Registration Dossier

Administrative data

Link to relevant study record(s)

Description of key information

Key value for chemical safety assessment

Additional information

Assessment of the toxicokinetic behavior

 

No studies are available investigating the toxicokinetic properties of the test substance. The test substance (molecular weight of 917 g/mol) is a black-brown to dark blue solid (Ciba-Geigy, 1994) with a log Pow of -13 (Ciba-Geigy, 1990), a water solubility of > 167 g/L (Ciba-Geigy, 1990) and a melting point of > 300°C (Ciba-Geigy, 1991).

 

Absorption

Absorption via the gastrointestinal tract:

Absorption through the gastrointestinal tract is favored for molecules with a molecular weight below 500 g/mol; molecular weights above 1000 g/mol are not easily absorbed (ECHA GD 7c, 2008). Based on molecular weight, absorption after oral ingestion is less favored for the test article. This is in line with the results obtained in an acute oral toxicity study. Five male and female rats were administered 2000 mg/kg body weight test substance. No mortality, clinical signs or necropsy findings were observed (RCC, 1990). This data does not indicate systemic availability. However, in a 28 day oral repeated dose study with Wistar rats (RCC, 1990), treatment with the test item caused systemic effects in the high dose group. The liver was identified as a potential target organ based on increases in liver weight, an increased severity of periportal mononuclear cell infiltration and reticulocyte counts. The kidney showed increases in organ weight and moderate hyaline droplet degeneration (in males). A further potential target organ may be the spleen, because of the increases in spleen weight in high dose males and the increases in reticulocytes in high dose females. From this data it must be concluded that the test article is absorbed during gastrointestinal passage and becomes systemically available thereafter. The water solubility is also in favor of absorption, since water-soluble substances will readily dissolve into the gastrointestinal fluids. In conclusion, although the substance is a rather large molecule, gastrointestinal absorption takes place as reflected by the results observed in the repeated dose study.

Dermal absorption:

Dermal uptake is favored for chemicals with a molecular weight < 100 g/mol, while for chemicals with a molecular weight > 500 g/mol, dermal uptake is not favored (ECHA GD 7c,2008). In addition, Log P values between 1 and 4 favor dermal absorption. With a molecular weight of > 900 g/mol and a log P of -13, the test article falls into the category of poorly absorbed substances. However, in a guinea pig maximization test the substance was found to cause skin sensitization. Although this finding could not be confirmed in two additional maximization tests, the substance is regarded as a mild sensitizer. In order to cause skin sensitization, a substance needs to penetrate the skin. Therefore, the test article seems to penetrate the skin at least partially. Based on the given physico-chemical parameters a skin penetration of 10% is assumed, which could be enough to cause a sensitization reaction and therefore explain the positive result in the maximization study. However, it cannot be ruled out that an impurity with a better dermal penetration profile rather than the test substance itself might be causing the effect. Nevertheless, based on the given data, the test substance is expected to penetrate the skin partially.

Absorption via inhalation:

No information from acute or repeated dose toxicity studies is available, which could provide information about the systemic distribution of the test substance after inhalation. The test substance is a solid which is produced and marketed exclusively in a wet process. Therefore, inhalation of dust particles can be excluded and exposure via inhalation is not relevant.

 

Metabolism

In two Ames studies the test article caused an increase in revertant colonies in the presence of a metabolizing agent prepared from rat liver fractions, indicating that the test substance is metabolized. However, this result could not be reproduced in two additional Ames tests, in an HPRT and in a chromosomal aberration study, therefore no final conclusion can be drawn regarding in vitro metabolization. The increases in liver weights observed in the 28-day study, however, might be the result of an increased workload due to administration of the test article indicating that the test article is metabolized in the liver. The liver metabolism simulator of the OECD toolbox predicts breaking of the azo-bonds resulting in various benzene or naphthalene based compounds depending on the number of azo-bonds being broken. The smaller fractions are predicted to be hydroxylated which might be the precursor for glucuronidation and eventually elimination.

Excretion

Smaller molecules (< 300 g/mol) tend to be excreted in the urine, especially when they are soluble in water. Larger molecules are expected to be eliminated via biliary excretion. The test substance is soluble in water and predicted to be broken down to smaller molecules in the liver followed by glucuronidation to enhance water solubility. Depending on the size of the molecules after metabolic breakdown, excretion might occur either by feces or by urine. In a 28-day study some animals showed colored feces on administration day 2, indicating that some part of the test article is excreted by feces.