Registration Dossier

Administrative data

Description of key information

In a subchronic study in Sprague-Dawley rats following vapour inhalation for 13-weeks, the NOAEC was 570 mg/m3 (108 ppm). The respective LOAEC based on reduced body weight, clinico-chemical changes and changed organ weights was 1100 mg/m3 (211 ppm). Following chronic exposure by the inhalation route (5 d/w, 6 h/d), the NOAEC for ocular effects in rats was 258 mg/m3 (45 ppm); the LOAEC for local effects on the nasal epithelium was 86 mg/m3 (15 ppm). The systemic NOAEC was >= 773 mg/m3 (135 ppm). Following a 90-day oral administration of BA in the drinking water, the NOAEL was 84 (male) and 111 (female) mg/kg bw/d for F344 rats, respectively.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study conducted in compliance with GLP regulations.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Deviations:
no
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals 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
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY: No mortality and clinical signs were observed.


BODY WEIGHT AND WEIGHT GAIN: 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.


WATER INTAKE (if drinking water study): 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.


FOOD CONSUMPTION: There were no differences betwen experimental and control groups.


HAEMATOLOGY: No treatment related effects were observed.


CLINICAL CHEMISTRY: Clinical chemistry determinations revealed no statistically significant differences between treated and control groups.


URINALYSIS: Results of urinalyses were similar for experimental and control rats.


ORGAN WEIGHTS: 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 PATHOLOGY: Findings were similar for control and experimental rats.


HISTOPATHOLOGY: NON-NEOPLASTIC: 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.


Dose descriptor:
NOAEL
Effect level:
84 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: high dose
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:
not specified

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.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
84 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
GLP and guideline equivalent study.

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
24 January 1977 to 25 April 1977
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study with acceptable restrictions (similar to OECD guideline 413, but no opthalmological examinations were made)
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
Deviations:
yes
Remarks:
no opthalmological examinations were made
GLP compliance:
no
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals 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)
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 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 of the theoritical concentrations of 20, 100, 200 and 550 ppm were 21, 108, 221 and 546 ppm, respectively.
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
6 h/day, 5 d/week for 13 weeks (63 exposures)
Remarks:
Doses / Concentrations:
0, 21, 108, 211, and 546 ppm (corresponding to 0, 0.11, 0.57, 1.11, 2.86 mg/L/day) Calculation of concentrations (mg/L) based on Derelanko MJ (2000). Toxicologist's Pocket Handbook, CRC Press, conversion table, p. 57.
Basis:
analytical conc.
No. of animals per sex per dose:
20
Control animals:
yes, sham-exposed
Positive control:
none
Observations and examinations performed and frequency:
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily


BODY WEIGHT: Yes
- Time schedule for examinations: weekly



HAEMATOLOGY: Yes
- Time schedule for 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.
- 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


CLINICAL CHEMISTRY: Yes
- 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: Yes. 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:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
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.
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. For urinalyses, assessment of whether or not certain pronounced characteristics are different in the control and test groups was carried out by means of the chi test in appropriate two-by-two contingency tables taking the Yates correction for continuity into account.
Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
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
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY: 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. 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.


BODY WEIGHT AND WEIGHT GAIN: Throughout the study, there was no significant influence on the body weight change of the male and female animals in the 21 ppm and 108 ppm dose groups compared with the control group, except in one weighing after 7 days, only the female animals of 108 ppm dose group exhibited a significant decrease in body weight caused by a very slight body weight gain in 4 animals. In the 211 ppm dose group, the body weight of the female rats was decreased from day 7 to day 77 after the beginning of the study (at a significance of 95-99%). The animals showed no significant body weight changes at the weighing after 85 and 91 days. At the final weighing, the body weight was decreased (at a significance of 95%). In the male rats, the body weight was significantly decreased after 63 days until the end of the study (at a significance of 95-99%).


HAEMATOLOGY: Hematocrit, hemoglobin content per erythrocytes, MCV (mean cell volume) and MCHC (mean corpuscular hemoglobin concentration) were unaffected. There was increase in hemoglobin content and erythrocytes in male and female animals of the 546 ppm dose group in blood sampling 1-3. The changes in the leukocyte and monocyte counts occured only in one sex, hence cannot be considered test substance specific.


CLINICAL CHEMISTRY: Total bilirubin, Creatinine, Inorganic phosphate, Calcium, Chloride, Triglycerides and enzymes (Glutamic pyruvic transaminaseand Glutamic oxalacetic transaminase) were unaffected. There was an increase in sodium level in male and female animals of the 546 ppm dose group in blood sampling 2 and 3. An increase in the level of Alkaline phosphatase was observed only in female animals of the 211 and 546 ppm dose groups, however a time- and dose-dependent trend was seen. There was a decrease in the levels of potassium, total protein, glucose and cholesterol in female animals only.


