Formaldehyde, oligomeric reaction products with aniline

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Acute/short term exposure

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Local effects

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Workers - Hazard via dermal route

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Additional information - workers

Justification on read-across of data for the 4,4´-isomer of MDA for oligomeric MDA in the scope of REACH.

 

Oligomeric MDA is produced by a condensation reaction between aniline and formaldehyde. The main component of the crude product is 4,4’-MDA, which makes up 25 -85 %. Further, the crude product contains methylene-2,4’-dianiline, minor amounts of methylene-2,2’-dianiline and higher oligomers.

The general molecular formula is

 H₂N-C₆H₄-[H₂N-C₆H₄]_m-C₆H₄-NH₂

 

The higher oligomers include mainly 3-ring (m=1; product of 3 aniline + 2 formaldehyde) together with other higher number ring types (m=4-6; 4 to 6 aniline with 3-5 formaldehyde). The mean number of additional rings in the oMDA (>2-ring) is m=0.33 (range 0.1-0.6).

 

Following nomenclature for the isoformes are defined:

1)  CAS name: Benzenamine, 4,4'-methylenebis- (mono constituent substance), CAS number: 101-77-9.

EC name: 4,4'-methylenedianiline,EC number:202-974-4

2)    CAS name: Formaldehyde, polymer with benzenamine (UVCB), CAS number 25214-70-4.

EC name: Formaldehyde, oligomeric reaction products with aniline, EC number500-036-1.

Table 1: Concentration ranges of MDA-isoforms [%]:

CONTENT	4,4’-MDA	oligomeric MDA
4,4’-MDA	75 – 100	25 – 85
2,4’-MDA	0 – 20	1 – 50
2,2’-MDA	0 - 5	0.01 – 10
Formaldehyde, oligomeric reaction products with aniline	0 - 15	5 - 60

2,4'-methylenedianiline: CAS number 1208-52-2,EC number214-900-8

2,2'-methylenedianiline: CAS number 6582-52-1,EC number229-512-4

 

Table 2: Comparison of physico-chemical properties of MDA-isoforms.

	4,4’-MDA	oligomeric MDA
Melting range	83 - 92°C	30 - 70°C
MW [g/mol]	198.26	233 (average)
water solubility [g/l]	1.01 (at 25°C)	0.36-1.22(at 20°C)
logPow(at 25°C)	1.55	1.3 - 2.5
Vapor pressure [hPa]	0.00025 Pa at 25°C	<0.000001hPa at 20°C

 

Since 4,4’-MDA is the main constituent of both isoforms, toxicological properties of the incompletely tested oMDA can be extrapolated from this isomer by means of a worst case consideration. All isomers and homologues have primary aromatic amino groups as a common property.

The leading health effects of 4,4’-MDA are liver toxicity, carcinogenicity and sensitization. These effects may, at least partly, be driven by the bifunctional diamine-structure of the 2-ring molecule in 4,4´-position. In higher-ring compounds it may be predicted that this functionality, at least partly and to an alleviated extend, still exists.

Taking into account the higher degree of saturation of functional groups and the altered physico-chemical properties (higher molecular weight, decreased vapour pressure, decreased water solubility, unchanged / decreased logP_owat physiological pH) a lower reactivity and bioavailability of oMDA can be anticipated.

As a proof of concept data from dated industrial hygiene studies and a chronic study in rats can be used:

• acute i.p. toxicity in mice was lower for oMDA (LD₅₀0,5 g/kg bw, BASF AG 1973) than for 4,4’-MDA (LD₅₀0.147 g/kg bw, BASF AG 1965).
• acute oral toxicity in rats was lower for oMDA (LD₅₀0,7 g/kg bw, BASF AG 1973) than for 4,4’-MDA (LD₅₀0.444 g/kg bw, BASF AG 1975).
• both isoforms are non irritating on skin and mucosa
• subcutaneous injections of 3- and 4-ring fractions of MDA into rats resulted in a significantly lower acute toxicity (LD₅₀2.5 g/kg bw) than 4,4’-MDA (LD₅₀0.2 g/kg bw, Bayer AG 1969). In the same study chronic subcutaneous injections of 3- and 4-ring fractions of MDA were tolerated way better than 4,4’-MDA. Life expectancy and tumour incidence of animals injected with a high total dose of 11.2 g/kg of 3- and 4-ring fractions of MDA was approximately identical to the animals injected with a lower total dose of 1.41 g/kg 4,4’-MDA. This trend of decreasing systemic toxicity with increasing number of aromatic rings in the amine molecule was supported by chronic subcutaneous injections of a 8-ring fraction of MDA.

Even though the quality of the cited studies does not comply with current guideline requirements, these considerations support the thesis that 4,4’-MDA can be taken as a reference molecule for oMDA. The data gained on 4,4’-MDA can therefore be considered representative for the category for the purpose of hazard evaluation and risk assessment. Accordingly, the classification of oMDA can be adapted from 4,4’-MDA by means of a worst case consideration:

DSD: 

Carc. Cat. 2; R45                 

Muta. Cat. 3; R68                            

T; R39/23/24/25                               

Xn; R48/20/21/22                             

R43                                                    

GHS:  

carc. cat. 1B

muta. cat. 2

STOT single exp. cat 1

STOT rep. exp. cat 2

skin sens. cat.1

In order to support the legal classification key studies of 4,4’-MDA for all relevant end point were included into the oMDA IUCLID.

General Population - Hazard via inhalation route

Systemic effects

Acute/short term exposure

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Local effects

Acute/short term exposure

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General Population - Hazard via dermal route

Systemic effects

Acute/short term exposure

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General Population - Hazard via oral route

Systemic effects

Acute/short term exposure

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