3-methyl-6-(p-toluidino)-3H-dibenz[f,ij]isoquinoline-2,7-dione

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics, other

Remarks:

TK assumption

Type of information:

other: Expert statement

Adequacy of study:

supporting study

Study period:

2018

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2018

Report date:

2018

Materials and methods

Objective of study:

absorption

distribution

excretion

metabolism

Test guideline

Qualifier:

no guideline available

Test material

Test material information

Constituent 1

Reference substance name:

3-methyl-6-[(4-methylphenyl)amino]-3H-naphthol[1,2,3-de]quinolone-2,7-dione

Cas Number:

81-39-0

Molecular formula:

C24H18N2O2

IUPAC Name:

3-methyl-6-[(4-methylphenyl)amino]-3H-naphthol[1,2,3-de]quinolone-2,7-dione

Test material form:

solid: particulate/powder

Applicant's summary and conclusion

Executive summary:

There are no experimental toxicokinetic data available for the substance and this statement is based on available data as physico-chemical data and toxicological data. This assumption was conducted based on the REACH ECHA “Guidance on information requirements and chemical safety assessment chapter R.7c” of the ECHA guidance document (Version 3.0, June 2017).

Available physico-chemical information taken into account:

Physical state:              The substance is a solid red powder

Identification: Macrolex Rot 5B

CAS Number: 81-39-0

Chemical Name: 3-methyl-6-[(4-methylphenyl)amino]-3H-naphtho[1,2,3-de]quinoline-2,7-dione

Molecular mass:             C₂₄H₁₈N₂O₂: 366.4 g/mol

Water solubility:            Very low solubility: 0.00075 mg/l at 20oC

Log Pow:                      logPow = 4.8 at 25 °C (pH 7).

Vapor pressure:            Very Low: 1.76*10-10 Pa at 25 °C (predicted by QSAR)

General considerations:

In general, logPow values between 1 and 4 and molecular weight below 500 are favourable for absorption regarding oral/GI absorption, respiratory absorption and dermal absorption. The higher logPow of 4.8 and the very low water solubility of 0.00075 mg/l might limit absorption. No information of metabolic transformation of Macrolex Red 5B is available.

Estimation of oral absorption:

In the acute oral study 10 male Wistar rates were dosed with 5000 mg/kg test item. No symptoms or mortality were observed. Consequently the discriminating dose is 5000 mg/kg (highest dose tested).

The oral (gavage) administration of Macrolex Rot 5B to rats, for twenty-eight days at dose levels of 100, 300 or 1000 mg/kg bw/day was well tolerated and did not result in any toxicologically significant effects. The ‘No Observed Adverse Effect Level’ (NOAEL) for systemic toxicity was 1000 mg/kg bw/day (highest dose tested) within the confines of this study type. Colored contents and/or discoloration were apparent for the stomach for the majority of males at 100 mg/kg bw/day, all males at 300 mg/kg bw/day and all males and one female at 1000 mg/kg bw/day. Colored contents were apparent in the cecum for one male and two females at 300 mg/kg bw/day and all males and the majority of females at 1000 mg/kg bw/day. Additionally, two males at 1000 mg/kg bw/day showed discoloration of the cecum. No other systemic-organ discoloration was reported.

Overall: the molecular weight is in the range of compounds absorbed after oral dosing. Based on the high LogPow (4.8) very low water solubility (0.00075 mg/l) an absorption following ingestion is not likely. This is supported by toxicological data after oral dosing. No toxicologically relevant effects were seen after acute or 28 days exposure. In conclusion, it is likely that oral absorption is low.

Estimation of dermal absorption:

There are no dermal studies available; the substance is not irritating to the skin or eyes. Based on the low water solubility low absorption after dermal contact is assumed.

Estimation of absorption via inhalation:

A study on the acute inhalation toxicity of Macrolex Rot 5B on rats has been conducted in accordance with OECD Test Guideline no. 403 (2009). The mean mass median aerodynamic diameter (MMAD) was 11.18µm and the mean geometric standard deviation (GSD) was 2.24. Animals exposed to the test item did not reveal any clinical symptoms. Nonetheless test-item dependent red discoloration of the fur was observed at the head, forelegs, neck and thorax. No findings were seen at the functional observation battery. No toxicological relevant test item-related changes in incremental body weight gain were observed. Statistically comparisons between the control and the exposure groups revealed no significantly changed body temperatures at 1175 mg/m3 test item when compared to control groups. Mortality did not occur at 1175 mg/m3. No gross pathological findings were found in animals exposed to the test item.

Based on the physicochemical parameters and the absence of effects in an acute inhalation study it is assumed that the absorption via inhalation is low.

Estimation of distribution:

Based on the low water solubility it is not assumed that the substance distributes into cells.

Estimation of accumulation:

In general substances with high log P values have long biological half-lives. Substances with log P values of 3 and less would be unlikely to accumulate with the repeated intermittent exposure patterns normally encountered in the workplace but may be accumulate if exposures are continuous.

Based on the log P of 4.8, and the very low solubility of 0.00075 mg/l accumulation is unlikely. No toxicity is seen in the sub-acute toxicity studies (28 days up to 52 days of exposure)

Estimation of metabolism:

An in vitro genotoxicity test in bacteria (Ames Test) showed positive results in particular in the presence of S9 mix. An in vivo Comet test conducted in the sub-acute toxicity study did not indicate mutagenic activity in vivo.

Overall, some metabolism of Macrolex Rot 5B might be assumed under the in vitro Ames test conditions but no mutagenicity is observed in an Comet test after 28 days of exposure to 1000 mg/kg/day.

Estimation of excretion:

Characteristics favorable for urinary excretion are low molecular weight (below 300 in the rat), good water solubility and ionization of the molecule at the pH of urine.

Based on the physicochemical data an excretion of via feces is assumed.