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EC number: 298-577-9 | CAS number: 93819-94-4
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data

Endpoint summary
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).
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