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Repeated dose toxicity: inhalation

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Administrative data

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

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1978
Report date:
1978

Materials and methods

Test guideline
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

Test material

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

Test animals

Species:
rat
Strain:
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

Administration / exposure

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
Doses / concentrationsopen allclose all
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

Examinations

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.

Results and discussion

Results of examinations

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

Effect levels

open allclose all
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

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

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).