Fatty acids, C14-18 and C16-18-unsatd., maleated

Endpoint summary

Description of key information

The test item (UVCB) is expected to be metabolized, high molecular weight reaction products might be excreted unchanges via feces. The test material is not expected to accumulate in the body.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

There are no studies available in which the toxicokinetic properties of the test substance were investigated. Based on the large molecular size, the absence of adverse findings in toxicity studies, and the presence of functional groups for metabolism, a potential for bioaccumulation is unlikely. Further details for this assessments are given below.

 

Chemistry

The test substance is a highly viscous UVCB of modified C14 - C18 fatty acids those water solubility (deionised water) is 74 - 243 mg/l water.The log Pow (calculated) is 6 - 8 and the material decomposes before boiling. A definite molecular weight of the substance does not exist (UVCB), the range of the molecular weight is from minimum 284 Da (saturated fatty acid) to 474 Da (modified fatty acid). With regard to the molecular structures of the substance hydrolysis may occur at low pH conditions at the acetic anhydride groups.

 

Absorption

In acute oral and dermal toxicity studies, rats were administered to an analogue test substance. No mortalities or clinical signs of toxicity were observed at dose levels of 2000 mg/kg bw, indicating primarily a very low level of oral and dermal toxicity. The NOAEL in male and female rats in a subacute oral repeated dose study on a structural analogue (OECD guideline 422) is 1000 mg/kg bw. Due to the high molecular weight of the modified fatty acid-complexes (~ 500 g/mol) gastrointestinal absorption is very limited. The single fatty acids of the UVCB mixture on the contrary may be taken up via micelles with bile acids.

Based on a model calculation (Fitzpatrick, et al., 2004) the substance is slightly skin permeable.

The test substance is highly viscous material and decomposes before boiling.This indicates that absorption of the substance via vapour inhalation is not relevant.

 

Metabolism

Single oral application of the test item (analogue) to male and female rats did not provoke any effect up to 14 days post observation period. Oral administration of the test substance to Wistar rats at doses of 100, 300 and 1000 mg/kg/day, for 28 days, resulted in no test item-related effects and no differences in food consumption or body weight development. The hematology, clinical biochemistry and urinalysis parameters did not show test item-related differences when compared with those of the controls. Organ weights of test item-treated animals were unaffected. Based on the results of this study, 1000 mg/kg/day was considered to be the no observed- adverse-effect-level (NOAEL).

Minimal liver cell hypertrophy, observed in mid- and high dose animals, was considered to be an adaptive change consequent to enhanced metabolic challenge with sustained microsomal enzyme induction resulting in centrilobular hepatocellular hypertrophy. It is suggestive that the long-term stimulation of the hypothalamic-pituitary-thyroid axis secondary to the increased clearance of thyroid hormones in the liver is likely correlated with consequent thyroid follicular cell hypertrophy in single males at 1000 mg/kg bw/day. The thyroid gland is highly sensitive to this phenomenon in rats which is particularly species-specific with no safety relevance for humans.

Stimulation of the hypothalamic-pituitary-thyroid axis and hepatocellular hypertrophy indicates systemic uptake of the substance or single components of the UVCB after oral administration and induction of phase II metabolizing enzymes (e.g. UGT).

Dermal application caused skin irritation in rats and rabbits, signs of systemic toxicity were not observed which suggests that the test item induces primarily local effects.

As mentioned before, the test material is an UVCB and consists of several compounds and reaction products. It is therefore difficult to make a detailed statement on the phase I and II metabolism. Fatty acids in general are metabolized by conjugation with acetyl-CoA and subsequent beta-oxidation. Excessive fatty acid uptake results in lipid storage. An increase in body weight, changes in food consumption or fatty changes in tissues and organs were not observed. This indicates that only a small part of the fatty acids are taken up (bolus effect) or the whole substrate is degradated and metabolized. Cyclic acid anhydrides bind to plasma proteins and haemoglobin and the primary binding amino acid appears to be lysine. This pronounced protein binding property might be an explanation for the strong skin sensitizing effect. Hexahydrophthalic anhydride is hydrolysed to the corresponding dicarboxylic acid and effectively excreted in urine. It is therefore expected that reaction products consisting of fatty acids and hexahydrophthalic anhydride are initially degradated by gastrointestinal bacteria (shortening of fatty acid chains). The downsized compound can be absorbed and metabolized by hydroxylation of the fatty acid chain residues. Subsequent conjugation by UGT and SULT and excretion via feces and urine seems plausible. An alternative scenario is a full degradation of the fatty acid residues and rapid renal excretion of hexahydrophthalic anhydride. Reaction products of high molcular weight (> 500 g/mol) are most likely not absorbed but exreted unchanged.

  

Excretion 

As described above, high molecular weight components of the UVCB are expected to be excreted unchanged via the feces. In case of gastrointestinal uptake and metabolism through hydroxylation and conjucation it is expected that the test substances might be excreted in urine and feces. Small metabolites like hexahydrophthalic dicarboxylic acid will be excreted via urine. Overall, the test material is not expected to accumulate in the body.

 

Used references:

Fitzpatrick, D., et al. (2004). "Modelling skin permeability in risk assessment-the future." Chemosphere 55 (10): 1309-14.