Phosphoric acid, C14-15-branched and linear alkyl esters, potassium salts

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics in vitro / ex vivo

Type of information:

not specified

Adequacy of study:

weight of evidence

Study period:

2018

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

abstract

Justification for type of information:

All available physical, chemical and toxicological information was evaluated, though no explicit studies on toxikokinetics (ADME) were available.
A summary of the available data as well as a hypothesis on toxicokinetic pathways are presented.

Qualifier:

no guideline available

Principles of method if other than guideline:

All available physical, chemical and toxicological information was evaluated, though no explicit studies on toxikokinetics (ADME) were available.

GLP compliance:

no

Specific details on test material used for the study:

Name: Phosphoric acid, C14-15 branched and linear alkyl esters, potassium salts
CAS No.: 1893414-79-3
Physical state: white solid at 20 °C
Batch No.: PU61810016
Re-certification date of batch: 09 March 2018
Purity: 100 % (UVCB, lyophilized solid, water content 0.85 % (w/w))
Stability: stable under test conditions
Storage condition of test material: Room temperature, protected from light

Introduction

Toxicokinetic parameters such as uptake, distribution, metabolism and excretion form part of the essential toxicological profile of a substance. Although the toxicokinetic behaviour of substances does not describe a toxicological endpoint itself, an approximate indication of the individual toxicokinetic parameters absorption, distribution, metabolism and excretion (ADME) can be gained from the results of basic toxicity testing. In this respect the following evaluation discusses results and observations from basic toxicity studies which can be used as approximate indications for the description of every individual toxicokinetic parameter. Such an approach is also justified by animal welfare considerations because additional animal testing can be avoided. The assessment of the toxicokinetic properties of the test item given below is based on the results obtained for the toxicological endpoints mentioned below. There are no studies available in which the toxicokinetic behaviour of the test item has been investigated.

An acute oral toxicity study was performed in rats with the test item accoridng to OECD guideline 423 indicating no markedly signs of systemic toxicity resulting in acute oral LD50 value >2000 mg/kg bw.

In addition, a read across skin sensitisation study according to OECD guideline 406 was assessed demonstrating no signs of systemic toxicity and no markedly skin reactions.

The test item gave negative results in Ames tests with S. typhimurium with and without metabolic activation and it did not induce mutations at the Thymidine Kinase Locus in Mouse Lymphoma L5178Y Cells in vitro with and without S9-mix. It was also not clastogenic in an in vitro test in Chinese hamster V79 cells.

Moreover, a Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test with the test item was performed according to OECD guideline 422 in rats via the oral route at dose levels up to 1000 mg/kg bw/day. No markedly signs of systemic toxicity were observed.

Therefore, in accordance with Annex VIII, Column 1, Item 8.8.1, of Regulation (EC) No 1907/2006 and with Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2017), assessment of the toxicokinetic behaviour of the test item is conducted to the extent that can be derived from the relevant available information.

Absorption

Absorption may take place via the skin due to surface active properties and logP value of the substance.

Neverthelss the substance is not a skin sensitizer and there is no evidence of dermal irritation from in vitro studies.

Therefore dermal absorption is not considered the main route of exposition.

The low vapour pressure value shows that the substance is not available as a vapour therefore inhalation is not a significant route of exposure. Refering to Chapter R.7c: Endpoint specific guidance (ECHA, 2017) section Derivation of TK information taking into account a basic data set support the gastric absorption of the test item. This hypothesis is supported by the amphiphilic nature of the substance (surface active substance), the moleculare weight ranges of the components present and a logPow of 2.59 - 3.99. This would suggest that the gastro-intestinal tract provides a likely route of absorption, following oral administration, before entering the circulatory system via the blood or lymphatic system.

The absorption of highly lipophilic metabolites (e.g. fatty alcohols wotj a logPow of 4 or above) may be limited by the inability of such substances to dissolve into GI fluids and hence make contact with the mucosal surface. However, the absorption of such substances will be enhanced if they undergo micellular solubilisation by bile salts (Aungst and Shen, 1986). Substances absorbed as micelles (aggregate of surfactant molecules, lowering surface tension) enter the circulation via the lymphatic system, bypassing the liver. Micellular solubilisation is considered a likely path of GI absorbtion of the components or their potential metabolites contained in the test item.

Distribution

Systemic distribution is evident from the repeated dose/reproductive screening study resulting in systemic effects at high doses.

Metabolism

Enzymatic hydrolysis by currently unknown enzyms may take place at the phosphoric acid ester site of the test item's components causing it to split in a polar and an apolar part. Further phase I and II biotransformation reaction are considered likely. Metabolites, if any are formed, appear less toxic than the parent compound. It is considered likely that the fraction of the material becoming bio-available in the organism undergoes relatively easy ester hydrolysis to produce fatty alcohols and inorganic phosphate derivatives. The linear fatty alcohols are likely to be channelled into the normal fatty acid metabolism by oxidation to produce carbon dioxide and water. Branched chain fatty alcohols are expected to be further oxidized in phase I biotransformations or by phase II glucoronidation. Inorganic phosphate as an easily water soluble molecule is renally excreted or metabolised to conjugates.

Excretion

There is no evidence to indicate the route of excretion. Substances absorbed as micelles are not favourable for urinary excretion and therefore biliary excretion may well be a significant route for this material. As there is a propbability of hepatic metabolism this does not, however, rule out urinary excretion. The main reason for xenobiotic metabolism is to render the product more water soluble thereby facilitating urinary excretion (e.g. inorganic phosphates). Any test item that is not absorbed will be excreted in the faeces.

Conclusions:

Toxicokinetic parameters such as uptake, distribution, metabolism and excretion form part of the essential toxicological profile of a substance. Although the toxicokinetic behaviour of substances does not describe a toxicological endpoint itself, an approximate indication of the individual toxicokinetic parameters absorption, distribution, metabolism and excretion (ADME) can be gained from the results of basic toxicity testing. In this respect the following evaluation discusses results and observations from basic toxicity studies which can be used as approximate indications for the description of every individual toxicokinetic parameter. Such an approach is also justified by animal welfare considerations because additional animal testing can be avoided. The assessment of the toxicokinetic properties of the test item given is based on the results obtained for the toxicological endpoints mentioned. There are no studies available in which the toxicokinetic behaviour of the test item has been investigated.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential