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Description of key information

Methylformate caused local effects in the respiratory tract (nasal epithelium degeneration) and systemic effects indicated by organ and body weight changes in several rodent inhalation studies. The lowest NOAEC was 0.25 mg/L.

 

Key value for chemical safety assessment

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
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
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
Species:
rat
Strain:
Sprague-Dawley
Details on species / strain selection:
TEST ANIMALS:
-Source: SLC Japan
Sex:
male/female
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
Remarks:
Doses/concentrations: 0, 100, 400, 1600 ppm (0, 0,25, 0,98, 3,92 mg/L)
Control animals:
yes, concurrent vehicle
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)

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

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
250 mg/m³
Study duration:
subchronic
Experimental exposure time per week (hours/week):
60
Species:
rat
System:
respiratory system: upper respiratory tract

Repeated dose toxicity: inhalation - local effects

Link to relevant study records
Reference
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
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
Species:
rat
Strain:
Sprague-Dawley
Details on species / strain selection:
TEST ANIMALS:
-Source: SLC Japan
Sex:
male/female
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
Remarks:
Doses/concentrations: 0, 100, 400, 1600 ppm (0, 0,25, 0,98, 3,92 mg/L)
Control animals:
yes, concurrent vehicle
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)

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

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
980 mg/m³
Species:
rat

Additional information

Oral, Dermal

In accordance with Annex IX, column 2, repeated toxicity testing was performed for the inhalation route because this is considered to represent the most relevant exposure route for humans, due to the high volatility of methylformate.

 

Inhalation

Methyl formate was administered as a vapour to Wistar rats (5/sex/dose) at concentrations of 0, 100, 500, or 1500 ppm (0, 0.252, 1.237, or 3.693 mg/L) for 2 weeks, 6 h/day, 5 days/week (GLP, OECD guideline No. 412). Terminal body weights were markedly decreased in both sexes at the highest concentration. Changes in several organ weights were observed (liver, lung, kidneys, and spleen) at the highest concentration. In addition, histopathological changes in the nasal epithelium (multifocal degeneration of the olfactory epithelium), squamoid metaplasia, and infiltration of inflammatory cells into the respiratory tract were observed at the middle and highest concentration in a concentration-related manner (BASF AG, 2003).

Based on respiratory tract changes and effects on body weight and organ weights, the NOAEC and LOAEC for local effects were 0.252 mg/L and 1.237 mg/L, respectively.

The NOAEC and LOAC for systemic effects were 1.273 mg/L and 3.693 mg/L, respectively, based on body weight and organ weight changes at the highest tested dose.

 

In a 90-day rat inhalation study (results have been derived from abstract, graphics and tables) (OECD guideline No. 413) Sprague-Dawley rats were exposed to methyl formate vapour at concentrations of 0, 100, 400 or 1600 ppm (0.245 , 0.98, 3.92 mg/L) (5 days/week and 6 hours/day). At 400 and 1600 ppm the terminal body weights were markedly decreased. At the highest tested concentration atrophy of respiratory epithelium, increased organ weights (adrenal grand, kidney, heart, lung, brain) and hematological changes were observed in both sexes (Kim et al. 2010).  

 

The NOAEC and LOAEC for local effects were 0.98 and 3.92 mg/l  based on athrophy of respiratory epithelium. For systemic effects the NOAEC and LOAEC were 0.25 and 0.98 mg/l based on body and organ weight changes.

 

Comparable respiratory tract effects were seen in a formic acid rat inhalation study. In an OECD guideline No. 413 test conducted under GLP conditions, 10 rats per sex and dose were exposed to formic acid vapor at 0, 0.015, 0.030, 0.062, 0.122, or 0.244 mg/l (0, 8, 16, 32, 64, or 128 ppm; dose selection based on results of a range finding study) via whole-body inhalation 6 hours/day, 5 days/week for 13 weeks. Histopathology revealed increased incidences of squamous metaplasia of the respiratory epithelium and degeneration of the olfactory epithelium in the high-dose male and female rat groups where most of the animals were affected. The severity was generally minimal to mild.

 

Based on the local histopathological changes in the respiratory tract the NOAEC in this study was determined to be 64 ppm (0.122 mg/l), and the LOAEC was 128 ppm (0.244 mg/l). Systemic toxicity was not achieved, the systemic NOAEC was therefore128 ppm (0.244 mg/l), the highest concentration tested (Leach, 1992).

In a weight of evidence approach the available data from a 90-d sub-chronic study and a 14-d sub-acute study after exposure to methyl formate and a 90-d sub-chronic study after exposure to formic acid via inhalation in rats are used for the assessment of repeated dose toxicity. The NOAEC values for methyl formate and for formic acid are in the same order of magnitude. The lower NOAEC for local effects of formic acid is attributed to the corrosive characteristics of the substance. The primary local and systemic effects of methyl formate and formic acid were indicated by changes of the respiratory tract and changes in body and organ weights. The NOAEC of 0.98 mg/l is used to support the justification of the DNEL-value.


Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
Body and organ weight effects

Repeated dose toxicity: inhalation - local effects (target organ) respiratory: nose


 

Justification for classification or non-classification

No classification for repeated dose toxicity as classification criteria of regulation 1272/2008/EC are not met.