Reaction mass of Cobaltate(3-), bis[2-[[[3-[2-[1-[[(2-chlorophenyl)amino]carbonyl]-2-(oxo-κO)propyl]diazenyl-κN1]-4-(hydroxy-κO)phenyl]sulfonyl]amino]benzoato(3-)]-, sodium (1:3) and tetrasodium bis[2-[[[3-[[1-[(2-chloroanilino)carbonyl]-2-oxopropyl]azo]-4-hydroxyphenyl]sulphonyl]amino]benzoato(3-)]cobaltate(4-)

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics

Type of information:

other: Expert statement

Adequacy of study:

supporting study

Study period:

2014

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Expert statement

Objective of study:

toxicokinetics

Qualifier:

no guideline required

Principles of method if other than guideline:

No ADME studies are available for FAT 92368/Y. Therefore, the toxicokinetic assessment of FAT 92368/Y is based on its physical-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.

GLP compliance:

no

Details on absorption:

Oral route:
A combined repeated dose oral toxicity study with the reproduction/ developmental toxicity screening test was performed in Wistar rats. Treatment-related adverse effects on mortality, body weight, food consumption and kidney weight were observed during the study. Adverse lesions were also seen in the kidney and adverse effects on litter data, litter weight data, percent post implantation loss and pup survival were associated with maternal systemic toxicity. These results indicate that all or part of the molecule has been absorbed.

Macroscopic yellow/yellowish discoloration recorded in some organs and tissues was considered to be due to the presence of the test item as luminal contents or due to distribution of the test item (or its metabolites) into the adipose tissues present in and around each organ, or due to the presence of it in the lympho-vascular system. This discolouration provides further evidence that FAT 92368/Y (or its metabolites) has been absorbed.

The OECD QSAR application toolbox was used to apply Lipinski's Rule of Five. FAT 92368/Y was predicted to be not orally bioavailable based on these rules, although it is clear that it (or possibly its coloured metabolites) is bioavailable from the repeated dose toxicity study. 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 92368/Y (or possibly one or more of its predicted metabolites) must have occurred.

Inhalation route:
There is no information available regarding the absorption or toxicity of FAT 92368/Y via inhalation.

The vapour pressure of FAT 92368/Y is predicted to be very low indicating that inhalation exposure from volatilisation is unlikely to be a potential route of exposure.

The particle size distribution (L50D = 10.8 µm, L10D = 1.1 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 48% of particles are <10 µm, and 32 % 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 via the inhalation route is expected to be moderate based on the particle size distribution and any particles that reach the alveoli would be expected to be absorbed to a relatively high degree based on the observed absorption via the oral route, as it is often the case that absorption via the alveoli is expected to be similar or higher than in the GI tract, with exceptions.

Dermal route:
There is no information available regarding the absorption or toxicity of FAT 92368/Y following dermal exposure. Dermal absorption is influenced inter alia by water solubility, log Pow and molecular weight. REACH endpoint specific guidance (R.7c) indicates that the log Pow of 1.24 together with the high water solubility of FAT 92368/Y of 182 g/L favours dermal absorption, but the molecular weight above 1000 may significantly reduce the likelihood of penetration.

In conclusion, dermal absorption of FAT 92368/Y is expected to be low.

Details on distribution in tissues:

In the repeated dose oral toxicity study, macroscopic examination indicated that there was a yellow or yellowish discolouration of various organs and tissues and treatment related adverse effects were observed in the kidney. This indicates that FAT 92368/Y 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 yellow coloured tissue. Based on the log Pow of FAT 92368/Y, the substance could bioaccumulate in fat. In conclusion, FAT 92368/Y and/or its metabolites are distributed extensively throughout the body, despite the OECD toolbox prediction of non-bioavailability.

Details on excretion:

The repeated dose toxicity study reports that the faeces of treated animals were stained a yellow colour. This yellow colouration wasn’t observed in the faeces of the control animals. This indicates several possibilities; the parent and/or its coloured metabolites were absorbed and then passed through the biliary duct and/or the unmetabolised parent and/or its coloured metabolites (formed in the intestine) passed through the GI tract unabsorbed. The molecular weight of FAT 92368/Y is much higher than 300 and therefore excretion via the bile duct would be expected, rather than via urine. For metabolites with molecular weights <300, urinary excretion is likely. Colourless or yellow urine was observed in the test animals and the control during the study. Since the colouration was also observed in the control animals it is likely that this colouration is actually due to the natural colour of urine. Any colouration caused by excretion of the test material would therefore be indistinguishable from the natural colour of urine. In conclusion, FAT 92368/Y is expected to be excreted via the biliary duct. Metabolites could be excreted via bile duct or in urine depending on their molecular weight.

