Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics
Type of information:
other: expert statement
Adequacy of study:
weight of evidence
Study period:
2013
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Reliable studies are gathered for the weight of evidence approach but this is rated with restrictions due to the submission of an expert statement rather than a toxicokinetic study.

Data source

Reference
Reference Type:
other: expert statement
Title:
Unnamed
Year:
2013
Report Date:
2013

Materials and methods

Test guideline
Qualifier:
no guideline required

Test material

Reference
Name:
Unnamed
Type:
Constituent

Results and discussion

Preliminary studies:
The toxicokinetic assessment of the 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.

Based on analytical characterisations, the substance meets the definition of a UVCB. This substance has an average molecular weight>1600 g/mol, a water solubility of 20 mg/L, log Kow of 10.5, vapour pressure too low to measure analytically, and it is stable in neutral or acidic environment.

Significance of Exposure Route
Dermal route: is considered a principal route for occupational exposure.
Inhalation route: the test material has an extremely low vapour pressure (essentially zero), OECD has indicated that inhalation exposure is negligible if the vapour pressure is less than 1 Pa and ECHA guidance places chemicals with less than 0.1 Pa vapour 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 vapours, gases, or mists is not expected to be relevant or significant, and no predictions on ADME were made.
Oral exposure: oral is not an anticipated route of exposure to workers or the general population.

Toxicokinetic / pharmacokinetic studies

Details on absorption:
In the following sections, absorption after each experimental exposure route was discussed individually.

Oral Route: Absorption of a toxicant from the gastrointestinal (GI) tract depends on its physical properties, including lipid solubility and its dissolution rate. EC# 306-111-3 has water solubility =20 mg/L; log KOW = 10.5 (values between 0 and 4 are the most suitable), and average MW >1600 (values < 500 the most suitable). These data indicate that the registered substance is not expected to participate in endogenous passive absorption within the mammalian GI tract to a great extent. Additionally, transportation 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 modelling using OECD ToolBox version 2.3). 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) in an acute oral study, rats treated with a single dose of test material did not exhibit significant signs of toxicity (LD50 > 5000 mg/kg). (ii) in a reproduction screening study on the similar material CAS # 61789-01-3, rats treated with doses up to 1000 mg/kg/day did not exhibit any signs of test article related toxicity (NOAEL > 1000 mg/kg/day).

Taken together, EC# 306-111-3 absorption by the GI tract is expected to be slow and inefficent. The low toxicity observed in animal studies indicate either low amount of test material was absorbed, and/or the test material has low inherent toxicity.

Dermal Route: Physicochemical properties have a decisive influence on the penetration of molecules through the skin. The registered substance has Log Kow = 10.5 (maximal absorption when Log Kow is between 1 and 2), average MW >1600 (absorption decreases as MW >500), [Guidance Document on Dermal Absorption, European Commission; 2004], these parameters are not favourable for absorption when in contact with skin. This prediction is supported by the results obtained from animal toxicity tests administrated dermally: (i) in an acute dermal study, rats treated with a single dose of test material did not exhibit significant signs of toxicity (LD50 > 2000 mg/kg). The absence of mortality or adverse effects suggest percutanous penetration in rats is low, and/or the substance is of low systemic toxicity.
Details on distribution in tissues:
With respect to MW, the lipophilic character, and water solubility, the substance is not ideally suited for absorption. If the substance is to enter the circulatory system, it could potentially traverse cellular barriers and distribute to fatty tissue or distant organs other than sites of exposure. Because no test article related toxicity were observed in acute or subchronic studies, it is suggested that there is no evidence of cumulative toxicity as would be manifested by an accumulation of this type of substance in tissues.
Details on 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 readily undergo routine renal and/or biliary excretion based the predicted structures.

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
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 is expected to be biotransformed in keratinocytes and/or fibroblasts. Eighteen metabolites are indicated in OECD ToolBox version 2.3, skin metabolism simulator.

Oral Route: QSAR approach was used to predict the metabolism and kinetic profile of the registered substance (OECD ToolBox version 2.3). Intestinal microflora are actively involved in metabolic processes, therefore, in addition to liver metabolism simulator, microbial metabolism simulator modeling was also used. The chemical structure showed few functional groups which were assumed to be candidate substrate(s) for various enzymatic reactions.

The metabolites possess functional groups that can undergo conjugation reactions catalyzed by Phase II enzymes.
Predictions from OECD Toolbox simulations of metabolism of the representative compound are attached.
Liver Metabolism Simulator (OECD ToolBox version 2.3) predicted 58 metabolites.
Microbial Metabolism Simulator (OECD ToolBox version 2.3) predicted 382 metabolites.

Any other information on results incl. tables

From SIDS, 2006 for Epoxidized Oils and Derivatives Chemical Category:

In mammalian species these materials are expected to be absorbed and metabolized in a similar fashion, resulting in the

release of similar free epoxidized fatty acids and lesser substituted alcohols or glycerides. Lipase is an enzyme that

assists in the breakdown and digestion of fat in the body. Pancreatic lipase works at the oil/water interface since

triglycerides are insoluble. During metabolism in the GI tract, pancreatic lipase preferentially hydrolyzes triglycerides to

release the free fatty acids from the SN-1 and SN-3 (terminal) positions of the glycerol backbone. Other products of

metabolism are mono- and diglycerides. The monoglycerides, diglycerides, and fatty acids can be absorbed. In a similar

manner, pancreatic lipase and other digestive enzymes have been shown to hydrolyze propylene glycol monoesters and

diesters in vitro. The absorption, metabolism and hydrolysis of propylene glycol distearate (which is structurally similar

to EODA) were studied in rats using isotopically labelled compounds. These processes for the propylene glycol esters

were found to be similar to those of the glycerol esters. So, there is evidence that the propylene glycol esters of fatty

acids are hydrolyzed to propylene glycol and fatty acids. The ETP structure is similar to that of the monoglycerides,

formed from the ELSO and ESBO. Further hydrolysis can also occur via carboxylesterase activity.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results
The physico-chemical properties and toxicity studies in animals provide sufficient support in determining the ADME profile for the registered substance, and therefore may substitute for animal tests.
Executive summary:

With respect to molecular weight (>1600), water solubility (20 mg/L), and Log Kow (10.5), the test material is not expected to be well absorbed in the gastro-intestinal tract after oral administration. Ingestion is not expected to be a major route of exposure for this chemical due to use patterns. Additionally, this compound shows low toxicity in acute and subchronic oral toxicity studies.

 

Absorption via skin is expected to be very low, since its high molecular weight impedes skin permeability [Guidance Document on Dermal Absorption, European Commission; 2004]. This is supported by the absence of systemic toxicity in the acute dermal study.

 

Inhalation exposure is of no relevance due to the low vapour pressure.

 

Once absorbed, distribution may be assumed, however, no signs of toxicity were observed in any of the organs or tissues assessed in subacute or reproduction toxicity studies. Enlarged liver weights were observed in repeated dose toxicity studies in the similar materials that make up the Epoxidized Oils and Derivatives Chemical Category (SIDS, 2006). In the absence of histopathology correlates, this was considered an adaptive response.

 

The test material is assumed to be subject to hydroxylation, oxidation and reduction reactions mediated by various liver enzymes or enzymes from intestinal microflora.

It can be assumed that elimination of the substance is relevant. Based on its physicochemical properties and lack of evidence of bioaccumulation potential, bioaccumulation in exposed organisms is not expected.