Trisodium 7-(4-(4-fluoro-6-(2-(2-vinylsulfonylethoxy)ethylamino)-1,3,5-triazine- 2-ylamino)-2-ureidophenylazo)naphthalene-1,3,6-trisulfonate

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics, other

Remarks:

basic assessment basis of physicochemical properties and toxicological studies.

Type of information:

other: basic assessment basis of physicochemical properties and toxicological studies.

Adequacy of study:

key study

Study period:

28 January 2021

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

accepted calculation method

Objective of study:

absorption

distribution

excretion

metabolism

toxicokinetics

Qualifier:

no guideline followed

Principles of method if other than guideline:

basic assessment basis of physicochemical properties and toxicological studies.

GLP compliance:

no

Details on absorption:

Oral/gastrointestinal absorption:
Based on the molecular weight of 885.75 g/mol for Reactive Yellow 174, it can be assumed to have low oral absorption. However, with high water solubility of 341 g/L, Reactive Yellow 174 may readily dissolve into the gastrointestinal fluids and may get absorbed via passive diffusion. Furthermore, in an acute oral toxicity study, no mortality or treatment related effects were observed, while, in the 28-days repeated dose oral toxicity study, no treatment related effects on mortality, clinical signs, food consumption, body weight, ophthalmoscopic examinations, clinical laboratory investigations and pathology were seen up to highest dose group. In the reproductive and developmental toxicity screening test, discoloured yellow testes (2/10 high dose males) and discoloured yellow oviduct and cervix (2/10 high dose females) were observed during the gross pathological examination. In addition, histologically, in male rats, yellow-brown pigment in interstitial macrophages was seen at a minimal or mild degree in the testis and at a minimal degree in the epididymis in all rats treated at 1000 mg/kg/day. These finding suggests that Reactive Yellow 174 may get absorbed to an extent when administered via oral route.

Dermal absorption:
The molecular weight (885.75 g/mol) for Reactive Yellow 174, indicates it being too large for dermal absorption. With high solubility in water (341 g/L) and low partition coefficient (<-10.8), dermal uptake is expected to be low as Reactive Yellow 174 considered to be too hydrophilic to cross the lipid rich environment of the stratum corneum. In the acute dermal toxicity study at 2000 mg/kg bw, female rats showed emaciation during the study, indicating absorption of the test substance by the dermal route. Reactive Yellow 174 was neither corrosive nor irritating to the skin as well as eyes. Reactive Yellow 174 (FAT 40224/C) lead to two deaths in the Guinea pig maximization test. The animal which died on day 6 after dermal injection with Reactive Yellow 174, was found to have yellowish lung during the necropsy. The second animal (vehicle control) died on day 37, after receiving Reactive Yellow 174 as dermal application, also had yellowish contents in the small intestine. These findings suggest that dermal exposure will lead to absorption at some levels. Thus, taking into account the findings from the acute dermal toxicity study, skin sensitization study and the reproduction and developmental toxicity screening test as discussed under oral absorption section, Reactive Yellow 174 is expected to get absorbed to some extent via dermal route.
Respiratory absorption:
No experimental data is available concerning the respiratory absorption of Reactive Yellow 174. However, high water solubility (341 g/L), indicates if dust is produced will get trapped in the mucus. However, very hydrophilic substances can be transported out of the respiratory tract, when molecular weights are larger than 200. Furthermore, the low partition coefficient (<-10.8) and hydrophilicity will further limit the respiratory absorption. However, as seen with oral and dermal routes, absorption via respiratory exposure may take place to a limited extent.

Details on distribution in tissues:

Systemic distribution due to 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 Yellow 174 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.

Details on excretion:

Route of excretion for Reactive Yellow 174 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 feces.

Metabolites identified:

no

Details on metabolites:

Currently no investigation regarding metabolism of Reactive Yellow 174 is available. Moreover, in the genetic toxicity studies with Reactive Yellow 174, there was no evidence to indicate Reactive Yellow 174 or metabolite influenced hepatic metabolism. However, as seen with the toxicity studies, Reactive Yellow 174 did lead to discoloration of internal organs (testes, oviduct, cervix, etc.), limited metabolism is expected to occur. However, the high-water solubility of Reactive Yellow 174 suggests that metabolism would be limited and not required to facilitate renal excretion.

