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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics
Type of information:
calculation (if not (Q)SAR)
Remarks:
Migrated phrase: estimated by calculation
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
A written assessment of toxicokinetic behaviour is considered appropriate for the substance. The substance displays no toxicological effects in any of the studies proposed, and is deemed to be be not harmful for health effects. As such, it is deemed inappropriate in terms of animal welfare to conduct a toxicokinetic assessment when no harmful effects are predicted based on known toxicology. A written assessment has therefore been prepared to address this endpoint.

Data source

Materials and methods

Objective of study:
other: Assessment of toxicokinetic behaviour
Principles of method if other than guideline:
Written assessment based on toxicological profile.
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Not applicable

Test animals

Species:
other: Not applicable

Administration / exposure

Details on exposure:
Not applicable
Duration and frequency of treatment / exposure:
Not applicable
Doses / concentrations
Remarks:
Doses / Concentrations:
Not applicable
No. of animals per sex per dose:
Not applicable
Positive control:
Not applicable
Details on study design:
Not applicable
Details on dosing and sampling:
Not applicable
Statistics:
Not applicable

Results and discussion

Metabolite characterisation studies

Metabolites identified:
not measured
Details on metabolites:
Not applicable

Any other information on results incl. tables

The following information about the toxicokinetics were based on examination of the toxicological test package and knowledge known historically about reactive dyes. Independent experimental studies on the toxicokinetics was not done.  Toxicokinetic parameters such as uptake, distribution, metabolism and excretion form the essential toxicological profile of a substance. The assessment of the toxicokinetic properties of Reactive Blue FC 75311 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 vivo micronucleus assay

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

 

General

 

The degree of purity of the substance is 44 - 64 %.Unknown byproducts of the dyestuff synthesis include water, alkaline salts and Copper (II) salts, which are given as impurities. By its chemical structure the main component is identified as a mixture of 2 azo-cuprates with the main fragments as aminobenzene and fluorotriazine.

 

Reactive blue FC 75311 is blue powdered solid at room temperature conditions. A vapour pressure determination was not performed because salts aromatic sulfonic acids at room temperature have no measurable vapour pressure. Therefore a significant inhalation exposure to vapours is not expected. The low n-octanol/water partition coefficient (log Pow <-2.7 at 20 ° C) as well as the relatively high molecular weight of the free acid (1000.4) a systemic bioavailability after dermal exposure is not anticipated.

 

Toxicological Profile:

 

Reactive Blue FC 75311 was tested for acute oral toxicity in male and female Wistar rats. After application of 2 000 mg/kg body weight by gavage, neither nor any clinical symptoms occurred. Based on the results of this study the median lethal dose (LD50) of Reactive Blue FC 75311in the rat is greater than 2 000 mg/kg body weight. Dermal treatment with 2 000 mg/kg body weight caused slight staining but caused no mortality or symptoms of toxicological relevance. Reactive Blue FC 75311 is not irritating to the skin but 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 and supported by the pronounced hydrophilic properties, Reactive Blue FC 75311 most probably has no significant dermal absorptive potential.

 

Reactive Blue FC 75311 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 Aroclor 1254 pre-treated rats) and was also not mutagenic in the preincubation method according to the Prival method. Reactive Blue FC 75311 did not induce chromosome mutations in an intraperitoneal mouse micronucleus assay in NMRI strain mice.After intraperitoneal application in mouse signs of  poisoning were detected indicating a certain toxic potential of the substance.  Most probably DNA reactive species are not formed in liver although liver enzymes lead to enhanced bacterial toxicity which suggests
biotransformation activation of the substance.

 

Results of subacute testing indicate little or no bioaccumulation. The results of studies in a 28-day subacute toxicity assessment in Wistar rats yielded qualitative information (bluish discoloration of the plasma samples, bluish-green yellowish discoloration of the urine sample collection in week 4) and the substance (or metabolites) was absorbed enteral and renal eliminated after 1000 mg / kg. Notes in this regard were made available after acute oral nor dermal administration. On the other hand the intensive faeces discoloration after acute and sub-acute application indicates that significant proportions of applied dye presumably are unabsorbed and instead are eliminated. As detailed above, results in the micronucleus test in mice with single intraperitoneal application of 300 mg / kg are due to the relatively significant symptoms of poisoning and if only low severity, increased mortality indicate acceptability of appropriate bioavailability certainly has some toxic potential. However, a significantly higher sensitivity of mouse species is possible. The results the sub-acute test in rats, a significant cumulative toxic potential of systemically available dye is not deemed not applicable.At 40 mg/kg there were no effect on the stomach. Males and females at 200 and 1000mg/kg had a gastritis with increased mucus production in the glandular stomach and hyperkeratosis at the limiting ridge between forestomach and glandular stomach. The latter finding was still present in one male animal at the end of the recovery period. Nevertheless reversibility can be assumed in principal but takes more than 2 weeks at least in some animals. The gastritis identified from 200 mg / kg in males and females is as a result of local irritation rather than toxicity effects. Degenerative kidney changes where noted in one animal, but again are thought to be adaptive changes rather than toxicological effects.There were no indications of significant concentrations beyond the blood-cerebrospinal fluid barrier.  Hematological, clinico-chemical, organ-gavimetric, gross pathological and histopathological investigations produced no evidence of damage to the other organs or tissues. Nevertheless the 'No Observed Adverse Effect Level' (NOAEL) was conservatively placed at 40 mg/kg body weight per day.

 

Evaluation :

Based on all available data, Reactive Blue FC 75311 does not exhibit a conspicuous toxicokinetic behaviour. Reactive Blue FC 75311 has a very low acute toxicity potential. The results from all studies with dermal exposure indicates that Reactive Blue FC 75311has insignificant or no dermal absorptive potential. Additionally, taking the results of the subacute oral toxicity study into account, Reactive Blue FC 75311 seems not to be absorbed from the gastrointestinal tract and therefore a significant bioaccumulation potential can most probably be excluded. This assumption is further supported by the marked hydrophilic character of Reactive Blue FC 75311. The observed inflammatory changes in the glandular stomach are regarded to be a local effect and thus, do not influence the evaluation of the systemic toxic potential. Moreover, from a histopathological point of view they are not regarded to be a serious effect. From the mutagenicity assays it appears that Reactive Blue FC 75311 is not metabolised toward genotoxic structures.

   

Summary:

The results of basic toxicity testing give no reason to anticipate unusual characteristics with regard to the toxicokinetics of Reactive Blue FC 75311. The data indicate that there is little or no dermal absorption. Although inflammatory changes interpreted as local effects occurred in the glandular stomach at higher doses in the subacute oral toxicity study, no signs of a significant systemic toxic potential have been observed. A bioaccumulation of Reactive Blue FC 75311 can most probably be excluded due to the marked hydrophilic properties and lack of solubility in fat. Based on the negative mutagenicity assays, a metabolisation towards genotoxic sub-structures can be ruled out.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): other: no bioaccumulation or toxicological potential based on study results
The substance is not deemed to pose any bioaccumulation or toxicological hazard based on the known profile and study data available.
Executive summary:

The results of basic toxicity testing give no reason to anticipate unusual characteristics with regard to the toxicokinetics of Reactive Blue FC 75311. The data indicate that there is little or no dermal absorption. Although inflammatory changes interpreted as local effects occurred in the glandular stomach at higher doses in the subacute oral toxicity study, no signs of a significant systemic toxic potential have been observed. A bioaccumulation of Reactive Blue FC 75311 can most probably be excluded due to the marked hydrophilic properties. Based on the negative mutagenicity assays, a metabolisation towards genotoxic sub-structures can be ruled out.