Formaldehyde, oligomeric reaction products with aniline

Endpoint summary

Description of key information

Read-across to 4,4' MDA
Oral LD50 is 444 mg/kg bw.
Dermal LD50 was affected by the vehicle and ranged from 1000 mg/kg bw for females when administered in DMSO to >2500 mg/kg bw in aqueous solution.
Inhalation, no mortality in rats with highest technically feasible and respirable inhalation atmosphere.

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.

Acute oral exposure:

The key study describing the oral toxicity of pure MDA in rats, resulted in a LD50 of 444 mg/kg bw (Munk, 1975). At a starting dose of 250 mg/kg bw, no mortalities or pathological effects have been observed. In a study in rats with oligomeric MDA a LD50 of 700 mg/kg bw was recorded. Whilst this study did not comply with current guidelines the results may be used to support the read-across to 4,4’ MDA (BASF AG 1973). Damage to the liver and kidneys has been reported to be the most prominent toxic effect in rats.

Orally administered MDA has shown to induce severe changes in the liver of male Sprague-Dawley rats with a threshold of toxicity between 25 and 75 mg/kg. MDA caused changes in markers for liver injury, including serum ALT, bile flow, serum bilirubin concentration, GGT activity, and liver weight. Liver sections of 100 mg/kg bw animals exhibited multifocal lesions consisting of hepatocellular necrosis with hemorrhage and moderate infiltration in neutrophils (Bailie et al., 1993).

Cats and dogs are more sensitive to MDA exposure. After treatment with 100 mg/kg bw 7/11 cats and 3/3 dogs died. MDA induced ophthalmologic damage and damage of the liver and kidney beginning with 10 mg/kg bw in cats and 50 mg/kg bw in dogs (lowest doses tested). Mortality in both species occurred due to organs disorder (BASF, 1961). Methemoglobin (MetHb) levels were moderately elevated in cats (up to 17% with a dose of 100 mg/kg bw). Regarding the ability of MetHb-formation the cat was identified as the species most similar to human. Therefore a slight ability for MetHb in humans has to be expected, but no classification regarding effects on the hematopoetic system is indicated. Retinal damage was reported in surviving cats.

Acute dermal exposure:

Acute mortality by the dermal route of exposure was highly dependent on the solute of the test substance (DMSO or water) and the sex of the animal. In the key study MDA was applied as a 50% aqueous solution as well as a 50% DMSO solution (Zeller & Hildebrand, 1976). While application of 2500 mg/kg bw MDA as a 50% aqueous solution caused no mortalities, 1000 mg/kg bw MDA as a 50% solution in DMSO killed 5 out of 10 female rats within 7 days. Male rats were not affected by treatment with 1000 mg/kg bw MDA in DMSO. A dose as high as 2000 mg/kg needed to be applied in order to kill male animals. Mortality increased dose dependently, resulting in an acute dermal LD50 value of 2080 mg/kg bw, with females being more susceptive than males. Apathy, hyperchromodacryorrhea, and jaundice as clinical signs of systemic toxicity have been observed in all treatment groups.

In an acute dermal toxicity with oligomeric MDA, rabbits were administered an occlusive treatment of 2000 mg/kg bw oMDA without vehicle for 24 hours with no deaths or signs of intoxication. Whilst this study (Hine 1967) was not performed according to current guidelines and was deficient in reporting it substantiates the findings noted with 4,4’ MDA.

Acute inhalation exposure:

After exposure of rats for 6 h with 0.46 mg/l MDA no mortality occurred and animals were in good condition (BASF, 1977a). Gravimetrical determination of the particle size distribution was performed, showing that most of the dust particles were within the respirable fraction.

Human exposure:

Acute intoxication of humans with MDA is reported after oral, dermal and inhalation exposure, leading to jaundice. In addition to acute hepatic illness, in some cases myocardial effects and persistent retinal damage were reported (European Chemical Bureau (2001) European Union Risk Assessment Report 4,4'-methylenedianiline, CAS No: 101 -77 -9, 1st Priority List Volume 9, Report No.: EUR 19727 EN.

Based on the animal data described, MDA is toxic after acute oral exposure (R25, GHS cat 3) and harmful in contact with skin (R21, GHS Cat 4). Though considerable dermal toxicity was only observed in presence of a solvent which can act as a carrier (DMSO).

From the animal data available for acute inhalation toxicity no classification is appropriate, since no severe signs of toxicity were reported.

Although due to severe liver toxicity of the substance at low dose levels (between 25 - 75 mg/kg), the test substance should be classified as a specific target toxicant Cat 1 (STOT single-dose Cat 1) and R39 based on GHS/EU standards.

Taking into account that rodents may not present the adequate model to predict acute toxicity of this substance to humans, human observations after several cases of acute poisoning at the workplace, and of consumers in 1965 (“Epping Jaundice”) need to be considered for classification. Since the substance is readily absorbed through the skin and the mucosa of the respiratory tract, classification as R39/23/24/25 (Toxic: danger of very serious irreversible effects through inhalation, in contact with skin and if swallowed) was agreed on the CMR Working Group Meeting, 7-9. October 1998. (STOT single Cat 1, causes damage to the liver on all routes of exposure). Furthermore irreversible damage of the retina should be taken into account.

Justification for classification or non-classification

For acute oral toxicity, cats and dogs are more sensitive than rats. The LD50 of 50 -100 mg/kg calls for an acute oral classification cat 3: H301: toxic if swallowed.

Considerable dermal toxicity was observed only if the solvent DMSO was used, which acts as a carrier. Therefore, no classification for acute dermal toxicity is proposed.

Although the cut-off limits for acute inhalative toxicity according to regulation 1272/2008/EC were not exceeded, the highest technically feasible concentrations did not cause mortalities. No classification for acute inhalative toxicity is proposed.

Due to irreversible liver and retina effects, classification as STOT single exp. cat 1 (R39/23/24/25) is appropriate.