N,N'-naphthalene-1,5-diylbis[4-[(2,3-dichlorophenyl)azo]-3-hydroxynaphthalene-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)

Data source

Reference

Reference Type:

other company data

Title:

Unnamed

Year:

2023

Report date:

2023

Materials and methods

Objective of study:

absorption

distribution

metabolism

toxicokinetics

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

N,N'-naphthalene-1,5-diylbis[4-[(2,3-dichlorophenyl)azo]-3-hydroxynaphthalene-2-carboxamide]

EC Number:

271-178-7

EC Name:

N,N'-naphthalene-1,5-diylbis[4-[(2,3-dichlorophenyl)azo]-3-hydroxynaphthalene-2-carboxamide]

Cas Number:

68516-75-6

Molecular formula:

C44H26Cl4N6O4

IUPAC Name:

N,N'-naphthalene-1,5-diylbis{4-[(2,3-dichlorophenyl)diazenyl]-3-hydroxy-2-naphthamide}

Test material form:

solid: nanoform, no surface treatment

Results and discussion

Main ADME results

Main ADME results 1

Type:

absorption

Results:

See Summary and discussion of toxicokinetics

Main ADME results 2

Type:

distribution

Results:

See Summary and discussion of toxicokinetics

Main ADME results 3

Type:

metabolism

Results:

See Summary and discussion of toxicokinetics

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. PB 41 can be considered insoluble because it has an extremely low solubility in water and n-octanol. Therefore, it is unlikely that PB 41 be-comes systemically bioavailable after oral, dermal or inhalation exposure.
Based on the sub-acute oral toxicity study with the close analogue C.I. Pigment Red 220 and the reproductive toxicity screening in C.I. Pigment Brown 41 absorption of toxicologically significant amounts of C.I. Pigment Brown 41 via the gastrointestinal tract is considered unlikely, since both Pigments did not show any effects on inner organs and blood or urine.
The skin sensitisation studies with the close analogues C.I. Pigment Red 144 and 242 indicate no local dermal bioavailability. This is supported by the acute dermal toxicity testing of C.I. Pigment Red 144, in which no mortality and no clinical symptoms was observed after dermal application in rabbits up to 2000 mg/kg bw. 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 166 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. This is supported by the subacute inhalation toxicity study in rats dosed with C.I. Pigment Brown 41 up to 0.03 mg/L air for 6 hours, 5 days per week revealed no compound-related toxicity. However, the internal dose delivered 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 the close analogue C.I. Pigment Red 220 and the Reproduc-tion/Developmental Toxicity Screening Test with C.I. Pigment Brown 41 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 physico-chemical 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 Brown 41 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).

Details on excretion:

Taking into account the physico-chemical properties, the molecular structure 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 reproductive toxicity study as the only alteration.

Metabolite characterisation studies

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 and genotoxicity tests provide useful indications for qualita-tive consideration of the metabolic fate of Pigment Brown 41. In the mutagenicity tests, the pigment proved to be non-mutagenic in the absence as well as in the presence of an exoge-nous metabolizing system, indicating that the pigment is not converted into toxic or geno-toxic 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 Combined Repeated Dose Toxicity Study with the Reproduction/ Develop-mental Tox-icity Screening Test with the close analogue C.I. Pigment Red 220. Furthermore, the miss-ing skin or eye irritating or skin sensitizing properties argue against any interaction with biological material.
Therefore, C.I. Pigment Brown 41 is considered to just pass through the intestinal tract with-out significant metabolism.

Applicant's summary and conclusion

Conclusions:

Based on all available data, C.I. Pigment Brown 41 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 Brown 41 has a no relevant dermal absorptive potential. C.I. Pigment Brown 41 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 and reproduction toxicity study, which points to no bio-accumulation potential and complete to excretion of all possibly available C.I. Pigment Brown 41 and/or metabolites.

Executive summary:

Based on the available data base on C.I. Pigment Brown 41 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 results of basic toxicity testing give no reason to anticipate unusual characteristics with regard to the toxicokinetics of C.I. Pigment Brown 41. The data indicate that there is no relevant dermal absorption. C.I. Pigment Brown 41 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 Brown 41 and/or metabolites via faeces is likely.