Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

Oral NOAEL 84 mg/kg (male) and 111 mg/kg (female) Rat; equivalent or similar to OECD Guideline 408 (Read-across to N-butyl Acrylate)

Inhalation NOAEC 2.86 mg/L (male/female) Rat; equivalent or similar to OECD Guideline 413 (Read-across to N-butyl Acrylate)

Link to relevant study records

Referenceopen allclose all

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
Reason / purpose for cross-reference:
reference to same study
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
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 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.
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.
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
Remarks on result:
not measured/tested
Reproductive effects observed:
not specified

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.

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.

Endpoint:
reproductive toxicity, other
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Justification for type of information:
See attached for Read-Across Justification
Reason / purpose for cross-reference:
read-across source
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 effects on reproductive organs
Remarks on result:
not measured/tested
Reproductive effects observed:
not specified

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.

Executive summary:

N-hexyl acrylate was evaluated for its potential toxicity to reproduction based on read-across to data of a structurally similar substance, N-butyl Acrylate. This read-across approach is based on the hypothesis that the hydrolysis of both substances to acrylic acid and the respective alcohols would show similar toxicity patterns. The effect of the parent compound from the target substance is also predicted based on the worst case approach as data indicate the parent structure of the source substance would be expected to have a higher electrophilic capacity. 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.

Endpoint:
reproductive toxicity, other
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
1978
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Reason / purpose for cross-reference:
reference to same study
Qualifier:
equivalent or similar to guideline
Guideline:
other: OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
Principles of method if other than guideline:
Group of rats (20 male and 20 female per dose and control group) were exposed to butyl acrylate vapors (6 h/ day) over a period of 13 weeks at concentrations(analytically measured) of 21, 108, 211, and 546 ppm. 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 seminal vesicles, prostate, epididymis/uterus, testes and ovary were examined histologically from all animals.
GLP compliance:
no
Remarks:
Study conducted prior to GLP
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: SPF breed supplied, WIGA, Sulzfeld
- Age at study initiation: 42 days
- Weight at study initiation: males-159 g and females-130 g
- Housing: 2-3 rats per cage
- Diet (e.g. ad libitum): Altromin-R supplied by Altrogge, Lage/Lippe
- Water (e.g. ad libitum): tap water
Route of administration:
inhalation: vapour
Type of inhalation exposure (if applicable):
whole body
Vehicle:
unchanged (no vehicle)
Details on exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
By means of a continuous infusion pump, the liquid product was metered onto a heated vaporizer (temperature about 80 °C) at a constant rate and vaporized there. A stream of supply air measured by means of a rotameter took up the vapors. This vapor-air mixture, after passing through a mixing device, was introduced into an inhalation chamber with a volume of 200 liters.
TEST ATMOSPHERE
- Brief description of analytical method used: The n-butyl acrylate air mixture was measured continuously using a flame ionization detector (FID). Apparatus used was FID total hydrocarbons analyzer (CARLO ERBA, mod. 370).
- Samples taken from breathing zone: yes. Sampling was carried out by means of a diaphragm pump which continuously passes the n-butyl acrylate air mixture to the FID. A second diaphragm pump continuously sweeped the sample tubes that were not needed for measurement in the chamber up to the pneumatic valve. The duration of measurement was 10 minutes per chamber, and the sweeping time 7 minutes (measuring cycle).
Details on mating procedure:
not applciable
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The analytical measurements were 21, 108, 221 and 546 ppm, respectively.
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
6 hr/day, 5 dy/week for 13 weeks
Dose / conc.:
0 ppm (analytical)
Dose / conc.:
21 ppm (analytical)
Remarks:
Corresponds to 0.11 mg/L
Dose / conc.:
108 ppm (analytical)
Remarks:
Corresponds to 0.57 mg/L
Dose / conc.:
211 ppm (analytical)
Remarks:
Corresponds to 1.11 mg/L
Dose / conc.:
546 ppm (analytical)
Remarks:
Corresponds to 2.86 mg/L
No. of animals per sex per dose:
20
Control animals:
yes, sham-exposed
Key result
Dose descriptor:
NOAEC
Effect level:
2.86 mg/L air (analytical)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no effects on reproductive organs
Remarks on result:
not measured/tested
Reproductive effects observed:
not specified

Data on reproductive organ toxicity were derived from a 90-day inhalation study. Respective results from animals exposed to the highest dose level of 546 ppm (2.86 mg/L) did not produce evidence of any impairment in the reproductive organs evaluated from both sexes in this study.

