3,7-dimethylocta-2,6-dienyl acetate

Endpoint summary

Key value for chemical safety assessment

Genetic toxicity in vitro

Description of key information

Neryl acetate multi is negative for gene mutation in bacteria (Ames test) based on read-across from Neryl acetate mono, which was tested negative in an OECD TG 471.

Neryl acetate multi is negative for gene mutation in mammalian cells (CHO) based on read-across from Geraniol/Nerol (60/40% reaction mass; Geraniol 60), which was tested negative in an OECD TG 476.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (negative)

Genetic toxicity in vivo

Description of key information

Neryl acetate multi is negative in an in vivo micronucleus test based on read-across from Geraniol mono (Geraniol EXTRA, E-isomer, pure): OECD TG 474

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (negative)

Additional information

Neryl acetate multi and its genetic toxicity is based on read-across from Neryl Acetate mono and Geraniol / Nerol (60/40% reaction mass; Geraniol 60). The executive summary of the source information is presented below followed by the read-across rationale.

Neryl acetate mono and its mutagenicity in Ames

The mutagenic activity of Neryl acetate mono was evaluated in a study according to OECD TG 471 and in compliance with GLP criteria. The test was performed in two independent experiments. The substance was dissolved in DMSO and tested in concentrations of 5 to 1500 µg/plate in the absence and of 5 to 5000 µg/plate in the presence of S9. In the absence of S9-mix the substance was bacteriotoxic towards the strain TA1535 at 500 µg/plate and towards the strains TA98, TA100, TA102, and TA1537 at 1500 µg/plate. In the presence of S9-mix the substance was bacteriotoxic towards the strain TA1535 at 500 µg/plate, towards the strains TA100 and TA102 at 1500 µg/plate and towards the strains TA98 and TA1537 at 5000 µg/plate. Precipitation of the test compound in the plates was not observed. Adequate negative and positive controls were included. The substance did not induce a significant dose-related increase in the number of revertant (His+) colonies in each of the five S. typhimurium tester strains (TA1535, TA1537, TA98, TA100 and TA102), both in the absence and presence of S9-metabolic activation. These results were confirmed in independently repeated experiments. Based on the results of this study it is concluded that the substance is not mutagenic in the Salmonella typhimurium reverse mutation assay.

Geraniol / Nerol (60/40% reaction mass; Geraniol 60) and the In vitro genemutations in mammalian cells

The substance was assessed for its potential to induce gene mutations at the hypoxanthine-guanine phosphoribosyl transferase (HPRT) locus in Chinese hamster ovary (CHO) cells in vitro. Two independent experiments were carried out, both with and without the addition of liver S9 mix from induced rats (exogenous metabolic activation), up to and including the concentration of 200 µg/mL (up to and including cytotoxic concentrations). Based on the results it was concluded that the test substance did not cause any relevant increase in the mutant frequencies both without S9 mix and after adding a metabolic system in two experiments performed independently of each other. Thus, under the experimental conditions of this study, the test substance Geraniol is not mutagenic in the HPRT locus assay under in vitro conditions in CHO cells in the absence and the presence of metabolic activation.

Geraniol mono (Geraniol EXTRA) information from the in vivo micronucleus test

For Geraniol mono (trade name Geraniol EXTRA, E-Geraniol mono constituent), an in vivo Micronucleus study is available, performed according to OECD TG 474, and in compliance with GLP. In this study, mice were exposed to a single dose of 375, 750 or 1500 mg/kg bw. Clinical signs (piloerection and hunched posture) were seen in the groups exposed to the highest dose. Mice (5/group) were sacrificed at 24 and 48 hours after exposure. As no statistical significances or biologically relevant differences in the frequency of erythrocytes containing micronuclei either between the vehicle control groups and the three dose groups or between the two sacrifice intervals (24 and 48 hours) were seen it was concluded that the test item has no chromosome-damaging (clastogenic) effect nor does it lead to any impairment of chromosome distribution in the course of mitosis (aneugenic activity) in bone marrow cells of NMRI mice in vivo.

Genotoxic properties of Neryl acetate multi using read across from Neryl acetate mono (CAS# 141-12-8) and Geraniol (CAS# 106-24-1)

Introduction and hypothesis for the analogue approach

Neryl acetate multi is a multi-constituent of Neryl acetate and Geranyl acetate, which are the Z and E-isomers (cis/trans) of each other. This ester has an unsaturated branched alkyl backbone to which an acetate group is attached. For this substance there is no experimental informationon genotoxic properties. In accordance with Article 13 of REACH, lacking information can be generated by means other than experimental testing, i.e. applying alternative methods such as QSARs, grouping and read-across. For assessing the genetic toxicity of Neryl acetate multi the analogue approach is selected because for the main constituent, Neryl acetate mono, and for a close structural analogues, Geraniol / Nerol (60/40% reaction mass; Geraniol 60) and for Geraniol mono (Geraniol EXTRA) information is available which can be used for read-across.

Hypothesis: Neryl acetate multi has the same genotoxicity as Neryl acetate mono and Geraniol / Nerol (60/40% reaction mass; Geraniol 60) and as Geraniol mono (Geraniol EXTRA) based on similarities in structure and electrophilicity. 

