N-(5-chloro-2-methoxyphenyl)-3-hydroxy-4-[[2-methoxy-5-[(phenylamino)carbonyl]phenyl]azo]naphthalene-2-carboxamide

Endpoint summary

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

TK assessment

Toxicokinetic behaviour (absorption – distribution – metabolism – excretion) of the pigments of the category of Naphtol AS Pigments has not been investigated experimentally. However, taking into account the physical-chemical data and the toxicological properties of the members of this category as well as existing data for other pigment groups with similar physical-chemical and toxicological properties, some conclusions on the toxicokinetics of the members of the category of Naphtol AS Pigments can be drawn.

No substance specific toxicity has been observed in several studies on toxicity of Naphtol AS Pigments after oral, dermal or inhalation exposure:

•       The substances of this category are not acutely toxic, neither after oral nor after dermal or inhalation application. The oral LD50 values are > 2000 mg/kg bw, the limit for classification. Even no mortality was observed after application of much higher doses up to 15000 mg/kg bw. The dermal LD50 value is > 2000 mg/kg bw, no animal died after testing of the limit dose. Also, single inhalation exposure of the highest technical feasible concentration of 1580 mg/m3 air for 4 h did not cause any lethality.

•       Investigations on the toxicity after repeated dosing did not reveal any toxicity up to the highest dose tested (NOAEL in an OECD TG 422 combined repeated dose and developmental/reproduction screening test in rats or OECD 421 developmental/reproduction screening test in rats: 1000 mg/kg bw/day); no toxicity in several subacute tests up to the highest dose tested (i.e. either 500 or 1000 mg/kg bw/day).

•       The substances of this category are not irritating to the skin, i.e. they do not damage the skin barrier, which would facilitate dermal absorption.

•       The substances of this category do not cause skin sensitisation.

•       Tests on mutagenicity in vitro (reverse mutation assays in vitro, gene mutation and cytogenicity assays) gave mostly negative results. Single reverse mutation assays in bacteria (Ames Test) showing positive or equivocal results are regarded not to be biologically relevant due to the negative findings in an in vivo UDS assay. The data on mutagenicity indicate that the azo-group of the chemical structure is very stable and is not cleaved, especially not under in vivo conditions.

These data on toxicity indicate that the members of this category are not bioavailable after oral, dermal or inhalation exposure.

Pigments of the Naphtol AS category are nearly insoluble in water (solubilities ranging from 3 to 34 μg/L) and only sparsely soluble in n-octanol (15 to 8630 μg/L). Due to this low solubility the members of this category are (nearly) not existent in a dissolved form on the skin or mucous membranes after dermal, oral or inhalation exposure, i.e. they could not be absorbed via skin and mucous membranes.

All these data indicate that Naphtol AS Pigments are not bioavailable. But, upon inhalation of a pigment product with a particle size distribution allowing deposition in the lower respiratory tract, uptake and transport of pigment particles by macrophages may occur as for other inert dust particles.

The conclusion that Naphtol AS Pigments are not bioavailable except after uptake from the lower respiratory tract by macrophages is supported by findings on other (nearly) insoluble and inert pigment particles like e.g. Mono-Azo Pigments, Diarylide Yellow Pigments, Quinacridone Pigments, Acetolone or Naphtolone Pigments. The members of these pigment groups have similar physical-chemical properties like the Naphtol AS Pigments under investigation, i.e. they are also nearly insoluble in water, n-octanol or other organic solvents. Like Naphtol AS Pigments the members of the other pigment groups did not show any substance related toxicity in several studies on acute or repeated toxicity. Published investigations on toxicokinetic behaviour revealed a negligible uptake, if at all, after oral (Decad et al., 1983; El Dareer et al., 1984;Leuschner 1978; Mondino et al., 1978; Nony et al., 1980; Sagelsdorff et al., 1996) , inhalative (Bartsch et al., 2001; Hofmann and Schmidt, 1993) or dermal application (Decad et al., 1983).

References

Bartsch,W, Berger-Preiß E, Dasenbrock C, Ernst H (2001), Bioverfügbarkeit von Azopigmenten nach Aufnahme über die Atemwege. Schriftenreihe der Bundesanstalt für Arbeitsschutz und Arbeitsmedizin. Fb 929, Wirtschaftsverlag NW Bremerhaven.

Decad GM, Snyder CD, Mitoma C (1983) Fate of water-insoluble and water-soluble dichlorobenzidine-based pigments in Fisher 344 rats. Journal of Toxicology and Environmental Health 11: 455-465.

El Dareer SM, Tillery KF, Hill DL (1984) Investigations on the disposition of oral doses of some water-insoluble pigments. Bulletin of Environmental Contamination and Toxicology 32: 171-174.

Hofmann T, Schmidt D (1993) Investigation of possible metabolism of pigment yellow 17, a 3,3'-dichlorobenzidine-based pigment, after inhalation exposure in rats. Archives of Toxicology 67: 141-144.

Leuschner F (1978) Carcinogenicity studies on different diarylide yellow pigments in mice and rats. Toxicology Letters 2: 253-260.

Mondino A, Achari R, Dubini M, Marchisio MA, Silvestri S, Zanolo G (1978) Absence of dichlorobenzidine in the urine of rats, rabbits and monkeys treated with C.I. pigment yellow 13. Medicina del Lavoro 69: 693-697.

Nony CR, Bowman MC, Cairns T, Lowry LK, Tolos WP (1980) Metabolism studies of an azo dye pigment in the hamster based on analysis of the urine for potentially carcinogenic aromatic amine metabolites. Journal of Analytical Toxicology 4: 132-140.

Sagelsdorff P, Haenggi R, Heuberger B, Joppich-Kuhn R, Jung R, Weideli HJ, Joppich M (1996) Lack of bioavailability of dichlorobenzidine form diarylide azo pigments: molecular dosimetry for hemoglobin and DNA adducts. Carcinogenesis 17: 507-514.