Hexyl acrylate

Endpoint summary

Description of key information

Oral NOAEL 84 mg/kg (male), 111 mg/kg (female) for Rat; equivalent or similar to OECD 408 (Read-Across to n-butyl acrylate)

Inhalation-systemic NOAEC 570 mg/m3 (male/female) for Rat; equiavlent or similar to OECD TG 413 (Read-Across to n-butyl acrylate)

Inhalation- local LOAEC 86 mg/m3 (male/female); systemic NOAEC 258 mg/m3 (male/female) for Rat; equivalent or similar to OECD TG 453 (Read-Across to n-butyl acrylate)

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Reference 1

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).

Reference 2

Endpoint:

sub-chronic toxicity: oral

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

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)

Deviations:

no

GLP compliance:

yes

Limit test:

no

Clinical signs:

no effects observed

Description (incidence and severity):

No mortality or clinical signs were observed.

Mortality:

no mortality observed

Description (incidence):

No mortality or 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

Description (incidence and severity):

There were no differences betwen experimental and control groups.

Food efficiency:

not examined

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

Immunological 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.

Executive summary:

The potential for repeat dose toxicity of N-hexyl acrylate has been evaluated based on data of a structurally similar substance, n-butyl acrylate. 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 of 0, 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).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

84 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Reference

Reference 1

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1978

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Qualifier:

equivalent or similar to guideline

Guideline:

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:

whole body

Vehicle:

other: Unchanged (no vehicle)

Details on inhalation 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).

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/day

Dose / conc.:

108 ppm (analytical)

Remarks:

Corresponds to 0.57 mg/L/day

Dose / conc.:

211 ppm (analytical)

Remarks:

Corresponds to 1.11 mg/L/day

Dose / conc.:

546 ppm (analytical)

Remarks:

Corresponds to 2.86 mg/L/day

No. of animals per sex per dose:

20

Control animals:

yes, sham-exposed

Observations and examinations performed and frequency:

DETAILED CLINICAL OBSERVATIONS: Daily
BODY WEIGHT: Weekly
HAEMATOLOGY: Parameters examined: hemoglobin content, erythrocytes, hematocrit, hemoglobin content per erythrocyte, mean corpuscular volume (MCV), mean corpuscular hemoglobin concentration (MCHC), platelets, leukocytes and differential blood count; collection of blood: 7 days before (sampling 0), and 4 (sampling 1), 8 (sampling 2) and 13 (sampling 3) weeks after the beginning of exposure.
CLINICAL CHEMISTRY: Parameters examined: Total bilirubin, creatinine, urea, sodium, potassium, total protein, glucose, inorganic phosphate, calcium, chloride, triglycerides, cholesterol and enzymes (Glutamic pyruvic transaminase, Alkaline phosphatase, Glutamic oxalacetic transaminase)
URINALYSIS: Urine was sampled individually from all animals overnight after 4 1/2 weeks (urine collection 1), 8 1/2 weeks (urine collection 2) and 12 1/2 weeks (urinalysis 3) after the beginning of the study; Parameters examined: pH, protein, glucose, urobilinogen and sediment microscopy.

Sacrifice and pathology:

At the end of the study period, the surviving animals were sacrificed after a fasting period of 16 hours. For reasons of organization, only half of the male group received no feed. Only this small group was used for calculating the organ weights. The sacrifice was carried out under anesthesia with CO2 by exsanguination (opening of the bracchial vessels) and subsequent decapitation. Then the animals were necropsied and assessed by gross-pathology. Subsequently the following organs were weighed: heart, liver, kidneys, spleen, testes, thyroid gland, adrenals and lungs. The relative organ weights (organ weight/100 g body weight) were calculated. Tissues including seminal vesicles, prostrate, epididymus/uterus, testes and ovary wer examined histologically from each animal.

Statistics:

For the statistical evaluation of the study, means, standard deviations (of the individual values) and standard errors were calculated for the variables body weight change and absolute and relative organ weights for the animals in each test group and collated in the form of tables together with the individual values. Statistical significance was determined by a t test generalized by Williams (Biometrics, 37: 103 - 117, 1971) for the simultaneous comparison of several dose groups with a control group.

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

No clinical signs were observed in animals of dose groups 21 and 108 ppm. All animals in the 211-ppm dose group exhibited distinct discharge from the eyes and noses from the first inhalation onward, however, the animals recovered quickly each time. Animals in the 546-ppm dose group exhibited pronounced discharge from the eyes and noses, however animals no longer recovered from day 11 of the exposure, and also exhibited severe dyspnoea, bloody discharge from the eyes and noses, extremely aggressiveness and a stronger inclination to cannibalism.

Mortality:

mortality observed, treatment-related

Description (incidence):

No mortality was observed in the 21, 108, and 211 ppm dose groups. Thirty one (16 male and 15 female) of 40 animals (77 %) in the 546 ppm dose group died between the 3rd and 13th week of the study.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Throughout the study, there was no significant influence on the body weight change in males or females in the 21 ppm and 108 ppm dose groups compared with the control group. In the 211 ppm dose group, the body weight of the female rats was significantly decreased from day 7 to day 77. The animals showed no significant body weight changes at the weighing after 85 and 91 days. At the final weighing, female body weight was significantly decreased. Body weight was significantly decreased in males from day 63 through the end of the study.

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:

effects observed, treatment-related

Description (incidence and severity):

Hematocrit, hemoglobin content per erythrocytes, MCV (mean cell volume) and MCHC (mean corpuscular hemoglobin concentration) were unaffected. Hemoglobin content and erythrocytes in male and female animals of the 546 ppm dose group were increased. The changes in the leukocyte and monocyte counts were observed only in one sex, and were not considered test substance specific.

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

No effect was observed for total bilirubin, creatinine, inorganic phosphate, calcium, chloride, triglycerides, glutamic pyruvic transaminase and glutamic oxalacetic transaminase. Increased sodium levels in males and females of the 546 ppm dose group was observed in blood samples 2 and 3. Females of the 211 and 546 ppm dose groups displayed an increase in Alkaline phosphatase levels in a time- and dose-dependent manner. Decreases in potassium, total protein, glucose and cholesterol levels were observed in female animals only.

Urinalysis findings:

no effects observed

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

An increase in the relative liver weights was observed in females in all dose groups. An increase in the relative lung weight was observed in both sexes only at the highest dose. Increased thyroid weight was observed in the females of highest dose group. Increased adrenal weight was observed in both sexes at the highest dose group and in males only at the intermediate dose group.

