2-tetradecyloxirane, reaction products with boric acid

Endpoint summary

Description of key information

The potential for exposure to this substance is limited by its use and physical chemical properties. The dermal contact route is considered to be the primary route of occupational exposure. Inhalation exposure is expected to be limited because this substance has a negligible vapour pressure (OECD 2003: negligible <1 Pa; ECHA R15.5: low < 0.1 Pa). Because of the use pattern oral exposure is not an anticipated route of exposure, either to workers or the general public.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

The following assessment of the toxicokinetic profile of C14-18 alpha-olefin epoxide, reaction products with boric acid, is based on the physical chemical properties and toxicity data on the substance. Metabolite and bioavailability predictions have also been determined using the OECD Toolbox software. No experimentally derived ADME data are available for this substance.

 

Substance Characterization

Analytical characterizations show that this substance meets the definition of a UVCB. This substance is a pale waxy solid at ambient laboratory temperature. It is used as lubricant additive.

 

Physical Chemical Properties

Molecular weight, water solubility, log Kow, and vapour pressure are key physical chemical properties for assessing the toxicokinetics of a substance. This substance is a pale waxy solid. The principle component (51.08%) has a molecular weight of 284.24 and the other major components have higher MWs in the range of 524.67 to 852.73. The substance is poorly soluble in water (less than 1 mg/L) having an experimentally determined water solubility of 0.17 mg/L. Physical chemical testing shows that nearly half of the components are strongly hydrophobic (~41% with a log Pow >9.4, and a significant proportion (~51%) has a measured log Pow of 6.24. However, the substance hydrolyses rapidly in the presence of water and it is considered that the log Pow value relates to the hydrolytic products rather than to the component itself and, on a weight of evidence basis, the log Pow value of >9.4 has been taken to apply to the substance as a whole. Consequently, more than 91% of the substance is outside the range that will be easily absorbed through biological membranes, particularly as the low water solubility will inhibit absorption. The substance has a negligible vapour pressure (0.009 Pa) .

 

Exposure Routes

The potential for exposure to this substance is limited by its use and physical chemical properties. The dermal contact route is considered to be the primary route of occupational exposure. Inhalation exposure is expected to be limited because this substance has a negligible vapour pressure (OECD 2003: negligible <1 Pa; ECHA R15.5: low < 0.1 Pa). Because of the use pattern oral exposure is not an anticipated route of exposure, either to workers or the general public.

 

Absorption

Dermal

The dermal absorption of the main components of this substance is expected to be limited but it is difficult to make a quantitative estimate. ECHA endpoint specific guidance chapter R.7C indicates that for substances with a MW >500 and a Log Pow >4, then a default absorption estimate should be taken to be 10%. The results of an acute dermal toxicity study in rats indicate that dermal absorption of this substance is limited. Animals were given a single dermal dose of 2000 mg/kg and observed for systemic and local effects for 14 days. No evidence of erythema was noted at the test sites of any of the animals. No clinical signs were observed that were indicative of systemic effects, and no gross pathological abnormalities were observed. Animals showed expected gains in bodyweight over the study period, except for one female which showed no bodyweight gain during the first week but the expected gain in bodyweight during the second week, and another female which showed the expected bodyweight gain during the first week but a slight loss in bodyweight during the second week. In a Buehler sensitisation test the substance was shown to be a sensitizer when tested at 100% (induction concentration) and 25% in mineral oil (challenge concentration). Based on the toxicological evidence, the test substance is absorbed following dermal application.

 

Oral

Absorption in the gastrointestinal tract is predominantly influenced by the water solubility, ionization state, lipophilicity, and molecular weight of a chemical. The substance is only slightly soluble in water (0.17 mg/L), has a non-ionisable nature, hydrophobic with the majority being strongly hydrophobic (log Pow >9.4), and with a range of molecular weights either side of 500. The results of a repeat dose oral toxicity studies in rats confirm that this substance (or at least some of its components) is absorbed. In an OECD 422 repeat dose toxicity and reproduction/developmental screen the results show that this substance may be absorbed because it caused test material-related non-adverse effects, granulomatous inflammation of the mesenteric lymph nodes and lower mean food consumption in males and females at 1000 mg/kg bw/day. In vitro studies with bacteria show that the substance is slightly toxic Salmonella typhimurium when formulated in tetrahydrofuran. In mammalian cell genotoxicity assaysin vitrothe substance was shown to be toxic in the absence of metabolic activation enzymes (S9 mix), at or close to the solubility limit where precipitate was observed. In the presence of S9 mix the substance was essentially non-toxic at soluble, non- or slightly-precipitating dose levels. The in vitro studies suggest that there may be some absorption of the test substance, which resulted in cell toxicity (but not mutagenicity) but that this was moderated by the presence of proteins (S9 mix).

