Registration Dossier

Diss Factsheets

Administrative data

Link to relevant study record(s)

Reference
Endpoint:
basic toxicokinetics, other
Type of information:
other: Basic TK assessment based on physico-chemical properties and available toxicological data
Adequacy of study:
supporting study
Study period:
2021
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
test procedure in accordance with national standard methods with acceptable restrictions
Principles of method if other than guideline:
Basic TK assessment based on physico-chemical properties and available toxicological data
GLP compliance:
no
Details on absorption:
Oral/gastrointestinal absorption:
Owing to the molecular weight (376.32 g/mol), high partition coefficient (log Pow >6.9) and poor solubility in water (<0.85 µg/L), absorption of Disperse Blue 077 is expected to occur via micellular solubilization by bile salts.
Several acute oral toxicity studies with Disperse Blue 077 are available. In these studies, clinical signs commonly associated with acute studies were seen at significantly high doses (>2000 mg/kg bw). In the acute toxic class study with Disperse Blue 077 (METI, Japan; 2011), the gavage of 2000 mg/kg bw dose (first and second step) to 3 females (per step) lead to decreased locomotor activity (slight), salivation, abnormal coloured urine (pale purple), soft stool soiled peritoneal region, black stool and/or decreased stool volume. No abnormalities were noted in the body weight observations and at necropsies. Here, the discoloration of urine and stool may be attributed to absorption of Disperse Blue 077.
Disperse Blue 077, was evaluated for short-term repeated dose toxicity by METI, Japan (2011) in a study conducted according OECD TG 422. In this study, four groups of rats (males and females) received the test substance at 0, 40, 200 and 1000 mg/kg bw/day via gavage for 42 days. In clinical signs, test article-colored feces were observed in all test article groups, and colored aqueous solution and retention of content was observed in the gastrointestinal tract at necropsy. In the 1000 and 200 mg/kg bw/day groups, discoloration (test article-like color) was observed in the mucosa in the stomach, ileum, cecum, and colon. In urine analysis, in males, changes in urine color which were considered to have reflected the color of the test article or its metabolite were noted in all animals in the 1000 and 200 mg/kg bw/day groups.
In an OECD TG 422 study, the oral administration of the structurally similar substance, Disperse Blue 054/077 (FAT 92504/C) to rats by gavage, at dose levels of 100, 300 and 1000 mg/kg bw/day lead to instances of blue fur staining frequently observed in both males and females from the first week of dosing at 1000 and 300 mg/kg bw/day and from the second week of dosing at 100 mg/kg bw/day. Blue colored faeces and staining of the cage bedding were also observed for animals of either sex from all treatment groups from the first week and second week of dosing (respectively). These observations generally persisted throughout the remainder of the study. Six litters from females treated with 1000 mg/kg bw/day were stained blue or had blue colored contents in the stomach, this finding indicates the transfer of the colored material to the offspring from mother. At necropsy, blue/green discoloration was observed for a number of tissues in adult animals of either sex from all treatment groups. These included gastrointestinal tract (stomach and small/large intestine), skin, mammary gland, mesenteric lymph nodes and adipose tissue. Green fluid in the urinary bladder was also evident in one 300 mg/kg bw/day male. These observations are indicative of the test substance getting absorbed when administered via oral route.
Based on the above discussion, Disperse Blue 077 can be expected to get absorbed when administered orally.

Dermal absorption:
Based on the molecular weight (376.32 g/mol), high partition coefficient (log Pow >6.9), and poor water solubility (<0.85 µg/L at 20 °C), a low dermal penetration rate is expected for Disperse Blue 077. The high molecular weight of Disperse Blue 077 means it has limited dermal absorption potential and the poor water solubility means the substance is not sufficiently soluble in water to partition from the stratum corneum into the epidermis, thereby further limiting the absorption.
Disperse Blue 077 was found to be neither corrosive nor irritating to the skin, while it did elicit sensitisation response in a Guinea pig maximisation test. No deaths or systemic toxicity occurred in these studies. Thus, no findings signifying absorption were reported in these studies.
The physicochemical properties of Disperse Blue 077 suggest low dermal absorption potential, however as was evident from repeated dose oral toxicity studies, it may get absorbed to a limited extent if exposed dermally at high doses.

Respiratory absorption:
Disperse Blue 077 can be considered to have low volatility based on high melting point (>230 °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 >6.9), and poor water solubility (<0.85 µg/L at 20 °C). Therefore, and also taking into account the evidence of absorption from repeated dose oral toxicity studies, Disperse Blue 077 can be expected to get 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. Also owing to the lipophilic nature of Disperse Blue 077, it may get distributed widely in the body with some accumulation in adipose tissue can also be expected. This hypothesis was further supported by the necropsy findings from the repeated dose oral toxicity study with reproduction and developmental screening with Disperse Blue 054/077, where blue/green discoloration was observed for a number of tissues in adult animals of either sex from all treatment groups. These included gastrointestinal tract (stomach and small/large intestine), skin, mammary gland, mesenteric lymph nodes and adipose tissue.
Details on excretion:
The route of excretion for Disperse Blue 077 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 test article colored faeces with all test article treated groups in the combined repeated dose toxicity study with reproduction/developmental screening test with Disperse Blue 077. Additionally, some degree of excretion through urine can also be expected at higher doses, as seen with the appearance of discolored urine in acute oral toxicity studies and at 200 and 1000 mg/kg bw/day in the combined repeated dose toxicity study with reproduction/developmental screening test.
Metabolites identified:
not measured
Details on metabolites:
Currently available oral toxicity studies do not provide information about the metabolic cleavage of the substance. However, Disperse Blue 077 being highly lipophilic, it can be expected to undergo phase I biotransformation. In the bacterial reverse mutation assay conducted in 2011 (METI, Japan), Disperse Blue 077 lead to a 2-fold or greater and dose-dependent increase in revertant colonies in TA98 and TA1537 strains without metabolic activation (-S9 mix) and in TA100, WP2uvrA, TA98, and TA1537 with metabolic activation (+S9 mix). Thus, metabolic activation seems to have played a role in positive outcome with TA100 and WP2uvrA strains, giving evidence that Disperse Blue 077 will undergo some degree of hepatic metabolism. However, it should be taken into consideration that rat S9 fraction is not equivalent to the human metabolism.
Conclusions:
Disperse Blue 077 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 it can be expected to get distributed throughout the body. 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 Blue 077 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 it can be expected to get distributed throughout the body. 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