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

Lesions were predominantly detected in the high dose male and female animals that died between days 17 and 69, and days 24 and 90 respectively. Raised foci of bronchopneumonia with sporadic whitish-gray or dark red spots were found across all the lobes of the lungs; in some animals a discharge from the bronchi could be seen on the plane of the section, other foci had, in parts, a compact appearance and resembled lard. A poor nutritional state was suspected for these rats as advanced autolysis was observed in many of them. All surviving animals showed pneumonic zones that were randomly distributed among various lobes, and a few female animals showed hydrometra.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Histopathological changes were found mostly in the respiratory tract of the animals in the 546 dose ppm group that died during the course of the study. In the male and female rats slight hyperemia of the nasal mucosa, edema and dysplasia of the epithelial mucosa was observed. Tracheal hyperemia and edema were observed in almost all males that died spontaneously but were observed in only half of the females. Metaplasia of the mucosa (multi-rowed, cornified epithelium) was detected in most of the rats and predominantly in males. One single animal even had necrosis of the mucosa. Metaplasia was found as far as the bronchioles and was observed in both sexes. In many animals multi-focal infiltration with various degrees of extension emerged from metaplasia on the one hand and from proliferation in the alveolar zone on the other. Multifocal infiltration, which was found more in the females, changed into bronchopneumonia in nearly the same number of male and female animals. Gram-positive germs could be detected in the area of the pneumonic foci in animals which were characterized by extensive and advanced necrosis of the lungs. Additionally hyperemia and necrosis of the liver together with fatty deposits predominantly in the peripheral zones of the lobules was observed in 1 male and 1 female. Glycogen content was slightly increased in one-third of males.
Hyperemia of the spleen was observed in two males, and in one female moderate fibrosis.
Hemorrhages in the thymus were observed in four males and one female. Hyperemia of the kidneys and meninges, and a cyst in the anterior lobe (two instances) was found in non-surviving animals of the high dose group.

Slight edema and erosions of the nasal mucosa were found in only 2 male animals of the 211 ppm dose group and in one female rat of the 108 ppm dose group. In female animals in the 211 ppm dose group, a slight increase in fatty deposits and the glycogen content in the liver were noted in comparison to the control group. In nearly half of all males in all exposure groups, an increase in the fat-free vacuoles (hematoxylin eosin stain), Kupffer cell fatty deposits and glycogen content was attributed to the fact that these animals had not been fasted prior to necropsy and were not considered treatment-related. No histopathological examinations were carried out in the 21 ppm group.

Histopathological findings: neoplastic:

no effects observed

Key result

Dose descriptor:

NOAEC

Effect level:

0.57 mg/L air (analytical)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: systemic effects

Key result

Dose descriptor:

LOAEC

Effect level:

1.11 mg/L air (analytical)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

clinical biochemistry

Key result

Dose descriptor:

NOAEC

Effect level:

0.11 mg/L air (analytical)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Local effects

Key result

Dose descriptor:

LOAEC

Effect level:

0.57 mg/L air (analytical)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

histopathology: non-neoplastic

Critical effects observed:

not specified

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).

Reference 2

Endpoint:

sub-chronic toxicity: inhalation

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):

No clinical signs were observed in animals of dose groups 21 and 108 ppm. All animals in the 211-ppm dose group exhibited distinct discharge from the eyes and noses from the first inhalation onward, however, the animals recovered quickly each time. Animals in the 546-ppm dose group
exhibited pronounced discharge from the eyes and noses, however animals no longer recovered from day 11 of the exposure, and also exhibited severe dyspnoea, bloody discharge from the eyes and noses, extremely aggressiveness and a stronger inclination to cannibalism.

Mortality:

mortality observed, treatment-related

Description (incidence):

No mortality was observed in the 21, 108, and 211 ppm dose groups. Thirty one (16 male and 15 female) of 40 animals (77 %) in the 546 ppm dose group died between the 3rd and 13th week of the study.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Throughout the study, there was no significant influence on the body weight change in males or females in the 21 ppm and 108 ppm dose groups compared with the control group. In the 211 ppm dose group, the body weight of the female rats was significantly decreased from day 7 to day 77. The animals showed no significant body weight changes at the weighing after 85 and 91 days. At the final weighing, female body weight was significantly decreased. Body weight was significantly decreased in males from day 63 through the end of the study.

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

no effects observed

Ophthalmological findings:

not examined

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

Hematocrit, hemoglobin content per erythrocytes, MCV (mean cell volume) and MCHC (mean corpuscular hemoglobin concentration) were unaffected. Hemoglobin content and erythrocytes in male and female animals of the 546 ppm dose group were increased. The changes in the leukocyte and monocyte counts were observed only in one sex, and were not considered test substance specific.

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

No effect was observed for total bilirubin, creatinine, inorganic phosphate, calcium, chloride, triglycerides, glutamic pyruvic transaminase and glutamic oxalacetic transaminase. Increased sodium levels in males and females of the 546 ppm dose group was observed in blood samples 2 and 3. Females of the 211 and 546 ppm dose groups displayed an increase in Alkaline phosphatase levels in a time- and dose-dependent manner. Decreases in potassium, total protein, glucose and cholesterol levels were observed in female animals only.

Urinalysis findings:

no effects observed

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

An increase in the relative liver weights was observed in females in all dose groups. An increase in the relative lung weight was observed in both sexes only at the highest dose. Increased thyroid weight was observed in the females of highest dose group. Increased adrenal weight was observed in both sexes at the highest dose group and in males only at the intermediate dose group.

