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Published on: April 6, 2017
2-week inhalation study of N-monomethylformamide in rats
G L Kennedy1, R L Ferenz, B A Burgess
1E. I. du Pont de Nemours & Company, Inc., Haskell Laboratory for Toxicology and Industrial Medicine, Newark, Delaware 19714.
Abstract:
N-Monomethylformamide (MMF) is a chemical intermediate with potential for inhalation exposure in humans. Human exposures to MMF have occurred in cancer chemotherapy but have been limited due to liver damage. To assess the toxicity of MMF, groups of 15 male rats each were exposed by nose-only inhalation, 6 hr/day, 5 days/week, for 2 weeks to either 0 (control), 50, 130, or 400 ppm MMF. Five rats per group were killed following the 10th exposure, five were killed after a 14-day postexposure recovery period, and five rats were used to determine urinary MMF excretion. Parameters investigated were clinical observations and body weights, clinical pathology, and gross and microscopic pathology including organ weights. Liver damage occurred in rats exposed to either 130 or 400 ppm. This was detected both by increases in serum enzyme activity indicative of liver injury and by microscopic changes in the liver. The changes were more severe in the 400-ppm rats and were partially reversible. Other organs were not adversely affected by inhalation of MMF. The amount of MMF excreted in the urine was dependent on the exposure concentration and MMF was present 14 days postexposure at the higher exposure levels. The no-observed-effect level under the conditions of this experiment was 50 ppm.
Insights
N-Monomethylformamide (MMF) inhalation exposure caused liver damage in rats at higher concentrations. The no-observed-effect level was determined to be 50 ppm, with some liver changes showing partial reversibility.
Area of Science:
- Toxicology
- Occupational Health
- Environmental Health
Background:
- N-Monomethylformamide (MMF) is an industrial chemical intermediate.
- Human exposure to MMF has been documented in cancer chemotherapy settings.
- MMF exposure is limited by observed liver toxicity.
Purpose of the Study:
- To assess the toxicity of N-Monomethylformamide (MMF) following inhalation exposure in male rats.
- To determine the no-observed-effect level (NOEL) for MMF inhalation.
- To evaluate the reversibility of MMF-induced toxic effects.
Main Methods:
- Male rats were exposed via nose-only inhalation to MMF (0, 50, 130, or 400 ppm) for 6 hours/day, 5 days/week, for 2 weeks.
- Animals were evaluated for clinical signs, body weight, clinical pathology, and gross/microscopic pathology, including organ weights.
- Urinary MMF excretion was measured, and tissues were examined at the end of exposure and after a 14-day recovery period.
Main Results:
- Liver damage, indicated by elevated serum enzymes and microscopic changes, was observed in rats exposed to 130 ppm and 400 ppm MMF.
- The observed liver damage was concentration-dependent and partially reversible during the 14-day recovery period.
- The no-observed-effect level (NOEL) for MMF inhalation under these experimental conditions was established at 50 ppm.
Conclusions:
- Inhalation of N-Monomethylformamide (MMF) at concentrations of 130 ppm and above causes significant liver toxicity in male rats.
- The liver damage induced by MMF is partially reversible, but prolonged exposure may lead to persistent effects.
- A safe exposure level, or no-observed-effect level, for MMF inhalation was identified as 50 ppm in this study.
