Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
other: expert statement
Adequacy of study:
key study
Study period:
2010
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Statement is based on valid study data.

Data source

Reference
Reference Type:
other: expert statement
Title:
Unnamed
Year:
2010
Report Date:
2010

Materials and methods

Objective of study:
toxicokinetics
Principles of method if other than guideline:
Toxicokinetic was not experimental determined, but created by prediction of toxicokinetic behavior based on valid toxicity study data.

Test material

Reference
Name:
Unnamed
Type:
Constituent
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:
no

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results
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 via GI-tract, skin or after inhalation is irrelevant; distribution via blood to target organs of toxicity is possible, and metabolic changes are assumed, elimination is expected, and bioaccumulation supposed to be not relevant.
Executive summary:

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.

The test material is the reaction products of bis(4-methylpentan-2-yl)dithiophosphoric acid with phosphorus oxide, propylene oxide and amines, C12-14-alkyl (branched), based on analytical characterizations, the substance subjected to toxicokinetic assessment meets the definition of a UVCB. This substance has an average molecular weight range from181.1 to 773.3; water solubility was loading rate dependent (39.4 mg/L at 100 mg/L loading rate, and 138 mg/L and 1000 mg/L loading rate); ranged from <0.30 to >7.10, with 62% of the substance possessed Log Kow values greater than 3.5; a low vapor pressure 0.032 Pa at 25oC, and it is stable in neutral or acidic environment.

Absorption

Due to the very low vapor pressure and the conditions of normal use and handling of this material, inhalation and respiratory absorption of the test substance in the form of vapors, gases, or mists is expected to be unlikely. The potential for oral exposure to humans 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 (< 3% of the test materials). Dermal route is considered a principle route for occupational exposure. Absorption potential after each route is discussed individually if exposure of humans occurs. 

Oral Route: Absorption of a toxicant from the gastrointestinal (GI) tract depends on its physical properties, including lipid solubility and its dissolution rate. The most suitable properties for absorption empirically determined to be Log Kow between 0 and 4, and molecular weight < 500. With respect to the above mentioned essential physicochemical properties for this substance (loading rate dependent water solubility, Log Kow, and molecular weight), the test material 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 prediction is supported by the results obtained from animal toxicity tests administrated via oral gavage: (i) treatment with a single dose of the test material did not result in abnormal necropsy in all survived animals. In-life signs of systemic toxicity observed included: tremors, hypoactivity, hypothermia, hyperactivity and convulsions (LD50of 2000 mg/kg). (ii) a repeated-dose toxicity study, test animals received doses of 50, 150 and 500 mg/kg/d, and the following treatment-related symptoms suggested test substance was absorbed: increased adrenal weight at the high dose level, landing foot splay was statistically significantly decreased in mid- and high-dose females, and rectal temperature was also statistically significantly decreased in the high dose females (NOAEL was determined to be 150 mg/kg/d). 

Taken together, the test material absorption by the GI tract is expected, and mostly by simple diffusion. The relatively low toxicity observed in the animal studies indicated either low amount of test material was absorbed, or the test material has low inherent toxicity. 

 

Dermal Route:Physicochemical properties have a decisive influence on the penetration of molecules through the skin: maximal absorption when Log Kow is between 1 and 2 and 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]. The physicochemical properties of the test material are not favorable for absorption when in contact with skin, and by using empirical formulas, low dermal penetration coefficient (Kp) was predicted (range 10-5to 10-2cm/h) (http://www.rivm.nl/en/healthanddisease/productsafety/ConsExpo.jsp, page 60). Therefore, this material was predicted to be absorbed relatively slowly, and no significant systemic uptake was expected.

 

Distribution

With respect to MW, the lipophilic character, and water solubility, the test material may be transported through the circulatory system. This substance could potentially traverse cellular barriers and distribute into fatty tissues or distant organs other than site of exposures. This argument is supported by (i) the observations of neurologic responses in the acute oral study; (ii) the observations of decreased landing foot splay and microscopic changes in adrenal glands and kidneys in the subacute oral study. However, because no test article related histopathological lesions were observed to account for the observed toxic effects, it suggested that there was no evidence of cumulative toxicity as would be manifested by an accumulation of this type of substances in tissues. 

Metabolism

The representative chemical structures show various function groups, such as –CH3, P=S, -P-O-R 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).Metabolites were not identified by skin metabolism simulator, but identified by microbial (may be similar to intestinal microflora) and liver metabolism simulators, and the representative function groups and possible transforming products were showed as following:

-CH3: Hydroxylation/dehydrogenation followed by undergoing series oxidation reaction mediated by P450 and transformed to -COOH.

-O-P-: Phosphoric acid esterase (microbial metabolism simulator);

-P=S: Oxidation probably mediated by monooxygenases to form –P=O (microbial metabolism simulator);

Based on QSAR assay, no structural alert identified for protein or DNA binding, indicating that the test substance was not transformed to toxic metabolites. This assumption was supported by genotoxicity tests (non-genotoxic, non-cytogenic), and repeated-dose toxicity tests on the test substance (no neoplastic lesions were observed in the 28 day study or OECD 421 study).

 

Excretion

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 be conjugated by phase II enzymes and readily undergo routine renal or biliary excretion, or eliminated unchanged.

SUMMARY

The physicochemical properties and toxicity studies in animals provide sufficient supports in determining the ADME profile for the test substance. It is concluded that absorption via GI-tract, skin or after inhalation is irrelevant; distribution via blood to target organs of toxicity is possible, and metabolic changes are assumed, elimination is expected, and bioaccumulation supposed to be not relevant, and therefore may substitute for animal tests.