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

Lesions were predominantly detected in the high dose male and female animals that died between days 17 and 69, and days 24 and 90 respectively. Raised foci of bronchopneumonia with sporadic whitish-gray or dark red spots were found across all the lobes of the lungs; in some animals a discharge from the bronchi could be seen on the plane of the section, other foci had, in parts, a compact appearance and resembled lard. A poor nutritional state was suspected for these rats as advanced autolysis was observed in many of them. All surviving animals showed pneumonic zones that were randomly distributed among various lobes, and a few female animals showed hydrometra.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Histopathological changes were found mostly in the respiratory tract of the animals in the 546 ppm group that died during the course of the study. In the male and female rats slight hyperemia of the nasal mucosa, edema and dysplasia of the epithelial mucosa was observed. Tracheal hyperemia and edema were observed in almost all males that died spontaneously but were observed in only half of the females. Metaplasia of the mucosa (multi-rowed, cornified epithelium) was detected in most of the rats and predominantly in males. One single animal even had necrosis of the mucosa. Metaplasia was found as far as the bronchioles and was observed in both sexes. In many animals multi-focal in filtration with various degrees of extension emerged from metaplasia on the one hand and from proliferation in the alveolar zone on the other. Multifocal infiltration, which was found more in the females, changed into bronchopneumonia in nearly the same number of male and female animals. Gram-positive germs could be detected in the area of the pneumonic foci in animals which were characterized by extensive and advanced necrosis of the lungs. Additionally hyperemia and necrosis of the liver together with fatty deposits predominantly in the peripheral zones of the lobules was observed in 1 male and 1 female. Glycogen content was slightly increased in one-third of males. Hyperemia of the spleen was observed in two males, and in one female moderate fibrosis. Hemorrhages in the thymus were observed in four males and one female. Hyperemia of the kidneys and meninges, and a cyst in the anterior lobe (two instances) was found in non-surviving animals of the high dose group.

Histopathological findings: neoplastic:

effects observed, non-treatment-related

Key result

Dose descriptor:

NOAEC

Effect level:

0.57 mg/L air (analytical)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Systemic effects

Key result

Dose descriptor:

LOAEC

Effect level:

1.11 mg/L air (analytical)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

clinical biochemistry

Key result

Dose descriptor:

NOAEC

Effect level:

0.11 mg/L air (analytical)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Local effects

Key result

Dose descriptor:

LOAEC

Effect level:

0.57 mg/L air (analytical)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

histopathology: non-neoplastic

Critical effects observed:

not specified

Executive summary:

N-hexyl acrylate was evaluated for its sub-chronic 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 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).

Reference 3

Endpoint:

chronic toxicity: inhalation

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:

no effects observed

Description (incidence and severity):

In general, the appearance and behaviour of the rats were normal. Overt signs of toxicity or reactions related to exposure were not observed.

Mortality:

mortality observed, non-treatment-related

Description (incidence):

The mean life-table-corrected cumulative mortality across all groups was approximately 20%. No significant difference between butyl acrylate and control groups was observe din male rats. In female rats, groups exposed to 15 and 135 ppm differed statistically significantly from the other Butyl acrylate exposed groups. On the whole, although heterogeneous, the data did not indicate that exposure to the test substance had an adverse effect on longevity. In general, the appearance and behaviour of the rats were normal. Overt signs of toxicity or reactions related to exposure were not observed.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

Throughout the study, there was no significant influence on the body weight change of the male and female animals in any dose group compared with the control group. Food consumption in the group exposed to 135 ppm butyl acrylate was consistently lower (approximately 4%) than that of the control groups. The food consumption returned to normal at the end of the exposure period.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

effects observed, treatment-related

Description (incidence and severity):

Centrally localized or diffuse stippling of the corneal epithelium and cloudiness of the corneal parenchyma with various degrees of neovascularization were observed in butyl acrylate treated rats. Across all timepoints examined, a significant increase of parenchymal changes was evident in males and females exposed to 135 ppm.

Haematological findings:

no effects observed

Description (incidence and severity):

Hematocrit, hemoglobin content per erythrocytes, MCV (mean cell volume), MCHC (mean corpuscular hemoglobin concentration) and reticulocyte parameters were unaffected.

Clinical biochemistry findings:

not examined

Urinalysis findings:

no effects observed

Description (incidence and severity):

No treatment-related effects of the test substance could be seen from the urinary findings. Elevated urinary erythrocyte counts and protein concentrations were observed in most of male and several females rats of all groups including control and were suggestive of spontaneous inflammatory changes common in ageing rats of this strain.

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

The autopsies performed after 24 months revealed 5-17% lower weight of kidneys, thyroid, heart and liver in some of the Butyl acrylate exposed groups (not specified). Despite the statistical significance, the findings were not considered to be toxicologically relevant because they were neither consistently dose-dependent nor did they correlate with histopathological changes.

Gross pathological findings:

no effects observed

Description (incidence and severity):

Autopsy revealed only incidental patho-anatomical changes or gerontic patho-anatomical changes typical of aged Sprague-Dawley rats.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Histological examinations revealed concentration dependent lesions in the nasal mucosa at the level of the dorsal lamella of the second turbinate. A significant incidence of stratified reserve cell hyperplasia in level 2 of the nasal mucosa was observed in all exposure groups. Slight atrophy of the neurogenic part of the olfactory epithelium was observed in a few male rats exposed to 15 ppm butyl acrylate. Most changes developed during the first 12 months of exposure and increased only moderately with ongoing exposure. Changes in the nasal cavity are mainly attributed to the irritating properties of acrylates. No irritative changes were observed in the larynx, trachea or lungs.

Histopathological findings: neoplastic:

no effects observed

Description (incidence and severity):

Leukemic changes were observed in some ale rats exposed to butyl acrylate but only at 45 ppm. For the females, only one case was recorded which occurred in the control group. The overall incidence of leukemic changes in the butyl acrylate exposed groups was well within the expected incidence of spontaneous leukemia in Sprague-Dawley Rats. A few other benign mesenchymal lesions and sarcomas of the soft tissue were distributed heterogeneously across butyl acrylate exposed groups. Overall there was no detectable dose dependency for any tumour type and were not considered to be treatment-related.

Key result

Dose descriptor:

LOAEC

Effect level:

0.086 mg/L air (analytical)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

histopathology: non-neoplastic

Key result

Dose descriptor:

NOAEC

Effect level:

0.258 mg/L air (analytical)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

ophthalmological examination

Critical effects observed:

not specified

Conclusions:

Under the test conditions of this study, the NOAEL for Butyl-Acrylate is 0.258 mg/L (45 ppm) based on ophthalmological findings, and 0.086 mg/L based on irritative histological changes in nasal mucosa.

