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Description of key information

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.
In addition, due to the lack of acute dermal toxicity data (sec. exposure route) p-isopropyl aniline was chosen as surrogate to fill the data gap. Both substances have similar physicochemical properties, are aromatic amines revealing equal main intrinsic properties as shown by methemoglobin formation and/or erythrocyte toxicity.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

Summary of Justification for Read Across to fill data gaps

m-Toluidine shall be registered according to Art 10 of Regulation EC No. 1907 / 2006 (REACh), for annual production of 100 tonnes (Annex VIII). However, the required toxicological data for information submitted for general registration purposes (Art 10) at this tonnage band are not complete For m-toluidine no reliable data are available for acute dermal toxicity (sec. exposure route).

According to ECHA Document: Guidance on information requirements and chemical safety assessment volume R 6: QSARs and grouping of chemicals (2008) section.2.3 p.: 89 and Practical Guide No. 6 (2012) an accepted method to fill data gaps is by read–across technique. Read across can be performed by different ways. In this case the One-to one approach is chosen. For this approach as analogue molecule p-Isopropyl aniline (CAS-No. 99-88-7) is chosen.

For both substances methemoglobinemia and / or erythrocyte toxicity seems to be the most relevant mechanism for systemic toxicity. Consequently, p-isopropyl aniline and m-toluidine were used as analogue substances in a read-across apporoach to fill the data gaps. This approach is justified because both substances have similar physicochemical properties, are aromatic amines revealing equal main intrinsic properties as shown by methemoglobin formation and/or erythrocyte toxicity.

Summary of Information/assumptions regarding Toxicokinetics, Metabolsim and Distribution

INTRODUCTION

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.

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 water 15 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

DISTRIBUTION and METABOLISM

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.

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.

ACCUMULATION

In general, substances with log Pow of 3 or less would be unlikely to accumulate in fatty tissue.

EXCRETION

On the basis of the molecular structure (Ammonium group), the molecular size and the water solubility excretion into the urine seems to be the main route of elimination. This assumption is supported by the findings of Cheever 1980 identifying 2.5 % m-toluidine in the unchanged form and the metabolites 2-amino-4-methyl-phenol and 4-amino-2-methyl-phenol in rat urine.

SUMMARY

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.

REFERENCES

Cheever K et al. 1980: Metabolism of ortho-, meta-, and para-toluidine in the adult male rats Toxicol Appl Pharmacol 56, 361-369

DuPont De Nemours, 1980a: Oral LD50 Test in rats of benzenamine, 3-methyl, NTIS Document OTS0557168

DuPont De Nemours, 1980b: Skin Irritation Test of benzenamine, 3-methyl in rabbits, NTIS- OTS0557170

Kiese M 1963: Effects of certain substituents upon the N-oxidation of aniline in vivo, Naunyn Schmiedeberg’s Arch Exp Pathol and Pharmacol 244, 387-404 cited by UNEP 2003

McLean S et al, 1967: Methaemoglobin formation induced by aromatic amines and amides J Pharm Pharmac 19, 146-154

McLean S et al 1969: Methaemoglobin formation by aromatic amines J Pharm Pharmac 21, 441-450

Ministry of Health, Labour and Welfare (MHLW) 1995a: m-Toluidine, Testing reports on environmental chemicals Vol 2, 79-81, 83 -97, 527-532

Ministry of Health, Labour and Welfare (MHLW) 1995: m-Toluidine, Testing reports on environmental chemicals Vol 2, 79-81, 99 -102, 539-542

Ministry of Health, Labour and Welfare (MHLW) 2002: m-Toluidine, Testing reports on environmental chemicals Vol 9, 195-201, 590-593

Senczuk W and Rucinska H 1984: Bromat Chem Toxsykol. 17, 241-243 cited by UNEP, 2003

United Nations Environmental Program – Chemical Branch (UNEP) 2003: OECD Screening Information Data Set (SIDS) for High Production Volume Chemicals: m-Toluidine

Vasilenko NM et al. 1977: Deposited Doc. ISS Viniti 4035-4077 cited by UNEP, 2003

Vohr HW 2009: m-Toluidine, local Lymphnode Assay in mice (LLNA/IMDS)Report No. AT05698, Bayer Schering Pharma AG

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