Phosphorodithioic acid, O,O-di-dodecyl-esters, zinc salts, neutral and basic

Endpoint summary

Description of key information

Oral absorption is limited for Phosphorodithioic acid, O,O-di-dodecyl-esters, zinc salts, neutral and basic (CAS 4563-56-8), dermal and inhalation absorption potential is assumed to be very low. Phosphorodithioic acid, O,O-di-dodecyl-esters, zinc salts, neutral and basic (CAS 4563-56-8) will be distributed in the body to a small content, since absorption cannot be completely excluded. The fraction that is not absorbed in the GI tract will be excreted via the faeces.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

There are no studies available in which the toxicokinetic behaviour of the target and source substance was investigated. In accordance with Annex VIII, Column 1, 8.8.1, of Regulation (EC) 1907/2006 and with ‘Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance’ (ECHA, 2017), an assessment of the toxicokinetic behaviour was conducted to the extent that can be derived from the relevant available information. This comprises a qualitative assessment of the available substance specific data on physico-chemical and toxicological properties according to Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2017) and taking into account further available information on structural analogue substances.

Based on the high similarities in structure and physico-chemical properties, similar toxicokinetic properties are expected for the target substance Phosphorodithioic acid, O,O-di-dodecyl-esters, zinc salts, neutral and basic (CAS4563-56-8) and for the source substance Zinc bis[O,O-bis(2-ethylhexyl)] bis(dithiophosphate) (CAS 4259-15-8). Both substances belong to the group of zinc dialkyldithiophosphates, which consist of a phosphorodithioic acid structure with alkyl or alkaryl ester substituent groups. Thus, target and source substance contain the same functional groups and only have difference on alkyl chain length (C12 – linear or branched - in target substance and C8 – branched - in source substance).

Phosphorodithioic acid, O,O-di-dodecyl-esters, zinc salts, neutral and basic (CAS4563-56-8) has a calculated molecular weight of 996.90 g/mol, a water solubility of 150 mg/L, log Pow of 3.4, and a vapour pressure of < 4.0 x 10^-2 Pa at 20 °C. The source substance Zinc bis[O,O-bis(2-ethylhexyl)] bis(dithiophosphate) (CAS 4259-15-8) has a calculated molecular weight of 772.50 g/mol, a water solubility of 9.1 mg/L,log Pow of 3.59 and a vapour pressure of < 4.2 x 10^-4 Pa at 25 °C.

Absorption

Absorption is a function of the potential for a substance to diffuse across biological membranes. The most useful parameters providing information on this potential are the molecular weight, the octanol/water partition coefficient (log Pow) value and the water solubility. The log Pow value provides information on the relative solubility of the substance in water and lipids (ECHA, 2017).

Oral

In general, molecular weights below 500 and log Pow values between -1 and 4 are favourable for absorption via the gastrointestinal (GI) tract, provided that the substance is sufficiently water soluble (> 1 mg/L). Lipophilic compounds may be taken up by micellar solubilisation by bile salts, but this mechanism may be of particular importance for highly lipophilic compounds (log Pow > 4), particularly those that are poorly soluble in water (1 mg/L or less) that would otherwise be poorly absorbed (ECHA, 2017).

An acute oral study, rats treated with the source substance, resulted in sublethal effects including depression, diarrhea, reduction of food intake and body fat, no specific organ toxicity is evident (LD50 of 3100 mg/kg bw). A 28-day repeated dose toxicity study was available for the source substance. In this study, rats treated with 10, 50, 125, 250 and 500 mg/kg bw/day showed increases in adrenal gland and liver weights (NOAEL is 125 mg/kg bw/day). These results confirm that absorption by the GI tract is expected, but the relatively low toxicity observed in the animal studies indicated either low amount of test material was absorbed, and/or the test material has low inherent toxicity.

Overall, a systemic bioavailability of the target and source substances in humans is considered possible but limited after oral uptake of the substance due to their high molecular weights, which is also supported by the available acute and repeated dose toxicity data with Zinc bis[O,O-bis(2-ethylhexyl)] bis(dithiophosphate) (CAS 4259-15-8).

Dermal

Molecular weights below 100 favour dermal uptake, while for those above 500 the molecule may be too large (ECHA, 2017). Therefore, the dermal absorption of the source and target substance is predicted to be very low, which is also supported by Dermwin v2.02, EpiSuite 4.1 analysis for the target substance (dermal penetration rate of 3.94 x 10E-12 mg/cm²/h) and for the source substance (dermal penetration rate of 4.36 x 10E-11 mg/cm²/h and the results of the acute dermal toxicity study for the source substance Zinc bis[O,O-bis(2-ethylhexyl)] bis(dithiophosphate) (CAS 4259-15-8). In the dermal acute toxicity study, necrotic-appearing areas of lung tissue were observed and the LD50 was determined to be 5000 mg/kg. These observations indicated systemic uptake; however, at such a high dose level, the absence of mortality or adverse effects suggested percutanous penetration in rats was low, and/or the substance is of low systemic toxicity.

