Chromate(2-), [2,4-dihydro-4-[(2-hydroxy-4-nitrophenyl)azo]-5-methyl-2-phenyl-3H-pyrazol-3-onato(2-)][3-[(4,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl)azo]-2-hydroxy-5-nitrobenzenesulfonato(3-)]-, disodium

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics

Type of information:

other: Expert statement

Adequacy of study:

key study

Study period:

2014

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

test procedure in accordance with national standard methods

Objective of study:

toxicokinetics

Qualifier:

no guideline required

Principles of method if other than guideline:

No ADME studies are available for FAT 20060/F. Therefore, the toxicokinetic assessment of FAT 20060/F 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:

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 effects were observed indicating all or part of the molecule has been absorbed. The data in the study also clearly shows a dose-response effect for red colouration of tissues/organs from low dose to high dose, and there is an absence of this red colour reported in the controls. Slight acute toxicity of FAT 20060/F was also observed in the acute oral toxicity study.

The OECD QSAR application toolbox was used to apply Lipinski's Rule of Five. FAT 20060/F was predicted to be not 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) biotransformation 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. The tool also predicted all metabolites would be non-bioavailable. In conclusion, it is clear from the repeated dose toxicity study that absorption of FAT 20060/F (or possibly one or more of its predicted metabolites, also expected to be red) must have occurred.

Inhalation route:
There is no information available regarding the absorption or toxicity of FAT 20060/F via inhalation. The vapour pressure of FAT 20060/F 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 = 20.3 µm, L10D = 5.1 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. Since 23 % of particles are below the lower limit of 10 µm, there is potential for particles of FAT 20060/F to reach the alveoli, where dissolution and absorption could occur. 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 20060 F into the alveolar is expected to be relatively low but any particles that reach the alveoli would be expected to be absorbed to a relatively high degree based on absorption via oral route.

Dermal route:
There is no information available regarding the absorption or toxicity of FAT 20060/F 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 water solubility (100-10000 mg/L) and log Pow (>1, <4) of FAT 20060/F favours dermal absorption, but the molecular weight above 500 reduces the likelihood. However, the REACH guidance on dermal absorption only allows a reduction from 100 % absorption to 10 % if molecular weight is >500 and log P is <1 or >4. In this case, only one of these criteria is met. Therefore, there is considered to be potential for some dermal absorption, but given a molecular weight over 800, any dermal absorption is likely to be low.

Details on distribution in tissues:

In the repeated dose oral toxicity study report, macroscopic examination indicated that most of the organs studied in many of the animals were discoloured red and there was clearly a dose-response effect for this red colouration, especially at the highest dose, and the controls also did not exhibit this effect. This indicates that FAT 20060/F 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 were stained a red colour. This indicates several possibilities; either the molecule was absorbed then passed through the biliary duct as unmetabolised parent or the red colour could be due to both unabsorbed parent and excreted parent/metabolite(s). Certainly, the molecular weight of the coloured metabolites is much higher than 300 and this increases the likelihood of excretion via the biliary duct rather than via urine, which is supported by the lack of any red colouration in the urine. In summary, excretion of FAT 20060/F and any of its predicted metabolites is expected via bile and the GI tract, but not via urine.

Details on metabolites:

Potential metabolites of FAT 20060/F in the liver and skin have been predicted using the OECD Toolbox. Fifteen metabolites were predicted for liver metabolism (1 is predicted to be bioavailable and 14 are predicted to be not bioavailable) and four metabolites for skin metabolism (1 is bioavailable and 3 not bioavailable). Two metabolites were common in both liver and skin. The OECD Toolbox has predicted that FAT 20060/F is likely to undergo at least phase I biotransformations (hydroxylations, nitrations and reductions) which would increase the water solubility even further. However, there is no evidence to indicate whether the molecule undergoes metabolism elsewhere in the body following passage through the liver. None of the metabolites were identified by the OECD QSAR application toolbox or by the websites PubChem and ChemSpider.

Toxicologically relevant metabolites:
Where there are no structural alerts and the metabolites are similar to the parent, it is expected that the toxicity will be similar to the parent.

Aromatic amines and aromatic nitro metabolites:
For metabolites where an aromatic amine is part of the structure, enhanced toxicity compared to the parent, cannot be excluded. 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 these metabolites are carcinogens, but the potential is considered to exist.

Phenolic metabolites:
All the metabolites which have phenolic groups present should be considered as potentially more toxic than the parent, due to oxidation of phenols to 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.

Conclusions:

FAT 20060/F is expected to be absorbed to some extent via oral route, while on dermal and inhalation exposure, the absorption is expected to be low. FAT 20060/F and/or its predicted metabolites are widely distributed throughout the body, as indicated by red colouration of organs and tissue. Excretion of FAT 20060/F and any of its predicted metabolites is expected via bile and the GI tract, but not via urine.

Executive summary:

The absorption, distribution, metabolism and excretion of FAT 20060/F have been predicted in the absence of toxicokinetic studies. FAT 20060/ F is absorbed to some extent via the oral route, based on red colouration of tissues/organs. Substance uptake via inhalation is expected to be low. FAT 20060/F is expected to have low dermal absorption. FAT 20060 F and/or its predicted metabolites are widely distributed throughout the body, as indicated by red colouration of organs and tissue. The OECD toolbox predicts that FAT 20060/F will undergo typical phase I biotransformations but these transformations do not lead to fragmentation of the molecule. Some of the predicted metabolites have the potential to be more toxic than the parent. Excretion of FAT 20060/F and any of its predicted metabolites is expected via bile and the GI tract, but not via urine.  

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 20060/F. Therefore, the toxicokinetic assessment of FAT 20060/F 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 20060 F have been predicted in the absence of toxicokinetic studies. FAT 20060/F is absorbed to some extent via the oral route, based on red colouration of tissues/organs. FAT 20060/F uptake via inhalation is expected to be low. FAT 20060/F is expected to have low dermal absorption. FAT 20060/F and/or its predicted metabolites are widely distributed throughout the body, as indicated by red colouration of organs and tissue. The OECD toolbox predicts that FAT 20060/F will undergo typical phase I biotransformations but these transformations do not lead to fragmentation of the molecule. Some of the predicted metabolites have the potential to be more toxic than the parent. Excretion of FAT 20060/F and any of its predicted metabolites is expected via bile and the GI tract, but not via urine.