Z-85

Endpoint summary

Description of key information

Minimal absorption via oral, dermal or inhalation routes of exposure is expected based on the experimental data and the physico-chemical properties of the substance. Distribution will be through blood to tissues and organs although absorption will be minimal. Metabolism and elimination are predicted to be rapid. The substance will not bioaccumulate.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

The following assessment of the toxicokinetic profile of Z-85 [EC482-100-8] Butanedioic acid, 2,3-dihydroxy-, mixed C12-16-alkyl and C13-rich C11-14-isoalkyl diesters, (2R,3R)-rel-, 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.

Analytical characterizations show that this substance meets the definition of a UVCB. This substance is a pale amber colored solid crystalline block with a separate tan-colored liquid at ambient laboratory temperature. It is used as lubricant additive.

The impurities within the notifiable substance are due to the starting materials and the result of side reactions between the tartaric acid and alcohol during the esterification.

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 amber crystalline solid with a separate tan coloured liquid. The principle component (96.5%) has a variable molecular weight of 509 to 551 and the other minor components have similar variable MWs. The substance is poorly soluble in water (less than 1 mg/L) having an experimentally determined water solubility of 0.26 mg/L at 20°C. Physical chemical testing shows that the substance is strongly hydrophobic and has a measured log PoW of 9.4 at 30°C. Consequently, the substance Log PoW is outside the range that will be easily absorbed through biological membranes, particularly as the low water solubility and high molecular weight will inhibit absorption. The substance has a negligible vapour pressure (1.2 x 10^-2Pa @ 25° C).

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 this substance is expected to be limited^1,2but 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 a proposed read-across 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 dermal irritation 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, and all animals showed expected gains in bodyweight over the study period. In a skin irritation test on the proposed read-across substance, reversible mild erythema and edema were observed but insufficient for classification as a skin irritant. Based on the toxicological evidence of a read-across substance, which has physico-chemical properties that would indicate a higher likelihood of absorption than Z-85, the test substance is likely to be minimally absorbed following dermal exposure.

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 (0.26 mg/L), is ionisable (estimated pKa -5.98), hydrophobic with the majority being strongly hydrophobic (log Kow >9.4), and with a range of molecular weight of 509 - 551. 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; modest, non dose-related, increases in liver weight in males at 500 and 1000 mg/kg bw/day. However, the effects were classified as non-adverse and were not observed in females or in the recovery groups. In vitro studies with bacteria show that the substance is non-toxic to Salmonella typhimurium when formulated in acetone. In a mammalian cell genotoxicity assayin vitrothe substance, after formulation in DMSO, was shown to be toxic in the absence and presence of metabolic activation enzymes (S9 mix). The in vitro mammalian cell study results 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).

However, it is also possible that significant absorption did not occur and the cell toxicity was due to a local irritant-type effect, perhaps exacerbated by the solvent DMSO.

Overall it is not possible to estimate what proportion of the substance is absorbed via the oral route but it is expected to be minimal.

Inhalation  

The substance is a crystalline solid with a separate liquid and has a relatively low vapour pressure (1.2 x 10^-2Pa @ 25° C; 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

Precautions have been taken to reduce exposure to this substance because it is considered to be a severe eye irritant by read-across to a similar substance; however, because there is no evidence of significant systemic exposure and no systemic toxicity it is not necessary to calculate a DNEL.     

Distribution

Once this substance is absorbed, it is expected to be distributed via the blood to the liver and other tissues; although it is likely that exposure to the liver is minimal because only minor non dose-related changes in male liver organ weights were observed in the repeat dose toxicity study. 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 will be limited. The representative structures are predicted to be not bioavailable according to the Oasis Lipinski Rules under OECD Toolbox v3.0.

Metabolism

This UVCB substance has been shown to be biodegradable and so is expected to be metabolized via a number of metabolic pathways. The OECD Toolbox v3.0 QSAR system was used to predict the metabolism of a C12 alkyl and C13 isolkyl diester representative structure. The rat liver S9 metabolism simulator predicts that the metabolism/bioaccumulation will be fast. 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 a representative structure of this UVCB substance was subjected to metabolite profiling using the OECD Toolbox v3.0 QSAR system and the predicted metabolites were partitioned into chemical categories based on USEPA rules (ECOSAR). The Toolbox predicted a total of 11 potential metabolites from the representative structure.

Elimination

The OECD Toolbox QSAR system predicts that all the metabolites will have moderate, fast or very fast bioaccumulation and metabolism half-lives and consequently it is likely that they will be eliminated very rapidly from the body.

References

1.                 Derivation of assessment factors for human health risk assessment. ECETOC Technical Repot No. 86. ISBN-0773-6347-86, Brussels, February 2003, page 13, paragraph 1.

2.                 Guidance document on dermal absorption. European Commission Sanco/222/2000 rev. 7. Page 7, paragraph 2.