N-(2,3-dihydro-2-oxo-1H-benzimidazol-5-yl)-3-hydroxy-4-[[2-methoxy-5-methyl-4-[(methylamino)sulphonyl]phenyl]azo]naphthalene-2-carboxamide

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics, other

Type of information:

other: Expert statement

Adequacy of study:

key study

Study period:

2021

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Evalation 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 185

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. PR 185 can be considered insoluble because it has an extremely low solubility in water and n-octanol (3.4 µg/L and 21.6 µg/L, respectively). Therefore, it is unlikely that PR 185 becomes systemically bioavailable after oral, dermal or inhalation exposure.

Based on the sub-acute oral toxicity study with read-across source substance C.I. Pigment Red 176, absorption of toxicologically significant amounts via the gastrointestinal tract is considered unlikely, since C.I. Pigment Red 176 did not show any effects on inner organs and blood or urine.
The skin sensitisation study with C.I. Pigment Red 185 as well as that with the read-across source substances C.I. Pigment Red 176 and C.I. Pigment Brown 25 indicate no local dermal bioavailability.

Systemic availability also seems to be negligible after dermal exposure since no systemic signs of intoxication were seen after administration of 2000 mg of the read-across source substance C.I. Pigment Brown 25 per kg body weight to rabbit skin in the acute dermal toxicity 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 dissolve 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 28-d oral toxicity study and the Reproduction/Developmental Toxicity Screening Test with read-across source substance C.I. Pigment Red 176 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. Likewise, pathological and histopathological changes were also not observed in an older and albeit incompletely documented 18-d Repeated Dose toxicity study on C.I. Pigment Red 185 itself. As indicated above, the physico-chemical parameters of the pigment support the conclusion that the pigment is not absorbed into the body and thus does not be-come 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 185 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.

Metabolite characterisation studies

Metabolites identified:

no

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 185. 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 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 28d-Repeated Dose Toxicity Study with C.I. Pigment Red 176 and in the incompletely documented 18d-Repeated Dose toxicity study on C.I. Pigment Red 185. Furthermore, the missing skin or eye irritating or skin sensitizing properties argue against any interaction with biological material.
Therefore, C.I. Pigment Red 185 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-accesability of Pigment Red 185.

Applicant's summary and conclusion

Conclusions:

Based on all available data, C.I. Pigment Red 185 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. C.I. Pigment Red 185 is most probably not absorbed from the gastrointestinal tract in significant amounts, nor is it absorbed following dermal administration.

Executive summary:

Based on the available database on C.I. Pigment Red 185 and the read-across source substances C.I. Pigment Red 176 and C.I. Pigment Brown 25, 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.

The physico-chemical parameters of C.I. Pigment Red 185, and in particular its very low solubility in both water and octanol, indicate that the substance will not be absorbed via the dermal or the oral route. The absence of all toxicological and histopathological effects in the available study reports further substantiates this finding. In the absence of absorption of PR 185, distribution and metabolism of are not expected to occur. Any PR 185 that enters the body via the gastro-intestinal tract is expected to be excreted unchanged in the faeces.