1,8-bis(phenylthio)anthraquinone

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

other: Expert statement

Adequacy of study:

weight of evidence

Study period:

2014

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

The absorption, distribution, metabolism and excretion of FAT 93450 Z have been predicted in the absence of toxicokinetic studies. There are no guidelines on how to conduct this type of modelling but the methods described are well accepted scientifically.

Data source

Reference

Reference Type:

other: Expert statement

Title:

Unnamed

Year:

2014

Report date:

2014

Materials and methods

Objective of study:

absorption

distribution

excretion

metabolism

Test guideline

Qualifier:

no guideline required

Principles of method if other than guideline:

The absorption, distribution, metabolism and excretion of FAT 93450/Z have been predicted in the absence of toxicokinetic studies. There are no guidelines on how to conduct this type of modelling but the methods described are well accepted scientifically.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

1,8-bis(phenylthio)anthraquinone

EC Number:

237-167-6

EC Name:

1,8-bis(phenylthio)anthraquinone

Cas Number:

13676-91-0

Molecular formula:

C26H16O2S2

IUPAC Name:

1,8-bis(phenylsulfanyl)-9,10-dihydroanthracene-9,10-dione

Test material form:

solid: particulate/powder

Remarks:

migrated information: powder

Details on test material:

Physico-chemical properties:

Appearance/colour: Orange solid

Molecular weight: 424.54

Boiling point: No boiling point up to 350 °C

Water solubility: 1.29 mg/L

Octanol-water 3.38
partition coefficient
(log Pow):

Vapour pressure: Very low (as predicted by EPIWIN QSAR)

Results and discussion

Preliminary studies:

None

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Oral route:
A combined repeated dose oral toxicity study with the reproduction/ developmental toxicity screening test was performed in Wistar rats. No treatment related mortality occurred in the control or any of the dose groups during the study period and there were no treatment related adverse effects of toxicological relevance on any of the parameters investigated (clinical signs, body weight, food consumption, organ weights, gross lesions, histopathology, reproduction, development of the pups, gross external abnormalities of the pups [with the exception of orange skin discolouration], macroscopic findings). There were no clinical signs of toxicological relevance in the dose groups, when compared to the control group. However, the skin of all male and female animals of the low dose, the medium dose and the high dose group was observed to be slightly discoloured yellowish from approximately the third week of treatment until the end of the study due to the properties of the coloured test item. The skin of all pups was also observed to be discoloured orange.There were no macroscopic findings of toxicological relevance noted in any of the groups. However, adipose tissue of each male and female animal of the low dose, the medium dose and the high dose group was noted to be discoloured yellow which was attributable to the treatment with the coloured test item. In addition, yellow discoloration was recorded in the pancreas and mammary glands of the euthanized female of the high dose group. Macroscopic yellow discoloration in these organs and tissues was considered to be due to distribution of the test item (or its metabolites) into the adipose tissues which are present in and around each organ, or to be due to the presence of it in the lympho-vascular system. However, in the adipose tissue, pancreas and mammary glands, there was no histologic alteration that correlated with the macroscopic findings. Discoloured yellow kidneys were observed in 8 males and one female of the low dose group, in all males and no females of the medium dose group and in 7 males and 3 females of the high dose group. It was assumed that the test item produces eosinophilic substance deposition in the kidney, which was considered to be related to the excretion process of the test item and/or its metabolites, being followed by the secondary changes including tubular degeneration/regeneration, granular casts and/or tubular dilatation due to excess deposition (re-absorption) without clear dose relationship in severity. These renal changes were not considered to be adverse. The discolouration of the skin and organs investigated and the effects seen in the kidneys indicate that all or part of FAT 93450 Z has been absorbed following oral intake. However, there is insufficient information available to determine how much of the substance is absorbed and in what form. The lack of oral toxicity seen in the repeated dose study is supported by the acute oral toxicity study. The OECD QSAR application toolbox was used to apply Lipinski's Rule of Five. FAT 93450 Z was predicted to be not orally bioavailable based on these rules. The toolbox is also designed to predict possible metabolites that can be produced by phase 1 (e.g. oxidation/reduction) and phase 2 (e.g. conjugation) biotransformations in the liver, based on the structure of the parent molecule. This biotransformation can occur during the first pass effect, but can also occur if the unmetabolised molecule passes into the systemic circulation and returns through the liver. In conclusion, it is clear from the repeated dose toxicity study that absorption of FAT 93450 Z (or possibly one or more of its predicted metabolites, also expected to be orange) must have occurred.

