Registration Dossier

Administrative data

basic toxicokinetics
Type of information:
other: Expert statement
Adequacy of study:
key study
Study period:
Study completion date: 20 November, 2020
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions

Data source

Reference Type:
study report
Report date:

Materials and methods

Objective of study:
Test guideline
no guideline required
Principles of method if other than guideline:
No ADME studies are available for FAT 36034. Therefore, the toxicokinetic assessment of FAT 36034 is predicted 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.
GLP compliance:

Test material

Constituent 1
Chemical structure
Reference substance name:
EC Number:
EC Name:
Cas Number:
Molecular formula:
Test material form:
solid: particulate/powder
migrated information: powder
Details on test material:
- Name of test material (as cited in study report): TERASIL BRILLANTROSA 2GL 50% FLUESSIG (MEL.11916/ 73)
- Purity: 50 %

Results and discussion

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 mortality occurred in the control or any of the dose groups during the study period and there were no adverse effects of toxicological relevance on clinical signs, clinical observations, FOB, body weight, food consumption, blood coagulation, clinical biochemistry, urine, gross lesions, reproduction and development of the pups.
There were findings of toxicological relevance on haematological parameters in medium dose and high dose groups. Treatment related changes were observed in the spleen. There was an increase in the spleen weight in medium and high dose groups when compared to the controls which correlated with the increase in mean severity of erythrocytic extramedullary hemopoiesis in the spleen recorded in both sexes of medium and high dose groups. These findings were considered to be adverse events attributable to treatment with the test item.
Treatment related findings were also recorded microscopically in the spleen and bone marrow. There was an increase in mean severity of erythrocytic extramedullary hemopoiesis in the spleen along with an increase in incidence and/or severity of hemosiderin deposition in the spleen and erythropoiesis in the bone marrow. These findings were most likely to be the histomorphologic indicator of haemolytic anaemia and were considered to be adverse events attributable to treatment with the test item. FAT 36034 is a red dye and would be expected to cause discolouration of the internal organs and/or urine if absorption had occurred, although it is uncertain if the colour would be discernible from the tissue colour. However, the colour would be obvious if present in urine, assuming that Phase 1 biotransformation did not remove the colour by oxidation of the conjugated electron system in the molecule. The study reports that the urine colour was generally unaffected indicating that no (visually detectable) FAT 36034 is present in the urine. However, a lack of red colour in the urine does not prove that absorption of the parent molecule did or did not occur, as the primary excretion could be via bile based on a molecular weight greater than 300. Although the study reports that the urine colour was generally unaffected and an insignificant number of rats showed any organ discolouration, the toxicologically adverse effects noted in the study indicate that some absorption has occurred. However, there is insufficient information available to determine how much of the substance is absorbed and in what form. The OECD QSAR application toolbox was used to apply Lipinski's Rule of Five. FAT 36034 was predicted to be 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, FAT 36034 or metabolites (formed in the intestine) must be absorbed based on the effects seen in the repeated dose oral toxicity study. The lack of colouration of the organs could indicate that FAT 36034 is metabolised into an uncoloured form (in the intestine and/or liver) and it is these metabolites, rather than the parent, that are then systemically bioavailable.

Inhalation route:

There is no information available regarding the absorption or toxicity of FAT 36034 via inhalation.
The vapour pressure of FAT 36034 is predicted to be low indicating that inhalation exposure from volatilisation is unlikely to be a potential route of exposure. No information is available on the particle size distribution of FAT 36034 as the molecule is described as a hard lumpy solid. Therefore, uptake via inhalation of the substance in this form is expected to be negligible. However, there is no information available to determine whether inhalable dust could be
formed by attrition.

