg bw/day group. Based on these preliminary findings, the main test was conducted by oral gavage at 0 (vehicle control), 8, 40, 200, and 1000 mg/kg bw/day and the recovery test at 0 (vehicle control), 200, and 1000 mg/kg bw/day.
- Rationale for animal assignment: Random
- Fasting period before blood sampling for clinical biochemistry: Yes, overnight
- Rationale for selecting satellite groups: To investigate the reversibility of the effects
- Post-exposure recovery period in satellite groups: 14 days
- Section schedule rationale: Random
Positive control:
Not used

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: The general condition of all animals was observed at least once per day.

DETAILED CLINICAL OBSERVATIONS: No

BODY WEIGHT: Yes
- Time schedule for examinations: At study days -2, 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, 26 and 28 and recovery days 1, 3, 5, 8, 10, 12 and 14.

FOOD CONSUMPTION: Yes
- Time schedule for examinations: Once before dosing was started and twice weekly during the dosing and recovery periods.

FOOD EFFICIENCY: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: At the end of dosing period and at the end of the recovery period
- Anaesthetic used for blood collection: Ether
- Animals fasted: Yes, overnight
- How many animals: All animals
- Parameters checked in Table 1 below were examined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: At the end of dosing period and at the end of the recovery period
- Animals fasted: Yes
- How many animals: All animals
- Parameters checked in Table 1 below were examined.

URINALYSIS: Yes
- Time schedule for collection of urine: On day 28 of the study period and on day 14 of the recovery period
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes
- Parameters checked in Table 1 below were examined.

NEUROBEHAVIOURAL EXAMINATION: No

IMMUNOLOGY: No
Sacrifice and pathology:
SACRIFICE:
Method not specified

GROSS PATHOLOGY: Yes
See Table 2 below

HISTOPATHOLOGY: Yes
See Table 2 below
Statistics:
The data for body weight, food consumption, haematological examination, blood chemical examination, urine volume and organ weights were analysed using Bartlett's test for homogeneity of variance at a significance level of 5%. The data of homogeneous variance were then analysed for significant difference by one way analysis of variance. If there was a significant difference, then the data were analysed for significant difference in comparison with that of the control group by Dunnett's test, in case of an equal number of data. Otherwise, in case of an unequal number, by Scheffé's test. The data of not homogenous variance was analysed by Kruskal-Wallis test. If there was a significant difference, then the data were analysed for significant difference in comparison with the control group by nonparametric Dunnet's test, in case of an equal number of data. Otherwise, in case of an unequal number, by nonparametric Scheffé's test.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
The test substance-related clinical signs observed at 200 and/or 1000 mg/kg bw/day are considered by the reviewer to be non-adverse or not toxicologically relevant (i.e., not indicative of signicant toxic effects).

Salivation in nearly all animals from both sexes from 200 mg/kg bw/day group and higher groups), decreased spontaneous locomotion, decreased respiratory rate and ptosis in males of 1000 mg/kg bw/day group and marks of reddish tears in both sexes of 1000 mg/kg bw/day group were observed and considered to be test substance-related. The salivation seen in the lower doses and vehicle control group was not identified as test substance-related because it occurred sporadically in 2 to 4 animals per group.
Mortality:
no mortality observed
Description (incidence):
No test or recovery animal deaths occurred during the study period.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No test substance-related changes to body weight or body weight gain were observed in the treated or recovery animals.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
No effects on food consumption of toxicological significance were observed in the treated or recovery animals.

High food consumption was noted in treated males from 1000 mg/kg bw/day group from day 22 to 28. This effect was not considered to be of toxicological significance since it did not affect the body weight gain for these animals. No effect on food consumption was seen in the treated females or the recovery animals.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Description (incidence and severity):
No test substance-related haematological changes were noted in the treated or recovery animals.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
No effects on clinical biochemistry of toxicological significance were observed in treated or recovery animals.

Increased chloride in treated males from 8 mg/kg bw/day group and increased alanine aminotransferase in treated males and females at 1000 mg/kg bw/day group was noted. These effects were not considered to be of toxicological significance as there were no effects seen at necropsy and histopathology to indicate changes in organ function. No test substance-related effects were seen in recovery group males. Increased potassium levels were noted in recovery females from 200 mg/kg bw/day.
Endocrine findings:
not examined
Urinalysis findings:
no effects observed
Description (incidence and severity):
No test substance-related urinalysis changes were seen in the treated or recovery animals.
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
No test substance-related organ weight changes were noted in the treated or recovery animals.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Test substance-related gross pathology was identified locally in the stomach of treated males and females at 1000 mg/kg bw/day, with these effects attributable to the corrosive properties of the substance. No pathology indicative of systemic toxicity was seen in test or recovery animals.

At the end of the dosing period In males at 1000 mg/kg bw/day, a blackish region of mucosa in the glandular stomach (2/6) was observed, with scab formation observed in a single male each at 8 and 40 mg/kg bw/day (1/6), but no gross findings reported for 200 mg/kg bw/day.

An elevated region of mucosa in the female forestomach (1/6) was observed at 1000 mg/kg bw/day.

At the end of the recovery period, no test substance-related effets were observed in recovery males, with scab formation (1/6 recovery females) at 1000 mg/kg bw/day.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Test substance-related histopathology was identified locally in the stomach of treated males (at 1000 mg/kg bw/day) and females (from 200 mg/kg bw/day), with these effects attributable to the corrosive properties of the substance. No pathology indicative of systemic toxicity was seen in test or recovery animals.

At the end of the dosing period, hyperplasia of the mucous epithelium at the limiting ridge in the forestomach (4/6) and necrosis of the mucous epithelium in the glandular stomach ((2/6) were observed in males at 1000 mg/kg bw/day. Hyperplasia of mucous epithelium at the limiting ridge in the forestomach of females at 200 mg/kg bw/day (2/6) and 1000 mg/kg bw/day (4/6) was observed. These findings were considered to be test substance-related.

No test substance-related histopathology was seen in recovery males. Hyperplasia of mucous epithelium at the limiting ridge of the forestomach of recovery females at 200 mg/kg bw/day (3/6) and 1000 mg/kg bw/day (1/6) was observed.
Histopathological findings: neoplastic:
not examined
Other effects:
not examined

Effect levels

open allclose all
Key result
Dose descriptor:
NOAEL
Remarks:
local effects
Effect level:
40 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
gross pathology
histopathology: non-neoplastic
Key result
Dose descriptor:
NOAEL
Remarks:
systemic effects
Effect level:
>= 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse or toxicologically relevant systemic effects seen.
Remarks on result:
other: As concluded by the reviewer. A systemic NOAEL was not identified by the study authors.

Target system / organ toxicity

Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
200 mg/kg bw/day (nominal)
System:
gastrointestinal tract
Organ:
stomach
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
not specified

Applicant's summary and conclusion

Conclusions:
For the 28-day oral repeated dose toxicity study with 3-(trimethoxysilyl)propyl acrylate, conducted according to OECD Test Guideline 407 and in compliance with GLP, the systemic NOAEL is considered to be equal to or higher than 1000 mg/kg bw/day, based on the lack of effects indicating adverse toxicity or toxicological relevance. The local NOAEL is considered to be 40 mg/kg bw/day, based on the local pathology in the stomach (in females from 200 mg/kg bw/day, males at 1000 mg/kg bw/day). The local stomach effects are attributed to the corrosive properties of the test substance.