[1,3-dihydro-5,6-bis[[(2-hydroxy-1-naphthyl)methylene]amino]-2H-benzimidazol-2-onato(2-)-N5,N6,O5,O6]nickel

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics, other

Type of information:

other: expert statement

Adequacy of study:

other information

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Evaluation of available information with regard to toxicokinetic properties

Data source

Reference

Reference Type:

other: Expert statement

Title:

Unnamed

Year:

2018

Report date:

2018

Materials and methods

Objective of study:

toxicokinetics

Test guideline

Qualifier:

no guideline required

Principles of method if other than guideline:

Available data from toxicity studies is evaluated with regard to indications of toxicokinetic properties of the test item.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

[1,3-dihydro-5,6-bis[[(2-hydroxy-1-naphthyl)methylene]amino]-2H-benzimidazol-2-onato(2-)-N5,N6,O5,O6]nickel

EC Number:

255-965-2

EC Name:

[1,3-dihydro-5,6-bis[[(2-hydroxy-1-naphthyl)methylene]amino]-2H-benzimidazol-2-onato(2-)-N5,N6,O5,O6]nickel

Cas Number:

42844-93-9

Molecular formula:

C29H18N4NiO3

IUPAC Name:

Nickel, [1,3-dihydro-5,6-bis[[[2-(hydroxy-kO)-1-naphthalenyl]methylene]amino-kN]-2H-benzimidazol-2-onato(2-)]-, (SP-4-2)-

Test material form:

solid: nanoform

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Based on the subacute (49-day) oral toxicity study absorption of toxicologically significant amounts of Pigment Orange 68 via the gastrointestinal tract has not to be assumed since neither obvious discoloration of inner organs nor any other effects on inner organs was observed throughout the body. There was only discoloration of digestive tract where direct exposure resulted from oral gavage.
Systemic availability seems to be negligible after exposure since no systemic signs of intoxication were seen after administration of 1000 mg Pigment Orange 68 per kg body weight in rats. Indications of a significant dermal absorptive potential were also not revealed by testing for primary irritation in rabbits. The notion of very limited dermal absorption is also corroborated by the very low solubility in water as well as octanol of 12.5 µg/L or less than 200 µg/L, respectively.

Details on distribution in tissues:

Based on the results of the subacute oral toxicity study discolorations were observed in the digestive tract lumen only. Thus, it can be concluded, that Pigment Orange 68 is not absorbed through the gastrointestinal tract and not systemically available within the organism. Histopathological findings indicate no deposition of the pigment in any tissue.
There were no signs of bioaccumulation of the test material. This view is supported by the physical-chemical properties (very low solubility in water and octanol) and the molecular structure.

Details on excretion:

Taking into account the physico-chemical properties and the molecular structure of the pigment and the considerations regarding absorption (above) it can be assumed that only traces of the applied dose will be available for excretion. The main route of excretion would most probably be the liver/bile. Nevertheless, the vast majority of the dose is expected to just pass through the digestive tract without being absorbed. This notion is confirmed by the discoloration of faeces observed in the subacute study.

Metabolite characterisation studies

Metabolites identified:

not measured

Details on metabolites:

Pigment Orange 68 proved to be inactive in the Ames-test with and without exogenous metabolic activation. It was not genotoxic in the HPRT and chromosomal aberration assay in vitro. This indicates that Pigment Orange 68 is not metabolically active. Metabolites, if any are formed, are not more toxic than the parent compound.
No effects were seen in the subacute study except for a discoloration of intestinal contents. No functional or structural impairments were detected. Therefore, Pigment Orange 68 is considered to just pass through the intestinal tract without significant metabolism.

Applicant's summary and conclusion

Conclusions:

Based on all available data, Pigment Orange 68 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 the study with dermal exposure do not indicate that Pigment Orange 68 has a definite dermal absorptive potential. Pigment Orange 68 is not absorbed from the gastrointestinal tract in significant amounts.
Indications of an intense metabolism or a bio-accumulative potential do not exist as no delayed toxicity occurred. Additionally no systemic effects were observed in the subacute oral toxicity study, which also points to no bio-accumulation potential as well as to excretion of any trace of Pigment Orange 68 absorbed.

Executive summary:

Based on the available database on Pigment Orange 68 relevant information exists to make a qualitative evaluation of the toxicokinetic profile of this compound. This is in line with animal welfare considerations because it avoids additional animal tests by such an evaluation.

 

The results of basic toxicity testing give no reason to anticipate unusual characteristics with regard to the toxicokinetics of Pigment Orange 68. The data indicate that there is no relevant oral or dermal absorption. Indications of a bio-accumulative potential as well as a metabolism towards genotoxic sub-structures do not exist. Excretion of systemically available traces of Pigment Orange 68 and/or potential metabolites via the bile can be assumed.