JAUNE REACTIF 181

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:

03 March 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 828.1 g/mol for Reactive Yellow 181, it can be assumed to have low oral absorption. However, with high water solubility of 332 g/L, Reactive Yellow 181 may readily dissolve into the gastrointestinal fluids and may get absorbed via passive diffusion. In the acute oral toxicity study and the 5-day range finding study with Reactive Yellow 181, no relevant systemic toxicity signifying absorption was reported. In the 28 day repeated dose oral toxicity study, a slight increase in liver and heart weights was observed in male rats treated at 1000 mg/kg bw/day after 4 weeks of treatment, which was found to regress during the recovery period. In the reproductive and developmental toxicity screening test, red coloured faeces were observed at low and high dose groups in either sex. These findings support the hypothesis that some absorption is to be expected via gastrointestinal tract. Thus, taking into account the physicochemical properties and the findings from the subacute toxicity studies, it can be reasonably concluded that Reactive Yellow 181 may get absorbed to some extent when administered at high doses via oral route.
Dermal absorption:
The molecular weight 828.1 g/mol for Reactive Yellow 181, indicates it being too large for dermal absorption. With high solubility in water (332 g/L) and low partition coefficient (-10), dermal uptake is expected to be low as Reactive Yellow 181 is considered to be too hydrophilic to cross the lipid rich environment of the stratum corneum. In the acute dermal toxicity, skin irritation and skin sensitisation studies, yellowish discoloration of the application sites was observed, however no systemic findings were reported. However, taking into account the findings from the repeat dose toxicity studies as discussed under oral absorption section, Reactive Yellow 181 can be expected to have limited absorption via dermal route at sufficiently high doses.
Respiratory absorption:
No experimental data is available concerning the respiratory absorption of Reactive Yellow 181. It was found to have low vapour pressure owing to high melting point >300 °C, hence low volatility is to be expected. The high water solubility (332 g/L), indicates if dust is produced, it may get trapped in the mucus and be transported out of the respiratory tract. Furthermore, the low partition coefficient (-10) and hydrophilicity will further limit the respiratory absorption. The median particle size for Reactive Blue 181 was determined to be 333 µm, hence this will limit the entry of Reactive Yellow 181 to lower respiratory tract, thereby further limiting the absorption. However, as seen with oral route, absorption via respiratory exposure may take place to a limited extent at sufficiently high doses.

Details on distribution in tissues:

The 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 181 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:

The route of excretion for Reactive Yellow 181 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. A deep yellow urine discoloration was observed in male rats receiving high dose (1000 mg/kg bw/day) of Reactive Yellow 181 at termination of the treatment in the 28-day repeated dose oral toxicity study. This finding supports the conclusion that excretion through urine will play major role in excretion of this hydrophilic substance. Also, red colored faeces were reported in the reproduction and developmental screening study, which might be the result of unabsorbed portion of Reactive Yellow 181 being excreted through the faecal matter.

Metabolites identified:

no

Details on metabolites:

Currently no investigation regarding metabolism of Reactive Yellow 181 is available. In the Salmonella typhimurium reverse mutation assay with Reactive Yellow 181, there was no evidence to indicate Reactive Yellow 181 or metabolite influenced hepatic metabolism. However, in the in vitro chromosomal aberration assay, at 18 hour fixation interval, mitotic indices pointed to slight toxicity only in the presence of metabolic activation. This finding indicates some hepatic metabolism occurring for Reactive Yellow 181. However, the high-water solubility of Reactive Yellow 181 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 181 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 828.1 g/mol for Reactive Yellow 181, it can be assumed to have low oral absorption. However, with high water solubility of 332 g/L, Reactive Yellow 181 may readily dissolve into the gastrointestinal fluids and may get absorbed via passive diffusion. In the acute oral toxicity study and the 5-day range finding study with Reactive Yellow 181, no relevant systemic toxicity signifying absorption was reported. In the 28 day repeated dose oral toxicity study, a slight increase in liver and heart weights was observed in male rats treated at 1000 mg/kg bw/day after 4 weeks of treatment, which was found to regress during the recovery period. In the reproductive and developmental toxicity screening test, red coloured faeces were observed at low and high dose groups in either sex. These findings support the hypothesis that some absorption is to be expected via gastrointestinal tract. Thus, taking into account the physicochemical properties and the findings from the subacute toxicity studies, it can be reasonably concluded that Reactive Yellow 181 may get absorbed to some extent when administered at high doses via oral route.

