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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:
weight of evidence
Study period:
2010
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
publication
Title:
Acute and Subchronic Inhalation Toxicity Evaluation of
Methyl Formate in Rats
Author:
Hyeon-Yeong Kim
Year:
2010
Bibliographic source:
ENVIRONMENTAL HEALTH & TOXICOLOGY, Vol. 25, No. 2, 13 1- 143 (20 10)

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 413 (90-Day (Subchronic) Inhalation Toxicity Study
Deviations:
not specified
GLP compliance:
not specified
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Methyl formate
EC Number:
203-481-7
EC Name:
Methyl formate
Cas Number:
107-31-3
Molecular formula:
C₂H₄O₂
IUPAC Name:
methyl formate

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on species / strain selection:
TEST ANIMALS:
-Source: SLC Japan
Sex:
male/female

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure:
not specified
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
5 days/week, 6 hours/day
Doses / concentrations
Remarks:
Doses/concentrations: 0, 100, 400, 1600 ppm (0, 0,25, 0,98, 3,92 mg/L)
Control animals:
yes, concurrent vehicle

Examinations

Observations and examinations performed and frequency:
BODY WEIGHT: YES
- Time schedule for examinations:  recorded on a weekly base

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at termination in week 13
- Parameters checked in table No. B1 (report, Appendix B) were examined

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at termination in week 13
- Parameters checked in table No. B1 (report, Appendix B) were examined.

- Histopathology: Yes
Organs were weighted: brain, spleen, liver, thymus, kidney (right/left), lung (right/left), heart, adrenal grand (right/left), ovary (right/left)

Results and discussion

Results of examinations

Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Reduced terminal body weight after exposure to 400 ppm (0.98 mg/L) and 1600 ppm (3.92 mg/L).
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Reduced food intake after exposure to 400 ppm (0.98 mg/L) and 1600 ppm (3.92 mg/L).
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
Increased level of neutrophils (male/female), monocytes (female), eosinophils (male) and decreased level of reticulocytes (male), lymphocytes (male/female) after exposure of 1600 ppm.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
Serum values: decreased level in Calcium (male/female) and increased A/G ratio (male/female).
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Increased weights of left ovary and brain in female rats after exposure to 400 ppm. After exposure to 1600 ppm increased adrenal grand, kidney, heart, lung, brain in both sexes and increased thymus in female, increased testis in male rats.
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Atrophy of nasal respiratory epithelium, degradation, regeneration and contraction of olfactory cells after exposure to 1600 ppm.

Effect levels

open allclose all
Dose descriptor:
LOAEC
Remarks:
systemic
Effect level:
400 ppm
Basis for effect level:
body weight and weight gain
food consumption and compound intake
organ weights and organ / body weight ratios
Dose descriptor:
NOAEC
Remarks:
systemic
Effect level:
100 ppm
Basis for effect level:
haematology
Remarks on result:
other: at the next higher dose level changes in body weight and organ weights were observed
Dose descriptor:
LOAEC
Remarks:
local
Effect level:
1 600 ppm
Basis for effect level:
body weight and weight gain
food consumption and compound intake
haematology
histopathology: non-neoplastic
organ weights and organ / body weight ratios
Dose descriptor:
NOAEC
Remarks:
local
Effect level:
400 ppm
Basis for effect level:
food consumption and compound intake
haematology
organ weights and organ / body weight ratios
Remarks on result:
other: at the next higher dose level nasal epithelial atrophy, olfactory cell degeneration/regeneration and the contraction of olfactory cells was observed

Target system / organ toxicity

Critical effects observed:
yes
Lowest effective dose / conc.:
1 600 ppm
System:
respiratory system: upper respiratory tract
Organ:
lungs
Treatment related:
yes

Applicant's summary and conclusion

Conclusions:
Based on significantly decreased body and organ weights at 400 ppm a NOAEC of 100 ppm for systemic effects was derived. At 1600 ppm significantly decreased body and organ weights, non-neoplastic findings of repiratory epithelium and hematological findings were observed and a NOAEC of 400 ppm for local effects was derived.
Executive summary:

In a 90-d repeated dose inhalation toxicity study Sprague-Dawley rats were exposed to methyl formate vapor at 0, 100, 400, 1600 ppm (0, 0,25, 0,98, 3,92 mg/L) 6 hours/day, 5 days/week for 13 weeks. No mortality was recorded throughout the study. A statistically significant reduced body weight development during the whole study period and reduced food consumption of male and female rats was observed after exposure to 400 and 1600 ppm compared to the control group. Reduction of body weight of 25% (male) and 20% (female) at the end of the study in the 1600 ppm group was observed. After exposure to 1600 ppm the organ weight of almost every examined organ was significantly increased (male/female) and hematologic and blood serum parameters indicate significant changes (reduced neutrophils and lymphocytes and increased albumin/globulin ratio) to the control group. At 1600 ppm atrophy of nasal respiratory epithelium, degeneration, regeneration and contraction of olfactory cells was found.