A mixture of: N-(4-chlorophenyl)-4-(2,5-dichloro-4-(dimethylsulfamoyl)phenylazo)-3-hydroxy-2-naphthalenecarboxamide; N-(4-chlorophenyl)-4-(2,5-dichloro-4-(methylsulfamoyl)phenylazo)-3-hydroxy-2-naphthalenecarboxamide

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

other: Toxicokinetic behavior of PO 74 has not been investigated experimentally.

Adequacy of study:

supporting study

Materials and methods

Test material

Test material information

Constituent 1

Details on test material:

Available information used for the assessment of toxicokinetic, metabloism and distribution are related to the substance defined in section 1 and in some cases to RA substances specified in section Genetic Toxicity / Mutagenicity or section Toxicity to Reproduction.

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results
Based on the assessment of the toxicokinetic behaviour of PO 74 to the extent that can be derived from the relevant available information PO 74 is considered not to be bioavailable.

Executive summary:

Toxicokinetic behavior of PO 74 has not been investigated experimentally. However, taking into account the physical-chemical data and the toxic properties of PO 74 and of pigments with similar chemical structures, some conclusions on the toxicokinetics of PO 74 can be drawn.

No relevant substance specific toxicity has been observed in several studies on toxicity after oral or dermal exposure:

• PO 74 is not acutely toxic, neither after oral nor after dermal application. The oral LD50 values are >2000 mg/kg bw, the limit for classification.
• Investigations on the toxicity after repeated dosing did not reveal any toxicity up to the highest dose tested (NOAEL in an OECD TG 407 repeated dose 28-day oral toxicity study in rats with PO 74, and in an OECD TG 422 combined repeated dose and developmental/reproduction screening test in rats with PR 22, or in an OECD TG 421 developmental/reproduction screening test in rats with PR 170: >=1000 mg/kg bw/d).
• PO 74 is not irritating to the skin, i.e. it does not damage the skin barrier, which would facilitate dermal absorption.
• PO 74 does not cause skin sensitisation.
• Tests on mutagenicity in vitro (reverse mutation assays in vitro with PO 74, gene mutation with PR 112, 146, 147, or 170 and a cytogenicity assay with PO 74) gave negative results. The data on mutagenicity indicate that the azo-group of the chemical structure is very stable and is not cleaved, especially not under conditions of metabolic activation.

These data on toxicity indicate that PO 74 is not bioavailable in toxic amounts after oral, dermal or inhalation exposure.

PO 74 is practically insoluble in water and n-octanol. Due to this fact PO 74 is (nearly) not existent in a dissolved form on the skin or mucous membranes after dermal, oral or inhalation exposure, i.e. it could not be absorbed via skin and mucous membranes.

All these data indicate that PO 74 is 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 PO 74 (as a member of the Naphtol AS Pigment group) is 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 PO 74 belonging to the Naphtol AS Pigments, i.e. they are also nearly insoluble in water, n-octanol or other organic solvents. Like PO 74 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).