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Toxicological information

Repeated dose toxicity: inhalation

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Administrative data

sub-chronic toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
24 January 1977 to 25 April 1977
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)

Data source

Referenceopen allclose all

Reference Type:
study report
Report date:
Reference Type:
study report
Report date:

Materials and methods

Test guideline
equivalent or similar to guideline
OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
no opthalmological examinations were made
GLP compliance:
Limit test:

Test material

Constituent 1
Chemical structure
Reference substance name:
Butyl acrylate
EC Number:
EC Name:
Butyl acrylate
Cas Number:
Molecular formula:
butyl prop-2-enoate
Test material form:
other: liquid

Test animals

Details on test animals or test system and environmental conditions:
- 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

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
other: unchanged (no vehicle)
Remarks on MMAD:
MMAD / GSD: no data
Details on inhalation exposure:
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.

- 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:
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)
Doses / concentrations
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.
analytical conc.
No. of animals per sex per dose:
Control animals:
yes, sham-exposed
Positive control:


Observations and examinations performed and frequency:
- Time schedule: daily

- Time schedule for examinations: weekly

- 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

- 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:
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.
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.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
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.

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.

Effect levels

open allclose all
Dose descriptor:
Effect level:
0.57 mg/L air (analytical)
Basis for effect level:
other: Systemic effects
Dose descriptor:
Effect level:
1.11 mg/L air (analytical)
Basis for effect level:
other: Systemic effects: body weight decrease, clinical chemistry (only in females)
Dose descriptor:
Effect level:
0.11 mg/L air (analytical)
Basis for effect level:
other: Local effects
Dose descriptor:
Effect level:
0.57 mg/L air (analytical)
Basis for effect level:
other: Local effects: histological changes in nasal mucosa

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion