Reaction mass of 1,5-dihydroxy-4-nitro-8-(phenylamino)anthraquinone and 1,8-dihydroxy-4-nitro-5-(phenylamino)anthraquinone

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics, other

Remarks:

Expert assessment

Type of information:

other: expert assessment

Adequacy of study:

key study

Study period:

15.03.2017

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Objective of study:

absorption

distribution

excretion

metabolism

Qualifier:

no guideline followed

Principles of method if other than guideline:

Expert assessment

GLP compliance:

no

TOXICOKINETIC BEHAVIOUR

The substance composed, as listed in Section 3 is a blue solid with a molecular weight of 376.32 g/mol and to have low water solubility and high melting and auto-ignition points. The supporting physicochemical properties indicate low volatility which together with supporting toxicological information from a single inhalation exposure (LC50: 72.6 mg/L body weight) indicates the risk of particle inhalation to be minimal. Results from genotoxicity assays indicate FAT 92504/C would be non-mutagenic.

Single dose oral and dermal toxicity estimated the oral LD50 to be >2000 mg/kg body weight and dermal LD50 as 12,800 mg/kg body weight. In addition, the chemical characteristics of FAT 92504/C would suggest this test material would have the potential to be mildly irritative to the skin and eyes and to cause

skin sensitization. An oral (gavage) combined repeat dose toxicity study with reproduction/developmental toxicity screening test in the rat (OECD 422) conducted for FAT 92504/C provided evidence of absorption, distribution, metabolism and excretion.

Absorption

The low water solubility and high octanol/water partition coefficient would inhibit passage across biological membranes. Furthermore the OECD 422 study conducted for FAT 92504/C revealed generalized blue staining of external body surfaces and blue/green discoloration internally in the following organs and tissues; gastrointestinal tract (stomach and small/large intestine), skin, mammary gland, mesenteric lymph nodes and adipose tissue. Furthermore, green fluid (presumably from FAT 92504/C and/or a metabolite) was observed in the urinary bladder. These findings together with evidence of staining of the faeces and bedding would indicate some passive absorption would occur through the gastro-intestinal tract following oral ingestion before entering the circulatory system via the blood. The potential of FAT 92504/C to cause skin sensitizer may also imply injury to the skin barrier could increase the chances of test item penetration with subsequent binding to carrier proteins in the circulatory system. However, in consideration of the hydrophilic nature and molecular weight of FAT 92504/C passage across biological membranes is likely to be limited.

Distribution

The physico-chemical properties suggest the possibility that some accumulation in adipose tissue could occur. However, the results from the oral (gavage) combined repeat dose toxicity study with reproduction/developmental toxicity screening test in the rat (OECD 422) provided sufficient evidence to establish the most probable route of absorption and systemic distribution to take place along the gastrointestinal tract and serum.

Metabolism

The results of the oral (gavage) combined repeat dose toxicity study with reproduction/developmental toxicity screening test in the rat (OECD 422) did not show any evidence of test material influenced hepatic metabolism. The results of the genotoxicity assays also proved negative. Furthermore, while the physico-chemical properties might suggest the test material to be lipophilic, the supporting evidence strongly suggest that metabolism to a more hydrophilic product to actuate excretion would take place.

Excretion

The most plausible route of clearance for low water soluble materials such as FAT 92504/C would be by transfer of test material and/or metabolites from the plasma to the bile through the hepatocytes and then by way of a process known as enterohepatic cycling finally lead to clearance of any metabolic breakdown products primarily via the faeces. To further support this viewpoint, dark blue stained faeces and bedding were identified from animals of all test groups in the OECD 422 study.

Conclusions:

The available information suggests that absorption of FAT 92504/C will primarily take place in the gastrointestinal tract following oral ingestion. Some absorption might also take place through damaged skin. Once absorbed, the substance would primarily be distributed in the serum with excretion primarily being via the faeces.

Executive summary:

The absorption, distribution, metabolism and excretion of FAT 92504/C have been predicted based upon the physico-chemical properties and supporting toxicological information provided for this test material. Based on the available study data it is reasonable to assume that FAT 92504/C would in all probability be absorbed via the gastrointestinal tract subsequently entering the circulatory system in the blood. It is also possible some absorption could take place through the skin. Supporting information including results from a single exposure inhalation study indicates the risk of systemic toxicity from particle inhalation to be minimal. Furthermore, the corroborating evidence from a single oral dosetoxicity study and from an oral (gavage) combined repeat dose toxicity study with reproduction/developmental toxicity screening test in the rat (OECD 422) demonstrate that the test item and/or its predicted metabolites to have only low toxic potential when absorbed or distributed through the gastro-intestinal tract and serum. Excretion of FAT 92504/C and any of its predicted metabolites is expected to be primarily from the faeces.

Description of key information

The absorption, distribution, metabolism and excretion of FAT 92504/C have been predicted based upon the physico-chemical properties and supporting toxicological information provided for this test material. Based on the available study data it is reasonable to assume that FAT 92504/C would in all probability be absorbed via the gastrointestinal tract subsequently entering the circulatory system in the blood. It is also possible some absorption could take place through the skin. Supporting information including results from a single exposure inhalation study indicates the risk of systemic toxicity from particle inhalation to be minimal. Furthermore, the corroborating evidence from a single oral dosetoxicity study and from an oral (gavage) combined repeat dose toxicity study with reproduction/developmental toxicity screening test in the rat (OECD 422) demonstrate that the test item and/or its predicted metabolites to have only low toxic potential when absorbed or distributed through the gastro-intestinal tract and serum. Excretion of FAT 92504/C TE and any of its predicted metabolites is expected to be primarily from the faeces.