m-toluidine

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

other: Information/ assumption regarding toxicokinetics, metabolism and distribution bsdrf on physico-chemical data and the available toxicological data

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: reliable toxicokinetic assumption based on available valid data

Data source

Reference

Reference Type:

other: Assumption based on available data

Title:

Unnamed

Year:

2014

Report date:

2014

Materials and methods

Objective of study:

other: Information/Assumption regarding toxicokineticx, metabolism and distribution

Test guideline

Qualifier:

according to guideline

Guideline:

other: The criteria outlined in the Reach Guidance on Information Requirements and Chemical Safety Assessment, Chapter R7c. Section R7.12: Guidance on Toxicokinetics

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

m-toluidine

EC Number:

203-583-1

EC Name:

m-toluidine

Cas Number:

108-44-1

Molecular formula:

C7H9N

IUPAC Name:

3-methylaniline

Test material form:

other: liquid

Details on test material:

no further data

Radiolabelling:

no

Administration / exposure

Details on exposure:

the following statements on toxicokinetics of m-toluidine are based on the physico-chemical data as well as on the toxicological studies described in the IUCLID database within the REACH process

Results and discussion

Main ADME results

Main ADME results 1

Type:

absorption

Results:

Based on physico-chemical data and the available toxicological data absorption via inhalation, gastro-intestinal tract or via skin is assumed

Main ADME results 2

Type:

distribution

Results:

Based on physico-chemical data and the available toxicological data it is assumed that the substance will be distributed in the body. Accumulation is not expected.

Main ADME results 3

Type:

metabolism

Results:

Based on the available literature it is assumed that the substance is metabolized not to DNA reactive substances by hepatic transformation; metabolites are indentified

Main ADME results 4

Type:

excretion

Results:

Based on physico-chemical data and the available toxicological data it is assumed that urinary excretion is the main elimination route

Main ADME results 5

Type:

other: methemoglobinemia/hematotoxicity

Results:

Based on the available data it is shown that depending on species and the applied dose/concentration, the ratio of methemoglobinemia increase up to 60 %

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Based on the boiling point of about 203-204 °C and a vapour pressure below 0.5 kPa it can be assumed that vapour inhalation is an unlikely route of exposure. However, the log Pow of 1.4 is in the range that is favorable for absorption after inhalation exposure directly across the respiratory tract epithelium by passive diffusion. There are no studies available using inhalation as exposure route to confirm this assumption. However, according to Reach Guidance on Information Requirements and Chemical Safety Assessment, Chapter R7c. Section R7.12: Guidance on Toxicokinetics, it is likely that the substance will also be absorbed if it is inhaled because there are signs of systemic toxicity present in an oral toxicity study. Respective findings are described in the section below.

The physico-chemical characteristics of m-toluidine (readily soluble in water15 g/l), log Pow of 1.4 and the molecular mass of 107 g/mol are in a range suggestive of absorption from the gastro-intestinal tract subsequent to oral ingestion, with absorption by passive diffusion as the assumed mechanism. This assumption of an oral absorption is confirmed by acute and sub-acute oral toxicity data. In the acute oral study (rat, LD50 922 mg/kg bw; DuPont De Nemours, 1980a) mortality occurred from 700 mg/kg bw onwards with all animals displaying cyanosis and moderate weight loss. Repeated administration of m-toluidine to rats by gavage in doses up to and including 300 mg/kg bw/day for at least 28 days (Japanese Ministry of Health, Labour and Welfare, MHLW, 1995a) resulted in a LOAEL of 30 mg/kg bw/day based on evidence of hemolytic anemia such as marginal pigment deposit and extra-medullary hematopoiesis in the spleen probably caused by hematotoxicity (methemoglobin formation).

Although no acute dermal study yielding a LD50 value, or no repeated dermal application study is available, dermal absorption can be assumed due to the physico-chemical properties of m-toluidine: log Pow of 1.4 favour dermal absorption particularly because water solubility is high (15 g/l) in addition with the low molecular mass of 107 g/mol. This assumption can be agreed because Senczuk and Rucinska. 1984 (cited in UNEP 2003) reported of dermal absorption after application of m-toluidine to the skin of rats evidenced by determination of up to 40 % methemoglobinemia. Hence, the substance is evaluated as only slightly irritating to the skin (DuPont de Nemours 1980b) and m-toluidine caused no sensitization reactions in the LLNA and no systemic intolerance reactions were reported (Vohr 2009).

