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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Administrative data

Endpoint:
basic toxicokinetics
Type of information:
other: Expert Statement
Adequacy of study:
key study
Study period:
2011
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Statement is based on valid study data.

Data source

Reference
Reference Type:
other:
Title:
Unnamed
Year:
2010
Report date:
2011

Materials and methods

Objective of study:
toxicokinetics
Principles of method if other than guideline:
The physicochemical properties of the test substance, and extensive toxicity studies in animals provide strong support in determining the ADME profile for this substance, and therefore may substitute for the experimentation of in vivo effects.
GLP compliance:
no

Test material

Radiolabelling:
no

Results and discussion

Main ADME resultsopen allclose all
Type:
absorption
Results:
Via GI-Tract and skin is possible; inhalation exposure is irrelevant and absorption is not applicable.
Type:
distribution
Results:
Via blood to target organs of toxicity
Type:
metabolism
Results:
Metabolic changes assumed
Type:
excretion
Results:
Elimination via urine or feces were supposed to be relevant

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
Therepresentative chemical structure was selected to show function groups that are assumed to be candidate substrates for various enzymatic reactions. QSAR approach was used to predict the metabolism and kinetic profiles (OECD ToolBox version 1.1).

Liver Metabolism Simulator
-CH3: Hydroxylation/dehydrogenation mediated by P450, followed by oxidations of alcohols to aldehydes and carboxylic acids by alcohol dehydrogenase and aldehyde dehydrogenase.
-CH2: Hydroxylation/dehydrogenation mediated by P450, followed by oxidations of alcohols to aldehydes and ketone.
-CH in the Benzene ring: hydroxylation

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): other: Bioaccumulation in exposed organisms is predicted to be unlikely.
The toxicokinetic profile of the test substance was not determined by actual absorption, distribution, metabolism or excretion measurements. Rather, the physical chemical properties of this substance were integrated with data from acute and repeated-dose toxicity studies to create a prediction of toxicokinetic behavior. And it is concluded that: Absorption in GI-Tract is relevant, dermal absorption is very low, and inhalation irrelevant
Distribution via blood to target organs of toxicity
Metabolic changes assumed
Elimination is assumed, bioaccumulation supposed to be irrelevant.
Executive summary:

Toxicokinetic

The toxicokinetic profile of the registered substance, phenol, tetrapropenyl-, hydrogen phosphorodithioate, zinc, was not determined by actual absorption, distribution, metabolism or excretion measurements. Rather, the physical chemical properties of this substance were integrated with data from acute and repeated-dose toxicity studies to create a prediction of toxicokinetic behavior.

The substance subjected to this toxicokinetic assessment is a zinc dialkylthiophosphate (ZDDP). Based on analytical characterizations, the substance meets the definition of a UVCB. This substance has an average molecular weight of 1301, a water solubility of<5 mg/L, log Kow> 2.59 (the upper limit is estimated to be < 3.6 by read across to another ZDDP substance, EC 224-235-5), vapor pressure 4.1x10-3Pa at 25oC, and it is stable in neutral or acidic environment. 

Significance of exposure routes

Dermal route: is considered a principle route for occupational exposure.

Inhalation route:the test material has a vapor pressure of4.1x10-3Pa at 25oC, OECD has indicated that inhalation exposure is negligible if the vapor pressure is less than 1 Pa and ECHA guidance places chemicals with less than 0.1 Pa vapor pressure in the low volatility band (OECD 2003; ECHA R15.5). Therefore, under normal use and handling conditions, respiratory absorption of the test material in the form of vapors, gases, or mists is not expected to be significant.

Oral exposure: human exposure to this route is limited. It may occur following accidental spills at a manufacturing site and during transport and exposure via the environmental compartment, or deliberate misuse or accidental ingestion of the finished motor oil (1~5% of ZDDP materials).

Absorption

There are toxicity data available from animal models andin vitrowork for this substance or analogues. From these studies, critical effects were noted mostly at the site of contact, and in combination of the observed systemic effects, the potentials for absorption after each exposure route was discussed individually. 

Dermal Route:Physicochemical properties have a decisive influence on the penetration of molecules through the skin. This registration substance has Log Kow > 2.59 (maximal absorption when Log Kow is between 1 and 2), MW of 1301 (absorption decreased as MW >500), [Guidance Document on Dermal Absorption, European Commission; Health and Consumer Protection Directorate-General. Sanco/222/2000 rev. 7, March 19, 2004], these parameters are not favorable for absorption when in contact with skin. 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.

