Methyl formate

Repeated dose toxicity: inhalation

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

Test material information

Constituent 1

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

1

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

2

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

3

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

4

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.