2-[(4-chloro-2-nitrophenyl)azo]-N-(2,3-dihydro-2-oxo-1H-benzimidazol-5-yl)-3-oxobutyramide

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics, other

Type of information:

other: Expert statement

Adequacy of study:

other information

Study period:

2020

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. As the size of particles is irrelevant after dissolution into molecules the description of kinetic properties in this chapter is valid for both nano- and bulk-material.

Objective of study:

other: Evaluation of ADME properties of Pigment Orange 36

Qualifier:

no guideline available

GLP compliance:

no

Type:

absorption

Results:

No absorption expected

Type:

distribution

Results:

Due to lack of absorption: no distribution expected

Type:

metabolism

Results:

No metabolism expected in relevant amounts

Type:

excretion

Results:

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

Details on absorption:

A prerequisite for a relevant absorption is that the substance can be dissolved in either aque-ous (e.g., gastrointestinal fluid, blood plasma, sweat) or lipophilic (e.g., lipoproteins, lipid membranes, triglycerides) media or in both. PO 36 can be considered insoluble because it has an extremely low solubility in water and n-octanol. Therefore, it is unlikely that PO 36 be-comes systemically bioavailable after oral, dermal or inhalation exposure.
Based on the sub-acute oral toxicity study with C.I. Pigment Orange 36 absorption of toxi-cologically significant amounts via the gastrointestinal tract is considered unlikely, since C.I. Pigment Orange 36 did not show any effects on inner organs and blood or urine.
The skin sensitisation studies with C.I. Pigment Orange 36 indicate no local dermal bioavail-ability. Systemic availability also seems to be negligible after dermal exposure since no sys-temic signs of intoxication were seen after occlusive administration of 500 mg C.I. Pigment Orange 36 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 phagocyto-sis 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 deliv-ered via this mechanism can be considered negligible.

Details on distribution in tissues:

The Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxici-ty Screening Test with C.I. Pigment Orange 36 did not indicate any relevant histopathologi-cal 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 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 Orange 36 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.

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 metabo-lizing systems in relevant amounts.
The results of the mutagenicity tests provide useful indications for qualitative consideration of the metabolic fate of C.I. Pigment Orange 36. In the mutagenicity tests, the pigment proved to be non-mutagenic in the absence as well as in the presence of an exogenous me-tabolizing 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 histo-pathological changes of organs involved in xenobiotic metabolism, such as the liver, in the Combined Repeated Dose Toxicity Study with the Reproduction/ Develop-mental Toxicity Screening Test with C.I. Pigment Orange 36. Furthermore, the missing skin or eye irritating or skin sensitizing properties argue against any interaction with biological material.
Therefore, C.I. Pigment Orange 36 is considered to just pass through the intestinal tract without significant metabolism.

Bioaccessibility (or Bioavailability) testing results:

There are no indications of bio-accesability of Pigment Orange 36.

Conclusions:

Based on all available data, C.I. Pigment Orange 36 does not exhibit conspicuous toxicoki-netic behaviour in the sense of accumulative and/or delayed effects with regard to the indi-vidual parameters absorption, distribution, metabolism and excretion.
The results from studies with dermal exposure indicate that C.I. Pigment Orange 36 has a no relevant dermal absorptive potential. C.I. Pigment Orange 36 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 tox-icity 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 Orange 36 and/or metabolites.

Executive summary:

Based on the available data base on C.I. Pigment Orange 36 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 substance is available in non-nano- as well as nano-form. The available data have been generated with non-nano material, but the conclusions drawn are considered valid for the nano form as well, because the material is chemically identical and the physical properties are widely overlapping.

 

The results of basic toxicity testing give no reason to anticipate unusual characteristics regarding the toxicokinetics of C.I. Pigment Orange 36. The data indicate that there is no relevant dermal absorption. C.I. Pigment Orange 36 is not absorbed from the gastro-intestinal tract in toxicologically significant amounts. Indications of a bio-accumulative potential as well as metabolism towards genotoxic sub-structures do not exist. Excretion of small amounts of possibly systemically available C.I. Pigment Orange 36 and/or metabolites via faeces is likely.

Description of key information

Based on all available data, C.I. Pigment Orange 36 does not exhibit conspicuous toxicoki-netic behaviour in the sense of accumulative and/or delayed effects with regard to the indi-vidual parameters absorption, distribution, metabolism and excretion.
The results from studies with dermal exposure indicate that C.I. Pigment Orange 36 has a no relevant dermal absorptive potential. C.I. Pigment Orange 36 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 tox-icity 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 Orange 36 and/or metabolites.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential