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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
reproductive toxicity, other
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Cross-reference
Reason / purpose for cross-reference:
reference to same study
Reference
Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study conducted in compliance with GLP regulations.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
Deviations:
no
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Wilmington, MA.
- Age at study initiation: 63-64 days
- Housing: singly in suspended wire-mesh bottomed stainless steel cages
- Diet (e.g. ad libitum): Purina Laboratory Chow
- Water: The test solutions were the only sources of water for the rats.
- Acclimation period: 3 weeks


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±2
- Humidity (%): 40-60
- Photoperiod (hrs dark / hrs light): 12/12


Route of administration:
oral: drinking water
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
Stability studies of butyl acrylate in water indicated some loss of the test material over a 4-day period (McCollister, et al, 1980). To compensate for the loss, the drinking water solutions containing butyl acrylate were prepared fresh daily, and at concentrations higher than those selected for test levels, as shown below:
Target Conc (w/v) Conc Prepared (w/v)
0.015% 0.02%
0.09% 0.12%
0.15% 0.22%

The solutions were prepared by adding 0.81 ml, 4.85 ml, or 8.9 ml of butyl acrylate to 3600 ml of fresh tap water in a one-gallon amber glass bottle in which a teflon rod was placed to facilitate mixing. Each bottle was mixed by rotation for approximately 1.5 hours.
McCollister, S. B. et al. Report No. HET K 23114- (6). The Dow Chemical Company, 1980.

Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The approximate actual concentrations for target levels of 0.015, 0.09 or 0.15 % butyl acrylate were 0.0162, 0.0997 or 0.1229 %, respectively.
Duration of treatment / exposure:
96-97 days
Frequency of treatment:
In an attempt to maximize ingestion of the test material, access to the drinking water was restricted to the time period from 4 p.m. to 8 a.m.
Remarks:
Doses / Concentrations:
0, 0.015, 0.09, 0.15 % in drinking water (males: 0, 12, 73, 84 mg/kg bw/d and females: 0, 15, 91, 111 mg/kg bw/d).
Basis:
nominal in water
No. of animals per sex per dose:
15
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale:
Based on the results of preliminary toxicity studies (McCollister, et al, 1980), levels of 0.015, 0.09 and 0.15% were selected as target concentrations.
McCollister, S. B. et al. Report No. HET K 23114- (6). The Dow Chemical Company, 1980.
Observations and examinations performed and frequency:
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily


BODY WEIGHT: Yes
- Time schedule for examinations: weekly


FOOD CONSUMPTION:
- Food consumption were recorded weekly on all rats throughout the study.


WATER INTAKE (if drinking water study): Yes
- Time schedule for examinations: once weekly


HAEMATOLOGY: Yes
- Time schedule for collection of blood: Males were evaluated after 78 days, and females, after 79 days on test. Blood was obtained from the tail vein.
- How many animals: 10 males and 10 females
- Parameters checked: Packed cell volume (PCV), erythrocyte count (RBC), hemoglobin (Hgb), and total and differential leukocyte counts (WBC).


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: After 63 days on test and at the termination of the experiment.
- Animals fasted: Yes, overnight
- How many animals: 5 males and 5 females after 63 days on test and rest all animals at the termination of the experiment.
- Parameters checked: blood urea nitrogen (BUN), serum glutamic pyruvic transaminase (SGPT) and serum alkaline phosphatase (AP).


