methyl acrylate; methyl propenoate

Repeated dose toxicity: inhalation

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

Reference

Reference 1

Reference Type:

study report

Title:

Unnamed

Year:

1978

Report date:

1978

Reference 2

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

Test material information

Constituent 1

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 prop-2-enoate

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

1

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.

2

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