Executive summary:

In a sub-chronic study, Sprague-Dawley rats (20 animals per sex and dose) were exposed to butyl acrylate vapours 6 hrs/day, 5 dys/week for 13 weeks. Mortality and treatment-related effects were reported in the highest dose group (546 ppm). Local effects were also observed such as histological changes in the nasal mucosa due to the irritating nature of the test substance. A NOAEC of 570 mg/m3 (108 ppm) was established based on systemic effects. The respective LOAEC of 1100 mg/m3 (211 ppm) was based on reduced body weight and clinical biochemistry changes (females). No effects on reproductive organs in either sex were reported up to the highest dose tested in this study.

Endpoint:
reproductive toxicity, other
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Justification for type of information:
See attached for Read-Across Justification
Reason / purpose for cross-reference:
read-across source
Key result
Dose descriptor:
NOAEC
Effect level:
2.86 mg/L air (analytical)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No effects on reproductive organs
Remarks on result:
not measured/tested
Reproductive effects observed:
not specified

Data on reproductive organ toxicity were derived from a 90-day inhalation study. Respective results from animals exposed to the highest dose level of 546 ppm (2.86 mg/L) did not produce evidence of any impairment in the reproductive organs evaluated from both sexes in this study.

Executive summary:

N-hexyl acrylate was evaluated for its potential toxicity to reproduction based on read-across to data of a structurally similar substance, N-butyl Acrylate. This read-across approach is based on the hypothesis that the hydrolysis of both substances to acrylic acid and the respective alcohols would show similar toxicity patterns. The effect of the parent compound from the target substance is also predicted based on the worst case approach as data indicate the parent structure of the source substance would be expected to have a higher electrophilic capacity. In a sub-chronic study, Sprague-Dawley rats (20 animals per sex and dose) were exposed to butyl acrylate vapours 6 hrs/day, 5 dys/week for 13 weeks. Mortality and treatment-related effects were reported in the highest dose group (546 ppm). Local effects were also observed such as histological changes in the nasal mucosa due to the irritating nature of the test substance. A NOAEC of 570 mg/m3 (108 ppm) was established based on systemic effects. The respective LOAEC of 1100 mg/m3 (211 ppm) was based on reduced body weight and clinical biochemistry changes (females). No effects on reproductive organs in either sex were reported up to the highest dose tested in this study.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
84 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Effect on fertility: via inhalation route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
2 860 mg/m³
Study duration:
subchronic
Species:
rat
Additional information

Reproductive toxicity: Oral

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.

Reproductive toxicity: Inhalation

In a sub-chronic study, Sprague-Dawley rats (20 animals per sex and dose) were exposed to butyl acrylate vapours 6 hrs/day, 5 dys/week for 13 weeks. Mortality and treatment-related effects were reported in the highest dose group (546 ppm). Local effects were also observed such as histological changes in the nasal mucosa due to the irritating nature of the test substance. A NOAEC of 570 mg/m3 (108 ppm) was established based on systemic effects. The respective LOAEC of 1100 mg/m3 (211 ppm) was based on reduced body weight and clinical biochemistry changes (females). No effects on reproductive organs in either sex were reported up to the highest dose tested in this study.

Effects on developmental toxicity

Description of key information

Inhalation NOAEC 0.52 mg/L Rat; based on maternal toxicity and fetal body weight

Inhalation NOAEC 0.13 mg/L Rat; based on maternal toxicity and fetal resorptions; according to the Guidelines for reproduction studies for safety evaluation of drugs for human use, FDA, Jan. 1966 and Guidance on reproduction studies from the Association of the British Pharmaceutical Industry, 1975.

Link to relevant study records

Referenceopen allclose all

Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
See attached for Read-Across Justification
Reason / purpose for cross-reference:
read-across source
Clinical signs:
not specified
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
During the entire exposure period, maternal weight gain was signifciantly reduced at 200 ppm and above compared to the control group. Absolute weight gains (expressed as the day 21 body weight minus the gravid uterus weight and minus the day 6 body weight) were reduced in a dose-rependent manner in all exposure groups.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Decreases in food consumption was observed during the first half of the study for the females in the 100 ppm dose group and throught the exposure period at 200 and 300 ppm. The maximum decrease was 40-50% at the highest concentration.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not examined
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in pregnancy duration:
not examined
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not examined
Changes in number of pregnant:
no effects observed
Key result
Dose descriptor:
LOAEC
Effect level:
0.52 mg/L air (nominal)
Based on:
test mat.
Basis for effect level:
body weight and weight gain
Fetal body weight changes:
effects observed, treatment-related
Description (incidence and severity):
Fetal body weight was significantly reduced at 200 ppm (for both sexes combined and males) and at 300 ppm (both sexes combined, males and females). These decreases amounted to 7-8 % (p<0.05) and 26-28 % (p<0.01) of control values for the 200 and 300 ppm groups, respectively.
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
not specified
Changes in postnatal survival:
no effects observed
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Description (incidence and severity):
A few sporadic malformations were seen in the 300 ppm and the control group. The incidence of indivi dual skeletal variations (mainly incomplete ossification of sternebrae and of vertebral centra) was similar in the control and treated groups.
Visceral malformations:
no effects observed
Key result
Dose descriptor:
NOAEC
Effect level:
0.52 mg/L air (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
fetal/pup body weight changes
Key result
Dose descriptor:
NOAEC
Effect level:
1.57 mg/L air (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: teratogenicity
Remarks on result:
other: highest dose tested
Developmental effects observed:
not specified
Executive summary:

