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Description of key information

Basic toxicokinetics:
The following information is taken into account for any hazard / risk assessment: An in vivo study in rats did find some evidence of systemic absorption of Monoazo Red pigments after a single oral or repeated oral administration. However based on the experimental toxicity data and the physico-chemical properties, the Monoazo Red pigments have no potential for bioaccumulation.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

The toxicokinetic profile of a substance comprises its absorption into the body, its distribution in the body, its metabolism in the body and its excretion from the body. Taking into account the physicochemical properties and the toxicological test results, qualitative estimates for these aspects may be deduced for the Monoazo Red Pigments (C.I. Pigment Red 3, C.I. Pigment Red 4, and C.I. Pigment5).

Absorption: a prerequisite for a relevant absorption is that the substance can be dissolved in either aqueous (e. g., gastrointestinal fluid, blood plasma, sweat) or lipophilic (e. g., lipoproteins, lipid membranes, triglycerides) media or in both. All Monoazo Red pigments can be considered insoluble because they have an extremely low solubility in water and n-octanol. Therefore, it is unlikely that they become systemically bioavailable to a large extent after oral, dermal or inhalation exposure.

An in vivo study in mice and rats found only limited evidence of systemic absorption of Pigment Red 3 after oral feed administration of up to 50,000 mg/kg in a 2 year carcinogenicity study. However a dose-related decreases in erythrocyte counts and hematocrit values and an increase in reticulocyte counts were observed in rats. There were also significant increases in relative liver and kidney weights of exposed rats. Increases in the relative liver weights in mice did not occur with a dose-related trend and thus they were not considered related to chemical administration. Sites for the toxicity of C.I. Pigment Red 3 were the bone marrow, kidney, liver, and spleen in rats. Lesions observed in rats included bone marrow hyperplasia, congestion and hematopoietic cell proliferation of the spleen, and iron-positive pigmentation of the spleen, kidney, and liver. This indicates that to some degree of absorption via the gastrointestinal tract has to be assumed.

The Monoazo Red pigments does not have particular skin or eye irritating or skin sensitizing properties that would imply a dermal absorptive potential.

Regarding the dermal route both acute (C.I. Pigment Orange 5 in rat) and chronic data (C.I. Pigment Orange 5 and C.I. Pigment Red 4 in mice) are available. In none of these studies, discolouration of urine or faeces was noted. During studies for acute dermal toxicity, no signs of clinical toxicity and no discolouration of urine or faeces were observed for C.I. Pigment5.

In the unlikely event of exposure to aerosolized pigment in respirable form, the substances are considered likely to behave like an inert dust. Therefore, the deposited pigment particles will mostly be cleared from the lung via the mucocilliary transport. As the pigment will not dissolve in the lung surfactant, the only way the pigment can enter the body is via phagocytosis of pigment particles by lung macrophages followed by migration of the macrophages into the interstitium and into the draining lymph nodes. However, the internal dose delivered via this mechanism can be considered negligible.

 

Distribution: The Monoazo Red Pigments are predominately excreted in the faces and is not distributed within the body in significant amounts. However faeces and urine were stained red when high doses of 10,000 mg/kg bw was ingested orally by gavage in an acute toxicity study to rats. The discoloration of the feces was observed up to 7 days after application. The occurrence of reddish skin discoloration after 24 hours was occasionally observed up to the end of study. As indicted above, the physico-chemical parameters of the pigments support the conclusion that the pigments, or their metabolites or impurities are only absorbed into the body to a limited degree and thus do only become systemically available to a limited degree. There were also no other signs of deposition of the pigment in any organ including excretory organs, like the kidney, indicating that even exposure to high doses of the pigment does not lead to bioaccumulation in special compartments of the body. 

 

Metabolism: Since the dissolution of the substance in cellular fluid or cellular membranes is a prerequisite for its metabolism, it is unlikely that under usual exposure conditions the insoluble pigment becomes accessible for metabolizing systems in relevant amounts. In the mutagenicity tests, the pigment proved to be largely non-toxic. However the substance, metabolites or impurities can be mutagenic in theassay in the absence as well as in the presence of an exogenous metabolizing system, indicating that the pigment is might be converted into genotoxic metabolites.

This conclusion is also supported consistent morphological and histopathological changes of organs involved in xenobiotic metabolism, such as the liver and kidney, in the repeated dose toxicity study in rats and mice.The appearance of these toxic effects in dosed rats and mice suggests that C.I. Pigment Red 3, metabolites or impurities were absorbed. Because C.I. Pigment Red 3 is insoluble in water and other solvents, it is unlikely that absorption of the chemical occurred in the gastrointestinal tract. In a preliminary disposition study in rats, it was concluded that a limited amount of C.I. Pigment Red 3 may be degraded by intestinal microflora since not all of the administered dose was recovered (El Dareer et all, 1984). Based on these observations, the active agent may have been one of the more readily absorbable potential aromatic amine metabolites of this pigment. Azo reduction of C.I. Pigment Red 3 by intestinal microflora would yield 4-methyl- 2-nitroaniline and 2-hydroxy-a-naphthylamine. The hematologic changes caused by C.I. Pigment Red 3 could be due to one or both of these metabolites. Structurally related aromatic amines have been reported to produce similar hematologic effects (Beard and Noe, 1981). Absorption and further metabolism of these aromatic amines may produce the n-hydroxy metabolites which are considered to be responsible for the hematologic changes (Weisburger, 1983). The histopathologic lesions (hemosiderin deposition in the spleen and hematopoietic cell proliferation in the bone marrow and liver) as well as the hematologic changes observed are all indicative of hemolytic anemia. Amino and nitro aromatic compounds produce this type of anemia and also produce methemoglobinemia (Beard and Noe, 1981; Beutler, 1985). Blood methemoglobin levels were determined in rats and mice only at the 15-month interim evaluations and values were only marginally increased in dosed animals. The hemolytic anemia in rats fed C.I. Pigment Red 3 was characterized by micro- cytosis, indicated by the decrease in the mean cell volume. There were chemical-related hematologic changes in rats at the end of the 2-week studies as well as at the end of the 13-week studies.

 

Excretion: Faeces and urine were stained red when high doses of 10,000 mg/kg bw was ingested orally by gavage in an acute toxicity study to rats. The discoloration of the feces was observed up to 7 days after application. The occurrence of reddish skin discoloration after 24 hours was occasionally observed up to the end of study. Moreover, from the faeces staining observed in the single and repeated oral toxicity studies, it can be concluded that, after oral exposure, the pigment is largely excreted unchanged via the faeces.

 

However based on the experimental toxicity data and the physico-chemical properties, the Monoazo Red pigments have no potential for bioaccumulation.