Furthermore, methemoglobin formation and consequently systemic availability is observed in different acute studies. UNEP 2003 summarizes:
Major reports of methemoglobin formation are shown in Table 1. A single administration of m-toluidine induces severe methemoglobinemia in rats, cats and dogs. Although species differences in methemoglobin reductase activity in vitro were reported [Stolk et al. 1966: Biochem Pharmacol. 15, 343-351], there is no information on species differences of chemical-induced methemoglobinemia in vivo, including m-toluidine.

Table 1: Methemoglobin induction in experimental animals

Route Animals ---- Dose ---- Methemoglobin ratio ------- References
oral rat 200 mg/kg bw 36.4 % Senczuk und Rucinska 1984
dermal rat 2.5-12.5 mg/ml 40 % Senczuk und Rucinska 1984
dermal rat 700 mg/kg bw 32.6 % Vasilenko et al 1977
i.v. cat 26.79 mg/kg bw 60.2 % McClean et al 1967, 1969
i.v. dog 111.1 mg/kg bw 56 % Kiese 1963

Details on distribution in tissues:

For m-toluidine as a small molecule with the given water solubility, a wide distribution in the body is expected. Based on the log Pow of 1.4 a distribution into the cells is likely. This assumption is confirmed by the variety of effects shown in the oral repeated dose toxicity study: male and female rats received by gavage doses of up to and including 300 mg/kg bw/day over a period of at least 4 weeks resulting in body weight gain reduction from the first week and macroscopic and microscopic changes in liver, kidney and spleen and in blood chemistry data (MHLW 1995) due to hematotoxicity of m-toluidine.

Based on the negative results in genotoxicity in-vitro tests (MHLW 1995b and 2002: Ames test, and Test for Chromosome aberrations, with and without metabolic activation) it is concluded that DNA reactive metabolites of m-toluidine will most probably not be generated in mammals in the course of hepatic transformation.
In general, substances with log Pow of 3 or less would be unlikely to accumulate in fatty tissue.

Furthermore, Cheever, 1980 (cited by UNEP 2003)investigated urinary excretion and metabolism after single oral administration of 500 mg m-toluidine to rats and reported that only 2.5 % of unchanged compound was recovered from urine and as main metabolites 2-amino-4-methyl-phenol and 4-amio-2-methyl-phenol were identified in the urine after hydrolysis.

Details on excretion:

Cheever, 1980 (cited by UNEP 2003) investigated urinary excretion and metabolism after single oral administration of 500 mg m-toluidine to rats and reported that only 2.5 % of unchanged compound was recovered from urine and as main metabolites 2-amino-4-methyl-phenol and 4-amio-2-methyl-phenol were identified in the urine after hydrolysis.

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

Based on the negative results in genotoxicity in-vitro tests (MHLW 1995b and 2002: Ames test, and Test for Chromosome aberrations, with and without metabolic activation) including HPRT in mammalian cells (Wollny 2014) it is concluded that DNA reactive metabolites of m-toluidine will most probably not be generated in mammals in the course of hepatic transformation.

Furthermore, Cheever, 1980 (cited by UNEP 2003)investigated urinary excretion and metabolism after single oral administration of 500 mg m-toluidine to rats and reported that only 2.5 % of unchanged compound was recovered from urine and as main metabolites 2-amino-4-methyl-phenol and 4-amio-2-methyl-phenol were identified in the urine after hydrolysis.

Any other information on results incl. tables

In summary, m-toluidine is assumed to be absorbed following inhalation, oral, or dermal exposure, readily distributed in the body and metabolized. Accumulation is not expected. Urinary excretion is assumed to be the main elimination route.

Applicant's summary and conclusion

Executive summary:

Only limited specific information on toxicokinetic, metabolism or distribution of m-toluidine in animals or in humans is available. Therefore, the following statements on toxicokinetics of m-toluidine are based on the physico-chemical data as well as on the toxicological studies described in the IUCLID database within the REACH process. The criteria outlined in the Reach Guidance on Information Requirements and Chemical Safety Assessment, Chapter R7c. Section R7.12: Guidance on Toxicokinetics, will be applied throughout the statement.

m-Toluidine (3 –methyl aniline) is a colourless liquid at room temperature with a molecular mass of 107.16 g/mol. The melting point of m-toluidine is -31°C, the boiling point is about 203 - 204°C at 1013 hPa. The relative density is 0.99 at 25°C and the vapour pressure of m-toluidine is given in IUCLID dataset as 0.2 hPa at 20°C. The log Pow of m-toluidine is 1.4, and the water solubility of m-toluidine is 15000 mg/L at 20°C.

In summary, m-toluidine is assumed to be absorbed following inhalation, oral, or dermal exposure, readily distributed in the body and metabolized. Accumulation is not expected. Urinary excretion is assumed to be the main elimination route.