URINALYSIS: No adverse effects of the test substance could be seen from the urinary findings.


ORGAN WEIGHTS: In females an increase in the relative liver weights was observed in all dose groups. Only in the highest dose group the relative lung weight was increased in both sexes. Increased thyroid weight was observed in the females of highest dose group. Increased adrenal weight was observed in the highest dose group of both sexes and males of 211 ppm dose group.


GROSS PATHOLOGY: In gross examination, lesions were detected mainly in the 16 male animals in the 546 ppm group that died intercurrently between days 17 and 69, and in the 15 female animals in the 546 ppm group that died between days 24 and 90. Raised foci of bronchopneumonia of about the size of a rice grain with sporadic whitish-gray or darkred 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 ressembled lard. In a few animals, fibrinous pleuritis was also to be seen. The nutritional state of these rats was poor. Many of them had advanced autolysis. Essentially, the animals of this group (4 males and 5 females) and of the 211, 108, 21 and 0 ppm groups that survived until the end of the study showed pneumonic zones that were randomly distributed among various lobes, and a few female animals showed hydrometra.


HISTOPATHOLOGY: NON-NEOPLASTIC:
546 ppm dose group: Histopathological changes were found mostly in the respiratory tract of the animals in the 546 dose ppm group that died intercurrently. In the male and female rats slight hyperemia of the nasal mucosa, edema and dysplasia of the epithelial mucosa was observed. In one female animal pronounced purulent rhinitis was noted. Hyperemia and edema were found also in the trachea in almost all males that died spontaneously and that were examined in this group; they were seen 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. It consisted of metaplastic epithelial cells still containing mucin and dark-nuclear cells (some of them mononuclear) and which had to be distinguished from the usual rat-specific infiltrates. 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. Male and female animals that died intercurrently were found to have hyperemia and necrosis in the liver (1 male and 1 female) together with fatty deposits predominantly in the peripheral zones of the lobules, these being more pronounced in the females. In one third of the male animals the glycogen content was slightly increased. The spleen of two male animals of the 546 ppm group showed hyperemia, of one female moderate fibrosis and the thymus of four males and one female hemorrhages. In the case of the bone marrow, erythropoesis prevailed in four male and three female rats and granulopoesis in four male and seven females, in some with a shift to the left. Hyperemia of the kidneys and meninges, and a cyst in the anterior lobe (twice) was found in the animals of the 546 ppm group that died spontaneously.
Other dose groups: 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 male animals of the 211, 108 and 0 ppm dose groups, the fat-free vacuoles (hematoxylin eosin stain), fatty deposits, mainly in Kupffer’s star cells, and increase of the glycogen content in the liver were attributed to the fact that these animals had not been fasted on the day before they were necropsied and therefore the findings are to be regarded normal. Using the Turnbull blue reaction, a slight decrease in the hematogenic iron pigment was seen above all in the females of the 211 and 108 ppm groups when compared with the control. No histopathological examinations were carried out in the 21 ppm group.

Dose descriptor:
NOAEC
Effect level:
0.57 mg/L air (analytical)
Sex:
male/female
Basis for effect level:
other: Systemic effects
Dose descriptor:
LOAEC
Effect level:
1.11 mg/L air (analytical)
Sex:
male/female
Basis for effect level:
other: Systemic effects: body weight decrease, clinical chemistry (only in females)
Dose descriptor:
NOAEC
Effect level:
0.11 mg/L air (analytical)
Sex:
male/female
Basis for effect level:
other: Local effects
Dose descriptor:
LOAEC
Effect level:
0.57 mg/L air (analytical)
Sex:
male/female
Basis for effect level:
other: Local effects: histological changes in nasal mucosa
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEC
570 mg/m³
Study duration:
subchronic
Species:
rat
Quality of whole database:
Guideline equivalent study

Repeated dose toxicity: inhalation - local effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
24 January 1977 to 25 April 1977
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study with acceptable restrictions (similar to OECD guideline 413, but no opthalmological examinations were made)
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
Deviations:
yes
Remarks:
no opthalmological examinations were made
GLP compliance:
no
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals 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)
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 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 of the theoritical concentrations of 20, 100, 200 and 550 ppm were 21, 108, 221 and 546 ppm, respectively.
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
6 h/day, 5 d/week for 13 weeks (63 exposures)
Remarks:
Doses / Concentrations:
0, 21, 108, 211, and 546 ppm (corresponding to 0, 0.11, 0.57, 1.11, 2.86 mg/L/day) Calculation of concentrations (mg/L) based on Derelanko MJ (2000). Toxicologist's Pocket Handbook, CRC Press, conversion table, p. 57.
Basis:
analytical conc.
No. of animals per sex per dose:
20
Control animals:
yes, sham-exposed
Positive control:
none
Observations and examinations performed and frequency:
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily


BODY WEIGHT: Yes
- Time schedule for examinations: weekly



HAEMATOLOGY: Yes
- Time schedule for 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.
- 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


CLINICAL CHEMISTRY: Yes
- 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: Yes. 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:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
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.
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. For urinalyses, assessment of whether or not certain pronounced characteristics are different in the control and test groups was carried out by means of the chi test in appropriate two-by-two contingency tables taking the Yates correction for continuity into account.
Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
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
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY: 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. 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.


BODY WEIGHT AND WEIGHT GAIN: Throughout the study, there was no significant influence on the body weight change of the male and female animals in the 21 ppm and 108 ppm dose groups compared with the control group, except in one weighing after 7 days, only the female animals of 108 ppm dose group exhibited a significant decrease in body weight caused by a very slight body weight gain in 4 animals. In the 211 ppm dose group, the body weight of the female rats was decreased from day 7 to day 77 after the beginning of the study (at a significance of 95-99%). The animals showed no significant body weight changes at the weighing after 85 and 91 days. At the final weighing, the body weight was decreased (at a significance of 95%). In the male rats, the body weight was significantly decreased after 63 days until the end of the study (at a significance of 95-99%).


HAEMATOLOGY: Hematocrit, hemoglobin content per erythrocytes, MCV (mean cell volume) and MCHC (mean corpuscular hemoglobin concentration) were unaffected. There was increase in hemoglobin content and erythrocytes in male and female animals of the 546 ppm dose group in blood sampling 1-3. The changes in the leukocyte and monocyte counts occured only in one sex, hence cannot be considered test substance specific.


CLINICAL CHEMISTRY: Total bilirubin, Creatinine, Inorganic phosphate, Calcium, Chloride, Triglycerides and enzymes (Glutamic pyruvic transaminaseand Glutamic oxalacetic transaminase) were unaffected. There was an increase in sodium level in male and female animals of the 546 ppm dose group in blood sampling 2 and 3. An increase in the level of Alkaline phosphatase was observed only in female animals of the 211 and 546 ppm dose groups, however a time- and dose-dependent trend was seen. There was a decrease in the levels of potassium, total protein, glucose and cholesterol in female animals only.


URINALYSIS: No adverse effects of the test substance could be seen from the urinary findings.


ORGAN WEIGHTS: In females an increase in the relative liver weights was observed in all dose groups. Only in the highest dose group the relative lung weight was increased in both sexes. Increased thyroid weight was observed in the females of highest dose group. Increased adrenal weight was observed in the highest dose group of both sexes and males of 211 ppm dose group.


GROSS PATHOLOGY: In gross examination, lesions were detected mainly in the 16 male animals in the 546 ppm group that died intercurrently between days 17 and 69, and in the 15 female animals in the 546 ppm group that died between days 24 and 90. Raised foci of bronchopneumonia of about the size of a rice grain with sporadic whitish-gray or darkred 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 ressembled lard. In a few animals, fibrinous pleuritis was also to be seen. The nutritional state of these rats was poor. Many of them had advanced autolysis. Essentially, the animals of this group (4 males and 5 females) and of the 211, 108, 21 and 0 ppm groups that survived until the end of the study showed pneumonic zones that were randomly distributed among various lobes, and a few female animals showed hydrometra.


HISTOPATHOLOGY: NON-NEOPLASTIC:
546 ppm dose group: Histopathological changes were found mostly in the respiratory tract of the animals in the 546 dose ppm group that died intercurrently. In the male and female rats slight hyperemia of the nasal mucosa, edema and dysplasia of the epithelial mucosa was observed. In one female animal pronounced purulent rhinitis was noted. Hyperemia and edema were found also in the trachea in almost all males that died spontaneously and that were examined in this group; they were seen 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. It consisted of metaplastic epithelial cells still containing mucin and dark-nuclear cells (some of them mononuclear) and which had to be distinguished from the usual rat-specific infiltrates. 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. Male and female animals that died intercurrently were found to have hyperemia and necrosis in the liver (1 male and 1 female) together with fatty deposits predominantly in the peripheral zones of the lobules, these being more pronounced in the females. In one third of the male animals the glycogen content was slightly increased. The spleen of two male animals of the 546 ppm group showed hyperemia, of one female moderate fibrosis and the thymus of four males and one female hemorrhages. In the case of the bone marrow, erythropoesis prevailed in four male and three female rats and granulopoesis in four male and seven females, in some with a shift to the left. Hyperemia of the kidneys and meninges, and a cyst in the anterior lobe (twice) was found in the animals of the 546 ppm group that died spontaneously.
Other dose groups: 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 male animals of the 211, 108 and 0 ppm dose groups, the fat-free vacuoles (hematoxylin eosin stain), fatty deposits, mainly in Kupffer’s star cells, and increase of the glycogen content in the liver were attributed to the fact that these animals had not been fasted on the day before they were necropsied and therefore the findings are to be regarded normal. Using the Turnbull blue reaction, a slight decrease in the hematogenic iron pigment was seen above all in the females of the 211 and 108 ppm groups when compared with the control. No histopathological examinations were carried out in the 21 ppm group.

