N-methylaniline

Endpoint summary

Description of key information

Regarding repeated dose toxicity adverse effects were observed for oral exposure (LOAEL rat= 5 mg/kg/bw) and for inhalator exposure (NOAEC different species = 10.7 mg/m^3). No data of repeated dose dermal toxicity are available. 
However, according to CLP Regulation (EC n.1272/2008) N-methylaniline is classified for repeated dose toxicity H373 (STOT.Rep. Exp.2)

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LOAEL

5 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

Data from National Institute of Health Sciences (NIHS) of Japan

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEC

10.7 mg/m³

Study duration:

subacute

Species:

other: rats, rabbit, guinea pig, dogs, cats and monkeys

Quality of whole database:

SCOEL/SUM/178 of December 2012 for N-methylaniline

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Oral exposure

In SCOEL/SUM/178 of December 2012 for N-methylaniline two studies are reported about repeated dose oral toxicity. In the first study (see Treon et all, J Ind Hyg Toxicol 31:1-20, 1949) a slight decrease in erythrocyte counts and Hb level in blood, but no sign of illness or death were observed in rabbits after oral administration of 24 mg/kg/day N-methylaniline in propane-1,2-diol, 5 days/week for 20 weeks. In the second study (see National Institute of Health and Safety of Japan (2010). N-methylaniline (summary), 2010) rats were treated for 28 days by gavage with 0, 5, 25 or 125 mg of N-methylaniline in corn oil/kg/day . In females, significant and dose dependent decreases of several haematological parameters [Hb concentration, mean cell volume (MCV), Hb amount/red blood cell (MCH)] and an increase in serum creatinine were seen at all dose levels. At 25 and 125 mg/kg/day, methaemoglobinaemia, cyanosis, anaemia and yellowish brown urine were observed in male and female rats. Macroscopically, enlargement and black changes of the liver were also observed in both sexes at 25 or 125 mg/kg/day. Histopathologically, congestion, increase in haematopoiesis or deposition of pigment in the spleen, increase in haematopoiesis in the bone marrow, extramedullary haematopoies is and deposits of pigments in the liver and proximal tubules of the kidney were observed in treated groups of both sexes. The absolute and relative spleen weights were also increased in both sexes at 125 mg/kg and in females at 25 mg/kg. Minimal spleen congestion was observed in all 5 necropsied male animals at every dose group but not in any of the control animals. In both sexes, the Hb content of the blood showed a dose-dependent decrease which was significant at all dose levels in females. The LOAEL in this study was 5 mg/kg/day.

Inhalator exposure

In SCOEL/SUM/178 of December 2012 for N-methylaniline with reference to Treon et all, Arch. Ind. Hyg. Occup. Med 1:506-524,1950 several species (rats, rabbits, guinea pigs, dogs, cats and monkeys) were exposed to different concentrations of N-methylaniline for 7 hours/day, 5 days/week for a different number of total exposures. The cat is generally considered as the most sensitive species to MetHb formation, the rabbit is the least sensitive. No signs of intoxication were seen at 2.4 or 2.3 ppm. Cyanosis, increased respiration, salivation, prostration, loss of body weight and death were observed at a concentration of 7.6 ppm (32.6 mg/m^3) and above. At 86 ppm (371 mg/m^3), animals displayed severe signs of poisoning and died. The concentration of MetHb in blood was correlated to the concentration of NMA in air. In cats exposed at 2.4 ppm, MetHb was at or below 5 % (as read from figure). In rabbits exposed to 26.6, 7.6 or 2.4 ppm, the MetHb level reached 6.3 %, 5.2 % or 1.7 %. Formation of Heinz bodies was also observed. In 4 cats exposed to 2.4 ppm, Heinz bodies were found on average in 12–29 % of erythrocytes and disappeared slowly over a period of several weeks after cessation of exposure. No Heinz bodies were observed in rabbits at 2.3 and 7.6 ppm. However, decreased erythrocyte count and haemoglobin (Hb) concentration, and hyperplasia of the bone marrow were observed at 7.6 ppm in this species. At the same concentration, pathologic effects (oedema, congestion) were observed in heart, lung, liver, spleen and kidneys of all species. No such effects were observed in animals exposed to 2.4 ppm. This level (2.4 ppm, 10.7 mg/m^3) is probably a NOAEL in this study but the low number of animals examined limits its validity. It is also possible that dermal uptake may have contributed to the total dose received by the animals, and 2.4 ppm may represent an underestimate of the true NOAEL. The conversion factor adopted in SCOEL/SUM/178 is 1 ppm = 4.45 mg/m^3.

Dermal exposure

No consistent data of repeated dose dermal toxicity are available. As reported in SCOEL/SUM/178 of December 2012 for N-methylaniline with reference to Treon et all, J Ind Hyg Toxicol 31:1-20, 1949 limited data were available from a study in rabbits which received repeated 1-hour applications of N-methylaniline on the shaved abdominal skin for 5 days/week. No death occurred after 50 doses of 100 mg/kg each (2 animals) and of 160 mg/kg (one animal). Two animals each died after 22 doses of 220 mg/kg or 12 doses of 380 mg/kg. At necropsy, degenerative alterations were seen in brain, heart, lung, liver and kidneys. One animal each survived 22 doses of 390 mg/kg or 27 doses of 720 mg/kg but both lost 18 % of their body weight. In this study only two/one animals were tested for each dose so we haven't sufficient data to define the dermal NOAEL.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Data from reliable source (National Institute of Health Sciences (NIHS) of Japan)

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
Data from reliable source (Scientific Commitee on Occupational Exposure Limit SCOEL)

Justification for classification or non-classification

Regarding repeated dose toxicity adverse effects were observed for oral exposure (LOAEL rat= 5 mg/kg/bw) and for inhalator exposure (NOAEC different species = 10.7 mg/m^3). No data of repeated dose dermal toxicity are available.

However, according to CLP Regulation (EC n.1272/2008) N-methylaniline is classified for repeated dose toxicity H373 (STOT.Rep. Exp.2)