URINALYSIS: Yes
- Time schedule for collection of urine: Males were evaluated after 78 days, and females, after 79 days on test.
- Parameters checked: urine samples were analyzed for specific gravity and pH; and semiquantitative evaluations were made of glucose, protein, ketones, bilirubin, blood and urobilinogen.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
After 96-97 days on test and following an overnight fast, male and female rats, respectively, were weighed, killed by decapitation and examined for gross pathologic alterations. Immediately after decapitation, the eyes were examined in situ by means of a glass slide technique and fluorescent light illumination. Any ocular abnormalities were recorded as part of the gross pathologic observations. Weights of the brain, heart, liver, kidneys and testes were recorded for each rat.
Statistics:
Data on food consumption, water consumption, body weights, hematology and clinical chemistry determinations, urinary specific gravity, and absolute (g) and relative (g/l00 g body weight) organ weights were evaluated by a one-way analysis of variance; differences between treated and control groups were examined using Dunnett's Test (Steel and Torrie, 1960). The level of significance for all cases was p<0.05. Body weight and food and water consumption values that were statistical outliers were identified using the sequential outlier test of Grubbs (1969).
Steel, and Torrie, McGraw-Hill Book Company, Inc., New York, New York, 1960. pp. 101-105 and 111-112.
Grubbs, F. E. Technometrics Vol. II, No. 1 (1969).
Clinical signs:
no effects observed
Description (incidence and severity):
No mortality and clinical signs were observed.
Mortality:
no mortality observed
Description (incidence):
No mortality and clinical signs were observed.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No treatment related significant effects were observed. Few cases of statistically significant differences between experimental and control means was not considered to be compound-related. The very slight decrease in average body weight gain of male rats receiving the highest concentration might be the result of ingestion of butyl acrylate in drinking water.
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Description (incidence and severity):
There were no differences betwen experimental and control groups.
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Description (incidence and severity):
Statistically significant decreases in water intake occurred at a number of the weekly measurements. All levels were affected, and the magnitude of the decreases were generally dose related. The approximate doses received from the drinking water on a mg butyl acrylate/kg body weight/day basis were calculated for each week using the overall mean actual concentrations, overall mean water consumption values, and weekly midpoint body weights for each group. The average doses received from target concentrations of 0.015, 0.09 and 0.15% were 12, 73, and 84 mg/kg/day, respectively, for males, and 15, 91, and 111 mg/kg/day, respectively, for females.
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Description (incidence and severity):
No treatment related effects were observed.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
Clinical chemistry determinations revealed no statistically significant differences between treated and control groups.
Urinalysis findings:
no effects observed
Description (incidence and severity):
Results of urinalyses were similar for experimental and control rats.
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
Few statistically significant differences occurred between treated and control groups of rats. These statistical deviations were mostly limited to increases in absolute and relative kidney weights. In the groups of males, the increases occurred at the 0.09 and 0.015% levels, but not at the highest concentration. The females showed statistically significant increases in absolute kidney weights at the 0.015 and 0.15% levels, and in relative kidney weights at all 3 levels. These statistically significant differences were not considered to be compound related due to non dose-dependent, no histo-pathological changes, and no effects during repeated dose gavage study with 150 mg/kg bw butyl acrylate for 96-97 days. The remaining statistically significant differences in mean organ weights were random and not considered to be associated with treatment.
Gross pathological findings:
no effects observed
Description (incidence and severity):
Findings were similar for control and experimental rats.
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
Findings were similar for control and experimental rats. Examination of the kidneys from experimental rats revealed no differences from controls to account for the increased weight of that organ.
Histopathological findings: neoplastic:
no effects observed
Key result
Dose descriptor:
NOAEL
Effect level:
84 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: high dose
Key result
Dose descriptor:
NOAEL
Effect level:
111 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: high dose
Critical effects observed:
no

The results reported herein indicates that butyl acrylate produced no definitive evidence of toxicity when administered to rats at a target concentration (0.15%) approaching the maximum attainable in drinking water for 96-97 days. A trend toward a decrease in body weight gain of male rats was judged to be the result of ingestion of this high dose level. Water consumption was decreased at all three levels of treatment (0.015, 0.09 and 0.15%), probably as a result of the unpalatability of the test substance in the drinking water. Thus, the results of this study indicate that rats maintained for 96-97 days on drinking water containing maximal soluble quantities of butyl acrylate had only minimal indications of toxicity.

Conclusions:
The NOAEL for rats orally exposed to Butyl Acrylate is 84 and 111 mg/kg body weight, for males and females respectively (the highest dose tested in each sex).
Executive summary:

A 90-day subchronic study was conducted in rats to assess the toxicity of Butyl Acrylate. The test mixture was administered in drinking water at a dose of0, 0.015, 0.09, and 0.15 % in drinking water (males: 0, 12, 73, 84 mg/kg bw/d and females: 0, 15, 91, 111 mg/kg bw/d) 7 days per week for a period of 13 weeks. The control group received standard drinking water. Observations were made as to the nature, onset, severity, and duration of toxicological signs. No mortality or overt clinical signs were observed in either sex at any dose. A trend toward a decrease in body weight gain of male rats was judged to be the result of ingestion of the high dose (0.15%). Water consumption was decreased at all three levels of treatment (0.015, 0.09 and 0.15%), probably as a result of the unpalatability of the test substance in the drinking water.Post mortem examinations revealed no abnormalities. Based on the data recorded in this study, the NOAEL for rats orally exposed to Butyl Acrylate is 84 and 111 mg/kg body weight, for males and females respectively (the highest dose tested in each sex).