Executive summary:

N-hexyl acrylate was evaluated for its chronic 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. N-Butyl Acrylate was administered by inhalation to Sprague-Dawley rats for 6 hours/day, 5 days/week for 24 months at nominal vapor concentrations of 0, 15, 45 and 135 ppm to assess chronic inhalation toxicity. No effect on longevity or treatment-related effects in any of the hematology or urinalysis values were observed. Decreases in organ weight (range 5-17%) of liver, kidney, thyroid and heart was reported in some exposure groups but not considered toxicologically significant asthey were neither consistently dose-dependent nor did they correlate with histopathological changes.As there were no pathologic changes, changes in organ weights mentioned above were judged to have been compensatory rather than toxic effects. A significant increase in incidence ofcorneal neovascularization or parenchymal cloudinesswas evident in males and females exposed to 135 ppm.A significant incidence of stratified reserve cell hyperplasia in level 2 of the nasal mucosa was observed at 45 and 135 ppm. Changes in the nasal cavity are mainly attributed to the irritating properties of acrylates. No irritative changes were observed in the larynx, trachea or lungs. Based on these results, the No Observed Adverse Effect Concentration (NOAEC) is 0.258 mg/L (45 ppm) based on ophthalmological findings, and 0.07 mg/L based on irritative histological changes in nasal mucosa.

Reference 4

Endpoint:

chronic toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)

Deviations:

yes

Remarks:

No clinical chemistry examinations were made

GLP compliance:

no

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: approximately 35 days
- Weight at study initiation: males-183 g and females-157 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:

whole body

Vehicle:

other: unchanged (no vehicle)

Remarks on MMAD:

MMAD / GSD: no data

Details on inhalation 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 120 °C) at a constant rate and vaporized there. A stream of supply air measured by means of a rotameter took up the vapors (0.3 - 3 m3/hr). The inhalation chambers had a volume of 4.9 m3 were constructed of stainless-steel and glass. Each chamber held 172 rats (1 dose group; 86 male, 86 female). The chambers were ventilated with a continous vertical stream of conditioned (21°C, 55% relative humidity) fresh air (approx. 60 m3/hr).

TEST ATMOSPHERE
- Brief description of analytical method used: The n-butyl acrylate air mixture was measured continously for ten minutes every hour using an infra-red gas photometer (Path length = 2.25m at a wavelength of 8.3μm; Miran IA, Foxboro Analytical, S. Norwalk, CT, USA) or a total hydrocarbon flame ionization detector (RS5; Ratfisch Instrumente, Munchen Germany).

- 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).

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The analytical measurements of the theoritical concentrations of 15, 45, 135 ppm were 14.8, 44.3 and 133.7 ppm, respectively.

Duration of treatment / exposure:

24 months

Frequency of treatment:

6 h/day, 5 d/week for 24 months

Dose / conc.:

0 ppm

Dose / conc.:

14.8 ppm

Remarks:

14.8 ppm analytical concentration (corresponding to 0.086 mg/L/day). Calculation of concentrations (mg/L) based on Derelanko MJ (2000). Toxicologist's Pocket Handbook, CRC Press, conversion table, p. 57.

Dose / conc.:

44.3 ppm

Remarks:

44.3 ppm analytical concentration (corresponding to 0.258 mg/L/day). Calculation of concentrations (mg/L) based on Derelanko MJ (2000). Toxicologist's Pocket Handbook, CRC Press, conversion table, p. 57.

Dose / conc.:

133.7 ppm

Remarks:

Doses / Concentrations:
133.7 ppm analytical concentration (corresponding to 0.773 mg/L/day). Calculation of concentrations (mg/L) based on Derelanko MJ (2000). Toxicologist's Pocket Handbook, CRC Press, conversion table, p. 57.

No. of animals per sex per dose:

86

Control animals:

yes, sham-exposed

Details on study design:

- Dose selection rationale: A high dose vapour concentration of 135 ppm was selected as the 'maximum tolerated dose' in accordance with NCI guidelines (Sontag et a. 1976).
- Rationale for selecting satellite groups: Interim groups were selected for autopsy at 12 and 18 months
- Post-exposure recovery period in satellite groups: 6 month post-exposure observation and recovery period following 24 months

Positive control:

No

Observations and examinations performed and frequency:

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

HEMATOLOGY: Yes
- Time schedule for collection of blood: at sacrifice
- Parameters examined: with respect to reticulocytes: normoblast and differential leucocyte counts; with respect to erythrocytes: hemoglobin content, mean corpuscular volume (MCV), mean corpuscular hemoglobin concentration (MCHC), and differential blood count

CLINICAL CHEMISTRY: No

URINALYSIS: Yes. Urine was sampled individually from all animals scheduled for autopsy.
- Parameters examined: volume, color, transparency, pH, protein, glucose, urobilinogen, ketone bodies, occult blood, and sediment microscopy.

OPHTHALMOLOGY: Yes. Eyes were examined at 12, 18, and 24 months. Eyes were also examined in a subset of animals allowed to recover for 6 months post 24 months exposure.

Parameters examined: external changes, pupillary reflex, changes in anterior part of the bulbus by slit lamp, and changes of the fundus

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
At the end of the study period, the surviving animals were sacrificed without previous diet deprivation. The sacrifice was carried out under anesthesia with diethyl ether by exsanguination. Then the animals were necropsied and assessed by gross-pathology. Subsequently the following organs were weighed: heart, liver, kidneys, spleen, testes, ovaries, thyroid gland, brain, lymph nodes, adrenals and lungs. The relative organ weights (organ weight/100 g body weight and brain weight) were calculated. All tissues with gross lesions and representative sections of organs and tissues were preserved in a 4% neutral formaldehyde solution. The testes were preserved in Bouins fixative and the lumbar vertebrae in Schaffer's fixative.

Statistics:

A comparison of the exposure groups with their respective control groups (each sex separately) was made setting the two-sided fiducial limit α =0.05 as a critical lebels of significance without corrections for multiple testing. Mortality was analyzed using the life-table method (Armitage et al. 1971). Body weight, food consumption, organ weights and all hematological paramaters were compared using Student's t-test or its modification according to Welch (Clauss and Ebner 1970). Moribund rats, rats found dead, and rats with apparently outlying values were excluded from routine statistics and interpreted separately. The total incidences of frequently observed histological changes were analyzed using contingency tables (Sokal and Rohlf 1969).

