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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
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)

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1978
Report date:
1978
Reference Type:
study report
Title:
Unnamed
Year:
1980
Report date:
1980

Materials and methods

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

Test material

Constituent 1
Chemical structure
Reference substance name:
Methyl acrylate
EC Number:
202-500-6
EC Name:
Methyl acrylate
Cas Number:
96-33-3
Molecular formula:
C4H6O2
IUPAC Name:
methyl acrylate
Details on test material:
- Name of test material (as cited in study report): Methyl acrylate
- Analytical purity: 99.5 % pure

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: WIGA, Sulzfeld, D (SPF breed)
- Age at study initiation: 42 d
- Weight at study initiation: mean males 150 g (121-173 g); mean females 131 g (113-146 g)
- Housing: 2-3/cage
- Diet (e.g. ad libitum): Altromin-R supplied by Altrogge, Lage/Lippe, D
- Water (e.g. ad libitum): tap water


ENVIRONMENTAL CONDITIONS
The animals were housed in conventionally heated and aired rooms.

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 (UNITA I, B. BRAUN, Melsungen, D) the liquid product was metered onto a vaporizer at a constant rate and vaporized there. A stream of supply air measured by means of a rotameter took up the vapors. This vapour-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 methyl acrylate air mixture was measured continuously using a flame ionization detector (FID). Apparatus used was FID total hydrocarbons analyzer (CARLO ERBA, mod. 370). In addition for calibration purposes, a Wilks Miran I A IR analyzer was used.
- Samples taken from breathing zone: yes. Sampling was carried out by means of a diaphragm pump which continuously passes the methyl 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 30 minutes per chamber, and the sweeping time 10 minutes (measuring cycle).
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The analytical measurements of the theoretical concentrations of 21, 117, 218 and 603 ppm after correction were 23, 124, 242 and 626 ppm, respectively.
Duration of treatment / exposure:
6 hours/day
Frequency of treatment:
5 times per week, for 12 weeks
Doses / concentrations
Remarks:
Doses / Concentrations:
626, 242, 124 and 23 ppm; i.e. 2.24, 0.86, 0.44 and 0.082 mg/L, respectively
Basis:
analytical conc.
No. of animals per sex per dose:
10
Control animals:
yes, sham-exposed
Details on study design:
Post-exposure period: one day
Positive control:
no

Examinations

Observations and examinations performed and frequency:
Animals were checked daily for clinical signs and lethality. Body weights were checked weekly. Ophthalmological examinations, using an ophthalmoscope, were not made.
Sacrifice and pathology:
At the terminal sacrifice (after a fasting period of 16 hours), organ weights were taken and samples were collected for histopathological examination, which included the gonads and accesory sex organs.
Other examinations:
Blood chemistry, enzyme levels, and hematology were performed 7 days before beginning of the exposure, and at 4, 8 and 12 weeks. Urinalysis was performed at 3, 7 and 11 weeks.
Statistics:
t-test according to Williams, 1971/2, and chi-square test.

Results and discussion

Results of examinations

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:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
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
All animals in the 626 ppm group died during the first half of the study. No animals died in the 23-242 ppm dose groups.
At the 23 and 124 ppm doses, the test substance was tolerated without any signs. At 242 ppm it caused nose and eye irritation, and dyspnoea at the beginning of exposure, but after 1/4 of the exposure period, these signs were no longer observed. At 626 ppm the animals exhibited laboured breathing, irritation of the mucosa, and hemorrhagic discharge from the eyes and nose that became increasingly severe.


BODY WEIGHT AND WEIGHT GAIN
A reduced body weight gain of the exposed animals in groups 2 - 4 (124 - 626 ppm) is to be regarded as treatment relevant. It is significant and dose-related in the male rats of groups 2 - 4 (124 - 626 ppm). In the female rats in these groups, test substance elicits an effect which is less pronounced, but also dose dependent in its trend and which also causes a reduced body weight change when compared with the control animals.


HAEMATOLOGY
Hematological parameters of the highest group were not determined because the animals died before the sampling time. No relevant substance-induced changes in the remaining dose groups were detectable in the hematological findings.


CLINICAL CHEMISTRY
Clinical chemistry parameters of the highest group were not determined because the animals died before the sampling time. No relevant substance-induced changes in the remaining dose groups were detectable in the clinicochemical findings. A rise in sodium values and a drop in potassium values was found in the 242 ppm group. No other clinical chemistry changes were seen.


ORGAN WEIGHTS
The increased relative lung and liver weights of the 242-ppm group are an indication of a relevant influence of the test substance. A similar trend can be recognized only in the female animals of the 124-ppm group. Absolute organ weights of heart, liver, kidney and spleen were decreased in males of the 242 ppm dose group, absolute spleen weight of males was also reduced in the 124 ppm group. None of these organ weight changes were substance induced since there is no correlation to other study results, and an equivalent pathological pattern was absent.

GROSS PATHOLOGY
All animals in the 626 ppm group died mainly due to strong irritation by the test substance to the repiratory tract (hyperemia in the trachea and lungs and bronchopneumonia). In the 23-242 ppm dose groups, gross pathology revealed no substance related changes.

HISTOPATHOLOGY: NON-NEOPLASTIC
Upon examination of the nasal mucosa, substance-induced changes were noted in the two higher dose groups. One animal in the 626 ppm dose group showed an atrophic epithelium, and in 3 animals a purulent-necrotic rhinitis was observed. Keratinisation of the transition epithelium between respiratory and olfactory epithelium was observed in 5 animals and damage to the olfactory epithelium was extensive (degeneration and vacuolization). The epithelium was atrophic in four of the 242 ppm rats, and in one rat keratinisation of the transition zone between respiratory and olfactory epithelium and necrosis were observed. No histopathological changes were found in the 23 and 124 ppm dose groups.

Effect levels

open allclose all
Key result
Dose descriptor:
NOAEC
Effect level:
0.082 mg/L air
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects were observed at this concentration.
Key result
Dose descriptor:
LOAEC
Effect level:
0.44 mg/L air
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: body weight change and organ weight changes (lung and liver)

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

BODY WEIGHTS

Body weight at the end of the study:
ppm male body weight female body weight
0 367.7 g 223.2 g
23 363.5 g (-1 %) 224.5 g (+1 %)
124 339.4 g* (-7.9 %) 212.8 g (-4.5 %)
242 312.9 g** (-14.2 %) 206.0 g (- 7 %)
626 n.d. n.d
*/** level of significance 5% / 1% in relation to control

Differences in body weight gain:
ppm male female
0 -- --
23 -1 % +2 %
124 -9 % -7 %
242 -17 % -9 %
626 n.d. n.d


ORGAN WEIGHTS:

males:
ppm 0 23 124 242 626
heart(g) 1.11 1.08 1.03 0.99* n.d.
liver(g) 8.72 8.34 8.52 7.34** n.d.
kidney(g) 2.22 2.20 2.17 1.90** n.d.
spleen(g) 0.67 0.64 0.57* 0.51** n.d.
gonads(g) 3.07 3.24 3.10 3.06 n.d.
lungs(g) 1.13 1.22 1.11 1.15 n.d

females:
ppm 0 23 124 242 626
heart(g) 0.76 0.73 0.70 0.71 n.d.
liver(g) 5.59 5.78 5.79 5.62 n.d.
kidney(g) 1.49 1.51 1.46 1.45 n.d.
spleen(g) 0.41 0.47 0.43 0.44 n.d.
lungs(g) 0.89 0.91 0.91 0.91 n.d.

*/** level of significance 5% / 1% in relation to control


Applicant's summary and conclusion