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Reference
Endpoint:
basic toxicokinetics, other
Type of information:
other: Basic toxicokinetic assessment according to ECHA Guidance on information requirments R7.c
Study period:
2018
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Objective of study:
absorption
distribution
excretion
metabolism
toxicokinetics
Qualifier:
according to guideline
Guideline:
other: ECHA Guidance r7.c
Deviations:
not applicable
GLP compliance:
no
Details on absorption:
Oral/gastrointestinal absorption:
Owing to the molecular weight (419.4 g/mol) and poor solubility in water (3.7 µg/L), it can be concluded that the substance Disperse Red 302:1 may have a limited absorption by means of passage through aqueous pores or be carried through the epithelial barrier by the bulk passage of water in the gastrointestinal tract. However, the substance being lipophilic (log Pow = 5.16) and poorly water soluble (3.7 µg/L), absorption is expected to occur via micellular solubilization.
In the acute oral toxicity study with Disperse Red 302:1, 3 males and 3 females received a single dose of 2000 mg/kg bw. 1 out of 3 females died on day 9. All three females showed a loss of body weight (23.7, 26.5 and 28 %) one week after treatment. Dark red discoloration of the digestive system was observed at the unscheduled necropsy of dead female. The above-mentioned findings indicate that Disperse Red 302:1 was absorbed from the gastrointestinal tract and thereby leading to systemic distribution.
In the combined repeated dose toxicity study with reproduction/developmental screening, three females receiving 300 mg/kg bw/day and three females receiving 1000 mg/kg bw/day showed red staining of the urine during behavioral assessments. At necropsy, red colored contents within the gastrointestinal tract and urinary bladder were observed in many animals at all doses. One female was found to have red discoloration of mammary gland at 300 mg/kg bw/day. These findings were without any toxicological significance, however are indicative of absorption of the substance taking place along the gastrointestinal tract.
Dermal absorption:
Based on the molecular weight (419.4 g/mol) and the high partition coefficient (log Pow = 5.16), a moderate dermal penetration rate is expected for Disperse Red 302:1. However, the poor water solubility (3.7 µg/L at 20 °C) means the substance is not sufficiently soluble in water to partition from the stratum corneum into the epidermis.
Disperse Red 302:1 was neither corrosive nor irritating to the skin as well as eyes, while, it was not sensitizing to the skin. No deaths or systemic toxicity was observed in the local lymph node assay or the skin irritation studies with the Disperse Red 302:1.
The physicochemical properties and evidence from the irritation studies and lymph node assay, suggest that Disperse Red 302:1 may get absorbed to a limited extent if it is exposed dermally at high doses.
Respiratory absorption:
Disperse Red 302:1 can be considered to have low volatility based on its low vapor pressure (4.65 × 10E-11 Pa at 25 °C), so the potential for the generation of inhalable forms is low. The substance may be taken up by micellular solubilization owing to it having high partition coefficient (Log Pow = 5.16), and poor water solubility (3.7 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:
Distribution
Findings of red stained urine during behavioral assessments and presence of colored content in urinary bladder during necropsy in the combined repeated dose toxicity study with reproduction/developmental screening, point to the substance/metabolites getting transported to the kidneys for excretion via urine. Further, a finding of red discoloration of mammary glands in a female at 300 mg/kg bw/day was also reported in the study, which points to a wider distribution throughout the body via circulation. The substance being lipophilic in nature, some accumulation in adipose tissue may occur.


Details on excretion:
Excretion
Route of excretion for Disperse Red 302:1 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. However, appearance of the red colored urine observed in the combined repeated dose toxicity study with reproduction/developmental screening with Disperse Red 302:1, indicates substance may get metabolized to a hydrophilic product and may also be excreted in urine especially at the high doses.
Metabolites identified:
not measured
Details on metabolites:
Metabolism
Currently available oral toxicity studies do not provide information about the metabolic cleavage of the substance. However, Disperse Red 302:1 was found to be mutagenic with Salmonella typhimurium strain TA 1537 in the presence of metabolic activation in the bacterial reverse mutation assay. Further it was also found to be clastogenic in the presence of metabolic activation in the in vitro mammalian chromosomal aberration assay. These findings indicate hepatic metabolism taking place, however, it should be taken into consideration that rat S9 fraction is not equivalent to the human metabolism.
The appearance of red colored urine after the oral administration of the substance in the combined repeated dose toxicity study with reproduction/developmental screening with Disperse Red 302:1, indicates that the substance may undergo phase I and phase II transformations in the liver and will most likely be metabolized to more hydrophilic products which are excreted via urine at high doses.

Absorption

Oral/gastrointestinal absorption:

Owing to the molecular weight (419.4 g/mol) and poor solubility in water (3.7 µg/L), it can be concluded that the substance Disperse Red 302:1 may have a limited absorption by means of passage through aqueous pores or be carried through the epithelial barrier by the bulk passage of water in the gastrointestinal tract. However, the substance being lipophilic (log Pow = 5.16) and poorly water soluble (3.7 µg/L), absorption is expected to occur via micellular solubilization.

