Anthranilamide

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.

Data source

Reference

Reference Type:

other company data

Title:

Unnamed

Year:

2017

Report date:

2017

Materials and methods

Objective of study:

other: Basic toxicokinetic assessment to support REACH Annex VIII registration.

Test guideline

Qualifier:

no guideline available

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:

Anthranilamide

EC Number:

201-851-2

EC Name:

Anthranilamide

Cas Number:

88-68-6

Molecular formula:

C7H8N2O

IUPAC Name:

2-aminobenzamide

Test material form:

solid: particulate/powder

Remarks:

tan

Results and discussion

Any other information on results incl. tables

INFORMATION BASED ON PHYSICO-CHEMICAL PROPERTIES

 

Anthranilamide is a benzamide derivative with a molecular weight of 136.15. It is a solid at room temperature and has a melting point of 110 – 115°C. The substance has only limited solubility in water at 16.6 g/l at 20 °C. The log Pow is 0.76 at 25°C which indicates that the substance will have some limited solubility in lipids. 

 

In its solid form Anthranilamide is a crystalline powder. Particle size analysis found that 36.67% of the particles are inhalable (particle size <100 µm), but that 0% were < 4 µm and therefore the sample was not considered to contain respirable particles.

 

There is no hydrolysis data on Anthranilamide as the REACH Annex VIII test was waivered due to Anthranilamide being readily biodegradable.

   

ABSORPTION, DISTRIBUTION AND EXCRETION

  

Absorption

 

Potential for Absorption

 

Anthranilamide in solid form contains 36.67% particles of a size that could be inhaled following exposure to airborne dusts. However as 0% of particles are respirable, little of an inhaled dose will reach the alveoli and most of the dose can be expected to be transferred to the stomach via mucocilliary action and swallowing.

 

Anthranilamide is a low molecular weight molecule and therefore its size is unlikely to present a significant barrier to absorption across the gastrointestinal mucosa, hence, uptake as it passes through the gastrointestinal tract may occur.  Anthranilamide uptake is likely to vary as it passes through the gut given that it will be ionised to differing degrees at the different pH’s encountered in the gastrointestinal tract. Anthranilamide has a log P value of 0.76 and therefore the non-ionised form is likely to have sufficient lipid solubility to pass across biological membranes. 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

 

An oral repeated dose reproductive developmental toxicity screening study has been conducted on Anthranilamide using doses of 30, 150 and 500 mg/kg/bw/day. There were some clear systemic toxicological effects in the study at 500 mg/kg bw/day and on offspring development at 150 and 500 mg/kg bw/day indicating thatAnthranilamide was absorbed and it, or its metabolites were at a sufficient concentration to exert effects.

 

 

There is no information on which to assess with certainty if Anthranilamide can be absorbed significantly via dermal exposure. Given its molecular weight it is conceivable that a dermal absorption could occur; however, factors such as its relatively low lipid solubility are likely to mean that absorption by this route is unlikely to be significant.

 

 

DISTRIBUTION

 

It is unlikely that Anthranilamide will exhibit any significant distribution within the body between plasma and tissues as its logP value (0.76) does not indicate it will have a strong affinity for fats. 

 

Minor developmental effects consisting of reductions in offspring body weight, body weight gains and general development were seen in the oral repeated dose reproductive developmental toxicity screening study. Effects were seen at doses below those which maternal toxicity occurred; however, it is not possible to draw any conclusions from the study about whether the effect was due to a direct action on the offspring and/or reproductive system and concomitantly conclusions cannot be drawn about whether the distribution of Anthranilamide in the body includes the reproductive organs.   

 

 

METABOLISM

 

Anthranilamide contains a water solubilising hydroxyl group which is likely to aid excretion and also metabolism of the molecule by cytochrome P450 enzyme metabolising system. Additionally, amine groups on the molecule are likely to undergo oxidation by amine oxidase enzymes. Hence, in organisms such as mammals and fish with significantly developed xenobiotic metabolising systems, Anthranilamide is expected to undergo a degree of metabolism resulting in breakdown of the molecule and ultimate excretion.

 

 

Reports in the literature indicate that Anthranilamide is metabolised principally to 3-hydroxy Anthranilamide-O-sulphate and 5-hydroxyanthrilamide-O-sulphate.[1] Anthranilamide is a metabolite of anthranilic acid and studies reported in the literature on the metabolism of anthranilic acid in mammals indicate that Anthranilamide generated from the metabolism of anthranilic acid is further metabolised so that only a small proportion (=<5%) of a dose could be detected as free Anthranilamide[2].

 

In two in vitro bacterial reverse mutation assay using S. typhimurium and E. coli, and an in vitro mammalian chromosome aberration assay in Chinese Hamster Ovary cells, Anthranilamide gave negative results in both the presence and absence of an S9 metabolising system. Given the negative results, no conclusions about the potential of Anthranilamide to undergo metabolic change can be drawn from these studies.

 

Excretion

 

Due to addition of water solubilising groups during metabolism the main route of excretion of absorbed Anthranilamide and/or its metabolites is likely to be via the kidneys into the urine. The molecular weight of Anthranilamideis below the biliary exclusion limit of circa 325 in the rat and 500 in humans and therefore elimination of any absorbed substance in the bile is not expected to be significant. 

 

 

[1]D E Hathway (Editor), Foreign Compound Metabolism in Mammals, Volume 5, 1979, Publisher: The chemical Society.

[2]Tjang Mushadji Sutamihardjaet al, Studies on the New Metabolic Pathway of Anthranilic Acid in the Rat I. Isolation and Urinary Excretion of Anthranilamide as a New Metabolite of Anthranilic Acid. Chem. Pharm. Bull, 20(12) 264-2700 (1972).

Applicant's summary and conclusion

Conclusions:

An assessment of the potential absorption of Anthranilamide based on its physico-chemical properties suggest that absorption across the gastrointestinal mucosa will occur although it likely to be slow and part of an oral dose can be expected to be excreted in the faeces. However, a proportion will be systemically absorbed as demonstrated by the observation of treatment related effects in a repeat dose toxicity and reproductive developmental toxicity screening study (OECD 422) conducted on the Anthranilamide.

The presence of a hydroxyl group on the structure can be expected to aid metabolism of systemically, absorbed Anthranilamide to water soluble products that will ultimately be excreted via the kidneys.

There is no expectation that Anthranilamide will preferentially distribute to particular organs or tissues in the body.

Executive summary:

Introduction

An expert review of the toxicokinetic profile of the test substance was undertaken based on its physiciochemical profile and available data from toxicolgical studies.

Conclusion

An assessment of the potential absorption of Anthranilamide based on its physico-chemical properties suggest that absorption across the gastrointestinal mucosa will occur although it likely to be slow and part of an oral dose can be expected to be excreted in the faeces.  However, a proportion will be systemically absorbed as demonstrated by the observation of treatment related effects in a repeat dose toxicity and reproductive developmental toxicity screening study (OECD 422) conducted on the Anthranilamide.

The presence of a hydroxyl group on the structure can be expected to aid metabolism of systemically, absorbed Anthranilamide to water soluble products that will ultimately be excreted via the kidneys.  

There is no expectation that Anthranilamide will preferentially distribute to particular organs or tissues in the body.