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Reference
Endpoint:
basic toxicokinetics, other
Type of information:
other: Basic assessment using physical-chemical data as well as 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
Principles of method if other than guideline:
Basic assessment using physical-chemical data as well as toxicological data.
GLP compliance:
no
Details on absorption:
Oral/gastrointestinal absorption:
Owing to the molecular weight (409.41 g/mol), high partition coefficient (log Pow = 5.02) and poor solubility in water (0.8 µg/L), absorption of Disperse Violet 057 is expected to occur via micellular solubilization by bile salts. Several acute oral toxicity studies with Disperse Violet 057 are available. No deaths occurred during these studies. Clinical signs commonly associated with acute studies were seen at significantly high doses (>3000 mg/kg bw), which were found to reverse within a week. No findings signifying absorption were reported in these studies.
In the combined repeated dose toxicity study with reproduction/developmental screening with Disperse Violet 057, black-coloured faeces were observed at mid (300 mg/kg bw/day) and high (1000 mg/kg bw/day) doses in both the sexes which recovered by Day 2 of recovery period. Similar finding of black-coloured faeces being excreted by animals treated at 1000 mg/kg bw/day was also reported in the 14-days range finding study. This finding suggests some passive absorption taking place in the gastrointestinal tract. No other systemic findings were reported in these studies. Based on the above discussion, Disperse Violet 057 can be expected to get absorbed to some extent if it is administered orally at high doses.

Dermal absorption:
Based on the molecular weight (409.41 g/mol), high partition coefficient (log Pow = 5.02), and poor water solubility (0.8 µg/L at 20 °C), a low dermal penetration rate is expected for Disperse Violet 057. The poor water solubility means the substance is not sufficiently soluble in water to partition from the stratum corneum into the epidermis. Disperse Violet 057 was neither corrosive nor irritating to the skin as well as eyes. No deaths or systemic toxicity occurred in these studies. Thus, no findings signifying absorption were reported in these studies. Disperse Violet 057 was found to be sensitizing in a Buehler as well as a GPMT study. In the study conducted according to Buehler method, 25 % of the test animals were observed with significant responses at either 24 or 48 hours when exposed epidermally with the test article at 50 %. The physical-chemical properties and evidence from the skin sensitization study conducted using the Buehler method suggest that Disperse Violet 057 may get absorbed to a limited extent if it is exposed dermally at high doses.

Respiratory absorption:
Disperse Violet 057 can be considered to have low volatility based on its low vapour pressure (0.0023 Pa at 20 °C), so the potential for the generation of inhalable forms is low. The substance may be taken up by micellular solubilisation owing to it having high partition coefficient (Log Pow = 5.02), and poor water solubility (0.8 µg/L at 20 °C). Therefore, it is possible that the substance will be absorbed to a limited extent if it is inhaled at high doses.
Details on distribution in tissues:
The findings of repeated dose oral toxicity studies suggest that the most probable route of absorption and systemic distribution to take place is along the gastrointestinal tract and serum. Also owing to the lipophilic nature of Disperse Violet 057, some accumulation in adipose tissue can be expected.
Details on excretion:
The route of excretion for Disperse Violet 057 has not been investigated. However, owing to the lipophilic nature of the substance and low water solubility, the substance is expected to be predominantly excreted via faeces. This hypothesis is further supported by the appearance of the black-coloured faeces observed in the combined repeated dose toxicity study with reproduction/developmental screening test as well as in the 14-days range finding study with Disperse Violet 057.

 


Metabolism:


Currently available oral toxicity studies do not provide information about the metabolic cleavage of the substance. However, findings of the bacterial reverse mutation assays conducted in presence and absence of metabolic activation with Disperse Violet 057 indicate some hepatic metabolism may taking place. In the bacterial reverse mutation assay conducted in 1994 (Ogorek, B.), Disperse Violet 057 (FAT 36038/F) exerted a weak mutagenic action on strains S. typhimurium TA 98 and TA 1535 in the absence of metabolic activation. The metabolites of the test material were weakly mutagenic with strain TA 1537 as well. In another bacterial reverse mutation assay (Fouillet, X.; 1979), Disperse Violet 057 (FAT 36038/C) was found to be mutagenic for S. typhimurium strain TA 1537 without metabolic activation. In the above discussed bacterial reverse mutation assays, it cannot be refused that presence or absence of metabolic activation played a significant role in the outcome of the study. Hence, Disperse Violet 057 can be assumed to undergo some degree of hepatic metabolism. However, it should be taken into account that rat S9 fraction is not equivalent to the human hepatic phase I and phase II metabolism.

Conclusions:
Disperse Violet 057 would be absorbed primarily in gastrointestinal tract, while limited absorption via dermal and inhalation exposure can be expected at high doses. Similarly, the systemic distribution is expected to occur along the gastrointestinal tract and serum. The substance being lipophilic in nature, some accumulation in adipose tissue may occur, while the predominant route of excretion is expected to be through faeces.
Executive summary:

Disperse Violet 057 would be absorbed primarily in gastrointestinal tract, while limited absorption via dermal and inhalation exposure can be expected at high doses. Similarly, the systemic distribution is expected to occur along the gastrointestinal tract and serum. The substance being lipophilic in nature, some accumulation in adipose tissue may occur, while the predominant route of excretion is expected to be through faeces.

Description of key information

Disperse Violet 057 would be absorbed primarily in gastrointestinal tract, while limited absorption via dermal and inhalation exposure can be expected at high doses. Similarly, the systemic distribution is expected to occur along the gastrointestinal tract and serum. The substance being lipophilic in nature, some accumulation in adipose tissue may occur, while the predominant route of excretion is expected to be through faeces.

Key value for chemical safety assessment

Additional information