In the acute oral toxicity study with Disperse Red 302:1, 3 males and 3 females received a single dose of 2000 mg/kg bw. 1 out of 3 females died on day 9. All three females showed a loss of body weight (23.7, 26.5 and 28 %) one week after treatment. Dark red discoloration of the digestive system was observed at the unscheduled necropsy of dead female. The above-mentioned findings indicate that Disperse Red 302:1 was absorbed from thegastrointestinal tract and thereby leading to systemic distribution.

In the combined repeated dose toxicity study with reproduction/developmental screening, three females receiving 300 mg/kg bw/day and three females receiving 1000 mg/kg bw/day showed red staining of the urine during behavioral assessments. At necropsy, red colored contents within the gastrointestinal tract and urinary bladder were observed in many animals at all doses. One female was found to have red discoloration of mammary gland at 300 mg/kg bw/day. These findings were without any toxicological significance, however are indicative of absorption of the substance taking place along the gastrointestinal tract.

Dermal absorption:

Based on the molecular weight (419.4 g/mol) and the high partition coefficient (log Pow = 5.16), a moderate dermal penetration rate is expected for Disperse Red 302:1. However, the poor water solubility (3.7 µg/L at 20 °C) means the substance is not sufficiently soluble in water to partition from thestratum corneuminto the epidermis.

Disperse Red 302:1 was neither corrosive nor irritating to the skin as well as eyes, while, it was not sensitizing to the skin. No deaths or systemic toxicity was observed in the local lymph node assay or the skin irritation studies with the Disperse Red 302:1.

The physicochemical properties and evidence from the irritation studies and lymph node assay, suggest that Disperse Red 302:1 may get absorbed to a limited extent if it is exposed dermally at high doses.

Respiratory absorption:

Disperse Red 302:1 can be considered to have low volatility based on its low vapor pressure (4.65 × 10E-11 Pa at 25 °C), so the potential for the generation of inhalable forms is low. The substance may be taken up by micellular solubilization owing to it having high partition coefficient (Log Pow = 5.16), and poor water solubility (3.7 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.

Distribution

Findings of red stained urine during behavioral assessments and presence of colored content in urinary bladder during necropsy in the combined repeated dose toxicity study with reproduction/developmental screening, point to the substance/metabolites getting transported to the kidneys for excretion via urine. Further, a finding of red discoloration of mammary glands in a female at 300 mg/kg bw/day was also reported in the study, which points to a wider distribution throughout the body via circulation. The substance being lipophilic in nature, some accumulation in adipose tissue may occur.

Metabolism

Currently available oral toxicity studies do not provide information about the metabolic cleavage of the substance. However, Disperse Red 302:1 was found to be mutagenic withSalmonella typhimuriumstrain TA 1537 in the presence of metabolic activation in the bacterial reverse mutation assay. Further it was also found to be clastogenic in the presence of metabolic activation in thein vitromammalian chromosomal aberration assay. These findings indicate hepatic metabolism taking place, however, it should be taken into consideration that rat S9 fraction is not equivalent to the human metabolism.

The appearance of red colored urine after the oral administration of the substance in the combined repeated dose toxicity study with reproduction/developmental screening with Disperse Red 302:1, indicates that the substance may undergo phase I and phase II transformations in the liver and will most likely be metabolized to more hydrophilic products which are excreted via urine at high doses.

Excretion

Route of excretion for Disperse Red 302:1 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. However, appearance of the red colored urine observed in the combined repeated dose toxicity study with reproduction/developmental screening with Disperse Red 302:1, indicates substance may get metabolized to a hydrophilic product and may also be excreted in urine especially at the high doses.
Conclusions:
Based on the above discussion, it can be concluded that Disperse Red 302:1 would be absorbed primarily in gastrointestinal tract, while limited absorption via dermal and inhalation exposure can be expected at high doses. Systemic distribution is expected to occur throughout the body. The substance being lipophilic in nature, some accumulation in adipose tissue may occur. Predominant route of excretion is expected to be through faeces, however, upon absorption the substance may undergo phase I and phase II transformations in the liver and will most likely be metabolized to more hydrophilic products which are excreted via urine at high doses.
Executive summary:

Disperse Red 302:1 would be absorbed primarily in gastrointestinal tract, while limited absorption via dermal and inhalation exposure can be expected at high doses. Systemic distribution is expected to occur throughout the body. The substance being lipophilic in nature, some accumulation in adipose tissue may occur. Predominant route of excretion is expected to be through faeces, however, upon absorption the substance may undergo phase I and phase II transformations in the liver and will most likely be metabolized to more hydrophilic products which are excreted via urine at high doses.

Description of key information

Disperse Red 302:1 would be absorbed primarily in gastrointestinal tract, while limited absorption via dermal and inhalation exposure can be expected at high doses. Systemic distribution is expected to occur throughout the body. Since the substance is lipophilic, some accumulation in adipose tissue may occur. Predominant route of excretion is expected to be through faeces, however, upon absorption the substance may undergo phase I and phase II transformations in the liver and will most likely be metabolized to more hydrophilic products which are excreted via urine at high doses.

Key value for chemical safety assessment

Additional information