REAKTIV-ORANGE DYPR 934

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

1999-07-23

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Expert Assessment based on guideline studies

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1999

Report date:

1999

Materials and methods

Objective of study:

toxicokinetics

Test guideline

Qualifier:

no guideline available

Deviations:

no

Principles of method if other than guideline:

Toxikenetic parameters such as uptake, distribution, metabolism, metabolism and excretion form the essential toxicological profile of a substance. The assessment of the toxicokinetic properties of Reaktiv-Orange DYPR 934 is based on the results obtained for the following toxicological endpoints with simultaneous reference to physico-chemical data such as solubility in various solvents and log Pow.
-Acute oral toxicity
-Acute dermal toxicity
-Subacute (28-day) oral toxicity
-Skin irritation
-Skin sensitization
-Mammalian erythrocyte micronucleus test in vivo.

GLP compliance:

yes (incl. QA statement)

Test material

Test material information

Constituent 1

Details on test material:

- Name of test material (as cited in study report): Reaktiv-Orange DYPR 934

Test animals

Sex:

male/female

Results and discussion

Any other information on results incl. tables

Toxicokinetic parameters such as uptake, distribution, metabolism and excretion form the essential toxicological profile of the substance.The assessment of the toxicokinetic properties of Reaktiv-Orange DYPR 934 is based on the results obtained for the following toxicological endpoints with simultaneous reference to physico-chemical data such as solubility in various solvents and log Po/w.

-Acute oral toxicity

-Acute dermal toxicity

-Subacute (28 day) oral toxicity

-skin irritation

-Eye irritation

-Mammalian erythrocyte micronucleus test in vivo.

Physico-chemical properties

Reaktiv-Orange DYPR 934 is a 1:1 mixture of two azo dyes with a molecular weight of 685 and 766 g/mol.

Extremly high water solubility (295 mg/L)

and a very low partition coefficient (logPow: -6.1)

Toxicological Profile:

Single oral treatment of male and female rats with Reaktiv-Orange DYPR 934 at a dose of 2000 mg/kg body weight. After administration of the substance orange discolored feces were observed. The animals killed at the end of the study showed no macroscopically visible changes.

Dermal treatment with 2000 mg/kg body weight caused no mortally or symptoms of toxicological relevance. The skin of the animals was orange discolored. In 8 of 10 animals this discoloration was reversible up to the end of the study.

In the acute eye irritation and acute dermal irritation test Reaktiv-Orange DYPR 934 was slightly irritating.

No evidence of skin sensitization was found in the maximization test of guinea pigs.

To assess the substance toxicity of Reaktiv-Orange DYPR 934 male and female rat received daily dose levels of 0, 62.5, 250 and 1000 mg/kg body weight by oral gavage over a period of 28 days.

No death occured throughout the study. Behavior and state of health remained unaffected by administration of the compound. Neurotoxicological parameters and hematological parameter examinations did not reveal any abnormalities.

Animals treated with the lowest dose (62.5 mg/kg body weight) showed no compound body related effects.

In the 250 mg/kg body weight group, sligthtly increased ALAT values in males and slight irritations of stomach of both sexes were observed. No other effects were found.

In the highest dose group (1000 mg/kg b.w.)slightly decrease body weights in males and markedly increased water consumption in both sexes was found. Also, urine volume was increased yielding in the decreased specific weigh of the urine. Increased ALAT- and alkaline phosphate activities were observed in males. However, histological examination of the liver did not reveal any compound related changes. Topical and reversible irritations of the stomach was found in some animals.Furthemore, 4 of 10 rats showed an orange discolored stomach was sacrified at the end of the treatment period. However the animals in the recovery group did not showed any stomach discoloration. Macroscopically, an orange discoloration was also present in the kidneys of 6 of 10 animals in the recovery group.This discoloration was not observed in the group sacrified immediately after the last treatment, when examined microscopically, 7 to 10 animals in the recovery group as well as 7 of 10 animals in the group killed after the treatment period showed intratubular depositions of yellowish pigment. Furthemore, the plasma of 2 animals was orange discolored.

In the erythrocytes micronucleus test in vivo Reaktiv Orange DYPR 934 was given orally to mice at 2000 mg/kg body weight. Orange discoloured feces and urine were observed up to the end of the study, but no signs of toxicity were found. Overall, the substance did not cause a substantial increase of micronucleated polychromatic erythrocytes and was therefore not mutagenic in this test.

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results
Based on the extremely high water solubility of the substance and possible metabolites and the results obtained in various toxicological examinations it can be assumed that Reaktiv-Orange DYPR 934 does not any toxicokinetic peculiarity.

Executive summary:

EVALUATION AND ASSESSMENT:

A dermal absorption of Reaktiv-Orange DYPR 934 is most unlikely due its excellent water solubility. This is confirmed by the skin sensitization and acute dermal toxicity study, in which skin coloration but no toxic or sensitizing effects were observed. After oral gavage the dye is at least partially absorbed. This can be concluded from the data obtained in the repeated and single dose studies, in which the plasma and kidneys of some animals were orange discolored.

Since Reaktiv-Orange DYPR 934 consists of two azo dyes, a partial metabolic cleavage of the azo bond by bacterial azoreductases in the intestine resulting in two amines seems to be likely. The discolored urine and kidney found in animals treated with high substance doses further support the breakdown into hydrophilic metabolites, since only small molecules are usually eliminated via renal excretion, whereas in rats substances with a molecular weight > 300 are preferentially excreted in the feces.

An accumulation of the substance or possible metabolites is unlikely. This is indicated by the excellent water solubility and the findings in the subacute toxicity study, where the kidneys of some animals were discolored, however, no other organs-besides stomach-were affected.

Furthermore, no substance related histopathological changes were observed. A discoloration of the stomach was found in the animals sacrificed at the end of the treatment period. In contrast, stomachs of the animals of the recovery group were not discolored, indicating that the coloration is reversible and was only due to the large amount of substance given directly into the stomach by gavage.

Reaktiv-Orange DYPR 934 and possible metabolites are eliminated via urine and feces. This became obvious since urine and feces of animals treated with high doses were orange discolored. In the subacute toxicity study macroscopical observations in the recovery group revealed discolored kidneys, due to intrabular yellowish depositions. In the group sacrificed two weeks earlier at the end of the treatment period only microscopically but no macroscopically visible substance depositions were found. This leads to the assumption, that the substance / metabolite concentration in the kidney two weeks after the last treatment is higher than immediately after the treatment period. This indicates a slow elimination of the substance / metabolites via the kidneys.

In summary, based on the extremely high water solubility of the substance and possible metabolites and the results obtained in various toxicological examinations it can be concluded that Reaktiv-Orange DYPR 934 does not show any toxicological peculiarity.