Dose descriptor:
NOAEC
Effect level:
0.57 mg/L air (analytical)
Sex:
male/female
Basis for effect level:
other: Systemic effects
Dose descriptor:
LOAEC
Effect level:
1.11 mg/L air (analytical)
Sex:
male/female
Basis for effect level:
other: Systemic effects: body weight decrease, clinical chemistry (only in females)
Dose descriptor:
NOAEC
Effect level:
0.11 mg/L air (analytical)
Sex:
male/female
Basis for effect level:
other: Local effects
Dose descriptor:
LOAEC
Effect level:
0.57 mg/L air (analytical)
Sex:
male/female
Basis for effect level:
other: Local effects: histological changes in nasal mucosa
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEC
110 mg/m³
Study duration:
subchronic
Species:
rat
Quality of whole database:
Guideline equivalent study

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

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 (Dow Chemical 1980). 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.

In a sub acute oral toxicity test, 3 rabbits were treated by gavage with 900 mg/kg bw of the test substance in a 10 % aqueous emulsion in traganth for 5 consecutive days/week over an exposure period of 14 days (9 applications). No mortality was observed. One animal exhibited a decrease of body weight during 14 days of experimental period. Basophilia was observed in all 3 animals (5-8 % increase) and individual animals exhibited polychromasia and eosinophilia. No effect on blood urea level was observed. No treatment related effects in the urine were observed. Blood of all animals was light red in colour, but no other gross changes were observed. In addition, no histopathological treatment related effects were observed. (BASF 1960)

Repeated dose toxicity: Inhalation:

Sprague Dawley rats (20 animals per sex and dose) were exposed by inhalation to measured concentrations of 0, 21, 108, 211 and 546 ppm (corresponding to approx. 0, 0.11, 0.57, 1.11, 2.86 mg/L) for 6 hours per day, 5 days/week for 13 weeks (BASF AG 1979, 1980). Clinical, clinico-chemical, haematological, gross-pathological, and histopathological examinations revealed no substance-related effects in the 21 and 108 ppm dose groups. At 211 ppm, the test substance caused eye irritation and irritation of the nasal mucosa. Significant reductions in body weight changes (13.3 %) were observed. In clinico-chemical examinations of females, decreased potassium values and an increase in alkaline phosphatase activity were observed. In the 546 ppm dose group, 31 of 40 animals (77 %) died. Hemorrhagic discharge from eyes and noses and severe dyspnoea were observed, which became constantly more severe. Many clinico-chemical and haematological parameters were affected in animals of this dose group. The animals died during exposure due to strong irritation of the respiratory tract. Metaplasia of the respiratory epithelium as far as the terminal bronchioles and proliferation of the bronchoalveolar epithelium could be detected in histopathological examinations.

The NOAEC for this study is 108 ppm (0.57 mg/L/day) and the LOAEC is 211 ppm (1.11 mg/L/day) based on body weight decrease, clinico-chemical changes, and changed organ weights. The NOAEC for local effects (histological changes in the nasal mucosa and olfactory epithelium) is 21 ppm (0.11 mg/L/day) and the LOAEC is 108 ppm (0.57 mg/L/day).

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.

In addition, two other studies are available, but for both the reliability was unknown (klimisch 4).

Repeated dose toxicity: Dermal:

No subacute or subchronic repeated dose studies with dermal application are available for Butyl acrylate. A lifetime dermal carcinogenesis study was conducted in mice. The dermal carcinogenic potential of butyl acrylate was assessed by applying 25 µL of a 1% (v/v) dilution in acetone (corresponding to approx. 8 mg/kg bw) to the backs of 40 male C3H/HeJ mice. Butyl acrylate was not carcinogenic when applied to the skin of C3H/HeJ mice throughout their lifetime.


Justification for classification or non-classification

CLP classification (Regulation (EC) No 1272/2008):

- Specific Target Organ Toxicity: Repeated Exposure: no classification required