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EC number: 500-036-1 | CAS number: 25214-70-4
Endpoint summary
Administrative data
Description of key information
The most relevant assessment of repeated dose toxicity in animals comes from an oral subchronic study with 4,4'-methylenedianiline (MDA) in rats (Ciba-Geigy, 1982). In this study rats were administered via the drinking water with 0, 80, 400 and 800 ppm MDA over a period of 3 months, followed by a 4-week recovery period. The calculated average intake of MDA was 0, 7.5, 23 and 31 mg/kg bw/day for males as well as 0, 8.0, 22 and 32 mg/kg bw/day for females. This study was accepted as valid restricted by missing ophthalmology examination. No animal died. Depressed body weight, food and water consumption was observed at 400 ppm and above. Hemotoxic effects indicated by anemia and extramedullary hemopoiesis in the spleen were evident in mid and high dose animals. Histopathological examination of the rats receiving 800 ppm revealed moderate or marked hyperplasia of small biliary ducts with initial fibrosis in the peripheral parts of the liver lobules. The changes persisted during the post-exposure period. Slight, moderate, or marked hypertrophy of the thyroid follicular epithelial cells, and diffuse hyperplasia of the glandular structures with marked colloid depletion, was noted in 90% of males and all females. At the end of the post-exposure period only 30% males and 20% females showed slight stimulation of the follicular epithelium. The rats receiving 400 ppm MDA displayed similar histopathological changes of a less severe nature. Elevated liver transaminase activities were observed at 400 ppm and above. One male rat of the high dose group and one male and one female of the mid dose groups showed a focal nodular hyperplasia of the thyroid. Histopathological examination of the rats receiving 80 ppm MDA did not find any liver lesions. Slight stimulation of the thyroid follicular epithelial cells was observed in 2/20 males and 2/20 females at 80 ppm. Kidney mineralisation was seen in all males of the mid dose group and in 21/30 males of the high dose group. One male of the 80 ppm group and none of the control males showed kidney mineralisation. The LOAEL in both sexes was identified to be 80 ppm (equivalent to 7.5 mg/kg bw/day in males and 8.0 mg/kg bw/day in females).
The primary target organs liver and thyroid were also confirmed in subchronic (13 weeks) and chronic (2 years) drinking water studies with 4,4'-methylenedianiline (MDA) dihydrochloride in rats and mice (NTP, 1983). The LOAEL from the subchronic Ciba-Geigy study is corresponding to the LOAEL of 150 ppm from the 2-year rat study on non-neoplastic effects (equivalent to 9.0 mg/kg bw/day in males and 10.0 mg/kg bw/day in females). Although the NTP-studies had not examined parameters of hematology, clinical chemistry and urinalysis, the LOAEL of 9.0 mg/kg bw/day from the long-term study in rats was considered to be the most appropriate value for quantitative risk assessment. This LOAEL is in line with the result of the 13-week study in rats. For mice a NOAEL of 100 ppm could be derived from the subchronic NTP-study (equivalent to 11.4 mg/kg bw/day in males and 14.4 mg/kg bw/day in females).
The dermal application of 4,4' diaminodiphenylmethane (MDA) to rats at doses of 3, 30, 60 or 90 mg/kg bw/day (6 hours/day, 5 days/ week) for 10 weeks, resulted in skin lesions both macroscopically (scabs) and microscopically (dermatitis). The NOEL for skin lesions was 3 mg /kg bw/day. However, systemically there were no treatment-related findings and the NOEL for systemic toxicity was 90 mg/kg bw/day (Williams, 1998).
Key value for chemical safety assessment
Repeated dose toxicity: via oral route - systemic effects
Endpoint conclusion
- Dose descriptor:
- LOAEL
- 7.5 mg/kg bw/day
- Study duration:
- subchronic
- Species:
- rat
Repeated dose toxicity: inhalation - systemic effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: inhalation - local effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: dermal - systemic effects
Endpoint conclusion
- Dose descriptor:
- NOAEL
- 3 mg/kg bw/day
- Study duration:
- subchronic
- Species:
- rat
Repeated dose toxicity: dermal - local effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Additional information
Justification on read-across of data for the 4,4´-isomer of MDA for oligomeric MDA in the scope of REACH is documented in IUCLID Toxicological information and described in sections 5.1 and 5.11 of the CSR.
