Methyl chloroformate

Endpoint summary

Description of key information

- local 90-day NOAEC = 1.6 mg/m3/day
- systemic 90-day NOAEC = 7.8 mg/m3/day

Key value for chemical safety assessment

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Dose descriptor:

NOAEC

1.6 mg/m³

Study duration:

subchronic

Species:

rat

Additional information

In an 28-day OECD TG 412 study, Sprague-Dawley rats (5/sex/dose) were exposed to 0 (air), 0.52, 1.48, 3.94, 12.14, or 34.46 mg/m³ MeCF (vapor, measured concentrations) for 5 days a week for 6 h (HRC, 1992). No effects were observed at concentrations up to 1.48 mg/m³. At 3.94 mg/m³, minimal localized squamous metaplasia of the laryngeal arytenoid process epithelia was noted in 1/5 males. As there was local squamous metaplasia of laryngeal arytenoid process epithelia also noted in 1/5 females in the control group, this observation was not considered treatment-related. Therefore, 3.94 mg/m³ is regarded as the NOAEC. Clear substance related effects were observed at higher concentrations. At 12.14 mg/m³, one male rat had noisy nasal breathing for 4 days during week 2 of exposure. Minor, localized squamous metaplasia of the laryngeal arytenoid process epithelia was noted in 2/5 males and 1/5 females at 12.14 mg/m³. One female had exudative sinusitis. Two males and 1 female exposed to 34.46 mg/m³ died during the final week of exposure. Clinical signs observed during exposure included blinking, hunched posture, and rapid breathing. Rats in this group were noted to have noisy breathing between exposures. Rats surviving to study termination had a rapid breathing pattern. Males and females had reduced body weight gain for the first 2 weeks of exposure. A marked reduction in food consumption occured during the first 2 weeks of exposure. Results of hematological studies showed changes in packed cell volume, hemoglobin concentration, cell type distribution, and cell numbers. Changes in blood protein levels and cholesterol were noted.  The following pathological changes were seen in rats sacrificed after 4 weeks of exposure: lungs that did not collapse upon opening of the thoracic cavity (3/3 males and 4/4 females), congestion of the lungs (1/3 males and 1/4 females), enlarged mediastinal lymph nodes (3/3 males and 3/4 females), and enlarged tracheobronchial lymph nodes (3/3 males and 3/4 females). Similar findings were seen in the animals that died before study termination. Lung weights of males and females and adrenal weights of males were increased. Microscopic examinations revealed exudative sinusitis in the nasal turbinates of 4/5 males and 5/5 females (but no evidence of degenerative or erosive lesions); localized areas of minimal squamous metaplasia of the epithelia overlying the arytenoid processes of the larynx in 3/5 males and 4/5 females (with occasional areas of ventral epithelial erosion and inflammation in some rats); localized squamous metaplasia of the ventral epithelia of the larynx in 3/5 females; minimal inflammatory changes with some minimal epithelial hyperplasia in the trachea (1/5 males); minimal to marked areas of pneumonitis in the lungs with intraalveolar exudation and aggregation of alveolar macrophages (all males and females); brohchiolitis (number of animals was not stated); squamous metaplasia of terminal bronchilar epithelia with occasional focal necrosis, edema and congestion (number of animals was not stated); and granulomatous lesions (1 female).

In a 90-day inhalation study (OECD TG 413 without hematology or clinical chemistry) focusing on respiratory tract irritation, Wistar rats (10/sex/concentration) were exposed to vapors of MeCF for 6 hours per day for 5 days per week, for 3, 10, 20, and 65 exposures (90-day study with interim necropsies after 3, 14 and 28 study days) (BASF AG, 1999c). Rats were exposed to 0 (air), 0 0.4, 2, 4 or 8 ppm (1.6, 7.8, 15.7, or 30.7 mg/m³). All organs were macroscopically examined and preserved. Weights of selected organs and body weights were reported. Intensive histology including a cell proliferation study was performed on the respiratory tract only. Four of 10 male animals from the 8 ppm group with 65 exposures died. Clinical signs of respiratory tract irritation were observed in this group. Significant body weight loss was recorded in males in the 4 and 8 ppm exposure groups. Inhalation of MeCF caused increased DNA replication in respiratory and transitional epithelium of the nose, ciliated and/or squamous epithelium in the larynx and cuboidal epithelium. Hyperplasia and metaplasia of the epithelia were noted for animals exposed to 2, 4, and 8 ppm. Location, incidence, and severity of lesions showed a concentration-time-response relationship mainly driven by the concentration and not the "cumulative dose". No substance related clinical and pathological alterations and no changes in DNA-replication could be detected at 0.4 ppm (1.6 mg/m³= NOAEC).

In a screening study with 109 chemicals (similar to OECD TG 412), rats (4/sex/concentration) were exposed to 3.9, 19.6, or 78.4 mg/m³ MeCF (vapor, 1, 5, or 20 ppm nominal) for 6 h/day, 5 d/wk for 3 weeks (15 exposures) (Gage, 1970). There were no signs of toxicity in rats exposed to 3.9 mg/m³ (1 ppm = NOAEC). Rats exposed to 19.6 mg/m³ exhibited irritation of the nose and lethargy but had normal appearing organs at necropsy. Rats exposed to 78.4 mg/m³ exhibited nasal irritation, respiratory difficulty, lethargy, poor condition, and weight loss. Autopsies of these animals revealed distension, edema and haemorrhage of lungs, with areas of consolidation and collapse. Kidneys were noted to be congested.

DNEL derivation:

Based on no treatment-related effects to the respiratory tract, the local 28-day NOAEC for MeCF was 3.94 mg/m3/day; based on decreased body weight and food consumption and changes in hematological/clinical chemistry parameters at 34.46 mg/m3/day, the systemic 28-day NOAEC for MeCF was 12.14 mg/m3/day.

Based on substance-related pathological alterations and changes in DNA-replication in the respiratory tract at 7.8 mg/m3/day and above, the local 90-day NOAEC for MeCF was 1.6 mg/m3/day; based on significant weight loss at 15.7 mg/m3/day, the systemic 90-day NOAEC for MeCF was 7.8 mg/m3/day.

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

Justification for classification or non-classification

No classification concerning repeated dose toxicity is warranted according to EU Regulation 67/548 and EU Regulation 1272/2008 as classification criteria are not met.