acrylic acid, 3-(trimethoxysilyl)propyl ester

Endpoint summary

Description of key information

In the key 28-day oral repeated dose toxicity study (CAS No. 4369-14-6, EC No. 419-560-6), conducted according to OECD Test Guideline 407 and in compliance with GLP (reliability score 2, Hita Research Laboratories, 1994b), the NOAEL for local effects was 40 mg/kg bw/day based on local effects seen in the stomach at higher doses; a NOAEL for systemic toxicity was not concluded in the study report, but it is the reviewer's opinion that it is at least 1000 mg/kg bw/day, the highest dose tested. The local stomach effects are attributed to the corrosive properties of the registered substance.

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:

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

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

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

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

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

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.

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

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.

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

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.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

Reliability 2, guideline study

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

3-(Trimethoxysilyl)propyl acrylate has been evaluated in the key 28-day oral repeated dose toxicity study, conducted according to OECD Test Guideline 407 and in compliance with GLP (reliability score 2, Hita Research Laboratories, 1994b), 6 male and 6 female Crj: CD(SD) rats were subject to daily oral (gavage, olive oil vehicle) administration of 0, 8, 40, 200 and 1000 mg/kg bw/day for 28 days. Additional 6 male and 6 female animals were included in the control, 200 and 1000 mg/kg bw/day groups, which were maintained without treatment for 14 days after the last test substance administration on day 28 in order to investigate the reversibility of effects.

 

No deaths occurred throughout the study period and no adverse effects were observed on body weight, food consumption, haematological examinations, urinalysis, and organ weights.

 

Salivation was observed in nearly all animals from both sexes from 200 mg/kg bw/day, decreased spontaneous locomotion, decreased respiratory rate and ptosis in males at 1000 mg/kg bw/day and mark of reddish tear in both sexes at 1000 mg/kg bw/day were observed and considered to be test substance-related. Salivation seen at the lower doses and in the vehicle control group was not considered to be test substance-related because it occurred sporadically in 2 to 4 animals per group.

 

Test substance-related gross pathology was identified locally in the stomach of treated males and females at 1000 mg/kg bw/day. At the end of the dosing period, a blackish region of mucosa in the glandular stomach (2/6) was observed in males at 1000 mg/kg bw/day. Scab formation was observed in males at 8 mg/kg bw/day (1/6) and at 40 mg/kg bw/day (1/6). An elevated region of mucosa in the forestomach (1/6) was observed in females at 1000 mg/kg bw/day. The effects in both sexes were considered to be test substance-related. At the end of the recovery period, no test substance-related gross pathology was observed in recovery males, with scab formation (1/6) in one recovery female at 1000 mg/kg bw/day. No gross pathology indicative of systemic toxicity was seen in test or recovery animals.

 

Test substance-related histopathology was identified locally in the stomach of treated males and females at 1000 mg/kg bw/day. At the end of the dosing period, hyperplasia of the mucous epithelium at the limiting ridge in the forestomach (4/6) and necrosis of mucous epithelium in the glandular stomach (2/6) were observed in males at 1000 mg/kg bw/day. Hyperplasia of the mucous epithelium at the limiting ridge in the forestomach of females at 200 mg/kg bw/day (2/6) and at 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, while hyperplasia of the mucous epithelium at the limiting ridge in the forestomach in recovery females at 200 mg/kg bw/day (3/6) and 1000 mg/kg bw/day (1/6) was still observed. No histopathology indicative of systemic toxicity was seen in test or recovery animals.

In the study report, a systemic NOAEL was not identified, but is considered by the reviewer to be equal to or higher than 1000 mg/kg bw/day, based on the lack of effects indicating adverse toxicity or toxicological relevance systemically. The local NOAEL is considered to be 40 mg/kg bw/day, based on the local histopathology in the stomach (in females from 200 mg/kg bw/day, males at 1000 mg/kg bw/day), with gross stomach pathology in both sexes at 1000 mg/kg bw/day. These local effects are attributed to the corrosive properties of the test substance.

Justification for classification or non-classification

Based on the findings in the 28-day oral study, 3-(trimethoxysilyl)propyl acrylate does not require classification for specific target organ toxicity following repeated exposure according to Regulation (EC) No. 1272/2008, as the observed effects in the classifiable range (30 to >= 300 mg/kg bw/day, for a subacute study) were not indicative of functional impairment of organs (significant toxic effects) as outlined in Section 3.9.2.7.3 of Regulation (EC) No. 1272/2008, but rather local effects in the stomach due to the corrosive nature of the registered substance.