Relevant physicochemical properties: MW = 1301, Log Kow = 2.59

·                 Dermwin:

Log Kp = -2.72 + 0.71 log Kow - 0.0061 MW,

Log Kp = - 8.8

Kp = 1.5x10-9cm/h

·                 Han L. et al, Journal of Pharmaceutical Science, 97(1): 2008:

Log Kp = 0.71* LogKow- 0.0061 MW – 6.3,

Log Kp = -12.4

Kp = 3.9 x10-13cm/h

·                 Human Health Evaluation Manual:

Log Kp = -2.80 + 0.66 logKow – 0.0056 MW,

Log kp = - 8.4

Kp = 4.1 x10-9cm/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= 2.9 x10-11cm/h cm/hr

Pd = 0.0018 Kow0.71e-0.014MW= 4.8 x10-11cm/hr

Log Pd = - 0.812 – 0.0104 MW + 0.616 log Kow; Pd = 1.7 x10-13cm/h

The Kp or Pd values range from 10-13to 10-9cm/h. It has been suggested that if Kp < 10-3cm/hr low skin penetration will be assigned (Michael S. Roberts, Kenneth A. Walters. Dermal Absorption and Toxicity Assessment, Second Edition, Drugs and the Pharmaceutical Sciences). 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 this substance supported this argument. In this study, no specific organ toxicity is evident, and an LD50 of > 25600 mg/kg was identified. The lack of adverse effects suggested percutanous penetration in rabbit was low, and/or the substance is acutely not toxic.

Inhalation Route: Irrelevant due to its low vapor pressure.

Oral Route: Absorption of a toxicant from the gastrointestinal (GI) tract depends on its physical properties, including lipid solubility and its dissolution rate. This substance has water solubility of <5 mg/L; log KOW>2.59 (values between 0 and 4 are the most suitable), and MW 1301 (values < 500 the most suitable). So the registration substance is expected to participate in endogenous passive absorption within the mammalian GI tract. However, transported across cell membranes by forming a complex with carrier protein(s) is unlikely to occur, because the material is not expected to bind to a protein (computer modeling using OECD ToolBox version 1.1). Therefore, the overall absorption rate is estimated to be slow and inefficient. This argument is supported by the results obtained from (i) acute oral animal toxicity tests administrated via oral gavage, LD50was determined to be 10,000 mg/kg (3/6 death), NOAEL 7500 mg/kg (0/6 death). (ii) There were no oral repeat dose toxicity data available for the registration substance, however an OECD 422 study was available for EC 270-608-0 (NOAEL 160 mg/kg/day), and an OECD 407 study was available for EC 224-235-5 (NOAEL 125 mg/kg/d). These study were conducted on structurally similar substances (ZDDP category) and suitable for read-across. In these studies, treatment-related symptoms were identified and suggested the test substances were bioavailable. For example, morbundity and adverse clinical effects were observed in rats treated with 160 mg/kg/day of EC 270-608-0. Rats treated with EC 224-235-5 at 250 and 500 mg/kg/day showed increases in adrenal gland and liver weights. Taken together, absorption by the GI tract is expected for ZDDP substances, and mostly by simple diffusion. 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. 

Distribution

With respect to MW, the lipophilic character, and water solubility, the registration substance may be transported through the circulatory system. This substance could potentially traverse cellular barriers and distribute to distant organs other than site of exposures. This argument is supported by the observations obtained from various toxicity tests. (i) In the acute oral study, mortalities were observed in the highest dose group. (ii) In the subacute oral study (OECD 422 study), administration of an analogous substance EC 224-235-5 caused systemic effects such as increases in adrenal gland and liver weights. Because no test article related histopathological lesions were observed, it suggested that there was no evidence of cumulative toxicity as would be manifested by an accumulation of this type of substances in tissues. A Japanese MITI publication cited a bioaccumulation factor of less than 100 for a C4-C5 ester zinc dithiophosphate indicating a low potential for bioconcentration or cumulative effects (Handbook of Existing and New Chemical Substances. Fifth Edition. Edited by the Chemical Products Safety Division, Basic Industries Bureau, Ministry of International Trade and Industry. Published by. The Chemical Daily Co. 1992). 

Metabolism

Acute and repeated-dose toxicity testing on the registered substance or analog substances supported that the registered substance was not transformed to toxic metabolites.

Dermal route:by modeling assay, the test material was expected to be biotransformed in keratinocytes and fibroblasts, and hydroxylation of the alkyl tail was possible and two kinds of metabolites were predicted (OECD ToolBox version 1.1,skin metabolism simulator).

Oral/Inhalation Route:QSAR approach was used on a representative chemical structure of the registration substance to predict the metabolism and kinetic profiles (OECD ToolBox version 1.1).

Liver metabolism simulator predicted the following metabolic reactions:

-CH3: Hydroxylation/dehydrogenation mediated by P450, followed by oxidations of alcohols to aldehydes and carboxylic acids by alcohol dehydrogenase and aldehyde dehydrogenase.

-CH2: Hydroxylation/dehydrogenation mediated by P450, followed by oxidations of alcohols to aldehydes and ketone.

-CH in the Benzene ring: hydroxylation

Skin metabolism simulator predicted the following metabolic reactions:

-CH3: Hydroxylation of the alkyl branches

 

Excretion

Only a small fraction of the test substance is expected to be exhaled unchanged due to its low vapor pressure. The metabolic assessment indicates that this substance will undergo biotransformation, and form breakdown products. If these metabolites were not assimilated into normal cellular metabolic pathways, they were expected to readily undergo routine renal and/or biliary excretion based the predicted structures.

SUMMARY

Thephysicochemical properties and toxicity studies in animals provide sufficient supports in determining the ADME profile for the registered substance, and therefore may substitute for animal tests.