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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics, other
Type of information:
(Q)SAR
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
results derived from a valid (Q)SAR model and falling into its applicability domain, with adequate and reliable documentation / justification

Data source

Materials and methods

GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Oral route: 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 alkyl dithiophosphate ester transformation product is the relevant form from an absorption standpoint. This is consistent with the molecular weight cut-offs of the basic (MW > 1000) and neutral (MW > 500) ZDDPs, which indicate low oral absorption. Furthermore, ZDDPs are manufactured in base oil, which is likely to decrease the absorption potential as the ZDDPs are designed to be soluble in base oil and will prefer to stay in this media (due to the alkyl side chain) as opposed to transitioning to an aqueous media like GI fluid. This hypothesis will be validated with the proposed TK studies for the ZDDP category.

The low oral absorption is consistent with the available toxicity data, both acute and repeat dose, which 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).

To confirm low oral absorption, various toxicokinetic parameters (including gastrointestinal absorption) were predicted using SwissADME - 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) 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 ATP-binding 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 in the illustrations section. 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.

Dermal Route: Physicochemical properties have a decisive influence on the penetration of molecules through the skin. ZDDPs have a MW > 500 and per EU guidance, the absorption decreases with the MW > 500 [Guidance Document on Dermal Absorption, European Commission; 2004; ECHA Guidance R.7.c].

This assumption was confirmed by a QSAR assay, which calculated dermal penetration coefficient (Kp) or Pd (the permeability of the skin) by using empirical formulas for an example ZDDP:

Relevant physicochemical properties: MW = 772, Log Kow = 3.59

• Dermwin:
Log Kp = -2.72 + 0.71 log Kow - 0.0061 MW,
Log Kp = - 4.9
Kp =1.3x10-5 cm/h
• Empirical equation of skin permeability (Potts, R.O., et al, 1992)
Log Kp = 0.71* LogKow- 0.0061 MW – 6.3,
Log Kp = -8.5
Kp = 3.4 x10-9cm/h

• Human Health Evaluation Manual:
Log Kp = -2.80 + 0.66 logKow – 0.0056 MW,
Log kp = - 4.8
Kp = 1.7 x10-5cm/h

• Equations on page 60 of ConsExpo Manual (http://www.rivm.nl/en/healthanddisease/productsafety/
ConsExpo.jsp):
Pd = 1/15 * (0.038 + 0.153 Kow) e-0.016 MW = 1.8 x10-7cm/h cm/hr
Pd = 0.0018 Kow0.71e-0.014MW = 9.3 x10-8cm/hr
Log Pd = - 0.812 – 0.0104 MW + 0.616 log Kow; # Pd = 2.2 x10-7cm/h
The Kp or Pd values range from 10-10 to 10-6 cm/h. It has been suggested that if Kp < 10-3 cm/hr low skin penetration will be assigned (Michael S. R., Kenneth A. W., 2007). Based on these calculations, this material was predicted to be absorbed very slowly and no significant systemic uptake was expected, therefore < 10% absorption for applied dose was used in the risk assessment.

Experimental results from the acute dermal study on EC# 224-235-5 supported this argument. In this study, necrotic-appearing areas of lung tissue observed, LD50 of 5000 mg/kg was determined. 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.
Details on distribution in tissues:
No data available

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
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 alkyl dithiophosphate ester molecule was modelled as this is the relevant, bioavailable part of the ZDDP. 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.

OASIS reports are attached in the IUCLID record. This includes a report with the quantity of each metabolite; a second report with a diagram of the metabolic pathways; and a third document that has the domain results. Note that all the ZDDPs were in the parametric and structural domain of the model.

Applicant's summary and conclusion

Executive summary:

ZDDPs are expected to have low oral and dermal absorption based on modeling, toxicity data, and physiochemical properties. Upon ingestion, ZDDPs are expected to be transformed in the GI fluid to the corresponding alkyl dithiophosphate ester (dissociated from the Zn). Any alkyl dithiophosphate ester that is bioavailable will undergo metabolism consistently across the category, ultimately being metabolized to the corresponding starting alkyl alcohol followed by typical alcohol metabolism.