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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 36014/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

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
The absorption, distribution, metabolism and excretion of FAT 36014/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.

Test material

Constituent 1
Chemical structure
Reference substance name:
4-anilino-3-nitro-N-phenylbenzenesulphonamide
EC Number:
225-862-7
EC Name:
4-anilino-3-nitro-N-phenylbenzenesulphonamide
Cas Number:
5124-25-4
Molecular formula:
C18H15N3O4S
IUPAC Name:
4-anilino-3-nitro-N-phenylbenzenesulfonamide
Test material form:
solid: particulate/powder
Remarks:
migrated information: powder
Details on test material:
- Name of test material (as cited in study report): FAT 36014 Z
- Molecular weight (if other than submission substance): 369.40
- Substance type: Powder
- Physical state: Solid

Administration / exposure

Statistics:
None

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
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 any of the parameters investigated (clinical signs, FOB, body weight, food consumption, haematology, blood coagulation, clinical biochemistry, urine, organ weights, pathology, histopathology, reproduction and development of the pups). The study reported that an insignificant number of rats showed any organ discolouration but this could be due to the yellow colour being indiscernible from the tissue colour, so absorption cannot be excluded. The lack of oral toxicity seen in the repeated dose study is supported by the acute oral toxicity study. The physical chemical properties of FAT 36014/Z (molecular weight <500, log Pow <3) indicate that absorption following oral exposure is likely. However, there is insufficient information available to determine how much of the substance is absorbed. In addition, the OECD toolbox was used to apply Lipinski's Rule of Five. FAT 36014/Z 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 36014/Z has the potential for absorption.


Inhalation route
There is no information available regarding the absorption or toxicity of FAT 36014/Z via inhalation. The vapour pressure of FAT 36014/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 = 181.8 µm, L10D = 19.1 µm) of the test material indicates the presence of inhalable particles. In addition, the test shows that approximately 7.5 % of particles have a particle size of <15 µm and 4.16 % of particles <10 µm. According to REACH endpoint specific guidance (R7c) particles below 15 µm diameter can reach the alveolar region of the respiratory tract where potential dissolution in the alveolar fluid could occur followed by absorption. However, according to other REACH guidance (chapter R.14) respirable particles are regarded as being <10 µm. Therefore, assessment of potential respiration will consider both these limits. Inhalable particles are likely to be cleared from the lungs by the mucociliary escalator and then swallowed making them potentially available for absorption via the GI tract. In conclusion, uptake into the alveoli would be severely limited by the particle size and even if all the respirable particles dissolved and absorbed, overall the uptake of FAT 36014/Z would be expected to be very low via the inhalation route.


Dermal route
There is no information available regarding the absorption or toxicity of FAT 36014/Z following dermal exposure. Dermal absorption is influenced inter alia by water solubility, log Pow and molecular weight. Although the log Pow molecular weight indicates that absorption would be favourable, this has to be considered against the relatively low water solubility of 5.7 mg/L. According to REACH guidance, a water solubility of <1 mg/L indicates a likelihood of low dermal uptake and low to moderate for 1-100 mg/L. On this basis, it is considered that insufficient substance would dissolve in the sweat on skin to facilitate absorption into the skin. In conclusion, dermal absorption for this compound would be expected to be low.
Details on distribution in tissues:
Distribution
There is minimal information available regarding the distribution of FAT 36014/Z. Upon single or repeated oral exposure with the test substance it cannot be ruled out that the dye - at least to a certain extent- is absorbed, possibly metabolised and then distributed either as the parent and/or the metabolites. In slices of different organs taken in course of the repeated dose toxicity study no intense staining of peripheral organs was noted.
Details on excretion:
Excretion
There was no reported discolouration of the faeces. Since the metabolites predicted by the toolbox all have an intact conjugated system, they are also predicted to be yellow in colour. However, the lack of yellow colouration in the faeces does not mean that no biliary excretion has occurred or that all the FAT 36014/Z has been absorbed because the brown colour of the faeces could disguise any yellow colouration. The repeated dose study reported some yellow discolouration of the urine but it was not stated whether this was due to the colour of the test material or unrelated to treatment, for example slight dehydration due to the animal not drinking enough water could cause yellow colouration of urine. Based on the presence of some polar groups in the molecule and the fact that its molecular weight is not much above 300 (cut off for molecules favoured for urinary excretion according to REACH guidance R7c), it is reasonable to expect that urinary excretion would be one of the routes of excretion for this molecule and its metabolites (which have increased polarity due to phase I biotransformations), in addition to the GI tract. In conclusion, excretion is considered possible via biliary duct, GI tract and urine.

Metabolite characterisation studies

Details on metabolites:
Metabolism
The OECD toolbox predicts that the chemical structure will stay intact with some slight chemical modifications introduced mainly by phase I enzymes. Potential metabolites of FAT 36014/Z in the liver and skin were determined by the OECD toolbox. Three metabolites were predicted for the liver metabolism and two metabolites for skin metabolism. No common metabolites where predicted. M4 is a mesomeric resonance structure of the parent, i.e. it is the same as the parent. Since dermal absorption cannot be excluded, the predicted skin metabolites could also be produced. The toolbox predicts that the parent molecule does not get fragmented into smaller units, but rather it undergoes the normal types of phase I and phase 2 biotransformations in the liver and similar transformations in the skin. None of the metabolites were identified by the OECD QSAR application toolbox or by the websites PubChem and ChemSpider.

Toxicologically relevant metabolites
None of the metabolites are considered to have any significant structural alerts for toxicity. M5 and M6 look like mesomeric resonance forms of each other, although it would effectively entail the loss of H2 in order to convert to M6. M6 is essentially a mesomeric resonance form of the parent but with a hydroxyl group present on the aromatic ring. Therefore, it is not expected that the toxicity would be particularly different to the parent. M1, M2 and M3 are structurally very similar to the parent and therefore also would not be expected to have toxicity significantly different to the parent. The parent and metabolites do contain a secondary amine grouping and nitro functional groups. It is known that certain aromatic amines are associated with human carcinogenicity and rat carcinogenicity. Similarly, metabolites with the nitro-functional group can be reduced to an amine either by phase I transformation in the liver or by the action of microflora in the intestine followed by absorption, resulting in the same potential carcinogens. This does not mean that either the parent or the relevant metabolites are carcinogens, but the potential is considered to exist. However, all the metabolites which have phenolic groups present should also be considered potentially more toxic than the parent, 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.

Bioaccessibility (or Bioavailability)

Bioaccessibility (or Bioavailability) testing results:
No data

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 36014 Z.
Executive summary:

No ADME studies are available for FAT 36014/Z. Therefore, the toxicokinetic assessment of FAT 36014/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 36014/Z have been predicted in the absence of toxicokinetic studies.

The observations are:

FAT 36014/Z is expected to be absorbed to some degree via the oral route.

FAT 36014/Z is expected to have very low uptake via the inhalation route.

FAT 36014/Z is expected to have low dermal absorption.

Although there is no evidence of distribution of FAT 36014/Z or its metabolites, it cannot be totally excluded. Metabolism of FAT 36014/Z, as predicted by the OECD toolbox indicates phase I and phase II biotransformations in the liver and similar transformations in the skin, with no fragmentation of the basic structure. The metabolites are predicted to retain relevant functional groups (e.g. nitro, secondary amine) and their toxicity would be expected to the similar to the parent. Metabolites predicted to have a phenolic group could have enhanced toxicity relative to the parent. Excretion is considered possible via biliary duct, GI tract and urine. 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 36014/Z.