Solsperse 22000-Wirksubstanz

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics, other

Type of information:

other: Expert statement

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Objective of study:

other: Assessment of toxicokinetic behaviour

Qualifier:

no guideline followed

Principles of method if other than guideline:

Available data on toxicity were evaluated for toxikokinetic behaviour

GLP compliance:

no

Metabolites identified:

no

Description of key information

An extensive toxicokinetic assessment is considered of limited value. Below, an assessment of the anticipated toxicokinetic behaviour is given. At neutral pH, the sulponated components will be completely ionised. The physico-chemical properties  make it unlikely that the compound will be absorbed to a hhigh extent from the gastro-intestinal tract. However, for some azo-dyes it has been shown that intact particles may also be taken up by the duodenum, although this is unlikely because of its high molecular weight and pigment characteristic.

Unlike for other azo-dyes, the azo-bonds of the azo-pigment components will not, or only to a very limited extent, be splitted in the gastro-intestinal ttract. For water-soluble PY12 derivatives (the sulphonated compound with Na+ as counter ion) it has been shown that it is not susceptible to gut bacterial metabolism in vivo. There are two reasons why Hypersol Synergist L 4722 does not show cleavage of the azo-bonds. The first reason is the very low solubility of the three components of Hypersol Synergist L 4722. The second reason  is the fact that the components do have chemical structures significantly different from benzidine and dichlorobenzidine derived azo dyes. The latter  is probably even more important than water solubility, since even when a water-soluble sulphonated analogue of Pigment YYellow 12 was administered orally to rats, over the next 24 hours only 0.02% of the radioactivity was found in  the urine and none in the blood or tissues. The remainder was recovered in the large intestine, the intestinal contents and faeces. Long-term studies (up to 2 years) with Pigment Yellow 12 by the US National Cancer Institute revealed absence of carcinogenicity and thus, there was no indication for formation of dichlorobenzidine from the pigment. For Pigment Yellow 13, Pigment Yellow 83, and Pigment Yellow 174, which are also diarylide azo- pigments, neither formation of dichlorobenzidine in metabolism studies nor carcinogenic potential was observed . Absence of the dichlorobenzidine in urine was also observed in a study with Pigment Yellow 13 after oral administration to rats, rabbits and monkeys.

Although it is difficult to extrapolate the azoreductase activity from animals to humans, it is generally assumed that the activity in rats is higher than in humans. Therefore, the rat is considered a good model for safety evaluation regarding drug metabolism. The very small fraction of absorbed Hypersol Synergist L 4722 will probably undergo cytochrome P450-mediated hydroxylation of the aromatic rings. However, the formed metabolites of Hypersol Synergist L 4722 are not expected to lead to toxic effects, since cleavage of the azo-bonds is not anticipated for the same reasons as mentioned above. The metabolites will show a toxicokinetic behaviour comparable to that of the unchanged Hypersol Synergist L 4722. The formed hydroxy-metabolites will probably be conjugated and excreted via urine or bile. Distribution of Hypersol Synergist L 4722 into peripheral tissues will be limited, because of the anticipated high plasma protein  binding.

Since it is generally accepted that substances with log Po/w ranging from 0.1 to 6 penetrate the skin easily, it is to be expected that Hypersol L4722 will be absorbed to some extent through the skin. However, following dermal application under cover, the total dose of Pigment Yellow 12 could be accounted for by the radioactivity at the site of
application and on the patch and pipette tip. Therefore, it is concluded that the dermal uptake of Hypersol Synergist L 4722 is negligible.

Taking into account the available physico-chemical data, it is expected that the systemic exposure to Hypersol Synergist L 4722 will be very low.

Based on the expected kinetic behaviour in the body, as described above, Hypersol L4722 will not accumulate in the body after prolonged exposure. This assumption is supported by the low toxicity observed during the 28-days repeated dose toxicity study.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential