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

Endpoint summary

Description of key information

The NOAEL is 100 mg/kg bw, based on read-across from Geraniol 60 (Geraniol 60/Nerol 40%). Two studies are used to cover this repeated dose endpoint: The repeated dose toxicity from the OECD TG 414 developmental toxicity study of Geraniol 60 is used for deriving the NOAEL. The 13 wk study (similar to OECD TG 408) of Geranyl (Citronellyl) Acetate is used to cover the key repeated dose toxicity parameters. Since the outcomes of the OECD TG 414 study with Geraniol 60 is more conservative than the outcomes of the Geranyl (Citronellyl) Acetate study and the observed effects are similar, the Geraniol 60 study is used as the leading result for NOAEL derivation and would also conservatively reflect the effects of the 13 wk sub-chronic study.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

100 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

The study used for read across was considered reliable (Klimisch 2).

Additional information

The Neryl acetate multi NOAEL of 100 mg/kg bw is based on read across from Geraniol / Nerol (60/40% reaction mass called Geraniol 60) from an OECD TG 414 is summarised first. Thereafter the 13 wk study with the analogue Geranyl (Cit.ronellyl) acetate is presented. Finally the read across rationale will be documented.

Geraniol / Nerol (60/40% reaction mass called Geraniol 60) repeated dose effects from the developmental toxicity: OECD TG 414

For Geraniol / Nerol (60/40% reaction mass, Geraniol 60) a prenatal developmental study was performed according to OECD TG 414 and in compliance with GLP criteria. In this study, doses were 100, 300 or 1000 mg/kg bw/day, test item in corn oil. The mean body weight gain of the mid and high dose rats was 13% and 14% below the control group. Based on these findings, the NOAEL for repeated dose toxicity in this study is 100 mg/kg bw.

Geranyl (Citronellyl as a minor constituent) acetate sub-chronic repeated dose toxicity similar to OECD TG 408

In a 13-week study, which was one of pre-studies done within a carcinogenicity study, with 10 rats/sex/dose, and test doses of 0, 250, 500, 1000, 2000 and 4000 mg/kg bw/day, rats were observed for clinical signs, morbidity, and mortality twice daily; rats were weighed weekly; necropsies were performed on all animals, histological examinations were performed on control and high-dose groups. In this study no test substance-related histopathological effects or increase in tumour-incidence were noted. Since the survival and the body weight gain was decreased in the high dose group (dosed at 4000 mg/kg bw/day) in males and females, the NOAEL of the 13-week study was established to be 2000 mg/kg bw/day.

In parallel the same set of tests (including the two-year carcinogenicity study) were performed with mice. The results in the mice studies were not considered to affect the conclusion based on the rat studies.

Other available information

This 13 wk study was a pre-study for a carcinogenicity study which is shortly presented below as well as an other preliminary study.

A carcinogenicity study was conducted in which rats (n= 50/sex/dose) were exposed daily by gavage to Geranyl Acetate in corn oil at doses of 1,000 and 2,000 mg/kg bw/day for two years. Several pre-tests were performed in order to determine the final test concentrations in the carcinogenicity test. These pre-studies were reported to be performed with Geranyl Acetate containing 6-17% Citronellyl acetate mono.

In a 14-day study with 5 rats/sex/dose, with test doses of 0, 62, 125, 250, 500 and 1000 mg/kg bw/day, rats were observed for clinical signs, morbidity, and mortality twice daily; rats were weighed weekly; necropsy was performed on all animals. No mortality was seen, weight gains by dosed and control groups were comparable. The activity of all rats that received 1,000 mg/ kg bw/day decreased after dosing between days 2 and 4 of the study. No compound-related effects were observed during necropsy.

The repeated dose toxicity of Neryl acetate multi using read across from Geraniol/Nerol (60/40% reaction mass also called Geraniol 60) and Geranyl (and Citronellyl) acetate

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. For this substance no repeated dose toxicity data are available. In accordance with Article 13 of REACH, lacking information should be generated whenever possible by means other than vertebrate animal tests, i.e. applying alternative methods such as QSARs, grouping and read-across. For assessing the repeated dose toxicity of Neryl acetate multi, the analogue approach is selected because for one of Neryl acetate multi metabolites and one of its constituents repeated dose toxicity information is available from which a NOAEL is selected. These substances are Geraniol / Nerol (60/40% reaction mass also called Geraniol 60) and Geranyl (and Citronellyl) acetate.

Hypothesis: Neryl acetate multi has the same systemic toxicity as Geraniol in Geraniol / Nerol (60/40% reaction mass; Geraniol 60) and Geranyl (and Citronellyl) acetate based on similarity in chemical structure and/or similar metabolite and therefore similar toxico-dynamics.

Available information: For Geraniol / Nerol (60/40% reaction mass also called Geraniol 60) systemic toxicity is available from an OECD TG 414 in which maternal body weight decrease was seen >=300 mg/kg bw. A key NOAEL of 100 mg/kg bw was derived based on this effect. For Geranyl (and Citronellyl) acetate a 13 wk repeated dose toxicity with is available similar to OECD TG 408. A NOAEL of 2000 mg/kg bw is derived based on body weight effects (and mortality) at the next higher dose of 4000 mg/kg bw. This information fulfils the Annex VIII requirements.

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 repeated dose oral toxicity, of all substances.

