1,1'-{(phenylmethanediyl)bis[(3-substituted benzene-4,1-diyl)diazene-2,1-diyl{1-[3-(dimethylamino)propyl]-2-hydroxy-4-methyl-6-oxo-1,6-dihydropyridine-5,3-diyl}]}dipyridinium chloride lactate salts

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

other: expert statement

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Well documented expert statement from an internationally recognized contract research organization. The expert statement has been based on a series of physicochemical and toxicology studies performed according to technical guidelines and in compliance with GLP in internationally recognized contract research organizations.

Cross-reference

Cross-reference 1

Reason / purpose for cross-reference:

reference to same study

Cross-reference 2

Reason / purpose for cross-reference:

reference to other study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2009

Report date:

2009

Materials and methods

Objective of study:

absorption

distribution

excretion

Test guideline

Qualifier:

no guideline required

Principles of method if other than guideline:

Expert statement based on a series of physicochemical and toxicology studies. Technical guidelines followed in these experimental studies are cited in the respective endpoint study records.

GLP compliance:

no

Remarks:

Considered unnecessary fo expert statement

Test material

Reference

Name:

Unnamed

Type:

Constituent

Radiolabelling:

no

Test animals

Species:

other: Detailed in endpoint study records of in-vivo studies referred to in the present expert statement

Strain:

other: Detailed in endpoint study records of in-vivo studies referred to in the present expert statement

Sex:

male/female

Details on test animals or test system and environmental conditions:

Detailed in the endpoint study records of in-vivo studies referred to in the present expert statement.

Administration / exposure

Route of administration:

other: Detailed in endpoint study records of in-vivo studies referred to in the present expert statement

Vehicle:

other: Detailed in endpoint study records of in-vivo studies referred to in the present expert statement, if appropriate

Details on exposure:

Detailed in endpoint study records of in-vivo studies referred to in the present expert statement.

Duration and frequency of treatment / exposure:

Detailed in endpoint study records referred to in the present expert statement.

Doses / concentrations

Remarks:

Doses / Concentrations:
Detailed in endpoint study records of in-vivo studies referred to in the present expert statement.

No. of animals per sex per dose / concentration:

Detailed in endpoint study records of in-vivo studies referred to in the present expert statement.

Control animals:

other: Detailed in endpoint study records referred to in the present expert statement, if applicable

Positive control reference chemical:

Detailed in endpoint study records referred to in the present expert statement, if applicable

Details on study design:

Detailed in endpoint study records referred to in the present expert statement, if applicable

Details on dosing and sampling:

Detailed in endpoint study records referred to in the present expert statement, if applicable

Statistics:

Detailed in endpoint study records referred to in the present expert statement, if applicable. Not applicable for the present expert statement.

Results and discussion

Preliminary studies:

Not applicable

Toxicokinetic / pharmacokinetic studies

Details on absorption:

After oral administration, the hydrophylic character of the test substance (log Pow -2.04) will limit passive diffusion in the gastrointestinal tract and although the water solubility is high (>1000 g/L), the large molecular weight (933 as free base) will prevent passage through the aqueous pores. Furthermore, the ionization of the test substance will impair the uptake since compounds need to pass the lipid membranes in the gastrointestinal wall. It is therefore unlikely that Orange the test substance will be absorbed to a high extent from the gastrointestinal tract. For risk assessment purposes the oral absorption of the test substance is set at 10%. The results of the toxicity studies do not provide reasons to deviate from this proposed oral absorption factor, as orange staining of the faeces is noted whereas orange contents of the stomach/jejenum and orange discolouration of the glandular mucosa of the stomach is noted only in animals sacrified prior to scheduled termination. Orange staining of organs/tissue was absent among surviving animals at scheduled sacrifice after overnight fasting.

Based on the particle size of the test substance, particles < 100 μm which have a potential to be inhaled, are present. Particles will predominantly settle in the nasopharyngeal region (particles with aerodynamic diameter > 10 μm), while those reaching the tracheobronchial or pulmonary region will be limited (6.17% < 10 μm and 0.47% < 4 μm). Based on the high water solubility, the test substance has the potential to diffuse readily into the mucus lining of the respiratory tract. Log Pow, molecular weight and ionization lower the potential for absorption. Therefore, for risk assessment purposes inhalatory absorption is expected to be less than the standard 100% and is set at 50%.

Details on distribution in tissues:

The azo bond might be reduced by intestinal microflora (1). The high molecular weight, high water solubility and low log Pow are not favourable for distribution of the test substance into organs and tissue after absorption. This corresponds with the observed absence of orange staining of organs and tissue in rats fasted overnight after oral administration of the test substance over 28 days. Only in non-fasted animals the contents of stomach/jejenum and glandular mucosa of the stomach were stained .
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1: A. Parkinson. In: Casarett and Doull’s Toxicology, The basic science of poisons. Sixth edition. Ed. C.D. Klaassen. Chapter 6: Biotransformation of xenobiotics. McGraw-Hill, New York, 2001.

Details on excretion:

The high molecular weight of the test substance is not favourable for urinary excretion. In the repeated dose toxicity study, excretion via faeces was observed by orange staining of the faeces.

Metabolite characterisation studies

Metabolites identified:

not specified

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): other: No bioaccumulation potential. Conclusion of submitter from the present expert statement.