Fatty acids, tall-oil, reaction products with boric acid (H3BO3) and diethanolamine

Endpoint summary

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

The toxicokinetic profile of the test item was predicted using the physical chemical properties of the substance, the data obtained from acute and repeated-dose toxicity studies, as well as information gained from genotoxicity assays.

 

Physico-chemical properties

 

The substance is a UVCB with an average molecular weight of 669 g/moL. The substance is poorly water soluble, < 4.93 mg/L from the results of an OECD 105 study (considered to be an over-estimate for various technical reasons), with a relative high octanol/water partition coefficient, log Pow 11.7 (which is > 4, the bioaccumulation limit), and a very low vapour pressure (3.5 x 10E-04 Pa at 25 °C).

Absorption

 

Oral Route

The physical chemical properties described above indicate that the substance has a molecular size (MW > 500, notable percentage > 1000) greater than that which may be expected to be easily absorbed within the mammalian gastrointestinal tract, should that material be ingested. Being highly lipophilic but with a Log Pow > 11 (log Pow = 11.7), the substance may be expected not to cross gastrointestinal epithelial barriers, and the high MW may also significantly restrict absorption, at least of a major proportion of this UVCB. It may also participate in micellar transport into the hepatic portal system along with other lipophilic substances (e.g., dietary fats). However, an acute oral gavage toxicity study identified no evidence of toxicity (LD50 > 5000 mg/kg bw). The repeat dose and the one- generation reproductive toxicology using the oral route gave a NOAEL of 1000 mg/kg bw/day and a 90-day repeat dose toxicology study indicated a NOAEL = 250 mg/kg bw/day (the adverse effects, such as centrilobular hepatocyte enlargement in females and sinus histiocytosis of the mesenteric lymph nodes of both sexes at 1000 mg/kg bw/day were considered of low toxicological concern). The lack of significant adverse findings following oral dosing may be due to limited gastrointestinal absorption of the test material after dosing, or a very low index of inherent toxicity for this substance, and/or its metabolite(s). However, the observation of systemic effects, even if minor in nature, indicates the potential for absorption of the test item, or its metabolites, or at least some components of this UVCB substance. There is some evidence that the substance readily hydrolyses, which may occur at the amide link producing an acid and a primary amine. Depending on the MW, these could be absorbed more easily than the parent molecules.

 

Dermal Route

Regarding the dermal absorption of the substance, its rate of uptake into the stratum corneum and its rate of transfer between the stratum corneum and the epidermis are likely to be slow considering both the high MW (>500 g/mol) and the log Pow value (11.7). Moreover, it is assumed that the dermal uptake of the test item is also limited based on its low water solubility (<4.93 mg/L). These assumptions were supported by the absence of observed systemic effects following dermal application of the substance in both the acute toxicity study at up to 2000 mg/kg bw and in the 28-day repeat dose toxicity study at up to 1000 mg/kg bw/day, which is considered as the NOEL.

 

Inhalation Route

The potential for inhalation toxicity was not studied directly in a toxicology study using the inhalation route. However, the low vapour pressure of the substance (3.5 x 10E-04 Pa) indicates a very low propensity to enter atmospheric air in a respirable form. Thus, respiratory absorption under normal use and handling of this material is expected to be inconsequential. The substance is used as a component in metal working fluids and as a consequence there is a potential for exposure via the production of aerosols. In this case the absorption across the respiratory epithelium is likely to be low, because of the physicochemical properties discussed previously, and hydrolysis in the aqueous environment of the respiratory system may also occur. For route-to-route extrapolation purposes (oral-to-inhalation extrapolation), it is proposed to include a default factor of 2, i.e. the absorption percentage by oral route is half that of the inhalation absorption.

 

Distribution

 

Systemic distribution of the test item can be predicted from the physical chemical properties of this substance. The relatively high log Pow and poor water solubility suggests that this substance, upon systemic absorption, may be transported through the circulatory system in association with a carrier molecule such as a lipoprotein or other macromolecule. The lipophilic character but high Log Pow > 11 (Log Pow 11.7) and high MW of the substance suggests that a major proportion of the substance will not readily traverse cellular barriers or distribute into fatty tissues. There is no evidence such as significant systemic toxicity and/or histopathological changes or increasing severity of clinical observations from repeated dose studies, of cumulative toxicity, as would be manifested by an accumulation of the test item or metabolites in tissues. There is evidence that the substance readily hydrolyses, which may facilitate distribution.

 

Metabolism

 

The test item is a UVCB. Like most xenobiotics, the substance may be expected to undergo phase I oxidation/reduction, esterase-catalyzed hydrolysis and subsequent Phase II conjugation. Acute and repeated-dose toxicity testing provided no evidence that the substance was metabolized into toxic metabolites. Data from bacteria mutagenicity and chromosomal aberration in mammalian cells, in which the substance was subjected to rat hepatic microsomal enzyme systems didn’t show any evidence of genotoxic activity from the substance or its metabolites. Furthermore, the in vitro toxicity of the test item was reduced in the presence of metabolic enzymes. This may indicate that the metabolites may be less toxic than the substance itself or that the presence of protein may bind the substance such that the toxicity is reduced.

 

Excretion

 

The structural characteristics (the amide link and borate moiety are the probable sites in the chemical structure that are susceptible to hydrolysis) of the substance suggest that this molecule may readily undergo phase I and phase II metabolic transformation. The resulting metabolic by-products are expected to undergo routine renal and or biliary excretion.