N-(4-chloro-2,5-dimethoxyphenyl)-3-hydroxy-4-[(E)-2-[2-methoxy-5-(phenylcarbamoyl)phenyl]diazen-1-yl]naphthalene-2-carboxamide; N-(5-chloro-2-methylphenyl)-3-hydroxy-4-[(E)-2-[2-methoxy-5-(phenylcarbamoyl)phenyl]diazen-1-yl]naphthalene-2-carboxamide

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics, other

Type of information:

other: Expert statement

Adequacy of study:

other information

Study period:

2021

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Evaluation of all available evidence for indications of toxicokinetic behavior

Justification for type of information:

According to the REACH-regulation all available information should be evaluated without requiring specific studies.

Data source

Reference

Reference Type:

other company data

Title:

Unnamed

Year:

2021

Report date:

2021

Materials and methods

Objective of study:

other: Evaluation of ADME properties of Pigment Red 184

Test guideline

Qualifier:

no guideline available

GLP compliance:

no

Results and discussion

Main ADME results

Main ADME results 1

Type:

absorption

Results:

No absorption expected

Main ADME results 2

Type:

distribution

Results:

Due to lack of absorption: no distribution expected

Main ADME results 3

Type:

metabolism

Results:

No metabolism expected in relevant amounts

Main ADME results 4

Type:

excretion

Results:

All of substance is expected to move through the intestinal tract unchanged

Toxicokinetic / pharmacokinetic studies

Details on absorption:

A prerequisite for a relevant absorption is that the substance can be dissolved in either aqueous (e.g., gastrointestinal fluid, blood plasma, sweat) or lipophilic (e.g., lipoproteins, lipid membranes, triglycerides) media or in both. PR184 can be considered insoluble because it has an extremely low solubility in water and n-octanol. Therefore, it is unlikely that PR184 becomes systemically bioavailable after oral, dermal or inhalation exposure.
Based on the sub-acute oral toxicity study with C.I. Pigment Red 112 absorption of toxicologically significant amounts via the gastrointestinal tract is considered unlikely, since C.I. Pigment Red 112 did not show any effects on inner organs and blood or urine.
The skin sensitisation studies with C.I. Pigment Red 184 indicate no local dermal bioavailability. Systemic availability also seems to be negligible after dermal exposure since no systemic signs of intoxication were seen after occlusive administration of 500 mg C.I. Pigment Red 184 per kg body weight in rabbits in the acute dermal irritation study.
Dermal absorption is, therefore, considered unlikely
In the unlikely event of exposure to aerosolized pigment in respirable form, the substance is considered to behave like an inert dust. Therefore, the deposited pigment particles will mostly be cleared from the lung via the mucocilliary transport. As the pigment will not dis-solve in the lung surfactant, the only way the pigment can enter the body is via phagocytosis of pigment particles by lung macrophages followed by migration of the macrophages into the interstitium and into the draining lymph nodes. However, the internal dose delivered via this mechanism can be considered negligible.

Details on distribution in tissues:

The Repeated Dose Toxicity Studies with C.I. Pigment Red 112 did not indicate any relevant histopathological changes in any of the investigated organs. This may indicate that the pigment either does not affect special organs as targets, i.e., is non-toxic, or is not distributed within the body in significant amounts. As indicated above, the physicochemical parameters of the pigment support the conclusion that the pigment is not absorbed into the body and thus does not become systemically available. There were also no other signs of deposition of the pigment in any organ including excretory organs, like the kidney, indicating that even exposure to high doses of the pigment does not lead to bioaccumulation in special compartments of the body.
Based on the available information on absorption distribution of the test material in the body in significant amounts is unlikely and specific hotspots of distribution cannot be identified.
Thus, it is concluded, that C.I. Pigment Red 184 is not systemically available at relevant concentrations within the organism.
There were no signs of bioaccumulation of the test material. This view is supported by the physical-chemical properties (solubility in water and octanol).

Details on excretion:

Considering the physico-chemical properties and the molecular structure and size of the material and the absence of any indication of absorption and/or metabolism it is assumed that excretion, if any, is likely to occur via faeces. This notion is confirmed by the discoloration of faeces observed in the subacute study as the only alteration.

Metabolite characterisation studies

Metabolites identified:

no

Remarks:

Since the solution of the substance in cellular fluid or cellular membranes is a prerequisite for its metabolism, it is unlikely that the insoluble pigment becomes accessible for metabo-lizing systems in relevant amounts. The results of the mutagenicity

Details on metabolites:

Since the solution of the substance in cellular fluid or cellular membranes is a prerequisite for its metabolism, it is unlikely that the insoluble pigment becomes accessible for metabolizing systems in relevant amounts.
The results of the mutagenicity tests provide useful indications for qualitative consideration of the metabolic fate of C.I. Pigment Red 184. In the mutagenicity tests, the pigment proved to be non-mutagenic in the absence as well as in the presence of an exogenous metabolizing system, indicating that the pigments are not converted into toxic or genotoxic metabolites. This conclusion is also supported by the lack of any morphological and histopathological changes of organs involved in xenobiotic metabolism, such as the liver, in the Repeated Dose Toxicity Studies with C.I. Pigment Red 112. Furthermore, the missing skin or eye irritating or skin sensitizing properties argue against any interaction with biological material.
Therefore, C.I. Pigment Red 184 is considered to just pass through the intestinal tract without significant metabolism.

Bioaccessibility (or Bioavailability)

Bioaccessibility (or Bioavailability) testing results:

There are no indications of bio-accessibility of Pigment Red 184

Applicant's summary and conclusion

Conclusions:

Based on all available data, C.I. Pigment Red 184 does not exhibit conspicuous toxicokinetic behaviour in the sense of accumulative and/or delayed effects with regard to the individual parameters absorption, distribution, metabolism and excretion.
The results from studies with dermal exposure indicate that C.I. Pigment Red 184 has a no relevant dermal absorptive potential. C.I. Pigment Red 184 is most probably not absorbed from the gastrointestinal tract in significant amounts.
Indications of an intense metabolism or a bio-accumulative potential do not exist as no toxicity occurred. Additionally, no systemic effects were observed in the subacute oral toxicity study, which points to no bio-accumulation potential and complete excretion of all possibly available C.I. Pigment Red 184 and/or metabolites.

Executive summary:

Based on the available data for C.I. Pigment Red 184 relevant information exists to make a qualitative evaluation of the toxicokinetic profile of this compound. This is in line with animal welfare considerations because additional animal tests can be avoided by such an evaluation.