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Description of key information

Methylformate caused local effects in the respiratory tract (nasal epithelium degeneration) in several rodent inhalation studies. The lowest NOAEC was 0.122 mg/L. 

Key value for chemical safety assessment

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEC
1 237 mg/m³

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEC
252 mg/m³

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

Methylformate 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.

 

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).

The NOAEC values for methyl formate and for formic acid are thus in the same order of magnitude. It should be noted that methylformate is cleaved in the nasal epithelium to methanol and formic acid in a 1:1 molar ratio. Consequences going beyond will be addresed in the DNEL derivation.

 

 

 

 

 



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

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

Repeated dose toxicity: dermal - systemic effects (target organ) respiratory: nose

Justification for classification or non-classification

A STOT RE 2 (in accordance with Table 3.93 of 1272/2008/EC; multifocal degeneration of the olfactory epithelium in the rat at 1.27 mg/L/6h/day) may be warranted based on the effect concentration. However, effect is a secondary effect of inhalative irritation. Finally, legally binding classification according to 1272/2008/EC Annex VI table 3.1 and Table 3.2 is "no classification" concerning this effect.