N-hexyl acrylate was evaluated for its developmental toxicity potential based on read-across to data of a structurally similar substance, N-butyl Acrylate. This read-across approach is based on the hypothesis that the hydrolysis of both substances to acrylic acid and the respective alcohols would show similar toxicity patterns. The effect of the parent compound from the target substance is also predicted based on the worst case approach as data indicate the parent structure of the source substance would be expected to have a higher electrophilic capacity. In a developmental toxicity study, pregnant Sprague-Dawley female rats (20-29 per dose) were exposed to the compound 6h/day on days 6 through 20 of gestation. Control animals were exposed concurrently to filtered room air. The test concentrations of n-butyl acrylate were 100, 200, and 300 ppm (corresponding to approx. 0.52, 1.05, and 1.57 mg/L). Significant decreases in maternal body weight gain were observed at 200 ppm and 300 ppm, and decreased absolute weight gain were observed in all dose groups through the entire exposure period. Decreased fetal body weight was observed at 200 ppm (7-8%) and 300 ppm (26-28%) in the presence of significant maternal toxicity. No significant increases in malformations was observed in n-butyl acrylate exposed fetuses.

Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
See attached for Read-Across Justification
Reason / purpose for cross-reference:
read-across source
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Distinct discharge from the eyes and noses and ruffled fur was observed in the 135 ppm dose groups, the severity of this effect was increased at 250 ppm.
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Body weight gain was significantly decreased in the 135 and 250 ppm dose groups during the period of treatment. Following the end of exposure (GD 16 - 20) body weight gain was similar to that of the control group.
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not examined
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
not examined
Number of abortions:
no effects observed
Pre- and post-implantation loss:
effects observed, treatment-related
Description (incidence and severity):
The number of corpora lutea and the number of implantations did not show any differences between the individual groups. However, the perecentage of live implantations per pregnant animal was decreased in the 135 and 250 ppm dose groups.
Total litter losses by resorption:
no effects observed
Early or late resorptions:
effects observed, treatment-related
Description (incidence and severity):
A significant increase in the percentage of dead resorptions was observed in the 135 and 250 ppm dose groups.
Dead fetuses:
not examined
Changes in pregnancy duration:
not examined
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not examined
Changes in number of pregnant:
no effects observed
Key result
Dose descriptor:
NOAEC
Effect level:
0.13 mg/L air (nominal)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity body weight, irritation to eyes and nose
Fetal body weight changes:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed
Reduction in number of live offspring:
not examined
Changes in sex ratio:
not examined
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
not examined
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed
Key result
Dose descriptor:
NOAEC
Effect level:
0.13 mg/L air (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: embryotoxicity resorptions
Key result
Dose descriptor:
NOAEC
Effect level:
1.31 mg/L air (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: teratogenicity
Key result
Abnormalities:
not specified
Key result
Developmental effects observed:
not specified

Maternal body weight development (mean values ± standard deviation):

 

Concentration [ppm]

Maternal body weight GD 0 [g]

Maternal body weight GD 20 [g]

Maternal body weight gain GD 0-20 [g]

0

209.38 ± 11.83

354.01 ± 36.66

144.64 ± 33.08

25

213.96 ± 13.94

359.62 ± 36.81

145.66 ± 29.87

135

213.68 ± 9.30

335.54 ± 43.00

121.87 ± 37.62*

250

218.64 ± 16.19

318.11 ± 42.79**

99.47± 33.68**

*  p < 0.05

** p < 0.01

Reproductive parameters:

 

Conc.  (ppm)   

no. pregnant/  total animals 

live fetuses/ animal 

resorptions (%)

weight of fetuses (g)

0

22/30

11.5 ± 5.34     

11.6

3.85 ± 0.41

25

23/30

10.6 ± 4.94     

13.8

4.08 ± 0.39

135

18/30

8.8 ± 5.14        

23.6*

4.09 ± 0.23

250

19/30

8.4 ± 5.68        

31.6*

4.08 ± 0.47

*: p<0.05

Conc.  (ppm)