Conclusions:

Based on the above discussion, it can be concluded that Reactive Yellow 174 would have some degree of absorption via oral, dermal and inhalation exposure. Systemic distribution would most likely occur via the serum, while metabolism is expected to occur but would be limited and not required to facilitate renal excretion.

Executive summary:

Absorption

Oral/gastrointestinal absorption:

Based on the molecular weight of 885.75 g/mol for Reactive Yellow 174, it can be assumed to have low oral absorption. However, with high water solubility of 341 g/L, Reactive Yellow 174 may readily dissolve into the gastrointestinal fluids and may get absorbed via passive diffusion. Furthermore, in an acute oral toxicity study, no mortality or treatment related effects were observed, while, in the 28-days repeated dose oral toxicity study, no treatment related effects on mortality, clinical signs, food consumption, body weight, ophthalmoscopic examinations, clinical laboratory investigations and pathology were seen up to highest dose group. In the reproductive and developmental toxicity screening test, discoloured yellow testes (2/10 high dose males) and discoloured yellow oviduct and cervix (2/10 high dose females) were observed during the gross pathological examination. In addition, histologically, in male rats, yellow-brown pigment in interstitial macrophages was seen at a minimal or mild degree in the testis and at a minimal degree in the epididymis in all rats treated at 1000 mg/kg/day. These finding suggests that Reactive Yellow 174 may get absorbed to an extent when administered via oral route.

 

Dermal absorption:

The molecular weight (885.75 g/mol) for Reactive Yellow 174, indicates it being too large for dermal absorption. With high solubility in water (341 g/L) and low partition coefficient (<-10.8), dermal uptake is expected to be low as Reactive Yellow174 considered to be too hydrophilic to cross the lipid rich environment of the stratum corneum. In the acute dermal toxicity study at 2000 mg/kg bw, female rats showed emaciation during the study, indicating absorption of the test substance by the dermal route. Reactive Yellow 174 was neither corrosive nor irritating to the skin as well as eyes. Reactive Yellow 174 (FAT 40224/C) lead to two deaths in the Guinea pig maximisation test. The animal which died on day 6 after dermal injection with Reactive Yellow 174, was found to have yellowish lung during the necropsy. The second animal (vehicle control) died on day 37, after receiving Reactive Yellow 174 as dermal application, also had yellowish contents in the small intestine. These findings suggest that dermal exposure will lead to absorption at some levels. Thus, taking into account the findings from the acute dermal toxicity study, skin sensitisation study and the reproduction and developmental toxicity screening test as discussed under oral absorption section, Reactive Yellow 174 is expected to get absorbed to some extent via dermal route.

 

Respiratory absorption:

No experimental data is available concerning the respiratory absorption of Reactive Yellow 174. However, high water solubility (341 g/L), indicates if dust is produced will get trapped in the mucus. However, very hydrophilic substances can be transported out of the respiratory tract, when molecular weights are larger than 200. Furthermore, the low partition coefficient (<-10.8) and hydrophilicity will further limit the respiratory absorption. However, as seen with oral and dermal routes, absorption via respiratory exposure may take place to a limited extent.

 

Distribution

Systemic distribution due to 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 Yellow 174 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.

 

Metabolism

Currently no investigation regarding metabolism of Reactive Yellow 174 is available. Moreover, in the genetic toxicity studies with Reactive Yellow 174, there was no evidence to indicate Reactive Yellow 174 or metabolite influenced hepatic metabolism. However, as seen with the toxicity studies, Reactive Yellow 174 did lead to discoloration of internal organs (testes, oviduct, cervix, etc.), limited metabolism is expected to occur. However, the high-water solubility of Reactive Yellow 174 suggests that metabolism would be limited and not required to facilitate renal excretion.

 

Excretion

Route of excretion for Reactive Yellow 174 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 feces.

 

CONCLUSION

Based on the above discussion, it can be concluded that Reactive Yellow 174 would have some degree of absorption via oral, dermal and inhalation exposure. Systemic distribution would most likely occur via the serum, while metabolism is expected to occur but would be limited and not required to facilitate renal excretion.