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
Butyl and Methyl Acrylate: 13-week oral toxicity studies in CDF Fischer 344 rats.
Author:
Gorzinski SJ et al.
Year:
1982
Bibliographic source:
Toxicologist. 2: 33
Reference Type:
review article or handbook
Title:
No information
Author:
Gorzinski S.J. et al.
Year:
1993
Bibliographic source:
Toxicologist. 2: 33, cited in Health Effects Assessment of Basic Acrylates, Ed.: Tyler, Murphy, Hunt, CRC-Press

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
other: OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Deviations:
no
Principles of method if other than guideline:
Groups of rats (15 male and 15 female per dose and control group) were exposed to butyl acrylate over a period of 13 weeks at concentrations (analytically measured) of 0.015, 0.09 or 0.15 % in drinking water. Animals were observed for clinical signs, body weight gain, hematological and biochemical parameters. Necropsies were performed on all animals and weight of the testes were measured. Tissues, including
GLP compliance:
not specified
Limit test:
no

Test material

Constituent 1
Reference substance name:
n-Butyl acrylate
IUPAC Name:
n-Butyl acrylate
Details on test material:
- Name of test material (as cited in study report): n-Butyl acrylate
- Analytical purity: no data

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Wilmington, MA.
- Age at study initiation: 63-64 days
- Housing: singly in suspended wire-mesh bottomed stainless steel cages
- Diet (e.g. ad libitum): Purina Laboratory Chow
- Water: The test solutions were the only sources of water for the rats.
- Acclimation period: 3 weeks
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±2
- Humidity (%): 40-60
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: drinking water
Vehicle:
unchanged (no vehicle)
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
Stability studies of butyl acrylate in water indicated some loss of the test material over a 4-day period (McCollister, et al, 1980). To compensate for the loss, the drinking water solutions containing butyl acrylate were prepared fresh daily, and at concentrations higher than those selected for test levels, as shown below:

Target Conc (w/v)
0.015%
0.09%
0.15%

Conc Prepared (w/v)
0.02%
0.12%
0.22%

The solutions were prepared by adding 0.81 ml, 4.85 ml, or 8.9 ml of butyl acrylate to 3600 ml of fresh tap water in a one-gallon amber glass bottle in which a teflon rod was placed to facilitate mixing. Each bottle was mixed by rotation for approximately 1.5 hours.
McCollister, S. B. et al. Report No. HET K 23114- (6). The Dow Chemical Company, 1980.
Details on mating procedure:
not applicable
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The approximate actual concentrations for target levels of 0.015, 0.09 or 0.15 % butyl acrylate were 0.0162, 0.0997 or 0.1229 %, respectively.
Duration of treatment / exposure:
96-97 days
Frequency of treatment:
In an attempt to maximize ingestion of the test material, access to the drinking water was restricted to the time period from 4 p.m. to 8 a.m.
Doses / concentrationsopen allclose all
Dose / conc.:
12 mg/kg bw/day (nominal)
Remarks:
0.015 % in drinking water; males
Dose / conc.:
73 mg/kg bw/day (nominal)
Remarks:
0.09% in drinking water; males
Dose / conc.:
84 mg/kg bw/day (nominal)
Remarks:
0.15% in drinking water; males
Dose / conc.:
15 mg/kg bw/day (nominal)
Remarks:
0.015% in drinking water; females
Dose / conc.:
91 mg/kg bw/day (nominal)
Remarks:
0.09% in drinking water; females
Dose / conc.:
111 mg/kg bw/day (nominal)
Remarks:
0.15% in drinking water; females
No. of animals per sex per dose:
15
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale:
Based on the results of preliminary toxicity studies (McCollister, et al, 1980), levels of 0.015, 0.09 and 0.15% were selected as target concentrations.

McCollister, S. B. et al. Report No. HET K 23114- (6). The Dow Chemical Company, 1980.

Results and discussion

Results: P0 (first parental generation)

Effect levels (P0)

open allclose all
Key result
Dose descriptor:
NOAEL
Effect level:
111 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: no effects on reproductive organs
Key result
Dose descriptor:
NOAEL
Effect level:
84 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: no effect on reproductive organs

Results: F1 generation

Effect levels (F1)

Remarks on result:
not measured/tested

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

Data on reproductive organ toxicity were derived from a 90-day oral drinking water exposure to n-butyl acrylate. Respective results from animals exposed to the highest dose level of 84 mg/kg and 11 mg/kg for males and females respectively did not produce evidence of any impairment in the reproductive organs evaluated from both sexes in this study.

Applicant's summary and conclusion

Executive summary:

In a 13 week-study, F344-rats (15 animals per sex and dose) received n-butyl acrylate via drinking water in concentrations of 0, 0.015, 0.09 and 0.15 % (0, 12, 73, 84 mg/kg body weight per day for males and 0, 15, 91, 111 mg/kg body weight per day for females). A satellite group (5 male and 5 female rats) was given 150 mg/kg bw butyl acrylate (in corn oil) via gavage 5 days a week for 13 weeks. The only effects reported were a slight reduction in water consumption, which occurred in all dose groups, and a decrease in weight gain for male rats in the highest dose group. No abnormal histopathology findings in either male or female reproductive organs were reported.