% fetuses per litter with anomalies

% litters with fetuses showing anomalies

% fetuses per litter with variations/ retardations

% litters with fetuses showing variations/ retardations

0

2.7

23.8

19.7

81.0

25

0.9

9.1

11.2

59.1

135

1.9

18.8

10.2

43.8

250

0

0

8.2

43.8

 

0 ppm

25 ppm

135 ppm

250 ppm

Skeletal findings

Anomalies:

- Cleft vertebral centra

7/170

2/162

4/105

0/107

Variations/retardations:

- incomplete ossification of skull bone

0/170

0/162

1/105

0/107

- aplasia of sternebrae

16/170

11/162

3/105

3/107

-incomplete ossification of sternebrae

30/170

18/162

14/105

9/107

- asymmetric sternebrae

4/170

1/162

0/105

0/107

-accessory rib, bilateral

2/170

3/162

0/105

0/107

-accessory rib, bilateral and rudimentary

1/170

0/162

0/105

0/107

-accessory rib, unilateral and rudimentary

1/170

0/162

0/105

0/107

-general incomplete ossification of bones

1/170

2/162

1/105

1/107

Organ findings

Variations/retardations:

-dilatation of pelvis, unilateral

2/82

0/81

1/54

0/53

Units given as number found/number examined

Executive summary:

N-hexyl acrylate was evaluated for its developmental toxicity potential based on read-across to data of a structurally similar substance, N-butyl Acrylate. This read-across approach is based on the hypothesis that the hydrolysis of both substances to acrylic acid and the respective alcohols would show similar toxicity patterns. The effect of the parent compound from the target substance is also predicted based on the worst case approach as data indicate the parent structure of the source substance would be expected to have a higher electrophilic capacity. In a developmental toxicity study, pregnant Sprague-Dawley female rats (30 per dose) were exposed to the n-butyl acrylate 6h/day on days 6 through 15 of gestation. Control animals were exposed concurrently to filtered room air. The test concentrations of n-butyl acrylate were 25, 135 and 250 ppm. Significant decreases in maternal body weight gain were observed at 135 and 250 ppm dose groups through the entire exposure period. The number of corpora lutea and the number of implantations did not show any differences between the individual groups. However, the percentage of live implantations per pregnant animal was decreased in the 135 and 250 ppm dose groups. No significant increases in malformations was observed in n-butyl acrylate exposed fetuses.

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
14 Feb 1979 - 13 Mar 1979
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Qualifier:
according to guideline
Guideline:
other: Guidelines for reproduction studies for safety evaluation of drugs for human use, FDA, Jan. 1966 and Guidance on reproduction studies from the Association of the British Pharmaceutical Industry, 1975.
GLP compliance:
no
Remarks:
Study conducted prior to GLP
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Iffa Credo, Lyon, France
- Body weight at study initiation:
The mean body weight ± SD in dose groups 0, 25, 135 and 250 ppm were 209±12, 214±14, 214±9 and 219±16, respectively.
- Age at study initiation: 9-11 week
- Diet (e.g. ad libitum): Herilan Mrh-Zucht, H. Eggermann KG, Rinteln.
- Water: ad libitum


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±2
- Humidity (%): 55±5
- Photoperiod (hrs dark / hrs light):12/12


Route of administration:
inhalation: vapour
Type of inhalation exposure (if applicable):
whole body
Vehicle:
unchanged (no vehicle)
Details on exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
By means of a continuous infusion apparatus (UNITA I, B. Braun, Melsungen, Federal Republic Germany) constant amounts of the liquid product were supplied to a heated (about 80°C) evaporator. The n-butyl acrylate vapors were diluted with dust-free, conditioned fresh air and passed through 200 L inhalation chambers (all-glass construction with steel frame) under dynamic airflow conditions at a flow rate of 20 changes of air per hour (4000 L/h; 200 L chamber). A mean temperature of 24.5°C and a mean relative humidity of 53% were measured during exposure.


TEST ATMOSPHERE
- Brief description of analytical method used: The n-butyl acrylate test atmosphere concentrations were monitored analytically by means of a total
hydrocarbon analyzer (R 5 of RATFISCH, Munich). The total hydrocarbon analyzer was calibrated using an infrared analyzer Miran I (WILKS) calibrated with standards of known concentrations of n-butyl acrylate.
- Samples taken from breathing zone: yes


Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The analytical concentrations (Mean ± SD) of the dose groups 25, 135 and 250 ppm were 25 ± 1, 137 ± 4 and 251 ± 3 ppm, respectively.
Details on mating procedure:
Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
Duration of treatment / exposure:
days 6-15 of gestation
Frequency of treatment:
6 hours per day
Duration of test:
21 days
Dose / conc.:
0 ppm (nominal)
Dose / conc.:
135 ppm (nominal)
Dose / conc.:
250 ppm (nominal)
No. of animals per sex per dose:
30
Control animals:
yes, sham-exposed
Maternal examinations:
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily


BODY WEIGHT: Yes
- Time schedule for examinations: day on which sperm had been detected (day 0) and on the 6th, 16th and 20th days post coitum.



POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on the 20th day post coitum.



Ovaries and uterine content:
Examinations included:
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of resorptions: Yes
Fetal examinations:
The weights and the length of fetuses were determined. After fixation in Bouin's solution, 1/3 of the fetuses were examined for organ changes according to the method of Wilson and Warkany (1965), and after staining of the skeleton (Dawson, 1926) 2/3 of the fetuses were investigated for skeletal changes.
Wilson, J.G. and Warkany, J. (1965). Teratology: Principles and Techniques. The University of Chicago Press, Chicago and London.
Dawson, A.B. (1926). Stain Technol. 1:123.
Statistics:
A trend analysis based on the generalization of the t-test according to Williams (1971, 1972) was carried out for the variables of maternal body weight and body weight gain, fetal weight and length, and placental weight in each case. The U-test (Krauth, 1971; Stucky and Vollmar, 1976) was carried out for the parameters of implantations per pregnant animal, live and dead embryos as percent per pregnant animal, and anomalies, variations and retardations as percent of live fetuses per litter.
Williams, D.A. (1971). Biometrics 27:103-117.
Williams, D.A. (1972). Biometrics 28:519-531.
Krauth, J. (1971). Ann. Math. Statist. 42:1949-1956.
Stucky, W. and Vollmar, J. (1976). J. Statist. Comput. Simul. 5:73-81.
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Distinct discharge from the eyes and noses and ruffled fur was observed in the 135 ppm dose groups, the severity of this effect was increased at 250 ppm.
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Body weight gain was significantly decreased in the 135 and 250 ppm dose groups during the period of treatment. Following the end of exposure (GD 16 - 20) body weight gain was similar to that of the control group.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not examined
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Number of abortions:
no effects observed
Description (incidence and severity):
The number of corpora lutea and the number of implantations did not show any differences between the individual groups. However, the perecentage of live implantations per pregnant animal was decreased in the 135 and 250 ppm dose groups.
Total litter losses by resorption:
no effects observed
Early or late resorptions:
effects observed, treatment-related
Description (incidence and severity):
A significant increase in the percentage of dead resorptions was observed in the 135 and 250 ppm dose groups.
Dead fetuses:
not examined
Changes in pregnancy duration:
not examined
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not examined
Changes in number of pregnant:
no effects observed
Key result
Dose descriptor:
NOAEC
Effect level:
ca. 0.13 mg/L air (nominal)
Basis for effect level:
other: maternal toxicity
Fetal body weight changes:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed
Reduction in number of live offspring:
not examined
Changes in sex ratio:
not examined
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
not examined
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed
Key result
Dose descriptor:
NOAEC
Effect level:
ca. 0.13 mg/L air (nominal)
Basis for effect level:
other: embryotoxicity
Key result
Dose descriptor:
NOAEC
Effect level:
ca. 1.31 mg/L air (nominal)
Basis for effect level:
other: teratogenicity
Abnormalities:
not specified
Developmental effects observed:
not specified

Maternal body weight development (mean values ± standard deviation):

 

Concentration [ppm]

Maternal body weight GD 0 [g]

Maternal body weight GD 20 [g]

Maternal body weight gain GD 0-20 [g]

0

209.38 ± 11.83

354.01 ± 36.66

144.64 ± 33.08

25

213.96 ± 13.94

359.62 ± 36.81

145.66 ± 29.87

135

213.68 ± 9.30

335.54 ± 43.00

121.87 ± 37.62*

250

218.64 ± 16.19

318.11 ± 42.79**

99.47± 33.68**

*  p < 0.05

** p < 0.01

Reproductive parameters:

 

Conc.  (ppm)   

no. pregnant/  total animals 

live fetuses/ animal 

resorptions (%)

weight of fetuses (g)

0

22/30

11.5 ± 5.34     

11.6

3.85 ± 0.41

25

23/30

10.6 ± 4.94     

13.8

4.08 ± 0.39

135

18/30

8.8 ± 5.14        

23.6*

4.09 ± 0.23

250

19/30

8.4 ± 5.68        

31.6*

4.08 ± 0.47

*: p<0.05

Conc.  (ppm)

