Registration Dossier

Administrative data

Link to relevant study record(s)

Description of key information

Toxicokinetic Evaluation of the Substances (see attached summary document)

A. Absorption

ZDDPs are expected to have low absorption. The constituent pool that may be absorbed are the alkyl

dithiophosphate esters, which will be metabolized to the corresponding alkyl alcohol.

Based on studies conducted in a laboratory to simulate the fate of a ZDDP in the GI tract, ZDDPs will

undergo transformation in the stomach. Specifically, the basic form of ZDDP is quickly and completely

broken down into the neutral form. Furthermore, based on hydrolysis studies, any ZDDP that is soluble

in the GI fluid is expected to be hydrolyzed resulting in the dissociation of the Zn from the alkyl

dithiophosphate ester moiety. Therefore, the amount of basic vs. neutral ZDDP is not relevant for the

toxicity assessment as all ZDDPs are expected to be in the neutral form upon ingestion. Figure 2 is an

example of the relevant absorption potential of the 3 types of molecules present (basic, neutral,

dissociated alkyl dithiophosphate ester) and further demonstrates that the basic form, due to its large

molecular weight and low bioavailability is not a relevant molecule for toxicity.

Figure 2. Relative GI Absorption of ZDDP structures (see attachment)

The absorption of ZDDPs was further assessed based on physiochemical properties, existing toxicity

studies, and modeling. The available toxicity data, both acute and repeat dose, suggest that the

substances have very low absorbance because of the absence of systemic toxic effects. The only toxic

effects that have been reported are linked to site of contact irritation (skin or GI tract), either as

primary (e.g. thickening of stomach mucosa) or secondary effects (e.g. premature death, salivation).

The primary factors that normally impact on GI tract absorbance are molecular weight, water solubility

and lipophilicity. All of the MW values are significantly greater than the usual cut-off value of 500 that

is considered commensurate with absorbance (ECHA R.7.c). The substances are not surface active so

there is no need to consider the possibility of micelle formation and passage via carrier proteins.

Regardless of the empirical evidence (toxicology studies) and standard toxicokinetic considerations a

formal ADME prediction has been performed to evaluate the potential for absorbance via the GI tract.

Various toxicokinetic parameters (including gastrointestinal absorption) were predicted using

SwissADME[4] - a freely available web-based tool. Gastrointestinal absorption and the Blood Brain

Barrier (BBB) permeation were calculated using the Brain or Intestinal EstimatedD permeation

(BOILED-Egg[5]) method applied by the SwissADME. The BOILED-Egg method calculates the lipophilicity

and polarity of substances to provide accurate predictions for both brain and intestinal permeation.

All of the alkyl ZDDP category members were outside the range of the BOILED-Egg plot, indicating they

were not absorbed and were non-permeant.

Additionally, the probability of the substances being a substrate or non-substrate of the permeability

glycoprotein (P-gp) was calculated for each category member. P-gp plays a primary role among ATPbinding

cassette transporters or ABC transporters, therefore the ability of a substance to be a

substrate or non-substrate of the P-gp is very important to better understand the active efflux through

biological membranes, for example from the gastrointestinal wall to lumen. The knowledge about

compounds being substrate or non-substrate of the permeability glycoprotein (P-gp, suggested the

most important member among ATP-binding cassette transporters or ABC-transporters) is key to

appraise active efflux through biological membranes, for instance from the gastrointestinal wall to the

lumen or from the brain. One major role of P-gp is to protect the central nervous system (CNS) from

xenobiotics.

The results of the SwissADME evaluation are presented in the table below. The potential for GI tract

absorbance is defined as ‘low’ but in fact may be considered as practically zero because all of the

substances were plotted outside of the grey zone on the BOILED Egg plot. Furthermore, all of the

substances are predicted to be a substrate of Pgp, which indicates that they will be actively ‘pumped’

out of GI tract cells and into the intestinal lumen. The prediction also indicates that the substances

cannot penetrate the blood-brain barrier.

SwissADME - Table of Predicted Gastrointestinal Tract Absorbance (see attachment)

B. Metabolism

The metabolism of ZDDPs was predicted using OASIS TIMES v.2.28.1.4 in vivo rat simulator, v.07.11.

The metabolic profile is important because it further informs the category similarity and the toxicity

contribution from the metabolites should be evaluated. The metabolism is consistent across different

ZDDPs, including linear, branched and secondary alcohols. Two pathways were predicted consistently

for each ZDDP: 1) Methylation of the sulfur and; 2) Oxidative desulfuration followed by phosphate

ester hydrolysis releasing the alcohol side chain and entering typical alcohol metabolic pathway

(oxidation, aldehyde dehydrogenase, alcohol dehydrogenase, Phase II metabolism including

glucuronidation; see OECD SIDS SIAR Report for Long Chain Alcohols, 2006). Similar concentrations of

transformation products were predicted for each alcohol.

Figure 3 provides a comparison of metabolic pathway predicted from OASIS TIMES for ZDDPs from the

3 main subcategories (linear, branched, secondary); the complete modelling reports for other

category members are found in the registration dossiers. The domain report for these 3 representative

ZDDPs is provided below, demonstrating a high reliability for the prediction as the chemical is in the

parametric domain and >90% is in the structural domain of the model. Figure 4 is a typical pathway

observed. (see attachment)

Figure 3. Comparison of metabolic pathway among ZDDPs predicted from OASIS TIMES

(see attachment)

Figure 4. Example of metabolic pathway predicted for ZDDPs (see attachment)

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

See above for discussion of overall toxicokinetics based on current data and modelling. Also see attachment for summary. It is the intent of the Registrant along with co-registrants of other ZDDP category members to perform in vivo toxicokinetics studies (OECD 417) on a number of the substances in the category, the results of which will be used in read-across for this registration substance when available. See Testing proposals in IUCLID sections for 90d repeat dose toxicity, and also developmental toxicity (OECD 414)

 

Discussion on bioaccumulation potential result:

This substance has a molecular weight of 576. It is hydrophilic, and modeling calculations predicted very low dermal absorption. Intestinal absorption was expected to be low as well, because no significant adverse effects were observed following oral dosing (LD50> 3100 mg/kg for acute toxicity; NOAEL 160 mg/kg/d for repeat dose toxicity). The lack of adverse effects may be at least partially due to limited gastrointestinal/dermal absorption of the test substance after treatment, and/or a very low index of inherent toxicity for this substance, and/or its metabolite(s).