1,7-Naphthalenedisulfonic acid, 2-[[4-chloro-6-(cyanoamino)-1,3,5-triazin-2-yl]amino]-5-hydroxy-6-[2-[2-methoxy-5-[[2-(sulfooxy)ethyl]sulfonyl]phenyl]diazenyl]-, lithium sodium salt (1:?:?)

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics

Type of information:

other: Evaluation and assessment of the toxicokinetic properties based on the results obtained for the toxicological end-points with simultaneous reference to physico-chemical data.

Adequacy of study:

key study

Study period:

1999

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Evaluation and assessment of the toxicokinetic properties based on the results obtained for the toxicological end-points with simultaneous reference to physico-chemical data such as solubility in various solvents and log Pow.

Reason / purpose for cross-reference:

reference to other study

Objective of study:

toxicokinetics

Principles of method if other than guideline:

Assessment of the toxicokinetic properties based on the results obtained for the toxicological end-points with simultaneous reference to physico-chemical data such as solubility in various solvents and log Kow.

GLP compliance:

no

Radiolabelling:

no

Sex:

male/female

Remarks:

Doses / Concentrations:
Not applicable

Type:

absorption

Results:

Dermal absorption is unlikely due to the negative log Pow and the acidic character of test substance

Type:

other: Oral resorption

Results:

Restricted due to the low log Pow of -5.1 since most substances with a log Pow<0.5 are only marginally resorbed. However, a partial resorption after oral gavage can be assumed.

Type:

other: Accumulation

Results:

A major accumulation of the test substance in the body is unlikely

Type:

excretion

Results:

via kidneys and additionally via feces is likely

Details on excretion:

No data

Evaluation and Assessment

 

Due to the negative log Pow and the acidic character of test substance a dermal absorption is unlikely. This is in accordance with the data obtained in the acute dermal toxicity and dermal irritation study.

An oral resorption of test substance is also restricted due to the low log Pow of -5.1 since most substances with a log Pow <0.5 are only marginally resorbed. However, a partial resorption after oral gavage can be assumed, since the substance caused discoloration of a few organs.

 

Due to the physico-chemical properties of the test substance a major accumulation of the chemical in the body is unlikely. This assumption is supported by the fact that the urine of the animals of the recovery group was salmon pink discolored, thus indicating an elimination of test substance via the kidneys. An additional elimination via feces is likely, since the molecular weight of the substance is >300.

Conclusions:

Based on the physico-chemical properties of test substance and the results obtained in various toxicological examinations, it can be concluded that the test substance does not show any toxicokinetic peculiarity

Executive summary:

Introduction

Toxicokinetic parameters such as uptake, distribution, metabolism and excretion form the essential toxicological profile of a substance. The assessment of the toxicokinetic properties of Reaktiv-Orange DYPR 1466 given below is based on the results obtained for the following toxicological end-points with simultaneous reference to physico-chemical data such as solubility in various solvents and logKow.

• Acute oral toxicity

• Acute dermal toxicity

• Skin irritation

• Eye irritation

• Skin sensitization

• Subacute (28-day) oral toxicity

• Bacterial reverse mutation test

• In vitro cytogenetic assay

Physico-chemical properties

Reaktiv-Orange DYPR 1466 is a disulfonic acid with a molecular weight of 769.16 g/mol .The substance is characterized by a very low partition coefficient (log Kow: -5.1) and a water solubility of 35.5 g/L.

Toxicological Profile

Single oral administration of Reaktiv-Orange DYPR 1466 at a dose leve.1 of 2,000 mg/kg body weight did not cause mortality to male and female rats, only discolored orange feces and diarrhea were noted.

After single dermal application of 2,000 mg/kg body weight Reaktiv-Orange DYPR 1466 onto male and female rats no deaths or symptoms of substance-toxicity occurred. The animals killed at the end of the observation period showed no macroscopically visible changes.

Consequently, the approximate median lethal dose (LD50) of Reaktiv-Orange DYPR 1466 after oral or dermal administration to rats lies above 2,000 mg/kg body weight.

Reaktiv-Orange DYPR 1466 is not irritating to skin. In the acute eye irritation test Reaktiv Orange DYPR 1466 showed persistent discoloration of the nictitating membranes up to the end of the study.

In the maximization test on guinea pigs none of ten animals of the treatment group showed a positive skin response after the challenge procedure. Hence, Reaktiv-Orange DYPR 1466 showed no evidence for sensitizing properties.