 

Overall it is not possible to estimate what proportion of the substance is absorbed via the oral route and its absorption may be affected by rapid hydrolysis in the stomach.

 

Inhalation  

The substance is a waxy solid and has a relatively low vapour pressure (0.009 Pa; OECD 2003: negligible <1 Pa; ECHA R15.5: low < 0.1 Pa), therefore the potential for inhalation exposure and uptake via the lungs is considered to be highly unlikely.

Summary

Risk mitigation measures are necessary because this chemical possesses skin-sensitizing properties.   

 

Distribution

Once this substance (or at least the absorbable components) is absorbed, it is expected to be distributed via the blood to the liver and other tissues; although it is possible that exposure to the liver is minimal because no changes in organ weights were observed in the repeat dose toxicity study. In fact the primary adverse effect noted in this study was in the mesenteric lymph nodes, which may indicate that absorption occurred primarily in the intestine and/or colon and not the stomach, in which case primary exposure to the liver may be minimal. Due to its strong lipophilic nature it is predicted to be absorbed by cells of the organs and tissues that it contacts, although the physicochemical properties indicate that absorption may be limited and may be related to the hydrolytic products and not the main components themselves. The representative structures are predicted to be not bioavailable according to the Oasis Lipinski Rules under OECD Toolbox v2.3.0, which provides further evidence that absorption may be restricted to the hydrolytic products.

 

Metabolism

The absorbable components of this UVCB substance are expected to be metabolized via a number of metabolic pathways although the OECD Toolbox v2.3.0 QSAR system predicts that the metabolism/bioaccumulation will be slow or very slow for the dimer and trimers and moderate for the monomer. Cytochrome P450 (CYP450) enzymes are a superfamily of oxidative catalysts important in the biosynthesis and metabolism of a wide range of endogenous molecules as well as the metabolism of xenobiotics. The four main components of this UVCB substance were subjected to metabolite profiling using the OECD Toolbox v2.3.0 QSAR system and the predicted metabolites were partitioned into chemical categories based on USEPA rules (ECOSAR). The Toolbox predicted a total of 52 potential metabolites from the representative structures, which are summarized in the table below:

 

US EPA chemical Categorization	Number	Percentage
Aldehydes (Acute toxicity) Boron Compounds	1	2%
Boron Compounds	51	98%
total	52	100%

 

 

Elimination

Because of the structural characteristics of this substance, Phase I and Phase II metabolic by-products are expected to be eliminated via renal and/or biliary excretion. The granulomas observed in the mesenteric lymph nodes are also likely to be related to a clearance mechanism often observed in animals dosed with high concentrations of materials such as white oils and waxes (Fleming et al., 1998).

Endocrine disruption potential

Borate esters are present as components of the UVCB substance. However, the UVCB as a whole is hydrophobic and relatively insoluble (water solubility < 0.17 mg/L at 20 °C and pH 4.4). As a result, borate esters will not be present in solution and hydrolysis and enzymatic metabolism of these components is not expected. This prediction is supported by the absence of reproductive effects characteristic of boric acid exposure in studies with the UVCB test material. There is no evidence that boric acid has a mechanism of action relating to endocrine disruption and whilst the exact mechanism has not been fully elucidated there are some proposed mechanisms but these do not involve endocrine disruption.

 

References

 

Granulomas in the livers of humans and Fischer rats associated with the ingestion of mineral hydrocarbons: a comparison. Fleming K A, Zimmerman H and Shubik P. 1998, Reg Toxicol Pharmacol 27: 75-81.