Moreover, the irritation study with the source substance Zinc bis[O,O-bis(2-ethylhexyl)] bis(dithiophosphate) (CAS 4259-15-8) showed no irritating effects towards the skinwhich excludes enhanced penetration of the substance due to local skin damage.Taking all the available information into account, the dermal absorption potential of the target and source substance is considered to be low. According to the ECHA Guidance on Toxicokinetics (ECHA, 2017) a dermal absorption value of 10% is chosen for risk assessment.

Inhalation

As the vapour pressure of the target and source substance is very low (< 0.1 Pa at 20 °C), the volatility is low and hence, the potential for absorption via inhalation during normal use and handling is considered to be negligible. In addition, aerosol formation is not expected from the use pattern. No acute inhalation toxicity studies were available for the source and the target substance.

Distribution and accumulation

Highly lipophilic substances tend in general to concentrate in adipose tissue, and depending on the conditions of exposure may accumulate. Although there is no direct correlation between the lipophilicity of a substance and its biological half-life, it is generally the case that substances with high log Pow values have long biological half-lives (ECHA, 2017). The log Pow of >3.4 – 5.6 implies that the target and the source substance may have the potential to accumulate in adipose tissue. Absorption is a prerequisite for accumulation within the body. Due to the high MW and high log Pow, absorption is expected to be low for the target and source substance, therefore accumulation is not favoured as well.

Distribution within the body through the circulatory system depends on the molecular weight, the lipophilic character and water solubility of a substance. In general, the smaller the molecule, the wider is the distribution. If the molecule is lipophilic, it is likely to distribute into cells and the intracellular concentration may be higher than extracellular concentration particularly in fatty tissues (ECHA, 2017). To a small extent distribution within the body can be assumed for both the target and the source substance as absorption cannot be completely excluded.

Metabolism

No data are available regarding metabolism. Prediction of compound metabolism based on physicochemical data is very difficult. Structure information gives some but no certain clue on reactions occurring in vivo. The potential metabolites following enzymatic metabolism were predicted using the QSAR OECD toolbox (v4.1, OECD, 2017). For the prediction the target substance without Zn with the following SMILES code: CCCCCCCCCCCCOP([S-])(=S)OCCCCCCCCCCCC) was used. This QSAR tool predicts which metabolites may result from enzymatic activity in the liver and in the skin, and by intestinal bacteria in the gastrointestinal tract. 8 hepatic and 2 dermal metabolites were predicted for the target substance, respectively. Primarily, the formation of mono esters with phosphorothioic acid and the formation of dodecanol by hydrolysis of the parent substance are the predicted metabolites which may occur in the liver. In the skin, hydrolysis of the terminal methyl group of the aliphatic side chain was predicted. For the prediction of compound metabolism of the source substance without Zn the following SMILES code: CCCCC(CC)COP([S-])(=S)OCC(CC)CCCC was used. 8 hepatic and 4 dermal metabolites were predicted for the source substance, respectively. Primarily, the formation of mono esters with phosphorothioic acid and the formation of 2-ethylhexanol by hydrolysis of the parent substance are the predicted metabolites which may occur in the liver. In the skin, hydrolysis of the terminal methyl group of the aliphatic side chain was predicted. These predicted metabolites can be regarded as phase I metabolites which are a common prerequisite for the phase II reactions or conjugation reactions, which transfer functional groups to the phase I metabolites to increase the water solubility and the excretion of the xenobiotic. Phase II metabolism by e.g. uridine 5′-diphospho(UDP)-glucuronosyltransferases (UGT) and sulfotransferases typically generate excretable hydrophilic metabolites by transferring activated glucuronic acid and sulfate-moiety to hydroxyl groups of the substrates, respectively (Aktories, 2005).

Besides the predicted liver and skin metabolites, up to 102 metabolites for the target substance and 34 metabolites for the source substance were predicted to result from all kinds of microbiological metabolism for the test substance. Most of the metabolites were found to be a consequence of the degradation of the molecule.

Excretion

The fraction of the target or the source substance that is not absorbed in the GI tract will be excreted via the faeces. If microbial metabolism occurs (as predicted in the OECD QSAR Toolbox, see above under ‘Metabolism’), then the smaller metabolites may be absorbed; thereby entering the systemic circulation. If these metabolites were not assimilated into normal cellular metabolic pathways, they were expected to readily undergo routine renal and/or biliary excretion after conjugation.

Overall, based on the evaluated data and the structural and physicochemical similarities, similar toxicokinetic behaviour is assumed for the target substance Phosphorodithioic acid, O,O-di-dodecyl-esters, zinc salts, neutral and basic (CAS4563-56-8) and for the source substance Zinc bis[O,O-bis(2-ethylhexyl)] bis(dithiophosphate) (CAS 4259-15-8).