Description of key information

Since no toxicokinetic studies are available for the test substance the following assessment is based on the available physicochemical properties and results from other toxicological studies.

The test substance is an orange powder with a molecular weight of 885.75 g/mol. The calculated log Pow value is ca. -10.8 and the solubility in water is 341 g/L.

 

Absorption

Oral/gastrointestinal absorption:

Based on the molecular weight of 885.75 g/mol for Reactive Yellow 174, it can be assumed to have low oral absorption. However, with high water solubility of 341 g/L, Reactive Yellow 174 may readily dissolve into the gastrointestinal fluids and may get absorbed via passive diffusion. Furthermore, in an acute oral toxicity study, no mortality or treatment related effects were observed, while, in the 28-days repeated dose oral toxicity study, no treatment related effects on mortality, clinical signs, food consumption, body weight, ophthalmoscopic examinations, clinical laboratory investigations and pathology were seen up to highest dose group. In the reproductive and developmental toxicity screening test, discoloured yellow testes (2/10 high dose males) and discoloured yellow oviduct and cervix (2/10 high dose females) were observed during the gross pathological examination. In addition, histologically, in male rats, yellow-brown pigment in interstitial macrophages was seen at a minimal or mild degree in the testis and at a minimal degree in the epididymis in all rats treated at 1000 mg/kg/day. These finding suggests that Reactive Yellow 174 may get absorbed to an extent when administered via oral route.

Dermal absorption:

Themolecular weight (885.75 g/mol) for Reactive Yellow 174,indicates it being too large for dermal absorption. With high solubility in water (341 g/L) and low partition coefficient (<-10.8), dermal uptake is expected to be low as Reactive Yellow 174 considered to be too hydrophilic to cross the lipid rich environment of the stratum corneum. In the acute dermal toxicity study at 2000 mg/kg bw, female rats showed emaciation during the study, indicating absorption of the test substance by the dermal route. Reactive Yellow 174 was neither corrosive nor irritating to the skin as well as eyes. Reactive Yellow 174 (FAT 40224/C) lead to two deaths in the Guinea pig maximisation test. The animal which died on day 6 after dermal injection with Reactive Yellow 174, was found to have yellowish lung during the necropsy. The second animal (vehicle control) died on day 37, after receiving Reactive Yellow 174 as dermal application, also had yellowish contents in the small intestine. These findings suggest that dermal exposure will lead to absorption at some levels. Thus, taking into account the findings from the acute dermal toxicity study, skin sensitisation study and the reproduction and developmental toxicity screening test as discussed under oral absorption section, Reactive Yellow 174 is expected to get absorbed to some extent via dermal route.

Respiratory absorption:

No experimental data is available concerning the respiratory absorption of Reactive Yellow 174. However, high water solubility (341 g/L), indicates if dust is produced will get trapped in the mucus. However, very hydrophilic substances can be transported out of the respiratory tract, when molecular weights are larger than 200. Furthermore, the low partition coefficient (<-10.8) and hydrophilicity will further limit the respiratory absorption. However, as seen with oral and dermal routes, absorption via respiratory exposure may take place to a limited extent.

 

Distribution

Systemic distribution due to 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 Yellow 174 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.

Metabolism

Currently no investigation regarding metabolism of Reactive Yellow 174 is available. Moreover, in the genetic toxicity studies with Reactive Yellow 174, there was no evidence to indicate Reactive Yellow 174 or metabolite influenced hepatic metabolism. However, as seen with the toxicity studies, Reactive Yellow 174 did lead to discoloration of internal organs (testes, oviduct, cervix, etc.), limited metabolism is expected to occur. However, the high-water solubility of Reactive Yellow 174 suggests that metabolism would be limited and not required to facilitate renal excretion.

Excretion

Route of excretion for Reactive Yellow 174 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. 

Based on the above discussion, it can be concluded that Reactive Yellow 174 would have some degree of absorption via oral, dermal and inhalation exposure. Systemic distribution would most likely occur via the serum, while metabolism is expected to occur but would be limited and not required to facilitate renal excretion.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

100

Absorption rate - inhalation (%):

100