Registration Dossier

Toxicological information

Repeated dose toxicity: inhalation

Currently viewing:

Administrative data

Endpoint:
short-term repeated dose toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Reliable with restrictions; acceptable, well- documented study report which meets basic scientific principles.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1984

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)
Deviations:
yes
Remarks:
14 days of exposure, 14 days of recovery
GLP compliance:
not specified
Limit test:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
3-methylpyridine
EC Number:
203-636-9
EC Name:
3-methylpyridine
Cas Number:
108-99-6
Molecular formula:
C6H7N
IUPAC Name:
3-methylpyridine

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals or test system and environmental conditions:
Rats were eight weeks old and weighing between 211 to 240 g.

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure:
nose only
Vehicle:
air
Details on inhalation exposure:
One group was exposed nose-only, six hours/day, five days/week for two weeks at a concentration of 290 ppm. One group was exposed simultaneously to air only. Five rats per group were sacrificed after the tenth exposure for pathologic examination and five rats per group were allowed to recover for 13 days post exposure.
Duration of treatment / exposure:
6 hours/day, 5 days/week for 14 days.
Frequency of treatment:
Once daily, 6 hours/day, 5 days/week
Doses / concentrations
Remarks:
Doses / Concentrations:
290 ppm
Basis:
nominal conc.
No. of animals per sex per dose:
10 per sex per group.
Control animals:
yes, concurrent vehicle
Details on study design:
290 ppm is equivalent to 1105 mg/m3 of 3-methylpyridine, with a molecular weight of 93.

Examinations

Observations and examinations performed and frequency:
Rats were weighed and observed daily throughout the exposure and recovery periods, weekends excluded
Sacrifice and pathology:
Organs and tissues examined were the heart, lungs, nasal cavities, trachea, liver, pancreas, esophagus, stomach, duodenum, jejunum, ileum, cecum, colon, kidneys, urinary bladder, bone marrow (sternal), spleen, thymus, mesenteric lymph nodes, thyroid, testes, epididymides, adrenal glands, brain and eyes. Mean organ weights and organ-to-body ratios were calculated for the heart, lungs, liver, spleen, kidneys, testes and thymus.
Other examinations:
At the end of the exposure period, blood and urine samples were collected for clinical analysis. Urine samples were collected overnight from ten rats per group prior to the first exposure and after the ninth exposure and from five rats per group on the twelfth day of recovery. Samples were analyzed for volume, osmolality, pH, blood, sugar, protein, bilirubin, urobilinogen and ketone. Each specimen was noted for color and transparency and the sediment from each sample was examined microscopically. Tail blood samples were collected from ten rats per group prior to the first exposure and after the tenth exposure and from five rats per group on the thirteenth day of recovery. Samples were analyzed for erythrocyte count, hemoglobin concentration, mean corpuscular volume, platelet count, leukocyte count and relative numbers of neutrophils, band neutrophils, lymphocytes, atypical lymphocytes, eosinophils, monocytes and basophils. Hematocrit, mean corpuscular hemoglobin and mean corpuscular hemoglobin concentration were calculated from the erythrocyte data. In addition, serum activities of alkaline phosphatase, alanine aminotransferase and aspartate aminotransferase and serum concentrations of urea nitrogen, creatinine, total protein and cholesterol were measured.
Statistics:
Least Significant Difference test and Dunnett’s test

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
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:
no effects observed
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Rats exposed to 290 ppm of the test substance had elevated mean liver weights and liver-to-body weight ratios compared to controls. This change was absent after 13 days of recovery.
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined
Details on results:
The only significant finding after exposure of male rats to 290 ppm of the test substance was elevated mean liver weights and liver-to-body weight ratios compared to controls. This effect resolved after 13 days of recovery. There were no significant findings on body weight, food consumption, haematology, clinical chemistry, gross or histopathology.

Effect levels

Dose descriptor:
NOAEC
Effect level:
> 290 ppm
Based on:
test mat.
Sex:
male
Basis for effect level:
other: see 'Remark'

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

An additional inhalation study of pyridine toxicity (Watanabe, et.al, 1979) is known to exist as part of the U.S.Voluntary HPV submission package on the Pyridine and Pyridine Derivatives Category (See: http://www.epa.gov/chemrtk/hpvis/hazchar/Category%20Pyr%20and%20Pyr%20Derivs_Sept2009.pdf.)  However, legal access to refer to the findings of this study was not able to be arranged. A publically-available robust summary of the study is provided as an attachment here. The conclusion of this 1979 subchronic study is that the NOAEC in CD rats after a 6-month inhalation study (6 hr/day, 5 days/week) is >100 ppm or 323 mg/m3, the highest concentration tested. This is consistent with the NOAEC seen herein, in the shorter Chen and Krauss study, of 290 ppm or 1105 mg/m3.

This assessment from read-across from 3 -Methylpyridine (the registered substance), applies to all members of the chemical category. The category of pyridine and methyl pyridine derivatives is comprised of: pyridine, 2-methylpyridine, 3-methylpyridine and 4-methylpyridine. The basis of the category is structural similarity (based on the pyridine unsaturated ring structure) and similar physical properties, environmental fate and ecotoxicity, and mammalian toxicity. Similar toxicological properties derive from similar physical-chemical properties and common pathways of metabolism and elimination among all members of the category. This category is accepted by the U.S. Environmental Protection Agency (EPA). 

Applicant's summary and conclusion

Conclusions:
The effect of 14-days of inhalatory exposure (nose-only) to 290 ppm (1105 mg/m3) of 3-methylpyridine in male rats was investigated. The only finding was an elevated mean liver weights and liver-to-body weight ratios compared to controls, which resolved after 13 days of recovery. The NOEC was greater than 1105 mg/m3.