Clinical signs:

no effects observed

Mortality:

mortality observed, non-treatment-related

Description (incidence):

The mean life-table-corrected cumulative mortality across all groups was approximately 20%. On the whole, although heterogeneous, the data did not indicate that exposure to the test substance had an adverse effect on longevity. In general, the appearance and behaviour of the rats were normal. Overt signs of toxicity or reactions related to exposure were not observed. No significant difference between butyl acrylate and control groups was observed in male rats. In female rats, groups exposed to 15 and 135 ppm differed statistically significantly from the other Butyl acrylate exposed groups.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

Throughout the study, there was no significant influence on the body weight change of the male and female animals in any dose group compared with the control group. Food consumption in the group exposed to 135 ppm butyl acrylate was consistently lower (approximately 4%) than that of the control groups. The food consumption returned to normal at the end of the exposure period.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

effects observed, treatment-related

Description (incidence and severity):

Centrally localized or diffuse stippling of the corneal epithelium and cloudiness of the corneal parenchyma with various degrees of neovascularization were observed in butyl acrylate treated rats. Across all timepoints examined, a significant increase of parenchymal changes was evident in males and females exposed to 135 ppm.

Haematological findings:

no effects observed

Description (incidence and severity):

Hematocrit, hemoglobin content per erythrocytes, MCV (mean cell volume), MCHC (mean corpuscular hemoglobin concentration) and reticulocyte parameters were unaffected.

Clinical biochemistry findings:

not examined

Urinalysis findings:

no effects observed

Description (incidence and severity):

No treatment-related effects of the test substance could be seen from the urinary findings. Elevated urinary erythrocyte counts and protein concentrations were observed in most of male and several females rats of all groups including control and were suggestive of spontaneous inflammatory changes common in ageing rats of this strain.

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

The autopsies performed after 24 months revealed 5-17% lower weight of kidneys, thyroid, heart and liver in some of the Butyl acrylate exposed groups (not specified). Despite the statistical significance, the findings were not considered to be toxicologically relevant because they were neither consistently dose-dependent nor did they correlate with histopathological changes.

Gross pathological findings:

no effects observed

Description (incidence and severity):

Autopsy revealed only incidental patho-anatomical changes or gerontic patho-anatomical changes typical of aged Sprague-Dawley rats.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Histological examinations revealed concentration dependent lesions in the nasal mucosa at the level of the dorsal lamella of the second turbinate. A significant incidence of stratified reserve cell hyperplasia in level 2 of the nasal mucosa was observed in all exposure groups. Slight atrophy of the neurogenic part of the olfactory epithelium was observed in a few male rats exposed to 15 ppm butyl acrylate. Most changes developed during the first 12 months of exposure and increased only moderately with ongoing exposure. Changes in the nasal cavity are mainly attributed to the irritating properties of acrylates. No irritative changes were observed in the larynx, trachea or lungs.

Histopathological findings: neoplastic:

no effects observed

Description (incidence and severity):

Leukemic changes were observed in some male rats exposed to butyl acrylate but only at 45 ppm. For the females, only one case was recorded which occurred in the control group. The overall incidence of leukemic changes in the butyl acrylate exposed groups was well within the expected incidence of spontaneous leukemia in Sprague-Dawley Rats. A few other benign mesenchymal lesions and sarcomas of the soft tissue were distributed heterogeneously across butyl acrylate exposed groups. Overall there was no detectable dose dependency for any tumour type and were not considered to be treatment-related.

Key result

Dose descriptor:

NOAEC

Effect level:

0.258 mg/L air (analytical)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

ophthalmological examination

Key result

Dose descriptor:

LOAEC

Effect level:

0.086 mg/L air (analytical)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

histopathology: non-neoplastic

Critical effects observed:

not specified

Conclusions:

Under the test conditions of this study, the NOAEL for N-butyl acrylate is 0.258 mg/L (45 ppm) based on ophthalmological findings, and 0.086 mg/L (15 ppm) based on irritative histological changes in nasal mucosa.

Executive summary:

In a 2-year inhalation study, Sprague-Dawley rats were exposed by whole body exposure 6 hours per day, 5 days a week to 0, 15, 45 or 135 ppm (0, 0.086, 0.258, 0.773 mg/L butyl acrylate. During the first 13 weeks of the study, the concentrations were lower: 0, 5, 15 or 45 ppm. The post observation period was 6 months (BASF AG 1985). There were no compound-related effects on general behaviour or appearance (no overt signs of toxicity and no effects on mortality). Body weight gain was normal in all groups, with only a slight decrease in food consumption in treated males and females. No compound-related effects were detected in haematological measurements or urinalysis. Organ weights were generally unaffected by treatment, except for slightly lower relative heart, kidney, liver and thyroid weights in the highest dose. Ophthalmological examinations demonstrated localized or diffuse stippling of the corneal epithelium, cloudiness of the cornea, and various degrees of vascularisation that increased with dose and duration of exposure. These effects were only significant in the highest dose group (compared with the controls), thus the NOAEC for effects on the eye is 45 ppm (0.258 mg/L). Histological changes in the nasal mucosa were dose-dependent and described as slight atrophy of the neurogenic part of the olfactory epithelium at 15 ppm, and partial loss of the columnar cell layer and stratified reserve-cell hyperplasia at 45 and 135 ppm. The frequency of reserve-cell hyperplasia in nasal mucosa was 0, 8/169, 41/170, and 105/170 (for males and females combined) at 0, 15, 45, and 135 ppm, respectively. Males and females were affected in the same manner. No changes were detected in the posterior nasal cavity, and no irritation effects were detected on the larynx, trachea or lungs. The changes in the nasal mucosa and cornea proved to be reversible up to a point during the follow-up period. For these histological changes of the nasal mucosa no NOAEC could be derived. The LOAEC is 15 ppm (0.086 mg/L). Examinations of tissues for neoplastic changes did not reveal any compound related increases or dose dependent effects.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEC

570 mg/m³

Study duration:

subchronic

Species:

rat

Repeated dose toxicity: inhalation - local effects

Link to relevant study records

Reference

Reference 1

Endpoint:

chronic toxicity: inhalation

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:

no effects observed

Description (incidence and severity):

In general, the appearance and behaviour of the rats were normal. Overt signs of toxicity or reactions related to exposure were not observed.

Mortality:

mortality observed, non-treatment-related

Description (incidence):

The mean life-table-corrected cumulative mortality across all groups was approximately 20%. No significant difference between butyl acrylate and control groups was observe din male rats. In female rats, groups exposed to 15 and 135 ppm differed statistically significantly from the other Butyl acrylate exposed groups. On the whole, although heterogeneous, the data did not indicate that exposure to the test substance had an adverse effect on longevity. In general, the appearance and behaviour of the rats were normal. Overt signs of toxicity or reactions related to exposure were not observed.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

Throughout the study, there was no significant influence on the body weight change of the male and female animals in any dose group compared with the control group. Food consumption in the group exposed to 135 ppm butyl acrylate was consistently lower (approximately 4%) than that of the control groups. The food consumption returned to normal at the end of the exposure period.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

effects observed, treatment-related

Description (incidence and severity):

Centrally localized or diffuse stippling of the corneal epithelium and cloudiness of the corneal parenchyma with various degrees of neovascularization were observed in butyl acrylate treated rats. Across all timepoints examined, a significant increase of parenchymal changes was evident in males and females exposed to 135 ppm.

