reaction mass of isomers of: C7-9-alkyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate

Endpoint summary

Description of key information

Short description of key information on bioaccumulation potential result: 
1. Expert statement
2. Prediction of metabolism by the TOXTREE modelling tool. (v2.1.0.)

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

100

Additional information

Z-72 (CASRN 125643-61-0) is described as "Benzenepropanoic acid, 3,5-bis(1,1-dimethylethyl)-4-hydroxy-, C7-C9-branched alkyl esters, with an average molecular weight of 390 g/mol for the prominent C8 alkyl structure. The new substance is poorly water soluble (< 3 x 10E-2 gm/L), with a relative high octanol/water partition coefficient (LogPow 7.18), and a very low vapour pressure (1 x 10E-5 mmHg @ 25°C).

Absorption

The physical chemical properties highlighted above suggest that Z-72 is of adequate molecular size to participate in endogenous absorption mechanisms within the mammalian gastrointestinal tract upon oral ingestion. Being highly lipophilic (LogPow 7.18) Z-72 is expected to readily cross gastrointestinal epithelial barriers, and may also participate in micellar transport into the hepatic portal system along with other lipophilic substances (e.g., dietary fats). Repeated-dose oral gavage toxicity studies in rats identified effects on the liver and thyroid which support an indeterminate degree gastrointestinal absorption of the test material after dosing. 50% of oral absorption is considered (worst-case in case of oral-to-inhalation extrapolation).

Z-72 was also tested for acute toxicity following dermal application (LD50 > 2000 mg/kg). Single-dose dermal application of the test material resulted in no manifestations of acute systemic toxicity, suggesting that absorption through cutaneous barriers is not a significant route of systemic bioavailability. 10% dermal absorption is considered due to the high lipophilicity of Z-72. The potential for inhalation toxicity was not measured for this chemical. However, the Z-72 vapour pressure 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. Due to the absence of substance-specific information on absorption by inhalation, 100% is considered (worst-case).

Distribution

Systemic distribution of Z-72 can be predicted from the physical chemical properties of this substance. The relatively high LogPow and the poor water solubility suggest that this substance, upon systemic absorption, may be transported through the circulatory system in association with a carrier molecule such as a lipoprotein or another macromolecule. The lipophilic character and the molecular size of Z-72 suggest that the molecule will readily cross cellular barriers and potentially distribute into fatty tissues. Studies in fish demonstrate that this chemical does not meet the criteria for classification as bioaccumulative. Participation in the metabolic pathways highlighted below likely limit the potential of this chemical to bioaccumulate.

Metabolism

Z-72 contains a hindered phenolic hydroxyl group, an internal carboxyl ester and alpha-olefin alkyl side chains. These types of moieties are recognized to participate in phase I oxidation/reduction and esterase cleavage, with subsequent Phase II conjugation. Data from Ames mutagenicity and chromosomal aberration testing in which Z-72 was subjected to phenobarbitone-induced rat hepatic microsomal enzyme systems revealed no evidence of genotoxic activity, suggesting that the metabolic by-products are not mutagenic or clastogenic. It is possible as well that Z-72 undergoes cutaneous metabolic transformation.

The chemical structure of the C9 -representative of the reaction mass of isomers (nonyl-3(3,5 -ditert-butyl-4 -hydroxyphenyl)propanoate) was assessed by Toxtree (v.2.1.0) modelling tool for possible metabolism. SMART Cyp is a prediction model, included in the tool, which identifies sites in a molecule that are labile for the metabolism by Cytochromes P450. Nonyl-3(3,5 -ditert-butyl-4 -hydroxyphenyl) propanote is estimated to be well metabolized by the Cytochrome P450 group of metabolizing enzymes. The molecule possesses more than three metabolizable sites. Carbon atoms of the propanoic acid moiety are the primary and secondary sites of metabolism. Secondary sites of metabolism are also parts of the benzene ring not hindered by halogens or comparable functional groups which can worsen metabolizing. The C9 alkyl chain is regarded as tertiary site. Tert-butyl branches at the benzene ring will be metabolized at last.

Excretion

The structural characteristics of Z-72 suggest that this molecule will readily undergo phase I and phase II metabolic
transformation. The resulting metabolic by-products are expected to undergo routine renal and or biliary excretion.