REAKTIVE GELB F 97494

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics, other

Type of information:

other: Based on available physico-chemical properties and toxicological data of the substance

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Assessment based on physico-chemical properties and toxicological data of the substance.

Objective of study:

other: Toxicokinetic assessment

Principles of method if other than guideline:

An expert assessment was made based on physical chemical properties and all toxicity data available.

Details on study design:

A toxicokinetic assessment has been performed based on available physico-chemical properties and toxicological data (i.e., acute oral toxicity, acute dermal toxicity skin irritation eye irritation skin sensitization subacute (28 d) oral toxicity, bacterial reverse mutation test, in vitro chromosome aberration test and in vivo micronucleus test) of the test substance.

Evaluation and assessment:

The data of the acute dermal toxicity, dermal irritation and skin sensitization test indicate little or no dermal absorption, owing to the fact that no irritating or sensitizing effects were observed. This is in accordance with the physico-chemical properties of test substance. Oral absorption of test substance is probably also restricted due to the low log Ko/w of <-4.9 since most substances with a log Ko/w <0.5 are only marginally absorbed. However, after oral gavage test substance is at least partially absorbed. This can be concluded from the data obtained in the acute oral toxicity study with females, in which yellowish discolorations of the urine between 1-2 and 4-8 h after administration were observed. As test substance is an azo dye, partial metabolic cleavage by bacterial azo reductases in the intestine resulting in more hydrophilic amines seems to be likely. Due to the physico-chemical properties of test substance an accumulation of the test substance in the fatty tissues of the body is unlikely. Likewise, distribution or accumulation in other organs was not observed after oral administration. The elimination of the absorbed test substance fraction seems to be very efficient, as urine discoloration disappeared 24 h after administration. It can be assumed that the test substance is also eliminated via faeces, as substances with a molecular weight above 300 g/mol are preferentially excreted via the faeces in rats.

In summary, based on the high water solubility, low log Ko/w, and the results obtained in various toxicological examinations it can be concluded that test substance does not show any toxicokinetic peculiarity.

Conclusions:

The test substance is not expected to be absorbed to a high extent via the oral or dermal exposure routes. Based on its physico-chemical properties, accumulation of the test substance in the fatty tissues of the body is unlikely. Elimination of the absorbed test substance fraction seems to be very efficient.

Executive summary:

A toxicokinetic assessment was conducted based on available physico-chemical properties and toxicological data of the test substance.

 

Based on physico-chemical properties of test substance, oral absorption is probably restricted due to the low log Kow of <-4.9. Most substances with a log Kow <0.5 are only marginally absorbed. Likewise, the data of the acute dermal toxicity, dermal irritation and skin sensitization tests indicates little or no dermal absorption, owing to the fact that no irritating or sensitizing effects were observed. However, an acute oral toxicity study with females in which yellowish discolorations of the urine between 1-2 and 4-8 h after administration were observed suggests that the test substance is at least partially absorbed after oral (gavage) exposure. As the test substance is an azo dye, it may undergo partial metabolic cleavage by bacterial azo-reductases in the intestine, resulting in more hydrophilic amines.

 

Based on its physico-chemical properties, accumulation of the test substance in the fatty tissues of the body is unlikely. Distribution or accumulation in other organs was not observed after oral administration. The elimination of the absorbed test substance fraction seems to be very efficient, as urine discoloration disappeared 24 h after administration. It can be assumed that the test substance is also eliminated via feces, as substances with a molecular weight above 300 g/mol are preferentially excreted via the feces in rats.

 

In light of available information, it can be concluded that test substance does not show any toxicokinetic peculiarity.

Description of key information

The test substance is not expected to be absorbed to a high extent via the oral or dermal exposure routes. Based on its physico-chemical properties, accumulation of the test substance in the fatty tissues of the body is unlikely. Elimination of the absorbed test substance fraction seems to be very efficient.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Physico-chemical properties: Test substance has a molecular weight of 888.6 g/mol. It is characterized by a very high water solubility of 108 g/L and a low partition coefficient (log Ko/w of <‑4.9).

Toxicological profile:

The toxicity after single oral administration of test substance at a dose level of 2000 mg/kg bw was tested in male and female rats. After administration of the test substance no deaths occurred. Female animals showed stilted gait and yellowish discoloured urine on the administration day. The animals killed at the end of the study showed no macroscopically visible changes. After single dermal application of 2000 mg/kg bw test substance onto male and female rats no deaths or significant symptoms of substance toxicity occurred. Consequently, the median lethal dose (LD50) of test substance after oral or dermal administration to rats lies above 2000 mg/kg bw.