Details on metabolites:

Potential metabolites of FAT 92368 Y in the liver and skin have been predicted using OECD Toolbox. Nine metabolites were predicted for liver metabolism (4 are bioavailable) and nineteen metabolites for skin metabolism (14 are bioavailable). Five metabolites were common in both liver and skin.

The OECD Toolbox has predicted that FAT 92368 Y will undergo phase I transformations (reductions, oxidations, hydroxylations).

Metabolites M1, M3, M6, M8 and M17 were identified by the OECD QSAR application toolbox or by the websites PubChem and ChemSpider.

Toxicologically relevant metabolites:

2-chloroaniline:
A search on Toxnet and HSDB was carried out. The main observations are nephrotoxicity (degenerative changes in proximal and distal tubular cells and occlusion of distal tubular segments) from acute exposure to i.p. dosage (HSDB) and damage to erythrocytes (subchronic (4 weeks), route not stated in HSDB, but believed to be inhalation, as dose stated in mg/cu m).
Toxline indicated dystrophic liver and kidney damage was observed following oral dosing over a prolonged period of several months. Toxline also stated that information on genotoxicity is ambiguous and no long-term carcinogenicity information is available.
It is worth noting that kidney effects were seen in the repeated dose study for FAT 92368 Y.

2, 3-dioxobutanoic acid:
A search on Toxnet did not indicate any information relevant to this report.

Metabolites with aromatic amino groups:
It is known that certain aromatic amines are associated with human carcinogenicity and rat carcinogenicity. Some of the metabolites have a more clearly defined aromatic amino group compared to the parent, so enhanced toxicity cannot be excluded.
However, this does not mean that the relevant metabolites are carcinogens, but the potential is considered to exist.

Metabolites with phenolic groups:
Metabolites which have phenolic groups present should also be considered potentially more toxic than the parent (which does not contain them), due to the oxidation of phenols which is known to produce quinones/semiquinones 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.

Conclusions:

The absorption, distribution, metabolism and excretion of FAT 92368/Y have been predicted in the absence of toxicokinetic studies. FAT 92368/Y (and/or its yellow-coloured metabolites) is absorbed via the oral route, based on the yellow colouration of tissues/organs and the treatment related adverse effects seen in the repeated dose oral toxicity study. FAT 92368/Y uptake via inhalation is expected to be moderate. FAT 92368/Y is expected to have low dermal absorption.
FAT 92368/Y and/or its predicted metabolites are widely distributed throughout the body, as indicated by the yellowish colouration of organs and tissues. The OECD toolbox predicts that FAT 92368/Y will undergo typical phase I biotransformations. Some of the predicted metabolites have the potential to be more toxic than the parent. FAT 92368/Y is expected to be excreted via the biliary duct. Metabolites could be excreted via bile duct or in urine depending on their molecular weight.

Description of key information

In accordance with REACH Regulation (EC) No 1907/2006 Annex VIII section 8.8.1, a toxicokinetics study is not required as assessment of the toxicokinetic behaviour of the substance has been derived from the relevant available information.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

5

Absorption rate - inhalation (%):

100

Additional information

No ADME studies are available for FAT 92368. Therefore, the toxicokinetic assessment of FAT 92368 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 92368 have been predicted in the absence of toxicokinetic studies. FAT 92368 (and/or its yellow-coloured metabolites) is absorbed via the oral route, based on the yellow colouration of tissues/organs and the treatment related adverse effects seen in the repeated dose oral toxicity study. FAT 92368 uptake via inhalation is expected to be moderate. FAT 92368 is expected to have low dermal absorption. FAT 92368 and/or its predicted metabolites are widely distributed throughout the body, as indicated by the yellowish colouration of organs and tissues. The OECD toolbox predicts that FAT 92368 will undergo typical phase I biotransformations. Some of the predicted metabolites have the potential to be more toxic than the parent. FAT 92368 is expected to be excreted via the biliary duct. Metabolites could be excreted via bile duct or in urine depending on their molecular weight.