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

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

Fertility NOAEL is >=1000 mg/kg bw, based on read-across from Geraniol / Nerol (reaction mass; Geraniol 60): OECD TG 421.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Study duration:

subacute

Species:

rat

Quality of whole database:

The study used for read across is considered reliable (Klimisch 1 study).

Additional information

The key fertility information is based on a Reproscreen study with Geraniol / Nerol (Geraniol 60). In addition, no fertility effects were seen in the repeated dose toxicity studies of the NTP e.g. the 13 wk study) in which Geranyl (and Citronellyl) which is also used for read across to Neryl acetate multi. The Reproscreen study is presented below including the developmental toxic effects and also the read across rationale.

Screening study for reproductive/ developmental toxicity on Geraniol 60 (Geraniol 60%/Nerol 40%): OECD 421

For Geraniol (trade name Geraniol 60, which is a 60/40% mixture of trans Geraniol and its isomer cis-Nerol), were exposed by gavage to 100, 300 or 1000 mg/kg bw/day of the test item in corn oil. Based on significantly lower body weight (gain) of high-dose animals, the parental NOAEL was concluded to be 300 mg/kg bw/day. The test compound did not adversely affect fertility of the F0 generation parental animals at all dose levels as there were no changes of male/female mating and fertility indices, time until successful copulation, duration of pregnancy and mean number of implantations. Hence, the respective NOAEL for fertility is 1000 mg/kg bw/day. This results therefore in a fertility NOAEL of >=1000 mg/kg bw and a NOAEL for systemic effects based on body weight reduction of 300 mg/kg bw.

The developmental toxicity is this study showed that number of live born pups was statistically significantly decreased in high-dose females, resulting from a lower number of pups delivered total and a higher number of stillborn pups. Furthermore, the viability index indicating pup mortality during early lactation (PD 0 - 4) was reduced in the high and mid dose group. Fetal weights were reduced in the high dose group. For developmental toxicity this means that the NOAEL needs to be set at 100 mg/kg bw/day, based on decreased pup viability in the group exposed to 300 mg/kg bw/day in absence of (significant) maternal toxicity. Further toxicity information was derived in a prenatal developmental toxicity test (OECD TG 414).

The reproductive and developmental toxicity of Neryl acetate multi using read across from Geraniol/Nerol (60/40% reaction mass; Geraniol 60)

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 are no experimentalreproduction and developmental 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 reproductive toxicity of Neryl acetate multi, the analogue approach is selected because for its key metabolites Geraniol /Nerol (60/40% reaction mass also called Geraniol 60) fertility and developmental toxicity information is available that can be used for read across.

Hypothesis: Neryl acetate multi has the same fertility and developmental toxicity effects as Geraniol / Nerol (60/40 reaction mass; Geraniol 60) based on similar backbones and functional primary alcohol-group after acetate metabolisation. Conversion is not needed because the alcohol has a lower MW and therefore will present a more conservative value.

Available information from a Reproscreen study: For Geraniol /Nerol (60/40% reaction mass; Geraniol 60) an oral/gavage Reproscreen study is available according to OECD TG 421, Rel. 1. Rats were exposed by gavage to 100, 300 or 1000 mg/kg bw of the test item in corn oil. Based on significantly lower body weight (gain) of high animals, the parental NOAEL was concluded to be 300 mg/kg bw/day. The test compound did not adversely affect fertility of the parental animals at all dose levels as there were no changes of male/female mating and fertility indices, time until successful copulation, duration of pregnancy and mean number of implantations. Hence, the respective NOAEL for fertility is 1000 mg/kg bw. In this Reproscreen study some developmental toxicity was seen. The number of live born pups was statistically significantly decreased in high-dose females, resulting from a lower number of pups delivered total and a higher number of stillborn pups. Furthermore, the viability index indicating pup mortality during early lactation (PND 0 - 4) was reduced in the high and mid dose group. Foetal weights were reduced in the high dose group. Based on these effects the NOAEL for development was considered to be 100 mg/kg bw based on decreased pup viability in the group exposed to 300 mg/kg bw. In view of the effects on the pups seen further testing was performed.

Available information from a developmental toxicity study: Geraniol / