tetrasodium 3-amino-4-{[4-({4-fluoro-6-[phenyl(2-{[2-(sulfonatooxy)ethyl]sulfonyl}ethyl)amino]-1,3,5-triazin-2-yl}amino)-2-sulfonatophenyl]diazenyl}-5-hydroxynaphthalene-2,7-disulfonate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

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

Adequacy of study:

supporting study

Study period:

2005 revised 2019

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Non-GLP assessment based on physico-chemical properties and toxicological data of the substance

Data source

Reference

Reference 1

Reference Type:

study report

Title:

Unnamed

Year:

2005

Report date:

2005

Reference 2

Reference Type:

study report

Title:

Unnamed

Year:

2019

Report date:

2019

Materials and methods

Objective of study:

other: Toxicokinetic assessment

Principles of method if other than guideline:

An expert assessment was made based on physico-chemical properties and all toxicity data available

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

-

EC Number:

457-630-8

EC Name:

-

Cas Number:

2138836-26-5

Molecular formula:

Hill formula: C29H23FN8Na4O16S5

IUPAC Name:

tetrasodium 3-amino-4-[(1E)-2-[4-({4-fluoro-6-[phenyl({2-[2-(sulfonatooxy)ethanesulfonyl]ethyl})amino]-1,3,5-triazin-2-yl}amino)-2-sulfonatophenyl]diazen-1-yl]-5-hydroxynaphthalene-2,7-disulfonate

Test material form:

solid: particulate/powder

Details on test material:

- Name of test material (as cited in study report): Reactive Red F00-0314

Administration / exposure

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 sensitisation, subacute (28 d) oral toxicity, bacterial reverse mutation test and in vitro chromosome aberration test) of the test substance.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

The data of the acute dermal toxicity, dermal irritation and skin sensitisation test indicate low dermal permeability, owing to the fact that neither systemic toxicity nor irritating or sensitizing effects were observed. This is in accordance with the physico-chemical properties of the test substance. Oral resorption of the substance is probably also restricted due to the high molecular weight, high number of H-bond acceptors and low log Kow since most substances with a molecular weight > 500, H-bond acceptors >10 and log Kow < -0.5 are only marginally resorbed. However, after oral gavage the test substance was considered to get partially absorbed. This can be concluded from urine and faeces discolorations after single oral exposure and from data obtained in the subacute oral toxicity study using daily doses up to 1000 mg/kg bw/day, in which test compound related discolorations were observed in various tissues and organs. As the test substance is an azo dye, partial metabolic cleavage by bacterial azoreductases in the intestine resulting in more hydrophilic amines seems to be likely.

Details on distribution in tissues:

After resorption following repeated oral administration in high doses, temporarily distribution in kidneys, skin, testes, epididymides, and/or rectum is possible as demonstrated by test substance related discolorations.

Details on excretion:

Reddish discoloured faeces and urine after oral administration of the test substance indicated that the compound can be eliminated both via kidneys and via intestine as confirmed by corresponding organ discolorations (kidneys and rectum).

Any other information on results incl. tables

Evaluation and assessment:

The data of the acute dermal toxicity, dermal irritation and skin sensitisation test indicate low dermal permeability, owing to the fact that neither systemic toxicity nor irritating or sensitizing effects were observed. This is in accordance with the physico-chemical properties of the test substance. Oral resorption of the substance is probably also restricted due to the high molecular weight, high number of H-bond acceptors and low log Kow since most substances with a molecular weight > 500, H-bond acceptors >10 and log Kow < -0.5 are only marginally resorbed. However, after oral gavage the test substance was considered to get partially absorbed. This can be concluded from urine and faeces discolorations after single oral exposure and from data obtained in the subacute oral toxicity study using daily doses up to 1000 mg/kg bw/day, in which test compound related discolorations were observed in various tissues and organs. As the test substance is an azo dye, partial metabolic cleavage by bacterial azoreductases in the intestine resulting in more hydrophilic amines seems to be likely.

After resorption following repeated oral administration in high doses, temporarily distribution in kidneys, skin, testes, epididymides, and/or rectum is possible as demonstrated by test substance related discolorations. Reddish discoloured faeces and urine after oral administration of the test substance indicated that the compound can be eliminated both via kidneys and via intestine as confirmed by corresponding organ discolorations (kidneys and rectum). Test-item related discolorations showed no correlated physiological or histopathological findings (like precipitate) and therefore did not represent toxic effects. The fact that less animals and less organs were affected at the end of the recovery period compared with the end of the treatment period indicated that organ discolorations were reversible and that no accumulation of the chemical occurred. This was supported by the observation that urine discoloration was still observed in the recovery period indicating ongoing elimination of the test item and it was in accordance with the physico-chemical properties of the test substance (high water-solubility, low partition coefficient).