Purity / Impurities

Neryl acetate multi is a multi-constituent. The other component is the E-isomer and called Geranyl acetate; together these have a purity of > 80%. There is one 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 repeated dose toxicity information is available from its key metabolites and one of its constituent that can be used for read across.

Structural similarities and differences: The Neryl acetate multi has two constituents: the acetylated versions of Nerol and Geraniol, which are each other’s Z- and E-isomers. The molecular weight is the same as well as the electrophilicity: both have a conjugated bond with the ester. Citronellyl acetate has the same unsaturated bond in the tail of the substance but not a double bond conjugated with the ester.

Toxico-kinetic: Neryl acetate multi’s constituents Neryl and Geranyl but also Citronellyl acetate have high absorption potential as do their metabolites, Nerol and Geraniol. This is based on their molecular weights and log Kows.Metabolism: Neryl acetate multi and Geranyl (and Citronellyl) acetate have the same metabolic behaviour because independent from the isomerisation the same cleavage of the ester bond will occur and result in the same (isomeric) alcohols as is experimentally shown for Geranyl acetate (see IUCLID section 7.1.1). All first metabolites are primary alcohols: Nerol/Geraniol, which can be further oxidised to acids and/or will be conjugated and as such excreted.

Toxico-dynamic:Neryl acetate multi will have the same repeated dose toxicity as Geraniol / Nerol (60/40% reaction mass also called Geraniol 60) and as Geranyl (and Citronellyl) acetate because the key effects seen in repeated dose toxicity studies is body weight decrease where Geranyl is the key constituent. ECHA dissemination site information on Nerol (CAS no.106-25-2) also shows body weight decrease as an effect resulting in a NOAEL 374 mg/kg bw in an OECD TG 422, further indicating a similar mode of action. If anything Geraniol has slightly lower NOAELs based body weight effects compared to Nerol.

Uncertainty of the prediction: Potentially cis-trans repeated dose effect differences between Neryl and Geranyl acetate are currently not identified based on information from Geranyl /Neryl acetates or their metabolites. If anything Geraniol-derivatives seem to have slightly lower systemic NOAELs and these are conservatively used for deriving the final NOAEL for Neryl acetate multi.

There are no other uncertainties than those addressed above.

Data matrix

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

Conclusions on repeated dose toxicity for hazard and risk assessment

For Neryl acetate multi no repeated dose toxicity information is available but for its metabolite Geraniol/ Nerol (60/40% reaction mass; Geraniol 60) and one of its isomers Geranyl (and Citronellyl) acetate such information is present, which can be used for read across and to fill the data gap. The present read across document shows that the result can be used forC&L and/or risk assessment From Geraniol / Nerol (60/40% reaction mass; Geraniol 60) OECD TG 414 the key maternal NOAEL of 100 mg/kg bw is derived based on body weight effects. Body weight effects are also seen for Nerol in a recent OECD TG 422 (ECHA dissemination site, resulting in a NOAEL of 374 mg/kg bw). The 13-wk information from Geranyl (and Citronellyl) acetate reliable repeated dose (similar to OECD TG 408) fulfils the repeated dose endpoint and a NOAEL of 2000 mg/kg bw. The NOAEL for systemic effects in the developmental toxicity study is conservative and is thererfore the key value for systemic toxicity.

Final conclusion: For Neryl acetate multi has a NOAEL of 100 mg/kg bw for repeated dose toxicity.

 

Data matrix supporting the read across to Neryl acetate multi from Geraniol / Nerol (60/40% reaction mass; Geraniol 60) and supported with Geranyl (Citronellyl) acetate for repeated dose toxicity

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)	Geranyl ( Citronellyl) acetate (E –isomer)
	Target	Target Major constituent	Target Minor constituent	Source	Source
Chemical name	Multi-constituent	(2Z)-3,7-dimethylocta-2,6-dien-1-yl acetate	(2E)-3,7-dimethylocta-2,6-dien-1-yl acetate	Reaction mass	Reaction mass
Chemical structure	Not applicable			Geraniol	Citronellyl acetate
% in product	>80%	55-65	35-45	60/40%	71( and 29)
CAS#	16409-44-2	141-12-8	105-87-3	106-24-1 / 106-25-2	105-87-3
EC#	240-458-0	205-459-2	203-341-5	906-125-5	Unknown
Empirical formula	C12H20O2	C12H20O2	C12H20O2	(C10H18O)	(C12H20O2)
MW	Not applicable	196	196	(154)	(196)
Phys-chem *
Appearance	Liquid	Liquid	Liquid	Liquid	Liquid
Ws (mg/L)	28.8 (exp.)	18.2 (est.)	18.2 (est.)	>1000	18.2 (est.)
log Kow	4.6 (exp.)	4.5 (est.)	4.5 (est.)	3.5	4.5
Human health
Repeated dose toxicity NOAEL mg/kg bw	100 (Read across)	100 (Read across)	100 (Read across)	100 (OECD TG 414)	2000 (Similar to OECD TG 408)

* Physico-chemical properties are calculated with EpiSuite unless stated otherwise i.e. ‘(exp.)’

Justification for classification or non-classification

For Neryl acetate multi repeated dose effects were seen but which does not warrant classification for repeated dose toxicity according to EU CLP (EC No. 1272/2008 and its amendments).