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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:
no data
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Peer reviewed literature data

Data source

Reference
Reference Type:
publication
Title:
The Mammalian Toxicity of Methacrylonitrile
Author:
Pozzani UC, Kinkead ER & King JM
Year:
1968
Bibliographic source:
American Industrial Hygiene Association Journal 29:202-210

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
other: No data
Deviations:
not specified
Principles of method if other than guideline:
Groups of Harla-Wister rats were exposed to a range of concentrations of methacrylanitrile vapor for 7 hours per day, 5 days per week, for a total of 91 days.
GLP compliance:
not specified
Limit test:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
Methacrylonitrile
EC Number:
204-817-5
EC Name:
Methacrylonitrile
Cas Number:
126-98-7
Molecular formula:
C4H5N
IUPAC Name:
methacrylonitrile
Details on test material:
- Name of test material (as cited in study report): Methacrylonitrile
- Molecular weight (if other than submission substance): 67.09
- Substance type: organic, monoconstituent
- Physical state: clear, colourless liquid
- Analytical purity: minimum of 99.0 wt %
- Boiling point at 760 mm, 90.3°C
- Specific gravity d 30°/4°, 0.7896
- Solubility in water: 2.54 wt % at 30°C
- Flash point (Tag open cup): 55°F
- Vapor pressure: 65 mm (sic) at 25 Degrees Centigrade
- Inhibitor (MEHQ): 35-45 ppm
- Other: Air saturated with methacrylonitrile at 25 degrees Centigrade and 760 mm contains 85,526 ppm vapor, which has a relative vapor density of 1.11 (dry air=1).
- Source: Vistron Corporation, Midland Building, Cleveland, Ohio.

Test animals

Species:
rat
Strain:
other: Harlan-Wister
Sex:
male/female
Details on test animals or test system and environmental conditions:
No data

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure:
not specified
Vehicle:
other: no data
Remarks on MMAD:
MMAD / GSD: No data
Details on inhalation exposure:
No data
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Median measured concentrations were obtained using an F and M Model 609 flame ionization Gas Chromatograph with the follow conditions:
Column: copper, 10' long, ¼" O.D.
Solid support: Gaschrome Q®, 60 -80 mesh.
Stationary phase: Tergitol® NP-44 (15%).
Column Temperature: 90 degrees Centigrade.
Pyrometer: 295 degrees Centigrade.
Injection port: 200 degrees Centigrade
Detector block: 185 degrees Centigrade
Carrier gas: helium, 90 mL/ min
Retention time: 3 min
Size of vapor samples: 1 -5 mL
Lower limit of detection: approximately 0.3 ppm methacrylonitrile vapor.
Duration of treatment / exposure:
7 hours per day
Frequency of treatment:
5 days per week for a total of 91 days
Doses / concentrations
Remarks:
Doses / Concentrations:
109.3, 52.6, 19.3 and 0 ppm
Basis:
no data
No. of animals per sex per dose:
12
Control animals:
yes
Details on study design:
No data
Positive control:
No data.

Examinations

Observations and examinations performed and frequency:
BODY WEIGHT: Yes

OTHER: Symptomatology with nineteen tissues, but not the brain, being sampled from each rat for microscopic examination.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Other examinations:
No data
Statistics:
Body weight changes and kidney and liver weights as percentage of body weight of all animal groups were intercompared statistically by use of the following tests:

Bartlett's homogeneity of variance, analysis of variance and Duncan's multiple range. The last test was used if F for analysis of variance was significantly high, to delineate which group differed from the control. If Bartlett's test indicated heterogeneous variances, the F-test was used for each group versus the control. If these individual F-tests were not significant, Student's t-test was used; if significant, the means were compared by the Cochran t-test. The fiducial limit of 0.05 ("P") was employed as the critical level of difference not to have been produced by chance.

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 specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Details on results:
CLINICAL SIGNS AND MORTALITY
Seven male rats died during the first day of exposure 109.3 ppm and one male died during the second day at 52.6 ppm. Loss of consciousness but no convulsions preceded death. One male rat was found prostrated by the end of the 11th exposure day at the 109.3 ppm level, but appeared normal the next morning. No additional symptoms attributable to exposure were observed for the remainder of the study.

BODY WEIGHT AND WEIGHT GAIN
The mean body weight gains of surviving rats were statistically compared after the 5th, 29th, 59th and 91st exposure days. The gains of both sexes at the 109.3 ppm level and of the females at the 52.9 ppm level were significantly lower than those of the control rats after 5 exposure days. No significant weight-gain differences were observed after the 29th, 59th and 91st exposure days, although the mean body weights of the surviving male rats at the 109.3 ppm level were consistently below those of the other groups.

ORGAN WEIGHTS
After the 91 exposure days the mean liver weights as a percentage of body weight of the males at the 109.3 ppm and the 52.6 ppm levels and of the females at the 109.3 ppm level were significantly higher than those of the control rats. There was no significant alteration of the relative kidney weights.
GROSS PATHOLOGY
There were no observable gross or microscopic lesions in the victims or survivors.

OTHER FINDINGS
Three control males and one control female died or were sacrificed before the end of the study because of a middle ear infection or pneumonia.

Effect levels

Dose descriptor:
NOAEL
Effect level:
19.6 - < 52.6 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Clinical signs; mortality; body weight; gross pathology; organ weights; histopathology

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Table II, Summary of Responses of Groups of 12 Rats of Each Sex Which Inhaled Methacrylonitrile Vapor 7 hours per Day for 91 Days

 

Males

Females

Median concentration (ppm)

109.3

52.6

19.3

0

109.3

52.6

19.3

0

Mean body weight of survivors at start (gm)

175.4

187.5

184.6

184.3

145.8

152.2

153.4

152.4

Mean body weight gain of survivors (gm)

358.2

408.1

419.5

420.0

208.3

192.2

220.2

220.9

Mean liver weight as % of body weight

4.23a

3.62b

3.18

3.30

3.98c

3.30

3.15

3.13

Mean kidney weight as % of body weight

0.63

0.64

0.64

0.63

0.64

0.66

0.63

0.63

Number of survivors

5

11

12

9

12

12

12

11

Number of deaths attributable to exposure

7

1

0

0

0

0

0

0

Number of sets of tissues examined microscopically

12

12

12

12

12

12

12

12

Number of sets with gross or micropathology attributable to exposure

0

0

0

0

0

0

0

0

a= 0.05 > P > 0.01; b= 0.01 > P > 0.001; c= P < 0.001; P= represents a fiducial limit of 0.05

Applicant's summary and conclusion

Conclusions:
The NOAEL for the rat is between 52.6 and 19.3 ppm.