N-(4-ethoxyphenyl)-3-hydroxy-4-[(2,4,5-trichlorophenyl)azo]naphthalene-2-carboxamide

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics, other

Type of information:

other: Expert statement

Adequacy of study:

weight of evidence

Study period:

2018

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Evaluation of existing data with regard to toxikokinetics

Data source

Reference

Reference Type:

other company data

Title:

Unnamed

Year:

2018

Report date:

2018

Materials and methods

Objective of study:

absorption

bioaccessibility (or bioavailability)

distribution

excretion

metabolism

Test guideline

Qualifier:

no guideline available

Principles of method if other than guideline:

Evaluation of all available information with regard to toxicokinetic properties of the tst material.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Pigment-Additive FGR

IUPAC Name:

Pigment-Additive FGR

Constituent 2

Reference substance name:

N-(4-ethoxyphenyl)-3-hydroxy-4-[(2,4,5-trichlorophenyl)azo]naphthalene-2-carboxamide

EC Number:

225-691-8

EC Name:

N-(4-ethoxyphenyl)-3-hydroxy-4-[(2,4,5-trichlorophenyl)azo]naphthalene-2-carboxamide

Cas Number:

5012-29-3

Molecular formula:

C25H18Cl3N3O3

IUPAC Name:

N-(4-ethoxyphenyl)-3-hydroxy-4-[(2,4,5-trichlorophenyl)diazenyl]-2-naphthamide

Test material form:

solid: particulate/powder

Remarks:

migrated information: powder

Details on test material:

Information as provided by the Sponsor. A Certificate of Analysis supplied by the Sponsor is given in Annex 1 (see attachment 1).
Identification: Pigment-Additive FGR
Batch: FB3212.013
CAS-No.: 5012-29-3
EINECS/EC-No.: 225-691-8
Purity: 94.51% (w/w)
Physical state/Appearance: red brown powder (Sponsor description)
brown solid (Envigo description)
Expiry Date: 10 May 2020
Storage Conditions: At room temperature (provided by the sponsor)
Stability in Solvent: >72h in DMSO and 1.2-propylene glycol at room temperature
Certificate of Analysis: AZ 577/Toxd2, dated 11 December 2015
Purpose of Use: Chemical

Results and discussion

Main ADME results

Main ADME results 1

Type:

absorption

Results:

No absorption expected

Main ADME results 2

Type:

distribution

Results:

No distribution expected

Main ADME results 3

Type:

metabolism

Results:

No metabolism expected

Main ADME results 4

Type:

other: Bio-accumulation

Results:

No bio-accumulation expected

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 mem-branes, triglycerides) media or in both. Pigment Additive FGR can be considered insoluble because it has an extremely low solubility in water and n-octanol. Therefore, it is unlikely that Pigment Additive FGR becomes systemically bioavailable after oral, dermal or inhalation ex-posure.
Based on the sub-acute oral toxicity study with the close analogue C.I. Pigment Red 170 ab-sorption of toxicologically significant amounts of Pigment Additive FGR via the gastrointes-tinal tract is considered unlikely, since C.I. Pigment Red 170 did not show any effects on inner organs and blood or urine.
The skin sensitisation as well as the acute dermal study (with the close analogue C.I. Pigment Red 170) indicate no local dermal bioavailability. Systemic availability also seems to be neg-ligible after dermal exposure since no systemic signs of intoxication were seen after occlusive administration of 2000 mg Pigment Red 170 per kg body weight in rats in the acute dermal toxicity study.
Dermal absorption, therefore, is 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:

close analogue C.I. Pigment Red 170 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 systemi-cally available. There were also no other signs of deposition of the pigment in any organ in-cluding 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 Pigment Additive FGR is not systemically available at relevant con-centrations 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:

Taking into account the physico-chemical properties and the molecular structure of the mate-rial and the absence of any indication of absorption and/or metabolism it is assumed that ex-cretion, 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

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 Pigment Additive FGR and the close analogue C.I. Pigment Red 170. In the mutagenicity tests, the pigments 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 xenobi-otic metabolism, such as the liver, in the Repeated Dose Toxicity Study and tie Reproduc-tion Toxicity Screening Test with the close analogue C.I. Pigment Red 170. Furthermore, 44 the missing skin or eye irritating or skin sensitizing properties argue against any interaction with biological material.
Therefore, Pigment Additive FGR is considered to just pass through the intestinal tract without significant metabolism.

Bioaccessibility (or Bioavailability)

Bioaccessibility (or Bioavailability) testing results:

see above: distribution

Applicant's summary and conclusion

Conclusions:

Based on all available data, Pigment Additive FGR does not exhibit conspicuous toxico-ki-netic behaviour in the sense of accumulative and/or delayed effects with regard to the individ-ual parameters absorption, distribution, metabolism and excretion.
The results from studies with dermal exposure indicate that Pigment Additive FGR has a no relevant dermal absorptive potential. Pigment Additive FGR 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 bioaccumulation potential and to complete excretion of all possibly avail-able Pigment Additive FGR and/or metabolites.

Executive summary:

Based on all available data, Pigment Additive FGR does not exhibit conspicuous toxico-ki-netic behaviour in the sense of accumulative and/or delayed effects with regard to the individ-ual parameters absorption, distribution, metabolism and excretion.

The results from studies with dermal exposure indicate that Pigment Additive FGR has a no relevant dermal absorptive potential. Pigment Additive FGR 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 bioaccumulation potential and to complete excretion of all possibly avail-able Pigment Additive FGR and/or metabolites.