Available information: Neryl acetate mono was negative in the Ames test (OECDTG 471, Rel. 1). Geraniol / Nerol (60/40% reaction mass; Geraniol 60) was negative in the genemutations in mammalian cells (HPRT, OECD TG 476, Rel. 1) and Geraniol mono (Geraniol EXTRA) was negative in the in vivo micronucleus test (OECD TG 474, Rel. 1). The study details are presented in the respective records.

Target chemical and source chemical(s)

Chemical structures of the target chemical and the source chemicals are shown in the data matrix, including physico-chemical properties and toxicological information, thought relevant for genotoxic properties, of all substances.

Purity / Impurities

Neryl acetate multi is a multi-constituent. The other component is the E-isomer Geranyl acetate; together these have a purity of > 80%. There is on known impurity, which is << 10% and is similar to Neryl acetate.

Analogue approach justification

According to Annex XI 1.5 read across can be used to replace testing when the similarity can be based on a common backbone and a common functional group. When using read across the result derived should be applicable for C&L and/or risk assessment and it should be presented with adequate and reliable documentation, which is presented below.

Analogue selection: For Neryl acetate multi its key constituent Neryl acetate mono is considered to be representative for the multi and for this substance an Ames test is available. For the key metabolites of Neryl acetate multi, Geraniol / Nerol (60/40% reaction mass; Geraniol 60) genemutation in mammalian cells is available and for the metabolite Geraniol mono (Geraniol EXTRA) in vivo cytogenicity are available.

Structural similarities and differences: Neryl acetate multi constituents and its respective alcohols have the same backbone containing the key features for electrophilicity: the conjugated unsaturated bond with the ester or the alcohol. The Z-and E-isomerisation does not influence in or decrease electrophilicity. The acetate ester functionality is somewhat more electrophilic compared to the alcohols.

Toxico-kinetic: Neryl acetate multi constituents and the alcohols will all have a similar high oral absorption potential due to the molecular weight and physico-chemical properties. Neryl acetate multi constituents will be metabolised into Nerol, Geraniol and acetic acid. Therefore the information on these alcohols can be used for assessing the genotoxicity.. This metabolisation has been experimentally shown for Geranyl acetate (IUCLID record 7.1.1).     

Genotoxic reactivity: Neryl acetate multi constituents and its respective alcohols have the same backbone and therefore the same electrophilic profile independent from isomerisation. This is because the unsaturated bond conjugated with the ester/alcohol site is not hindered in both isomers. The esters and alcohol show the same profile in the OECD Toolbox (v4.2, 2019). The alarm fired for acetates is related to aromatic substances and therefore not considered applicable.

Uncertainty of the prediction: There are no uncertainties other than those already discussed above. To further support the prediction Nerol is negative in the base set for in vitro genotoxicity (ECHA dissemination site: Cas no. 106-25-2).

Data matrix

The relevant information on physico-chemical properties and toxicological characteristics are presented in the Data Matrix.

Conclusions genetic toxicity

For Neryl acetate multi no genotoxicity information is available but for one of its constituents and its metabolites such information is available, which can be used for read across and adequately and reliably be documented. For Neryl acetate mono a negative Ames test is available (OECD TG 471, Rel. 1). For Geraniol /Nerol (60/40% reaction mass; Geraniol 60) a negative in vitro mammalian gene mutation study is available (OECD TG 476, Rel. 1) and for Geraniol mono (EXTRA) a negative on vivo cytogenicity test is available (OECD TG 474, micronucleus test). This information can be used for read across to Neryl acetate multi.

Final conclusion: Neryl acetate multi is negative for genemutations in bacterial and mammalian cells and is negative in vivo for cytogenicity.

Data matrix supporting the read across to Neryl acetate multi from Neryl acetate mono, Geraniol / Nerol and Geraniol for genotoxicity

Common name	Neryl Acetate Multi (Z and E-isomer)	Neryl acetate mono (Z-isomer)	Geranyl acetate (E-isomer)	Geraniol (/Nerol, (60/40 reaction mass; Geraniol 60) (E- and Z-isomer)	Geraniol mono (Geraniol EXTRA) (E-isomer)
	Target	Source	Source	Source	Source
Chemical structure	Not applicable
% in product	>80%	55-65	35-45	60/40	Not applicable
CAS#	16409-44-2	141-12-8	105-87-3	106-24-1 / 106-25-2	106-24-1
EC#	240-458-0	205-459-2	203-341-5	906-125-5	203-377-1
Empirical formula	(C12H20O2)	C12H20O2	C12H20O2	C10H18O1	C10H18O1
MW	(196)	196	196	154	154
Phys-chem*
Appearance	Liquid	Liquid	Liquid	Liquid	Liquid
Ws (mg/L)	28.8 (exp.)	18.2	18.2	>1000	>1000
log Kow	4.6 (exp.)	4.5	4.5	3.5	3.5
Human health
Genotoxicity - Ames	Negative (Read across)	Negative (OECD TG 471)	--	--	--
Genotoxicity - Genemutations in mammalian cells	Negative (Read across)	--	--	Negative (OECD TG 476)	--
Genotoxicity - In vivo MNT	Negative (Read across)	--	--	--	Negative (OECD TG 474)

* Physico-chemical properties are calculated with EpiSuite unless stated otherwise i.e. ‘(exp.); CHO-HPRT = hypoxanthine-guanine phosphoribosyl transferase (HPRT) locus in Chinese hamster ovary (CHO) cells

Justification for classification or non-classification

Based on the results presented, the substance does not need to be classified for genetic toxicity according to EU CLP (EC No. 1272/2008 and its amendments).