N-(4-aminophenyl)aniline

Endpoint summary

Description of key information

Methemoglobinemia was observed in cats after single oral administration of a non-lethal dose (Bayer AG 1957). In rats, the oral LD50 value was determined as 336 mg/kg bw in a GLP and guideline study (Monsanto Co. 1991b). Clinical signs of toxicity included ataxia, nasal, oral and ocular discharge, difficult breathing, and hypoactivity. The most notable internal necropsy observations for animals which died consisted of abnormalities of the digestive tract, urinary bladder, brain, lymph nodes, thymus and adrenal glands. In addition, observations of animals which survived showed also adverse effects on the digestive tract which may represent an irritant effect of the test material.
The acute dermal toxicity of 4-ADPA was very low with an LD50 value of greater than 5000 mg/kg bw in rabbits. The only clinical signs noted in some animals were nasal and ocular discharge and single occurrence of red and/or swollen eyes.

Key value for chemical safety assessment

Acute toxicity: via oral route

Endpoint conclusion

Dose descriptor:

LD50

Value:

336 mg/kg bw

Acute toxicity: via dermal route

Endpoint conclusion

Dose descriptor:

LD50

Value:

5 000 mg/kg bw

Additional information

Acute toxicity: oral

The acute oral toxicity of 4-Aminodiphenylamine (4-ADPA) was evaluated in a GLP and Guideline study using Sprague Dawley rats. A variety of adverse clinical signs was noted in treated animals. The most notable clinical signs included piloerection, decreased activity, urine/faecal strains, decreased defecation, reddish/orange coloured urine, breathing abnormalities and dark material around the facial area. The majority of these signs occurred during days 1 to 5. Body weight loss was noted in one female at 350 mg/kg bw dose level. All other surviving animals exhibited body weight gains during the test period. In the animals surviving until necropsy on study day 15, one animal from the 250 mg/kg level exhibited adhesions involving the stomach and surrounding tissues. The most notable internal necropsy observations for animals which died consisted of abnormalities of the digestive tract, urinary bladder, brain, lymph nodes, thymus and adrenal glands. The acute oral LD50 for 4 -ADPA for male rats was calculated to be 370 mg/kg bw. In female rats, the acute oral LD50 of 4-ADPA was calculated to be 300 mg/kg bw. In the sexes combined, the acute oral LD50 of 4 -ADPA was calculated to be 336 mg/kg bw (Monsanto Co. 1991b).

In a previous study which was done with CDR rats an acute oral LD50 of 720 mg/kg bw was calculated for both sexes combined. In this study toxicological signs were seen during the 24 hours after dosing in all groups including ataxia nasal, oral and ocular discharge, hyperpnea, and hypopnea, wet rales, urinary and faecal staining, unthrifty coat, alopecia, hypoactivity, prostration and decreased food consumption. Necropsy observations found were reddening of the stomach and intestinal walls, which may represent an irritant effect of the test material on the gastrointestinal mucosa (Monsanto Co. 1984a).

In an acute oral toxicity study with cats, a single dose of 25 mg 4 -ADPA/ kg bw led to slight and reversible increase in methemoglobin levels in 2 female cats (maximal value of 11% at 3 hours p.a.), whilst Heinz bodies were not increased in comparison to reference values (Bayer AG 1985). The ability to induce methemoglobinemia is supported by results of a former study (Bayer AG 1957), but no quantitative information can be derived from this investigation due to a number of restrictions (e.g. only one cat/dose, determination of methemoglobin only 1 and 2 hours after dosing, no reverence value given). Additionally in this study cyanosis was observed in cats dosed with 25 or 100 mg/kg bw, whilst 10 mg/kg bw were without evident effects.

Acute toxicity: inhalation

There are no valid data available for the acute inhalation toxicity.

Acute toxicity: dermal

The acute dermal toxicity of the test substance 4-ADPA was evaluated with New Zealand White rabbits in a GLP and Guideline study. No mortality was observed in the dose range finding study up to 5000 mg/kg bw. Thus, in the main study five male and five female rabbits were treated with 5000 mg/kg bw test substance for 24 hours, followed by a 14 d observation period. All animals survived throughout the study. Therefore, the dermal LD50 of 4-ADPA in rabbits is greater than 5000 mg/kg bw. Most animals were free of significant signs of systemic toxicity, although some occurrence of nasal discharge were seen as were single occurrence of red and/or swollen eyes, food consumption decrease and ocular discharge. One animal exhibited a swollen left eye and a red nictitating membrane in the same eye during the day of dosing and or the day after dosing (Monsanto Co. 1984b).

Acute toxicity: other routes

There are no data available.

Human information

There are no valid data available.

Justification for classification or non-classification

Based on the findings of the above mentioned GLP and OECD guideline study (Monsant Co. 1991b, LD50 336 mg/kg bw) the test substance 4-ADPA is classified as harmful if swallowed to the classification criteria 67/548/EWG and regulation no. 1272/2008 (GHS).