Reaction mass of 3,7-dimethyl-1-octyl acetate and citronellyl acetate

Endpoint summary

Description of key information

Repeated dose toxicity: 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

Species:

rat

Quality of whole database:

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

Additional information

Repeated dose toxicity is assessed based on read-across from Geraniol 60 (Geraniol 60/Nerol 40%) and Geranyl (Citronellyl) Acetate and to Citronellyl Acetate Multi. The executive summaries of the source studies and additional information are presented below, followed by the read-across rationale.

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 and 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% lower than 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 studywas 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 studywith 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 Citronellyl Acetate Multi using read across from Geraniol (Citronellyl) Acetate and Geraniol (CAS# 106-24-1)

Introduction and hypothesis for the analogue approach

Citronellyl Acetate Multi is a multi-constituent. The main constituent of Citronellyl Acetate Multi is Citronellyl Acetate mono. It has an unsaturated hydrocarbon backbone to which an acetic ester is attached. The minor constituent is Dihydro-Citronellyl Acetate which has the same structure except that it has a saturated hydrocarbon backbone. 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 Citronellyl Acetate Multi, the analogue approach is selected because for its key constituent Citronellyl Acetate mono and closely related analogues, Geraniol acetate and Geraniol 60 (Geraniol/Nerol reaction mass), repeated dose toxicity information is available, which can be used for read across.

Hypothesis: Citronellyl Acetate Multi has similar repeated dose toxicity as Citronellyl Acetate mono, Geranyl Acetate and Geraniol 60 based on similarities in hydrocarbon backbone, functional groups and similar metabolites. Conversion of toxicity values is not needed because the toxicity will be derived from its metabolites and these have lower NOAELs and MW compared to the acetate and as such conservative.

Available information: Citronellyl Acetate mono was tested in a 13 wk study as a mixture in Geranyl/Citronellyl Acetate (61/29%) with similar parameters recorded as in an 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.

In addition, repeated dose toxicity information from Geraniol 60 (Reaction mass Geraniol 60/Nerol 40%), metabolites of impurities of Citronellyl Acetate mono) can be used for Citronellyl Acetate Multi 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.

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 acute oral and dermal toxicity.

Purity / Impurities

The purity and impurities of the target chemical do not indicate acute oral toxicity potential other than indicated by the parent substance. The impurities are all below < 10%.

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: The one study performed with metabolites of the impurities (Geraniol 60) is selected as key study because this study and these metabolites are considered to present conservative values for repeated dose toxicity.

Structural similarities and differences: All constituents of Citronellyl Acetate Multi, including Citronellyl Acetate mono, have a similar backbone and functional group. These are all acetate esters of a 3,7-dimethyloctanol chain only differing in the number and/or position of the unconjugated double bonds in the hydrocarbon chain.

One analogue is Geranyl Acetate/Citronellyl Acetate (61/29% as tested in the NTP repeated dose toxicity study). The minor constituent tested in the NTP study is the key constituent in the current test substance.

The other analogue used is Geraniol 60, which consists of ca 60% of geraniol (‘trans-geraniol’) and 40% Nerol (‘cis-geraniol’). These have the same similar backbone. Instead of the acetate ester a primary alcohol is the functional group.

Toxico-kinetic: Systemic exposure: Citronellyl Acetate Multi, Geranyl /Citronellyl acetate and Geraniol will give similar systemic exposure based on the similarity in backbone structure and metabolites. Metabolism: The ester bond present in the acetate ester of all components of Citronellyl Acetate Multi and Geranyl Acetate is expected to behydrolysed into the respective alcohol and acetic acid due to activity of carboxylases in e.g. gut and liver and other living ti. For Geranyl acetate this has been experimentally shown (see toxico-kinetic record). This shows that there will be no systemic exposure to the acetates.

Compared to Citronellyl Acetate Multi’ key constituents Geraniol has some more metabolites (5 and 6 versus 14 metabolites) and several of these are more reactive ones due to conjugation of the ester or alcohol bond as predicted by the OECD Toolbox, See Annex 1 and 2).