Dermal route:
There is no information available regarding the absorption or toxicity of FAT 36034 following dermal exposure. Dermal absorption is influenced inter alia by water solubility, log Pow and molecular weight. Although the log Pow of 1.98 and molecular weight of 422.45 indicate that absorption would be favourable, this has to be considered against the relatively low water solubility of 3.26 mg/L. According to REACH guidance, a water solubility of < 1 mg/L indicates a likelihood of low dermal uptake and low to moderate absorption for 1-100 mg/L. On this basis, it is considered that insufficient substance would dissolve in the sweat on skin to facilitate significant absorption into the skin. In conclusion, dermal absorption for this compound would be expected to be low.
Details on distribution in tissues:
There is minimal information available relating to the distribution of FAT 36034. The repeated dose oral toxicity study does not indicate any significant discolouration of the internal organs which could indicate that either FAT 36034 is not extensively distributed or the molecule is metabolised into an uncoloured and hence undetected form. However, the toxicologically adverse effects noted in the study indicate that FAT 36034 or metabolites have, to some extent, been distributed through the body.
Details on excretion:
The repeated dose toxicity study reports that the faeces were stained a red colour. 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. Colourless or yellow urine was observed in the test animals and the control during the study. There was no observed red discolouration of the urine which could indicate that either excretion via urine is minimal or the parent molecule is being metabolised into smaller molecules (e.g. M2, M18) which are colourless and which could pass into the urine undetected. The molecular weights of the parent and unfragmented metabolites are greater than 300 which increases the likelihood of excretion via the biliary duct rather than via urine. This could also explain the lack of red colouration in the urine. In summary, excretion of FAT 36034 is expected via bile and GI tract, but not via urine. Excretion via bile is expected for metabolites with molecular weights greater than 300. Excretion of smaller noncoloured metabolites (M2 and M18) via urine is possible.

Metabolite characterisation studies

Metabolites identified:
Details on metabolites:
Potential metabolites of FAT 36034 in the liver and skin have been predicted using OECD Toolbox. Nine metabolites were predicted for liver metabolism (all are bioavailable) and twenty-three metabolites for skin metabolism (all are bioavailable). Five metabolites were common in both liver and skin. The main predicted biotransformations in liver and skin include hydroxylation, demethylation, oxidation and reduction reactions, which are considered as the normal types of phase I transformations.

Toxicologically relevant metabolites
Where there are no additional structural alerts and the metabolites are similar to the parent, it is expected that the toxicity will be similar to the parent.
Formaldehyde and formic acid:
Formaldehyde is known to be potentially toxic. It is regarded as carcinogenic to humans (group 1) according to the Hazardous Substance DataBase (HSDB).
However, it should be stressed that the underlying data for this is based on the inhalation route, and confined to site-specific respiratory neoplasms, specifically nasal area. The data is also related to inhalation of formaldehyde, whereas in this case any inhalation will be for the FAT 36034. It is also expected that any formation of formaldehyde in vivo will be rapidly followed by phase I transformation (oxidation) to formic acid and this would be rapidly excreted probably as a formate salt. Therefore, if this possible metabolite forms, it is not considered to present any concern.

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

FAT 36034 W is expected to be absorbed via oral route, though physicochemical properties indicate low absorption via inhalation and dermal routes. It is expected to be distributed throughout the body and be excreted via bile and the GI tract.
Executive summary:

The absorption, distribution, metabolism and excretion of FAT 36034 have been predicted in the absence of toxicokinetic studies.

FAT 36034 (and/or red-coloured metabolites formed in the GI tract) is absorbed via the oral route, based on the adverse effects seen in the repeated dose oral toxicity study.

FAT 36034 uptake via inhalation is expected to be negligible based on the fact that the substance is a hard lumpy solid. There is no information available regarding whether inhalable dust could be formed from attrition.

FAT 36034 is expected to have low dermal absorption.

FAT 36034 and/or its predicted metabolites are clearly distributed throughout the body, as indicated by the treatment related effects seen in the spleen and bone marrow.

The OECD toolbox predicts that FAT 36034 will undergo typical phase I biotransformations but these transformations do not lead to significant fragmentation of the molecule. Some of the predicted metabolites have the potential to be more toxic than the parent.

Excretion of FAT 36034 and any of its predicted metabolites is expected to be via bile and the GI tract. Excretion of smaller non-coloured metabolites via urine is possible.