N,N'-(2-(4-(2-aminobenzamido)butyl)pentane-1,5-diyl)bis(2-aminobenzamide)

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics, other

Type of information:

other: Expert review and assessment

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Not assignable as the result is from expert assessment

Materials and methods

Objective of study:

other: Basic toxicokinetic assessment to support REACH Annex VIII registration

Test guideline

Qualifier:

no guideline required

Principles of method if other than guideline:

Expert review of available data.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

2-amino-N-{6-[(2-aminophenyl)formamido]-2-{3-[(2-aminophenyl)formamido]propyl}hexyl}benzamide

EC Number:

951-985-7

Molecular formula:

C30H38N6O3

IUPAC Name:

2-amino-N-{6-[(2-aminophenyl)formamido]-2-{3-[(2-aminophenyl)formamido]propyl}hexyl}benzamide

Test material form:

solid: crystalline

Administration / exposure

Details on exposure:

Expert assessment of available data.

Results and discussion

Any other information on results incl. tables

INFORMATION BASED ON PHYSICO-CHEMICAL PROPERTIES

N,N'-(2-(4-(2-aminobenzamido)butyl)pentane-1,5-diyl)bis(2-aminobenzamide) is a benzamide derivative with a molecular weight of 530.66. It is a solid at room temperature and on heating decomposes from approximately 130°C. The substance is for practical purposes insoluble in water with a water solubility of 0.00396 g/l at 20 °C and ca. pH7, while its partition coefficient is 281,  log10 Pow is 2.45.  Based on its Log10 Pow it can be expected that the substance will show solubility in lipids. 

 

 In its solid form the substance is a crystalline powder. Particle size analysis found that the percentage of test item having an inhalable particle size of less than 100 µm was 1.07%. The substance is therefore considered to be essentially non-inhalable.

 

The substance hydrolyses at pH 4 with an estimated half-life of 16.3 hours at 25°C.  However, at pH 7 and pH 9 no hydrolysis was observed so the estimated half-life at these pH values is considered to be > 1 year.   

 

ABSORPTION, DISTRIBUTION AND EXCRETION

 

Potential for Absorption

 

N,N'-(2-(4-(2-aminobenzamido)butyl)pentane-1,5-diyl)bis(2-aminobenzamide) in solid form contains only 1.07% particles of a size that could be classed as inhalable (respirable) following exposure to airborne dusts. Therefore, little of an inhaled dose can be expected to reach the alveoli and most of the dose can be expected to be transferred to the stomach via mucociliary action and swallowing.

 

The substance has a log Pow value of 2.45 and therefore the non-ionised form is likely to have sufficient lipid solubility to pass across biological membranes, including the gastrointestinal mucosa although its relatively large molecular size may present some barrier to absorption.  Its low water solubility may also impede its solubilisation and hence bioavailability for transport across the gastrointestinal mucosa, as the insoluble form may be more likely to pass unabsorbed through the gut until it is excreted.

 

It is unlikely that active transport mechanisms will be a significant uptake route due to a lack of similarity with endogenous molecules.

 

Overall, it can be expected that absorption of the intact molecule across the gastrointestinal mucosa will occur, but a proportion of an oral dose is likely to not be absorbed and subsequently be excreted in the faeces.

 

Evidence for Absorption -acute studies

 

Oral

An acute oral toxicity study conducted at 2000 mg/kg body weight on the substance showed no test substance related effects. 

 

Dermal

There is no information on which to assess with certainty if the substance can be absorbed significantly via dermal exposure. Nor acute dermal toxicity study was conducted on the substance as the study requirement was waivered because skin contact in use is not likely.  Given its expected high lipid solubility, it is conceivable that a dermal absorption could occur, although its relatively high molecular weight may slow dermal update.

 

Inhalation

An acute inhalation study has been conducted on the substance at a concentration of 5 mg/L.  Although on day 2 following exposure body weight loss was observed.  Body weight gain recovered during the study and the reduction at day 2 was considered to be a consequence of the exposure (duration and removal of food and water) and therefore not test-item related. No other test substance effects were observed. Given the substance is essentially non-inhalable as outlined in the physicochemical profile section, the lack of effects in the inhalation study is not unexpected given that absorption via the inhalation route is considered unlikely.

 

In conclusion, it is not possible to definitely conclude whether absorption of N,N'-(2-(4-(2-aminobenzamido)butyl)pentane-1,5-diyl)bis(2-aminobenzamide) following acute exposure could occur based on available acute studies.   However, data available indicates that absorption  following acute exposure is probably very limited.

 

Evidence for Absorption - repeated dose

 

Repeated Dose Study

An oral repeated dose reproductive developmental toxicity screening study (OECD 422) has been conducted on the substance using doses of 500, 750 and 1000 mg/kg/bw/day. There were some toxicological effects on the adrenal glands and increases in thyroid organ weights indicating that the substance is absorbed to some degree and it, or its metabolites were at a sufficient concentration to exert effects.

 

In conclusion, following repeat oral exposure there is clear evidence that the substance is absorbed given effects seen in adrenal and thyroid glands.

 

DISTRIBUTION

 

It is unlikely that N,N'-(2-(4-(2-aminobenzamido)butyl)pentane-1,5-diyl)bis(2-aminobenzamide) will exhibit any significant distribution preferences within the body between plasma and tissues as its log P value (2.45) although indicating affinity for fats, is below the value (Log Pow >4) at which accumulation in fats and lipids is considered to be a potential concern.  

 

In the OECD 422 study effects were seen in parental thyroid and adrenal glands and also in thyroid glands of offspring indicating that the substance targets the endocrine system and hence it must be distributed to organs in this system.  The observations of effects in offspring indicate that the substance can cross the placenta allowing foetal exposure to the substance.

 

METABOLISM

 

As a water insoluble compound N,N'-(2-(4-(2-aminobenzamido)butyl)pentane-1,5-diyl)bis(2-aminobenzamide is most likely to be metabolised by the cytochrome P450 enzyme metabolising system to water soluble metabolites which can be excreted. It contains amine groups (primary - NH2 and secondary – NH) which are likely to undergo oxidation by amine oxidase enzymes which are widely distributed throughout the body. 

 

An in vitro bacterial reverse mutation assay using S. typhimurium and E. coli, an in vitro mouse lymphoma test and a in vitro Micronucleus test have been conducted on, N,N'-(2-(4-(2-aminobenzamido)butyl)pentane-1,5-diyl)bis(2-aminobenzamide).  These studies gave negative results in both the presence and absence of an S9 metabolising system. Given the negative results, no conclusions about the potential of the substance to undergo metabolic change can be drawn from the studies.

 

EXCRETION

 

 N,N'-(2-(4-(2-aminobenzamido)butyl)pentane-1,5-diyl)bis(2-aminobenzamide) is water insoluble and contains no water solubilising groups. Consequently, the kidneys are unlikely to be a significant route of excretion of the substance itself.

 

The molecular weight of the substance at 530.66 is above the biliary exclusion limit of circa 325 in the rat and 500 in humans and therefore elimination of a certain proportion any absorbed substance and/or its metabolites via the bile could be anticipated. 

 

Overall the most likely route of excretion from the body is by water soluble metabolites following metabolism of the parent compound.