Haematological findings:

no effects observed

Description (incidence and severity):

Hematocrit, hemoglobin content per erythrocytes, MCV (mean cell volume), MCHC (mean corpuscular hemoglobin concentration) and reticulocyte parameters were unaffected.

Clinical biochemistry findings:

not examined

Urinalysis findings:

no effects observed

Description (incidence and severity):

No treatment-related effects of the test substance could be seen from the urinary findings. Elevated urinary erythrocyte counts and protein concentrations were observed in most of male and several females rats of all groups including control and were suggestive of spontaneous inflammatory changes common in ageing rats of this strain.

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

The autopsies performed after 24 months revealed 5-17% lower weight of kidneys, thyroid, heart and liver in some of the Butyl acrylate exposed groups (not specified). Despite the statistical significance, the findings were not considered to be toxicologically relevant because they were neither consistently dose-dependent nor did they correlate with histopathological changes.

Gross pathological findings:

no effects observed

Description (incidence and severity):

Autopsy revealed only incidental patho-anatomical changes or gerontic patho-anatomical changes typical of aged Sprague-Dawley rats.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Histological examinations revealed concentration dependent lesions in the nasal mucosa at the level of the dorsal lamella of the second turbinate. A significant incidence of stratified reserve cell hyperplasia in level 2 of the nasal mucosa was observed in all exposure groups. Slight atrophy of the neurogenic part of the olfactory epithelium was observed in a few male rats exposed to 15 ppm butyl acrylate. Most changes developed during the first 12 months of exposure and increased only moderately with ongoing exposure. Changes in the nasal cavity are mainly attributed to the irritating properties of acrylates. No irritative changes were observed in the larynx, trachea or lungs.

Histopathological findings: neoplastic:

no effects observed

Description (incidence and severity):

Leukemic changes were observed in some ale rats exposed to butyl acrylate but only at 45 ppm. For the females, only one case was recorded which occurred in the control group. The overall incidence of leukemic changes in the butyl acrylate exposed groups was well within the expected incidence of spontaneous leukemia in Sprague-Dawley Rats. A few other benign mesenchymal lesions and sarcomas of the soft tissue were distributed heterogeneously across butyl acrylate exposed groups. Overall there was no detectable dose dependency for any tumour type and were not considered to be treatment-related.

Key result

Dose descriptor:

LOAEC

Effect level:

0.086 mg/L air (analytical)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

histopathology: non-neoplastic

Key result

Dose descriptor:

NOAEC

Effect level:

0.258 mg/L air (analytical)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

ophthalmological examination

Critical effects observed:

not specified

Conclusions:

Under the test conditions of this study, the NOAEL for Butyl-Acrylate is 0.258 mg/L (45 ppm) based on ophthalmological findings, and 0.086 mg/L based on irritative histological changes in nasal mucosa.

Executive summary:

N-hexyl acrylate was evaluated for its chronic 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. N-Butyl Acrylate was administered by inhalation to Sprague-Dawley rats for 6 hours/day, 5 days/week for 24 months at nominal vapor concentrations of 0, 15, 45 and 135 ppm to assess chronic inhalation toxicity. No effect on longevity or treatment-related effects in any of the hematology or urinalysis values were observed. Decreases in organ weight (range 5-17%) of liver, kidney, thyroid and heart was reported in some exposure groups but not considered toxicologically significant asthey were neither consistently dose-dependent nor did they correlate with histopathological changes.As there were no pathologic changes, changes in organ weights mentioned above were judged to have been compensatory rather than toxic effects. A significant increase in incidence ofcorneal neovascularization or parenchymal cloudinesswas evident in males and females exposed to 135 ppm.A significant incidence of stratified reserve cell hyperplasia in level 2 of the nasal mucosa was observed at 45 and 135 ppm. Changes in the nasal cavity are mainly attributed to the irritating properties of acrylates. No irritative changes were observed in the larynx, trachea or lungs. Based on these results, the No Observed Adverse Effect Concentration (NOAEC) is 0.258 mg/L (45 ppm) based on ophthalmological findings, and 0.07 mg/L based on irritative histological changes in nasal mucosa.

Reference 2

Endpoint:

chronic toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)

Deviations:

yes

Remarks:

No clinical chemistry examinations were made

GLP compliance:

no

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: approximately 35 days
- Weight at study initiation: males-183 g and females-157 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:

whole body

Vehicle:

other: unchanged (no vehicle)

Remarks on MMAD:

MMAD / GSD: no data

Details on inhalation 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 120 °C) at a constant rate and vaporized there. A stream of supply air measured by means of a rotameter took up the vapors (0.3 - 3 m3/hr). The inhalation chambers had a volume of 4.9 m3 were constructed of stainless-steel and glass. Each chamber held 172 rats (1 dose group; 86 male, 86 female). The chambers were ventilated with a continous vertical stream of conditioned (21°C, 55% relative humidity) fresh air (approx. 60 m3/hr).

TEST ATMOSPHERE
- Brief description of analytical method used: The n-butyl acrylate air mixture was measured continously for ten minutes every hour using an infra-red gas photometer (Path length = 2.25m at a wavelength of 8.3μm; Miran IA, Foxboro Analytical, S. Norwalk, CT, USA) or a total hydrocarbon flame ionization detector (RS5; Ratfisch Instrumente, Munchen Germany).

- 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).

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The analytical measurements of the theoritical concentrations of 15, 45, 135 ppm were 14.8, 44.3 and 133.7 ppm, respectively.

Duration of treatment / exposure:

24 months

Frequency of treatment:

6 h/day, 5 d/week for 24 months

Dose / conc.:

0 ppm

Dose / conc.:

14.8 ppm

Remarks:

14.8 ppm analytical concentration (corresponding to 0.086 mg/L/day). Calculation of concentrations (mg/L) based on Derelanko MJ (2000). Toxicologist's Pocket Handbook, CRC Press, conversion table, p. 57.

Dose / conc.:

44.3 ppm

Remarks:

44.3 ppm analytical concentration (corresponding to 0.258 mg/L/day). Calculation of concentrations (mg/L) based on Derelanko MJ (2000). Toxicologist's Pocket Handbook, CRC Press, conversion table, p. 57.

Dose / conc.:

133.7 ppm

Remarks:

Doses / Concentrations:
133.7 ppm analytical concentration (corresponding to 0.773 mg/L/day). Calculation of concentrations (mg/L) based on Derelanko MJ (2000). Toxicologist's Pocket Handbook, CRC Press, conversion table, p. 57.

No. of animals per sex per dose:

86

Control animals:

yes, sham-exposed

Details on study design:

- Dose selection rationale: A high dose vapour concentration of 135 ppm was selected as the 'maximum tolerated dose' in accordance with NCI guidelines (Sontag et a. 1976).
- Rationale for selecting satellite groups: Interim groups were selected for autopsy at 12 and 18 months
- Post-exposure recovery period in satellite groups: 6 month post-exposure observation and recovery period following 24 months

Positive control:

No

Observations and examinations performed and frequency:

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

HEMATOLOGY: Yes
- Time schedule for collection of blood: at sacrifice
- Parameters examined: with respect to reticulocytes: normoblast and differential leucocyte counts; with respect to erythrocytes: hemoglobin content, mean corpuscular volume (MCV), mean corpuscular hemoglobin concentration (MCHC), and differential blood count

CLINICAL CHEMISTRY: No

URINALYSIS: Yes. Urine was sampled individually from all animals scheduled for autopsy.
- Parameters examined: volume, color, transparency, pH, protein, glucose, urobilinogen, ketone bodies, occult blood, and sediment microscopy.

OPHTHALMOLOGY: Yes. Eyes were examined at 12, 18, and 24 months. Eyes were also examined in a subset of animals allowed to recover for 6 months post 24 months exposure.

Parameters examined: external changes, pupillary reflex, changes in anterior part of the bulbus by slit lamp, and changes of the fundus

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
At the end of the study period, the surviving animals were sacrificed without previous diet deprivation. The sacrifice was carried out under anesthesia with diethyl ether by exsanguination. Then the animals were necropsied and assessed by gross-pathology. Subsequently the following organs were weighed: heart, liver, kidneys, spleen, testes, ovaries, thyroid gland, brain, lymph nodes, adrenals and lungs. The relative organ weights (organ weight/100 g body weight and brain weight) were calculated. All tissues with gross lesions and representative sections of organs and tissues were preserved in a 4% neutral formaldehyde solution. The testes were preserved in Bouins fixative and the lumbar vertebrae in Schaffer's fixative.

Statistics:

A comparison of the exposure groups with their respective control groups (each sex separately) was made setting the two-sided fiducial limit α =0.05 as a critical lebels of significance without corrections for multiple testing. Mortality was analyzed using the life-table method (Armitage et al. 1971). Body weight, food consumption, organ weights and all hematological paramaters were compared using Student's t-test or its modification according to Welch (Clauss and Ebner 1970). Moribund rats, rats found dead, and rats with apparently outlying values were excluded from routine statistics and interpreted separately. The total incidences of frequently observed histological changes were analyzed using contingency tables (Sokal and Rohlf 1969).

Clinical signs:

no effects observed

Mortality:

mortality observed, non-treatment-related

Description (incidence):

The mean life-table-corrected cumulative mortality across all groups was approximately 20%. On the whole, although heterogeneous, the data did not indicate that exposure to the test substance had an adverse effect on longevity. In general, the appearance and behaviour of the rats were normal. Overt signs of toxicity or reactions related to exposure were not observed. No significant difference between butyl acrylate and control groups was observed in male rats. In female rats, groups exposed to 15 and 135 ppm differed statistically significantly from the other Butyl acrylate exposed groups.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

Throughout the study, there was no significant influence on the body weight change of the male and female animals in any dose group compared with the control group. Food consumption in the group exposed to 135 ppm butyl acrylate was consistently lower (approximately 4%) than that of the control groups. The food consumption returned to normal at the end of the exposure period.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

effects observed, treatment-related

Description (incidence and severity):

Centrally localized or diffuse stippling of the corneal epithelium and cloudiness of the corneal parenchyma with various degrees of neovascularization were observed in butyl acrylate treated rats. Across all timepoints examined, a significant increase of parenchymal changes was evident in males and females exposed to 135 ppm.

Haematological findings:

no effects observed

Description (incidence and severity):

Hematocrit, hemoglobin content per erythrocytes, MCV (mean cell volume), MCHC (mean corpuscular hemoglobin concentration) and reticulocyte parameters were unaffected.

Clinical biochemistry findings:

not examined

Urinalysis findings:

no effects observed

Description (incidence and severity):

No treatment-related effects of the test substance could be seen from the urinary findings. Elevated urinary erythrocyte counts and protein concentrations were observed in most of male and several females rats of all groups including control and were suggestive of spontaneous inflammatory changes common in ageing rats of this strain.

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

The autopsies performed after 24 months revealed 5-17% lower weight of kidneys, thyroid, heart and liver in some of the Butyl acrylate exposed groups (not specified). Despite the statistical significance, the findings were not considered to be toxicologically relevant because they were neither consistently dose-dependent nor did they correlate with histopathological changes.

Gross pathological findings:

no effects observed

Description (incidence and severity):

Autopsy revealed only incidental patho-anatomical changes or gerontic patho-anatomical changes typical of aged Sprague-Dawley rats.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Histological examinations revealed concentration dependent lesions in the nasal mucosa at the level of the dorsal lamella of the second turbinate. A significant incidence of stratified reserve cell hyperplasia in level 2 of the nasal mucosa was observed in all exposure groups. Slight atrophy of the neurogenic part of the olfactory epithelium was observed in a few male rats exposed to 15 ppm butyl acrylate. Most changes developed during the first 12 months of exposure and increased only moderately with ongoing exposure. Changes in the nasal cavity are mainly attributed to the irritating properties of acrylates. No irritative changes were observed in the larynx, trachea or lungs.

Histopathological findings: neoplastic:

no effects observed

Description (incidence and severity):

Leukemic changes were observed in some male rats exposed to butyl acrylate but only at 45 ppm. For the females, only one case was recorded which occurred in the control group. The overall incidence of leukemic changes in the butyl acrylate exposed groups was well within the expected incidence of spontaneous leukemia in Sprague-Dawley Rats. A few other benign mesenchymal lesions and sarcomas of the soft tissue were distributed heterogeneously across butyl acrylate exposed groups. Overall there was no detectable dose dependency for any tumour type and were not considered to be treatment-related.