To assess the toxicity of Reaktiv-Orange DYPR 1466 after repeated administration, male and female rats received the substance at dose levels of 0, 62.5, 250 or ]000 mg/kg body weight per day for a period of 28 days by oral gavage.

No deaths occurred throughout the study. Increased salivation was observed in some animals of the median and high dose group from day 10 on until day 28 of the study. Behavior and state of health remained unaffected by the administration of the test compound in all animals of the other groups. Neurotoxicological parameters, body weight gains and food consumption were not affected by administration of Reaktiv Orange DYPR 1466.

Water consumption was distinctly increased in all animals of the high dose in the course of the treatment period. Consequently, the urine volume was increased in this group during the treatment period. The urine of most male animals of the 28-day treatment and the recovery high-dose groups was discolored salmon-pink in different intensities.

Hematological and clinical chemistry investigations and organ weights did not exhibit treatment related adverse effects. The serum of almost all animals of the high-dose recovery and the intermediate and high dose final groups was discolored by the dye.

At necropsy of the final and/or recovery value animals of the intermediate and/or high dose groups showed reddish discolored kidneys, skin, adipose tissue, testes, epididymes, stomach, and small intestines. Microscopical examination showed submucosal mixed -cellular inflitrations in the stomach and intratubular deposition of yellowish pigment in the kidneys. The cellular infiltration in the submucosal area of the stomachs of the high dose animals should be discussed as a topical but reversible slight acute irritation, obviously caused by the application of the test article. The histopathological equivalent to the reddish discoloration of the kidneys was an accumulation of test material in the tubular cells, mainly in form of small or mid-sized droplets. This substance deposition did not cause morphological changes in the kidneys, consequently, it is, although substance related, of no toxicological relevance.

Reaktiv-Orange DYPR 1466 did not cause a significant increase in the number of revertant colonies in the bacterial reverse mutation test (plate incorporation) at doses up to 5,000 µg/plate with the strains TA100, TA1535, TA1537, and TA98 of Salmonella typhimurium and WP2uvrA of Escherichia coli. Using the preincubation test without metabolic activation Reaktiv-Orange DYPR 1466 was mutagenic. This is in contrast to the results of the preincubation test using hamster liver S9-mix whereas no significant increase in the number of revertant colonies occurred.

Chromosome aberrations were investigated in V79 cells of the Chinese hamster lung in vitro. Reaktiv-Orange DYPR 1466 induced chromosome aberrations in the absence of a metabolic activation system and was considered to be mutagenic in this test system.

Evaluation and Assessment

Due to the negative log Kow and the acidic character of Reaktiv-Orange DYPR 1466 a dermal absorption is unlikely. This is in accordance with the data obtained in the acute dermal toxicity and dermal irritation study.

An oral resorption of Reaktiv-Orange DYPR 1466 is also restricted due to the low log Kow of -5.1 since most substances with a log Kow <0.5 are only marginally resorbed (according to Smith DA, Humphrey MJ, and Charuel C.(1990).Design of toxicokinetic studies.20:1187-1199).

However, a partial resorption after oral gavage can be assumed, since the substance caused discoloration of a few organs.

Due to the physico-chemical properties of Reaktiv-Orange DYPR 1466 a major accumulation of the chemical in the body is unlikely. This assumption is supported by the fact that the urine of the animals of the recovery group was salmon pink discolored, thus indicating an elimination of Reaktiv-Orange DYPR 1466 via the kidneys. An additional elimination of Reaktiv-Orange DYPR 1466 via feces is likely, since the molecular weight of the substance is >300.

In summary, based on the physico-chemical properties of Reaktiv-Orange DYPR 1466 and the results obtained in various toxicological examinations, it can be concluded that the substance does not show any toxicokinetic peculiarity.

Description of key information

Short description of key information on bioaccumulation potential result:
Based on the physico-chemical properties of test substance and the results obtained in various toxicological examinations, it can be concluded that the test substance does not show any toxicokinetic peculiarity

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Evaluation and assessment of the toxicokinetic properties of the test substance was carried out based on the results obtained for the toxicological end-points with simultaneous reference to physico-chemical data such as solubility in various solvents and logPow.

Based on the physico-chemical properties of test substance and the results obtained in various toxicological examinations, it can be concluded that the test substance does not show any toxicokinetic peculiarity