 

The test for skin irritating properties of test substance in rabbits showed no signs of irritation during the whole observation period. The administration of test substance into the conjunctival sac of rabbit eyes did not result in severe irritations. Based on the system of evaluation, the following group mean scores for ocular lesions after 24,48and 72 h were calculated: Redness of conjunctiva: 1.22; opacity of cornea: 0.0, chemosis of conjunctiva: 0.33, Iris: 0.0. 7 d after administration all signs of irritation had completely disappeared. Based on these results, test substance is not irritating to skin and eyes according to the classification criteria of EU.

 

Testing for sensitizing properties of test substance was performed in female guinea pigs according to the method of Magnusson & Kligman. Intradermal induction was done with 5% dermal induction and challenge treatment with 25% test substance in deionized water. No evidence of skin sensitization was found.

 

To assess the toxicity of test substance after repeated administration, male and female rats received the test substance at dose levels of 50, 200, or 800 mg/kg bw/day for a period of 28 d by oral gavage. 14 d recovery groups (controls and high dose animals) were induced in the study. One female animal in the high dose group showed respiratory sounds from 2 d onwards with subsequent signs of poor general condition and had to be killed for animal welfare reasons on 6 d. The symptoms were considered to be not test substance related. No deaths occurred throughout the study in the other animals. Behaviour, state of health, neurotoxicological parameters and food consumption were not adversely influenced by the administration of the test substance in all dose groups. Analysis of haematological parameters, clinical chemistry parameters and urine revealed no test substance related alterations. Slightly reduced body weight development was noted in high dose males throughout the study period as a secondary effect of local inflammation of the stomach due to gavage. After the recovery period, incidentally lowered liver and kidney weights were noted in these animals. In addition, there were signs of local irritations in the stomach (cellular infiltrations) due to gavage of the highly concentrated test substance in particular in high dose group males and females, without giving evidence of systemic toxicity and without toxicologically relevance.

In conclusion, the 'no observed adverse effect level '(NOAEL) was considered to be 800 mg/kg bw/day.

 

Test substance was tested for mutagenicity with the strains TA100, TA1535, TA1537, and TA98 of Salmonella typhimurium and with the strain WP2uvrA of Escherichia coli in the bacterial reverse mutation test. The test substance was tested in a standard plate test and in a preincubation test according to the method of Prival in the absence and in the presence of a metabolizing system (S9-mix) at doses up to 5000 µg/plate. The test substance did not cause any relevant increases in the number of revertant colonies with any of the tester strains and is considered to be non-mutagenic in the bacterial reverse mutation test.

 

Moreover, test substance was assessed for its clastogenic potential in a chromosome aberration study in vitro. An enhancement of the aberration rates was observed with and without S9-mix at concentrations of 3000 and 3500 µg/mL after short term treatment (3 h). Both concentrations caused a distinct reduction in cell survival and also a moderate to distinct decrease in the mitotic index. In summary, the test substance induced structural chromosome aberrations at cytotoxic concentrations in vitro.

 

In the mammalian erythrocyte micronucleus test, male and female Sprague Dawley rats were treated with 2000 mg/kg bw of test substance. No signs of toxicity were observed. The dissection of the animals revealed an ochre-coloured content of the gastrointestinal tract. No statistically significant increase in micronucleated polychromatic erythrocytes was observed in the dose group indicating that test substance is not clastogenic in the micronucleus test in vivo.

 

Evaluation and assessment:

The data of the acute dermal toxicity, dermal irritation and skin sensitization test indicate little or no dermal absorption, owing to the fact that no irritating or sensitizing effects were observed. This is in accordance with the physico-chemical properties of test substance. Oral absorption of test substance is probably also restricted due to the low log Ko/w of <-4.9 since most substances with a log Ko/w <0.5 are only marginally absorbed. However, after oral gavage test substance is at least partially absorbed. This can be concluded from the data obtained in the acute oral toxicity study with females, in which yellowish discolorations of the urine between 1-2 and 4-8 h after administration were observed. As test substance is an azo dye, partial metabolic cleavage by bacterial azo reductases in the intestine resulting in more hydrophilic amines seems to be likely. Due to the physico-chemical properties of test substance an accumulation of the test substance in the fatty tissues of the body is unlikely. Likewise, distribution or accumulation in other organs was not observed after oral administration. The elimination of the absorbed test substance fraction seems to be very efficient, as urine discoloration disappeared 24 h after administration. It can be assumed that the test substance is also eliminated via faeces, as substances with a molecular weight above 300 g/mol are preferentially excreted via the faeces in rats.

In summary, based on the high water solubility, low log Ko/w, and the results obtained in various toxicological examinations it can be concluded that test substance does not show any toxicokinetic peculiarity.