Key result

Dose descriptor:

NOAEC

Effect level:

0.258 mg/L air (analytical)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

ophthalmological examination

Key result

Dose descriptor:

LOAEC

Effect level:

0.086 mg/L air (analytical)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

histopathology: non-neoplastic

Critical effects observed:

not specified

Conclusions:

Under the test conditions of this study, the NOAEL for N-butyl acrylate is 0.258 mg/L (45 ppm) based on ophthalmological findings, and 0.086 mg/L (15 ppm) based on irritative histological changes in nasal mucosa.

Executive summary:

In a 2-year inhalation study, Sprague-Dawley rats were exposed by whole body exposure 6 hours per day, 5 days a week to 0, 15, 45 or 135 ppm (0, 0.086, 0.258, 0.773 mg/L butyl acrylate. During the first 13 weeks of the study, the concentrations were lower: 0, 5, 15 or 45 ppm. The post observation period was 6 months (BASF AG 1985). There were no compound-related effects on general behaviour or appearance (no overt signs of toxicity and no effects on mortality). Body weight gain was normal in all groups, with only a slight decrease in food consumption in treated males and females. No compound-related effects were detected in haematological measurements or urinalysis. Organ weights were generally unaffected by treatment, except for slightly lower relative heart, kidney, liver and thyroid weights in the highest dose. Ophthalmological examinations demonstrated localized or diffuse stippling of the corneal epithelium, cloudiness of the cornea, and various degrees of vascularisation that increased with dose and duration of exposure. These effects were only significant in the highest dose group (compared with the controls), thus the NOAEC for effects on the eye is 45 ppm (0.258 mg/L). Histological changes in the nasal mucosa were dose-dependent and described as slight atrophy of the neurogenic part of the olfactory epithelium at 15 ppm, and partial loss of the columnar cell layer and stratified reserve-cell hyperplasia at 45 and 135 ppm. The frequency of reserve-cell hyperplasia in nasal mucosa was 0, 8/169, 41/170, and 105/170 (for males and females combined) at 0, 15, 45, and 135 ppm, respectively. Males and females were affected in the same manner. No changes were detected in the posterior nasal cavity, and no irritation effects were detected on the larynx, trachea or lungs. The changes in the nasal mucosa and cornea proved to be reversible up to a point during the follow-up period. For these histological changes of the nasal mucosa no NOAEC could be derived. The LOAEC is 15 ppm (0.086 mg/L). Examinations of tissues for neoplastic changes did not reveal any compound related increases or dose dependent effects.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LOAEC

86 mg/m³

Study duration:

chronic

Species:

rat

Additional information

Repeated dose toxicity: Oral:

In a 13 week-study, F344-rats (15 animals per sex and dose) received 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 (Gorzinski 1982). 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 haematology, clinical chemistry, urinalysis, or histopathology findings were reported. In the gavage satellite group, the only effect observed was a slight increase in relative liver weight. The highest level administered in drinking water approaches the maximum solubility limit of butyl acrylate in water and thus was the highest concentration that could be reasonably given. The NOAEL for the drinking water study is 84 (male) and 111 (female) mg/kg body weight per day.

Repeated dose 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).

In a 2-year inhalation study, Sprague-Dawley rats were exposed by whole body exposure 6 hours per day, 5 days a week to 0, 15, 45 or 135 ppm (0, 0.086, 0.258, 0.773 mg/L butyl acrylate. During the first 13 weeks of the study, the concentrations were lower: 0, 5, 15 or 45 ppm. The post observation period was 6 months (Reininghaus 1985). There were no compound-related effects on general behaviour or appearance (no overt signs of toxicity and no effects on mortality). Body weight gain was normal in all groups, with only a slight decrease in food consumption in treated males and females. No compound-related effects were detected in haematological measurements or urinalysis. Organ weights were generally unaffected by treatment, except for slightly lower relative heart, kidney, liver and thyroid weights in the highest dose. Ophthalmological examinations demonstrated localized or diffuse stippling of the corneal epithelium, cloudiness of the cornea, and various degrees of vascularisation that increased with dose and duration of exposure. These effects were only significant in the highest dose group (compared with the controls), thus the NOAEC for effects on the eye is 45 ppm (0.258 mg/L). Histological changes in the nasal mucosa were dose-dependent and described as slight atrophy of the neurogenic part of the olfactory epithelium at 15 ppm, and partial loss of the columnar cell layer and stratified reserve-cell hyperplasia at 45 and 135 ppm. The frequency of reserve-cell hyperplasia in nasal mucosa was 0, 8/169, 41/170, and 105/170 (for males and females combined) at 0, 15, 45, and 135 ppm, respectively. Males and females were affected in the same manner. No changes were detected in the posterior nasal cavity, and no irritation effects were detected on the larynx, trachea or lungs. The changes in the nasal mucosa and cornea proved to be reversible up to a point during the follow-up period. For these histological changes of the nasal mucosa no NOAEC could be derived. The LOAEC is 15 ppm (0.086 mg/L). Examinations of tissues for neoplastic changes did not reveal any compound related increases or dose dependent effects.

Justification for classification or non-classification

N-hexyl acrylate was evaluated for its specific target organ 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 local effects 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 showed no toxicity in a 90 -day oral drinking water study with a NOAEL of 84 mg/kg and 111 mg/kg for males and females respectively based on the highest dose (maximum water solubility limit). In a sub-chronic inhaltion study, mortality and treatment-related effects were reported in the highest dose group (546 ppm), with a NOAEC of 570 mg/m3 (108 ppm). In a 2 -year chronic inhalation study, no significant increase or treatment-related effects on systemic toxicity were observed.

However, local effects related to the irritating nature of the test substance was observed including histological changes in the nasal mucosa in the subchronic study which was also observed as slight atrophy of the neurogenic olfactory epithelium, accompanied by partial loss of the columnar cell layer and reserve cell hyperplasia in the chronic study. The LOAEC for these changes in the chronic study was the lowest dose tested (86 mg/m3). As n-hexyl acrylate is expected to be equally irritating, classification of n-hexyl acrylate as a Specific Target Organ Category 3 Respiratory Irritant is warranted under the Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP).