Disodium 6-(4,6-dichloro-1,3,5-triazin-2-ylamino)-1-hydroxy-2-(4-(2-(sulfonatooxy)ethylsulfonyl)phenylazo)naphthalene-3-sulfonate

Basic toxicokinetics

Administrative data

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:

1998

Reliability:

2 (reliable with restrictions)

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

Cross-reference

Reason / purpose for cross-reference:

reference to other study

Data source

Reference

Reference Type:

other: Expert statement

Title:

Unnamed

Year:

2003

Report date:

1998

Materials and methods

Objective of study:

toxicokinetics

Principles of method if other than guideline:

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 solvents, log Pow and hydrolytic stability is included

GLP compliance:

no

Remarks:

The studies this assessment is based on were conducted according to GLP

Test material

Test material information

Constituent 1

Reference substance name:

Disodium 6-(4,6-dichloro-1,3,5-triazin-2-ylamino)-1-hydroxy-2-(4-(2-(sulfonatooxy)ethylsulfonyl)phenylazo)naphthalene-3-sulfonate

EC Number:

404-600-7

EC Name:

Disodium 6-(4,6-dichloro-1,3,5-triazin-2-ylamino)-1-hydroxy-2-(4-(2-(sulfonatooxy)ethylsulfonyl)phenylazo)naphthalene-3-sulfonate

Cas Number:

129009-88-7

Molecular formula:

Hill formula: C21H14Cl2N6Na2O10S3 CAS formula: C21H16Cl2N6O10S3.2Na

IUPAC Name:

disodium 7-[(4,6-dichloro-1,3,5-triazin-2-yl)amino]-4-hydroxy-3-(2-{4-[2-(sulfonatooxy)ethanesulfonyl]phenyl}diazen-1-yl)naphthalene-2-sulfonate

Test material form:

solid: particulate/powder

Details on test material:

- Name of test material (as cited in study report): Reaktiv-Orange FD 19969 FW

Radiolabelling:

no

Test animals

Species:

other: Not applicable

Strain:

other: Not applicable

Details on test animals or test system and environmental conditions:

Not applicable

Results and discussion

Main ADME results

Main ADME results 1

Type:

absorption

Results:

Insignificant or no dermal absorptive potential. Seems not to be absorbed from the gastrointestinal tract and therefore a significant bioaccumulation potential can be excluded

Main ADME results 2

Type:

other: accumulation

Results:

Accumulation of the test substance in the body is unlikely.

Any other information on results incl. tables

Evaluation and Assessment:

 

Based on all available data, test substance does not exhibit conspicuous toxicokinetic behaviour. Test substance has a very low acute and systemic toxic potential. The result from all studies with dermal exposure indicates that test substance has insignificant or no dermal absorptive potential. Additionally, taking the results of the subacute oral toxicity study into account, test substance seems not to be absorbed from the gastrointestinal tract. Thus, a major systemic burden is not to be expected pointing also to low or lacking bioaccumulation properties

Applicant's summary and conclusion

Conclusions:

Based on the results obtained in various toxicological examinations, it can be concluded that the test substance does not exhibit conspicuous toxicokinetic behaviour.

Executive summary:

Toxicokinetic parameters such as uptake, distribution, metabolism and ex­cretion form the essential toxicological profile of a substance. An ap­proximate indication of the toxicokinetic pattern can be gained from the results of basic toxicity testing. The assessment of the toxicokinetic properties of Reaktiv-Orange FD 19969 FW given below is based on the results obtained for the following toxicological endpoints:

• Acute oral toxicity


• Acute dermal toxicity


• Skin irritation


• Skin sensitisation


• Ames-Test


• In vitro cytogenetic assay


• Micronucleus-Test


• Subacute (28-day) oral toxicity

All studies were carried out according to the principles of Good Labora­tory Practice and met the requirements of the OECD an EU-Guideline for the Testing of Chemicals.

Simultaneously reference to physico-chemical data such as solubility in solvents, log Pow and hydrolytic stability is included.

Toxicological Profile:

Reaktiv-Orange FD 19969 FW was tested for acute oral toxicity in male and female Wistar rats. After application of 2000 mg/kg body weight by gavage, only short-lasting unspecific clinical symptoms but no lethality occurred. Based on the results of this study the median lethal dose (LD50) of Reaktiv-Orange ED 19969 FW in the rat is greater than 2 000 mg/kg body weight. Dermal treatment with 2000 mg/kg body weight also caused no mortality nor symptoms of toxicological relevance. Reaktiv-Orange FD 19969 FW is not irritating to skin and is not a skin sensitiser in the maximisation test. According to the results of the acute dermal toxicity study as well as the skin irritation and sensitisation data it can be concluded that Reaktiv-Orange ED 19969 FW has no significant dermal absorptive potential.

Reaktiv-Orange FD 19969 FW was not mutagenic in a standard Ames-Test in Salmonella typhimurium TA100, TA1535, TA1537 and TA98 either with or without an exogenous metabolising system (S9-mix from Arocior 1254 pre-treated rats) and was also not mutagenic in the preincubation method according to Prival, Reaktiv-Orange FD 19969 FW induced chromosome mutations (aberrations) in V79 Chinese hamster cells both in the presence as well as in the absence of a metabolic activation system. However, a micronucleus-test has not shown any indications of chromosome mutations under condition in vivo.

Based on the results of a subacute (28-day) oral toxicity study, daily ad­ministration of doses up to 1 000 mg/kg body weight to rats has not caused compound-related lethality. Beside orange faeces indicating the excretion of Reaktiv-Orange FD 19969 FW in unchanged form, no side effects oc­curred. Body weight development, haematological and clinical chemistry parameters as well as organ weights were unaffected. Macroscopical and histo-pathological examinations have not revealed a compound-related ef­fect. Thus the 'No observed Adverse Effect Level' (NOAEL) was 1000 mg/kg body weight per day.

Evaluation and Assessment:

Based on all available data, Reaktiv-Orange FD 19969 FW does not ex­hibit a conspicuous toxicokinetic behaviour. Reaktiv-Orange FD 19969 FW has a very low acute and systemic toxic potential. The results from all studies with dermal exposure indicates that Reaktiv-Orange FD 19969 FW has insignificant or no dermal absorptive potential. Additionally, taking the results of the subacute oral toxicity study into account, Reaktiv-Orange FD 19969 FW seems not to be absorbed from the gastrointestinal tract and therefore a significant bioaccumulation potential can be excluded. From the mutagenicity assays it appears that Reaktiv-Orange has some clastogenic potential. However, a positive response was only seen in vitro whereas under conditions in vivo no chromosome mutation occurred. Since Reaktiv-Orange FD 19969 FW is not expected to be absorbed from the gastrointestinal tract, this suspected clastogenic potential most likely does not represent a significant risk under conditions in vivo. This view is also supported by the negative micronucleus-test.

Summary:

The results of basic toxicity testing give no reason to anticipate unusual characteristics with regard to the toxicokinetics of Reaktiv-Orange FD 19969 FW. The data indicate that there is little or no dermal absorptive potential. Likewise, the data from the subacute oral toxicity study are not indicative of a significant uptake of Reaktiv-Orange FD 19969 FW from the gastrointestinal tract. Thus, a major systemic burden is not to be ex­pected pointing also to low or lacking bioaccumulation properties. Although from limited in vitro studies a clastogenic potential of Reaktiv-Orange FD 19969 FW must be assumed, a significant risk under conditions in vivo can be excluded because of the very low or lacking systemic uptake of Reaktiv-Orange FD 19969 FW as demonstrated in the subacute oral toxicity study and further supported by the negative micronucleus-test.