Discussion
The most relevant assessment of repeated dose toxicity in animals comes from an oral subchronic study with 4,4'-methylenedianiline (MDA) in rats (Ciba-Geigy, 1982). In this study rats were administered via the drinking water with 0, 80, 400 and 800 ppm MDA over a period of 3 months, followed by a 4-week recovery period. The calculated average intake of MDA was 0, 7.5, 23 and 31 mg/kg bw/day for males as well as 0, 8.0, 22 and 32 mg/kg bw/day for females. This study was accepted as valid restricted by missing ophthalmology examination. No animal died. Depressed body weight, food and water consumption was observed at 400 ppm and above. Hemotoxic effects indicated by anemia and extramedullary hemopoiesis in the spleen were evident in mid and high dose animals. Histopathological examination of the rats receiving 800 ppm revealed moderate or marked hyperplasia of small biliary ducts with initial fibrosis in the peripheral parts of the liver lobules. The changes persisted during the post-exposure period. Slight, moderate, or marked hypertrophy of the thyroid follicular epithelial cells, and diffuse hyperplasia of the glandular structures with marked colloid depletion, was noted in 90% of males and all females. At the end of the post-exposure period only 30% males and 20% females showed slight stimulation of the follicular epithelium. The rats receiving 400 ppm MDA displayed similar histopathological changes of a less severe nature. Elevated liver transaminase activities were observed at 400 ppm and above. One male rat of the high dose group and one male and one female of the mid dose groups showed a focal nodular hyperplasia of the thyroid. Histopathological examination of the rats receiving 80 ppm MDA did not find any liver lesions. Slight stimulation of the thyroid follicular epithelial cells was observed in 2/20 males and 2/20 females at 80 ppm. Kidney mineralisation was seen in all males of the mid dose group and in 21/30 males of the high dose group. One male of the 80 ppm group and none of the control males showed kidney mineralisation. The LOAEL in both sexes was identified to be 80 ppm (equivalent to 7.5 mg/kg bw/day in males and 8.0 mg/kg bw/day in females).
The primary target organs liver and thyroid were also confirmed in subchronic (13 weeks) and chronic (2 years) drinking water studies with 4,4'-methylenedianiline (MDA) dihydrochloride in rats and mice (NTP, 1983). The LOAEL from the subchronic Ciba-Geigy study is corresponding to the LOAEL of 150 ppm from the 2-year rat study on non-neoplastic effects (equivalent to 9.0 mg/kg bw/day in males and 10.0 mg/kg bw/day in females). Although the NTP-studies had not examined parameters of hematology, clinical chemistry and urinalysis, the LOAEL of 9.0 mg/kg bw/day from the long-term study in rats was considered to be the most appropriate value for quantitative risk assessment. This LOAEL is in line with the result of the 13-week study in rats. For mice a NOAEL of 100 ppm could be derived from the subchronic NTP-study (equivalent to 11.4 mg/kg bw/day in males and 14.4 mg/kg bw/day in females).
The dermal application of 4,4' diaminodiphenylmethane (MDA) to rats at doses of 3, 30, 60 or 90 mg/kg bw/day (6 hours/day, 5 days/ week) for 10 weeks, resulted in skin lesions both macroscopically (scabs) and microscopically (dermatitis). The NOEL for skin lesions was 3 mg /kg bw/day. However, systemically there were no treatment-related findings and the NOEL for systemic toxicity was 90 mg/kg bw/day (Williams, 1998).
Repeated dose toxicity: via oral route - systemic effects (target organ) digestive: liver; glandular: thyroids; urogenital: kidneys
Repeated dose toxicity: dermal - systemic effects (target organ) other: skin
Justification for classification or non-classification
In regulation 1272/2008/EC, MDA is classified as
STOT SE 1, H370: causes damage to the liver
STOT RE 2, H373: may cause damage to (liver, thyroid gland, kidney) through prolonged or repeated exposure.
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