Applicant's summary and conclusion

Conclusions:

The test substance is expected to have partial oral absorption, low dermal absorption and no accummulation in the body. Excretion via urine and predominantly faeces can be expected.

Executive summary:

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

The data of the acute dermal toxicity, dermal irritation and skin sensitisation test indicate low dermal permeability, owing to the fact that neither systemic toxicity nor irritating or sensitizing effects were observed. This is in accordance with the physico-chemical properties of the test substance. Oral resorption of the substance is probably also restricted due to the high molecular weight, high number of H-bond acceptors and low log Kow since most substances with a molecular weight > 500, H-bond acceptors >10 and log Kow < -0.5 are only marginally resorbed. However, after oral gavage the test substance was considered to get partially absorbed. This can be concluded from urine and faeces discolorations after single oral exposure and from data obtained in the subacute oral toxicity study using daily doses up to 1000 mg/kg bw/day, in which test compound related discolorations were observed in various tissues and organs. As the test substance is an azo dye, partial metabolic cleavage by bacterial azoreductases in the intestine resulting in more hydrophilic amines seems to be likely.

For any test item that is absorbed following oral ingestion, the high water solubility should facilitate the distribution of the test substance throughout the body in the water compartment of circulatory systems. This assumption was confirmed by the discoloration of the serum and a distribution in kidneys, skin, testes, epididymides, and/or rectum as demonstrated by test substance related discolorations. However, the passage of test item across specialized biological membranes such as the blood/brain or blood/placental barrier will be subject to the same physical limitations (high molecular weight and low octanol: water partition coefficient) as with absorption from the gastro-intestinal tract and may therefore suggest that biological distribution will be inhibited across such biological structures. This suggestion may be supported by the lack of test item stained cellular structures such as brain identified from histopathological assessment of treated animals from the repeated dose toxicity study.

According to the molecular weight, Reactive Red F00-0314 is most likely predominantly eliminated via faeces – as it has been shown that substances with molecular weight above 300 g/mol are preferentially excreted via faeces in rats. However, as reddish discoloured faeces and urine after oral administration of the test substance in the acute and repeat-dose studies showed, a fraction of the absorbed test substance and most likely its metabolites are excreted via as confirmed by corresponding organ discolorations (kidneys and rectum). Test-item related discolorations showed no correlated physiological or histopathological findings (like precipitate) and therefore did not represent toxic effects.

Accumulation of the test substance in body fat is not expected due to the high water solubility and low octanol: water partition coefficient value. The fact that less animals and less organs were affected at the end of the recovery period compared with the end of the treatment period indicated that organ discolorations were reversible and that no accumulation of the chemical occurred. This was supported by the observation that urine discoloration was still observed in the recovery period indicating ongoing elimination of the test item and it was in accordance with the physico-chemical properties of the test substance (high water-solubility, low partition coefficient).

In sumary, the results of basic toxicity testing give no reason to anticipate unusual characteristics with regards to the toxicokinetics of Reactive Red F00-0314. The data indicate that there is little or no dermal absorption. No signs of a significant systemic toxicity associated with absorption through skin have been observed. Based on exposure model from AG Textilien des Bundesinstituts fur Risikobewertung (BfR), the dermal penetration rate for dyes through the skin was found to be less than 2%. Based on physico-chemical data and the results of oral toxicity studies, Reactive Red F00-0314 has a limited oral bioavailability.

The substance is considered to have low volatility as evident from the vapour pressure measurement and the calculated melting point of > 300°C, so the potential for the generation of inhalable forms is low. The molecular weight is higher than 500 g/mol and the chromophore is negative charged. This together with the high water solubility and low partition coefficient value, indicate the substance is not able to cross the mucous layer of the respiratory tract. Due to the high water solubility, vapours if generated/inhaled, will be trapped in the mucus of the respiratory tract, thereby further limiting the absorption. Hence, the main route of exposure of the substance, if inhaled, will be due to swallowing of particles deposited in the nose/mouth. Therefore, the bioavailability for inhalation is considered the same as for oral intake.

Bioaccumulation of Reactive Red F00-0314 can most probably be excluded due to the available data. Based on the results of genotoxicity assays, a metabolisation towards genotoxic metabolites can also be excluded for mammalian species.

The substance is therefore not considered to be of concern for ADME related effects.