% fetuses per litter with anomalies

% litters with fetuses showing anomalies

% fetuses per litter with variations/ retardations

% litters with fetuses showing variations/ retardations

0

2.7

23.8

19.7

81.0

25

0.9

9.1

11.2

59.1

135

1.9

18.8

10.2

43.8

250

0

0

8.2

43.8

 

0 ppm

25 ppm

135 ppm

250 ppm

Skeletal findings

Anomalies:

- Cleft vertebral centra

7/170

2/162

4/105

0/107

Variations/retardations:

- incomplete ossification of skull bone

0/170

0/162

1/105

0/107

- aplasia of sternebrae

16/170

11/162

3/105

3/107

-incomplete ossification of sternebrae

30/170

18/162

14/105

9/107

- asymmetric sternebrae

4/170

1/162

0/105

0/107

-accessory rib, bilateral

2/170

3/162

0/105

0/107

-accessory rib, bilateral and rudimentary

1/170

0/162

0/105

0/107

-accessory rib, unilateral and rudimentary

1/170

0/162

0/105

0/107

-general incomplete ossification of bones

1/170

2/162

1/105

1/107

Organ findings

Variations/retardations:

-dilatation of pelvis, unilateral

2/82

0/81

1/54

0/53

Units given as number found/number examined

 

Executive summary:

In a developmental toxicity study, pregnant Sprague-Dawley female rats (30 per dose) were exposed to the n-butyl acrylate 6h/day on days 6 through 15 of gestation. Control animals were exposed concurrently to filtered room air. The test concentrations of n-butyl acrylate were 25, 135 and 250 ppm. Significant decreases in maternal body weight gain were observed at 135 and 250 ppm dose groups through the entire exposure period. The number of corpora lutea and the number of implantations did not show any differences between the individual groups. However, the percentage of live implantations per pregnant animal was decreased in the 135 and 250 ppm dose groups. No significant increases in malformations was observed in n-butyl acrylate exposed fetuses.

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Principles of method if other than guideline:
Groups of 20-29 bred female rats (17-25 pregnant) were exposed to the compound 6h/day on days 6 through 20 of gestation. Control animals were exposed concurrently to filtered room air. The test concentrations of n-butyl acrylate were 100, 200, and 300 ppm (corresponding to approx. 0.52, 1.05, and 1.57 mg/L)*.
* Calculation of concentrations (mg/L) based on Derelanko MJ (2000). Toxicologist's Pocket Handbook, CRC Press, conversion table, p. 57
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: IFFA CREDO Breeding Laboratories (Saint-Germain-sur-l' Arbresle, France)
- Age at study initiation: Young, nulliparous females
- Weight at study initiation: 200-220 g
- Housing: Single in clear polycarbonate cages with stainless-steel wire lids and hardwood shaving as bedding.
- Diet: Food pellets (UAR Alimentation Villemoisson, France), ad libitum
- Water: Filtered tap water, ad libitum


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 ± 2
- Humidity (%): 50 ± 5
- Photoperiod (hrs dark / hrs light): 12 hrs dark/12 hrs light
Route of administration:
inhalation: vapour
Type of inhalation exposure (if applicable):
whole body
Vehicle:
unchanged (no vehicle)
Details on exposure:
EXPOSURE
Exposures were conducted in 200-L glass/stainless-steel inhalation chambers with dynamic and adjustable laminar air flow (6-20 m3/h). The chamber temperature was set at 23 ± 2°C, and the relative humidity at 50 ± 5 %. The air-flow rate passed through the fritted disk of a heated bubbler containing the test chemical. Concentrations of acrylate ester were monitored continuously with a gas-chromatograph equipped with a flame ionization detector and an automatic gas-sampling valve. In addition, exposure levels were determined once during each 6-h exposure period by collecting atmosphere samples through glass tubes packed with activated charcoal. The charcoal samples were then desorbed with carbon disulfide. The resulting samples were analyzed by gas chromatography using appropriate internal standards.


GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Glass/stainless-steel inhalation chambers
- Source and rate of air: Test atmospheres were generated through an additional air-flow  rate passed through the fritted disk of a heated bubbler containing ethylhexyl acrylate. The vaporized compound was introduced into the main air inlet pipe of the exposure chamber.
- Air flow rate: 6-20 m3/h


TEST ATMOSPHERE
- Brief description of analytical method used: GC/FID
- Samples taken from breathing zone: yes
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Analytical concentrations (mean ± SD):
103.3 ± 6.7 ppm (nominal: 100 ppm)
202.8 ± 9.7 ppm (nominal: 200 ppm)
302.5 ± 10.1 ppm (nominal: 300 ppm)
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1/2-3
- Length of cohabitation: Overnight
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
Duration of treatment / exposure:
days 6 to 20 of gestation
Frequency of treatment:
6 hours/day
Duration of test:
until gestation day 21
No. of animals per sex per dose:
20
Control animals:
yes, sham-exposed
Details on study design:
- Dose selection rationale:
Exposure concentrations were based on preliminary studies in which marked decreases in maternal weight gain were observed at 200 and 300 ppm of butyl acrylate. Results from previous prenatal inhalation toxicity studies on butyl acrylate were also considered (Merkle and Klimisch, 1983). The high concentrations of butyl acrylate for the definitive study (200 and 300 ppm, respectively) were chosen to maximize the opportunity of identifying embryolethal or teratogenic potential.
Maternal examinations:
BODY WEIGHT: Yes
- Time schedule for examinations: On gestation day (GD) 0, 6, 13 and 21.


FOOD CONSUMPTION: YES
Food consumption was measured for the intervals GD 6-13 and 13-21.


POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 21
- Organs examined: The uteri were removed and weighed. The number of implantation sites, resorptions, and dead and live fetuses were recorded.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
The number of implantation sites, resorptions, and dead and live fetuses were recorded. Uteri which had no visible implantation sites were stained with ammonium sulfide (10 %) to detect very early resorptions.

Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: No data
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Fetal examinations:
Live fetuses were weighed, sexed, and examined for external anomalies including those of the oral cavity. Half of the live fetuses from each litter were preserved in Bouin's solution and examined for internal soft tissue changes. The other half were fixed in ethanol (70 %), eviscerated, and then processed for skeletal staining with alizarin red S for subsequent skeletal examination.

- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: Yes: all per litter
Statistics:
Data were presented as mean ± SD. The number of  implantation sites and live fetuses and the various body weights were analyzed by one-way analysis of variance (ANOVA), followed by Dunnett's test if differences were found. The percentages of non-live  implants and  resorptions and the proportions of fetuses with alterations in each litter were evaluated by using the Kruskal-Wallis test, followed by the Dixon-Massey test where appropriate. Rates of pregnancy, fetal sex ratio, and percentage of litters with malformations or external, visceral, or skeletal variations were analyzed by using Fisher's test. Where applicable, least-squares analysis was carried out. For all statistical tests, the level of significance was set a priori at alpha = 0.05.
Clinical signs:
not specified
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
During the entire exposure period, maternal weight gain was signifciantly reduced at 200 ppm and 300 ppm compared to the control group. Absolute weight gains (expressed as the day 21 body weight minus the gravid uterus weight and minus the day 6 body weight) were reduced in a dose-rependent manner in all exposure groups.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Decreases in food consumption was observed during the first half of the study for the females in the 100 ppm dose group and throught the exposure period at 200 and 300 ppm. The maximum decrease was 40-50% at the highest concentration.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not examined
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in pregnancy duration:
not examined
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not examined
Changes in number of pregnant:
no effects observed
Key result
Dose descriptor:
LOAEC
Effect level:
ca. 0.52 mg/L air (nominal)
Basis for effect level:
other: maternal toxicity
Fetal body weight changes:
effects observed, treatment-related
Description (incidence and severity):
Fetal body weight was significantly reduced at 200 ppm (for both sexes combined and males) and at 300 ppm (both sexes combined, males and females). These decreases amounted to 7-8 % (p<0.05) and 26-28 % (p<0.01) of control values for the 200 and 300 ppm groups, respectively.
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
not specified
Changes in postnatal survival:
no effects observed
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Description (incidence and severity):
A few sporadic malformations were seen in the 300 ppm and the control group. The incidence of individual skeletal variations (mainly incomplete ossification of sternebrae and of vertebral centra) was similar in the control and treated groups.
Visceral malformations:
no effects observed
Key result
Dose descriptor:
NOAEC
Effect level:
ca. 0.52 mg/L air (nominal)
Basis for effect level:
other: fetotoxicity
Key result
Dose descriptor:
NOAEC
Effect level:
ca. 1.57 mg/L air (nominal)
Basis for effect level:
other: teratogenicity
Abnormalities:
not specified
Developmental effects observed:
not specified

Maternal body weights:

Concentration [ppm/6h/d]

Maternal body weight GD 6 [g]

Absolute weight gain [g]

0

294 ± 23

32 ± 15

100

289 ± 23

18 ± 14*

200

299 ± 24

-16 ± 20**

300

292 ± 23

-60 ± 26**

Absolute weight gain: (Day 21 body weight) - (gravid uterus weight) - (Day 6 body weight)

Reproductive parameters:

Conc. [ppm/6h/d]

No. of litters

No. of implantation sites/litter

% of non-live implants/litter

% of resorption sites/litter

No. of live fetuses/litter

Average fetal body weight/litter [g]

0

25

15.68 ± 3.17

10.9 ± 15.49

10.64±15.62

14.12 ± 4.01

5.74 ± 0.43

100

24

15.58 ± 3.05

6.82 ± 10.19

6.82 ± 10.19

14.71 ± 3.57

5.71 ± 0.35

200

24

15.08 ± 4.23

4.72 ± 5.96

4.72 ± 5.96

14.46 ± 4.20

5.33 ± 0.40*

300

25

15.40 ± 5.24

6.48 ± 15.94

6.48 ± 15.94

14.68 ± 5.38

4.25 ± 0.94**

Concentration [ppm/6h/d]

0

100

200

300

Mean % of fetuses with:

- any malformations/litter

2.00 ± 7.33

0

0

0.62 ± 2.65

- external variations/litter

1.33 ± 6.67

0

0

0.22 ± 1.11

- visceral variations/litter

8.81 ± 14.64

0

0

4.17 ± 20.41

- skeletal variations/litter

13.70 ± 15.48

17.01 ± 14.53

18.71 ± 24.21

24.65 ± 20.69

- any variations/litter

12.60 ± 10.80

13.27 ± 15.07

10.10 ± 10.32

15.90 ± 19.98

* ,** Significant differences from the control (0 ppm) value, p 0.05, and p 0.01, respectively.

Executive summary:

In a developmental toxicity study, pregnant Sprague-Dawley female rats (20-29 per dose) were exposed to the compound 6h/day on days 6 through 20 of gestation. Control animals were exposed concurrently to filtered room air. The test concentrations of n-butyl acrylate were 100, 200, and 300 ppm (corresponding to approx. 0.52, 1.05, and 1.57 mg/L). Significant decreases in maternal body weight gain were observed at 200 ppm and 300 ppm, and decreased absolute weight gain were observed in all dose groups through the entire exposure period. Decreased fetal body weight was observed at 200 ppm (7-8%) and 300 ppm (26-28%) in the presence of significant maternal toxicity. No significant increases in malformations was observed in n-butyl acrylate exposed fetuses.

Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
130 mg/m³
Study duration:
subacute
Species:
rat
Additional information

Developmental Toxicity: Inhalation

In a developmental toxicity study, pregnant Sprague-Dawley female rats (20-29 per dose) were exposed to the compound 6h/day on days 6 through 20 of gestation. Control animals were exposed concurrently to filtered room air. The test concentrations of n-butyl acrylate were 100, 200, and 300 ppm (corresponding to approx. 0.52, 1.05, and 1.57 mg/L). Significant decreases in maternal body weight gain were observed at 200 ppm and 300 ppm, and decreased absolute weight gain were observed in all dose groups through the entire exposure period. Decreased fetal body weight was observed at 200 ppm (7-8%) and 300 ppm (26-28%) in the presence of significant maternal toxicity. No significant increases in malformations was observed in n-butyl acrylate exposed fetuses.

In a developmental toxicity study, pregnant Sprague-Dawley female rats (30 per dose) were exposed to the n-butyl acrylate 6h/day on days 6 through 15 of gestation. Control animals were exposed concurrently to filtered room air. The test concentrations of n-butyl acrylate were 25, 135 and 250 ppm. Significant decreases in maternal body weight gain were observed at 135 and 250 ppm dose groups through the entire exposure period. The number of corpora lutea and the number of implantations did not show any differences between the individual groups. However, the percentage of live implantations per pregnant animal was decreased in the 135 and 250 ppm dose groups. No significant increases in malformations was observed in n-butyl acrylate exposed fetuses.

Justification for classification or non-classification

N-hexyl acrylate was evaluated for its potential toxicity to reproduction based on read-across to data of a structurally similar substance, N-butyl Acrylate. This read-across approach is based on the hypothesis that the hydrolysis of both substances to acrylic acid and the respective alcohols would show similar toxicity patterns. The effect of the parent compound from the target substance is also predicted based on the worst case approach as data indicate the parent structure of the source substance would be expected to have a higher electrophilic capacity. N-butyl acrylate produced no abnormal histopathology findings in either male or female reproductive organs in subchronic studies by the oral or inhalation routes. In two developmental toxicity studies, exposure of fetuses to n-butyl acrylate vapors produced no increase in malformations. As the read-across is considered valid, classification of N-hexyl acrylate as a Reproductive toxicant is not warranted under the Regulation (EC) 1272/2008 on classification, labeling, and packaging of substances and mixtures (CLP).

Additional information