Dermal absorption:

The molecular weight 828.1 g/mol for Reactive Yellow 181, indicates it being too large for dermal absorption. With high solubility in water (332 g/L) and low partition coefficient (-10),dermal uptake is expected to be low as Reactive Yellow 181 is considered to be too hydrophilic to cross the lipid rich environment of the stratum corneum. In the acute dermal toxicity, skin irritation and skin sensitisation studies, yellowish discoloration of the application sites was observed, however no systemic findings were reported. However, taking into account the findings from the repeat dose toxicity studies as discussed under oral absorption section, Reactive Yellow 181 can be expected to have limited absorption via dermal route at sufficiently high doses.

Respiratory absorption:

No experimental data is available concerning the respiratory absorption of Reactive Yellow 181. It was found to have low vapour pressure owing to high melting point >300 °C, hence low volatility is to be expected. The high water solubility (332 g/L), indicates if dust is produced, it may get trapped in the mucus and be transported out of the respiratory tract. Furthermore, the low partition coefficient (-10) and hydrophilicity will further limit the respiratory absorption. The median particle size for Reactive Blue 181 was determined to be 333µm, hence this will limit the entry of Reactive Yellow 181 to lower respiratory tract, thereby further limiting the absorption. However, as seen with oral route, absorption via respiratory exposure may take place to a limited extent at sufficiently high doses.

Distribution

The 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 181 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 181 is available. In the Salmonella typhimurium reverse mutation assay with Reactive Yellow 181, there was no evidence to indicate Reactive Yellow 181 or metabolite influenced hepatic metabolism. However, in the in vitro chromosomal aberration assay, at 18 hour fixation interval, mitotic indices pointed to slight toxicity only in the presence of metabolic activation. This finding indicates some hepatic metabolism occurring for Reactive Yellow 181. However, the high-water solubility of Reactive Yellow 181 suggests that metabolism would be limited and not required to facilitate renal excretion.

Excretion

The route of excretion for Reactive Yellow 181 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. A deep yellow urine discoloration was observed in male rats receiving high dose (1000 mg/kg bw/day) of Reactive Yellow 181 at termination of the treatment in the 28-day repeated dose oral toxicity study. This finding supports the conclusion that excretion through urine will play major role in excretion of this hydrophilic substance. Also, red colored faeces were reported in the reproduction and developmental screening study, which might be the result of unabsorbed portion of Reactive Yellow 181 being excreted through the faecal matter.

 

CONCLUSION

Based on the above discussion, it can be concluded that Reactive Yellow 181 would have some degree of absorption from gastrointestinal tract when administered via oral route, however poor absorption is expected on dermal and inhalation exposure. The 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

Based on the physicochemical properties of the substance and results from toxicological studies, it can be concluded that Reactive Yellow 181 would have some degree of absorption from gastrointestinal tract when administered via oral route, however poor absorption is expected on dermal and inhalation exposure. The 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

Additional 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 a dark red powder with a molecular weight of 828.1 g/mol. The calculated log Pow value is ca -10 and the solubility in water is 332 g/L.

Based on the physicochemical properties of the substance and results from toxicological studies, it can be concluded that Reactive Yellow 181 would have some degree of absorption from gastrointestinal tract when administered via oral route, however poor absorption is expected on dermal and inhalation exposure. The 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.