Inhalation route:
There is no information available regarding the absorption or toxicity of FAT 93450 Z via inhalation. The vapour pressure of FAT 93450 Z is predicted to be low indicating that inhalation exposure from volatilisation is unlikely to be a potential route of exposure. The particle size distribution (L50D = 116.8 µm, L10D = 11.6 µm) of the test material indicates the presence of inhalable and respirable particles. REACH endpoint specific guidance (R.7c) states that respirable particles are < 15 µm. However, according to other REACH guidance (chapter R.14) respirable particles are regarded as being < 10 µm. According to the particle size distribution study, more than 8% of particles are < 10 µm, and nearly 3% are < 5 µm. Therefore, there is potential for deposition in the alveoli, where dissolution in the alveolar fluid could occur followed by absorption. Inhalable particles are likely to be cleared from the lungs by the mucociliary escalator, but then swallowed making them potentially available for absorption via the GI tract. In conclusion, uptake of FAT 93450 Z via the inhalation route is expected to be very low based on the particle size distribution and low water solubility.

Dermal route:
There is no information available regarding the absorption or toxicity of FAT 93450 Z following dermal exposure. Dermal absorption is influenced inter alia by water solubility, log Pow and molecular weight. Although the log Pow and molecular weight indicate that absorption would be favourable, this has to be considered against the relatively low water solubility of 1.29 mg/L. According to REACH guidance, a water solubility of < 1 mg/L indicates a likelihood of low dermal absorption. For water solubility between 1-100 mg/L, low to moderate absorption is expected. So, in this case where the solubility is very near to the bottom of this range, it is considered that dermal absorption would be low. In conclusion, dermal absorption for this compound would be expected to be low.

Details on distribution in tissues:

In the repeated dose oral toxicity study, macroscopic examination indicated that there was an orange or yellowish discolouration of various organs including the adipose tissue, pancreas, mammary glands, kidneys and/or skin. This indicates that FAT 93450/Z and/or its coloured metabolites are distributed extensively throughout the body. The extent to which this absorption and distribution occurs is unknown as it is possible that only a very small amount of the test substance or coloured metabolites can lead to the appearance of orange or yellow coloured tissue. The presence in adipose tissue and skin may indicate that the substance has the potential to bioaccumulate, which would be expected based on its log Pow and poor water solubility. In conclusion, FAT 93450/Z and/or its metabolites are distributed extensively throughout the body, despite the OECD toolbox prediction of non-bioavailability.

Details on excretion:

Excretion
The repeated dose toxicity study reports that effects were seen in the kidneys of treated animals that were related to the test material (although not considered toxicologically adverse). This indicates that excretion of FAT 93450/Z and/or relevant metabolite is probably via urine. There was no reported discolouration of the faeces in the repeated dose toxicity study. Since the metabolites predicted by the toolbox all have an intact conjugated system, they are also predicted to be orange in colour. However, the lack of any reported orange or yellow colouration in the faeces does not mean that no biliary excretion has occurred or that all the FAT 93450/Z has been absorbed because the brown colour of the faeces could disguise any orange or yellow colouration. Based on the effects seen in the kidneys, excretion of FAT 93450/Z and/or a relevant metabolite is probably via urine. However, some excretion via the GI tract cannot be ruled out.

Metabolite characterisation studies

Details on metabolites:

The main predicted biotransformations in liver and skin include hydroxylation and oxidation reactions, which are considered the normal types of phase I transformations. Only metabolite M25 was identified by the OECD QSAR application toolbox or by the websites PubChem and ChemSpider.

Toxicologically relevant metabolites
The toolbox predicts that the parent molecule undergoes minimal biotransformations and remains largely intact. Therefore, the toxicity of these unfragmented metabolites will be similar to the parent.

Metabolites with aromatic –OH present:
All the metabolites which have phenolic groups present should be considered potentially more toxic than the parent, due to the oxidation of phenols which is known to produce quinones/ semi-quinones which can become involved in binding to the –SH or –NH2 groups in proteins leading to inactivation of the protein. They are also associated with superoxide anion production ultimately leading to formation of hydroxyl radicals which can cause cell damage.

Applicant's summary and conclusion

Conclusions:

There is insufficient information available to be able to determine the rate and extent of any absorption that may occur and the true toxicokinetic pathway of FAT 93450/Z.

Executive summary:

No ADME studies are available for FAT 93450/ Z. Therefore, the toxicokinetic assessment of FAT 93450/Z is based on its physico-chemical properties and available toxicological study data. The OECD QSAR application toolbox v3.2 was also utilized to make a qualitative prediction of metabolites formed in the liver and skin.

The absorption, distribution, metabolism and excretion of FAT 93450/Z have been predicted in the absence of toxicokinetic studies.

 -FAT 93450/Z (and/or its metabolites formed in the GI tract) is absorbed via the oral route, based on the effects seen in the kidneys and the yellow colouration of tissues/organs.

 -FAT 93450/Z uptake via inhalation is expected to be low.

 -FAT 93450/Z is expected to have low dermal absorption.

 -FAT 93450/Z and/or its predicted metabolites are widely distributed throughout the body, as indicated by yellow colouration of organs, tissues and skin.

 -The OECD toolbox predicts that FAT 93450/Z will undergo typical phase I biotransformations but these transformations lead to only minimal fragmentation of the molecule.

- Excretion of FAT 93450/Z and any of its predicted metabolites is expected to be via urine. However, some excretion via the GI tract cannot be ruled out.