2-Naphthalenesulfonic acid, 7-amino-4-hydroxy-8-[2-[2-sulfo-4-[[2-(sulfooxy)ethyl]sulfonyl]phenyl]diazenyl]-, potassium sodium salt (1:?:?), coupled with diazotized 2-[(4-amino-5-methoxy-2-methylphenyl)sulfonyl]ethyl hydrogen sulfate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics, other

Type of information:

other: Basic assessment based on physchem properties and available toxicological data

Adequacy of study:

supporting study

Study period:

2021

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2021

Report date:

2021

Materials and methods

Test material

Test material information

Constituent 1

Test material form:

solid: particulate/powder

Remarks:

migrated information: powder

Details on test material:

- Name of test material (as cited in study report): FAT 40'812/A
- Batch Number: WP 3/03
- Expiration date: 23-04-2010
- Storage: RT
- Purity: Approx. 75%

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Oral/gastrointestinal absorption:
The molecular weight of 849.8 g/mol for Reactive Red 278 suggests low oral absorption. However, with the high water solubility of ≥419 g/L, Reactive Red 278 may readily dissolve into the gastrointestinal fluids and be absorbed via passive diffusion.
In the acute oral toxicity study with Reactive Red 278, no findings signifying absorption were reported. In the 5 day range finding study, dark feces were noted in all test item-treated groups. This was considered to be a passive effect without toxicological relevance and is commonly seen in studies where dyestuffs are administered orally. Slightly reduced body weight gain was noted in the females treated with 1000 mg/kg bw/day when compared with the control females. The test item-related males were considered to be unaffected. At 1000 mg/kg bw/day, increased mean absolute and relative liver weights were noted in males and increased absolute and relative kidney weights were seen in both sexes.
In the 28 day repeated dose oral toxicity study, test item-related findings were generally restricted to slightly lower mean body weights in males treated with 200 mg/kg bw/day and 1000 mg/kg bw/day during the treatment period, passive fecal and urine discoloration, as well as minor macroscopical discoloration of some tissues of the excretory pathway.

Reactive Red 278, when administered orally at 500, 1000 and 2000 mg/kg bw as a single dose in the micronucleus test, lead to reduction in the spontaneous activity, which was observed in increased numbers of animals with the increasing dose.

Taking into account the hydrophilic nature of Reactive Red 278 and the findings of the toxicological studies as discussed above, Reactive Red 278 is expected to be absorbed to some extent from the gastrointestinal tract when administered orally.
Dermal absorption:
The molecular weight of 849.8 g/mol for Reactive Red 278, indicates it being too large for dermal absorption. With high solubility in water (≥419 g/L) and low partition coefficient (< -5.5), dermal uptake is expected to be low for Reactive Red 278 as it is considered to be too hydrophilic to cross the lipid rich environment of the stratum corneum.
Reactive Red 278 was neither corrosive nor irritating to the skin as well as eyes, while, it was found to be sensitising to the skin. No systemic toxicity was observed in these studies.
In the acute dermal toxicity study with Reactive Red 278, neither mortality nor systemic findings were observed. No abnormalities were noted at necropsy. These findings support the assessment that low absorption is expected via dermal route.
Respiratory absorption:
Reactive Red 278 is expected to have low volatility based on the low vapour pressure, and hence may not be available for inhalation as dust/aerosol. Further, the high water solubility (≥419 g/L), indicates if dust is produced, it may get trapped in the mucus and cleared via cilia. However, taking into consideration the effects observed in the oral toxicity studies with Reactive Red 278, it can be considered possible that the substance will also be absorbed to some extent if it is inhaled. Nonetheless, respiratory absorption will be limited and will occur mostly at higher dosage.

Details on distribution in tissues:

The systemic distribution due to the high water solubility would most likely occur via the serum. Owing to the high molecular size and hydrophilic nature of the substance (low n-octanol/water partition coefficient and high water solubility), access of Reactive Red 278 to the central nervous system (CNS) or testes is likely to be restricted by the blood-brain and blood-testes barriers, while accumulation in body fat is unlikely to occur. As seen from the findings of the oral toxicity studies with Reactive Red 278, absorption and systemic distribution will mostly take place along the gastrointestinal tract.

Details on excretion:

The route of excretion for Reactive Red 278 has not been investigated. However, owing to the hydrophilic nature of the substance, it will be expected to be predominantly excreted via urine, while any unabsorbed remaining fraction being excreted in the faeces.
Reactive Red 278, when administered orally at 500, 1000 and 2000 mg/kg bw as a single dose in the micronucleus test, lead to urine discoloration, which became more pronounced with the increasing dose. In the 5-day range finding study, dark faeces were noted in all test item-treated groups.

In the 28-day repeated dose oral toxicity study conducted in rats at 50, 200 and 1000 mg/kg bw/day, a dose-related discoloration of the urine was noted after 4 weeks' treatment in both sexes treated with 200 mg/kg bw/day and at 1000 mg/kg bw/day. This finding was considered to indicate the kidney as the excretory pathway of the test item, and not as an adverse finding. The urinary discoloration was reversible after the recovery period. Similarly, dark red discoloration of the faeces was noted in both sexes treated with 200 mg/kg bw/day from day 4 of treatment onwards and in both sexes treated with 1000 mg/kg bw/day from day 2 of treatment onwards. Faecal discoloration continued for the first two days of the recovery period in both sexes treated previously with 1000 mg/kg bw/day. At the end of the treatment and following recovery period, the following test item-related gross lesions were observed in rats at 1000 mg/kg bw/day: reddish or dark red discoloration of the mucosa of the stomach (two males and two females), of the mucosa of the rectum (nine males and six females), of the kidneys (all animals), of the mucosa of the urinary bladder (eight males and eight females), of the mesenteric lymph node (four males and three females), as well as of the trachea and of the lung (one female).

Taking the above discussion into consideration, Reactive Red 278 can be expected to be excreted through urine for major part, while the unabsorbed dyestuff can be expected to be excreted through faeces.

Metabolite characterisation studies

Metabolites identified:

not measured

Details on metabolites:

Currently no investigation regarding metabolism of Reactive Red 278 is available. In the genetic toxicity studies including bacterial reverse mutation assay, in vitro mammalian cell gene mutation assay and in vitro mammalian chromosomal aberration assay, the outcome was not affected by the presence of metabolic activation. Similarly, there was no evidence to indicate Reactive Red 278 or metabolite influenced hepatic metabolism in the available toxicity studies.
Further, the high water solubility of Reactive Red 278 suggests that metabolism would be limited and not required to facilitate the renal excretion.

Applicant's summary and conclusion

Conclusions:

Reactive Red 278 would be absorbed in gastrointestinal tract, and distribution would most likely occur via the serum, while metabolism would be limited and not required to facilitate renal excretion.

Executive summary:

Reactive Red 278 would be absorbed in gastrointestinal tract, while limited absorption via dermal and inhalation exposure can be expected. Systemic distribution would most likely occur via the serum, while metabolism would be limited and not required to facilitate renal excretion.