Toxico-dynamics: The effects of Citronellyl acetate Multi are expected to be body weight (gain) decrease type of effects at high doses as was seen for Geranyl/Citronellyl acetate in the NTP study and for Geraniol 60, despite that Geraniol has some more reactive metabolites compared to Citronellyl Acetate Multi’s constituents as presented in the Annexes below. Therefore the read across may be considered conservative.

Uncertainty of the prediction: There are or no uncertainties other than 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 Citronellyl Acetate Multi as such no repeated dose toxicity information is available but for its constituents/impurity or the metabolites such information is available. For Geranyl/Citronellyl Acetate and for Geraniol/ Nerol (60/40% reaction mass; Geraniol 60) there is repeated dose toxicity information which can be used for read across, can fill the data gap and the read across is adequately and reliably documented.The 13-wk information from Geranyl (and Citronellyl) acetate repeated dose (similar to OECD TG 408) fulfils most of the repeated dose parameters and a NOAEL of 2000 mg/kg bw is derived.For deriving the NOAEL for repeated dose toxicity the maternal toxicity in an OECD TG 414 with Geraniol / Nerol (60/40% reaction mass; Geraniol 60) is used because this is the lower NOAEL: 100 mg/kg bw. Conversion is not needed because the available repeated dose toxicity shows that the NOAEL for non pregnant females is higher. Also no MW conversion is needed because Geraniol 60 has the lower MW.

Final conclusion: For Citronellyl Acetate Multi the NOAEL is 100 mg/kg bw

Data matrix presenting the information relevant for read across to Citronellyl Acetate Multi from Geranyl Acetate/Citronellyl acetate and Geraniol for repeated dose toxicity

Substance	Citronellyl Acetate Multi	Citronellyl Acetate mono constituent	Dihydro-Citronellyl Acetate constituent	Geranyl acetate impurity	Geraniol (trade name: Geraniol 60)
Read-across	Target	Target	Target	Source	Source
Structure	See constituents
% in product	See constituents	60-75	10-20	<10	n.a.
CAS	See constituents	150-84-5	20780-49-8	105-87-3	106-24-1/106-25-2
EC number	904-114-0	205-775-0	244-034-6	203-341-5	906-125-5
REACH	Registered	Registered	Registered	Registered	Registered
MW	See constituents	198	200	196	154
Phys-chem
Appearance	Liquid	--	Liquid (ECHA site)	Liquid (ECHA site)	Liquid (ECHA site)
Log Kow	4.6 (exp)	4.6 (ECHA site)	4.6 (ECHA site)	4.5 (ECHA site)	3.5 (ECHA site)
Ws (mg/L)	12.1 (exp)	5.7 (ECHA site)	4.7 (ECHA site)	18.2 (ECHA site)	>1000 (ECHA site)
Vp (Pa)	2.6 (exp)	7.0 (ECHA site)	12.9 (ECHA site)	6.2 (ECHA site)	2.12 (ECHA site)
Human health
Repeated dose toxicity mg/kg bw	NOAEL: 100 (RA from Geraniol 60)	See Multi	See Multi	NOAEL: 2000 (Geranyl 61%/ Citronellyl 29 %) tested in a similar to OECD TG 408)	NOAEL: 100 (OECD TG 414)

RA = read-across.

 

Annex 1: OECD Toolbox Profiling of Citronellyl Acetate mono, Dihdro-Citronellyl Acetate and Geraniol and the metabolites

OECD Toolbox profiler for Citronellyl Acetate mono, Dihydro-Citronellyl Acetate and Geraniol

 

OECD Toolbox Metabolite profiling of metabolites of Citronellyl Acetate mono, Dihydro-Citronellyl Acetate and Geraniol

Justification for classification or non-classification

Based on the absence of adverse effects in reliable repeated dose toxicity studies, the substance does not need to be classified for repeated dose toxicity by the oral route according to EU CLP (EC No. 1272/2008, and its amendments).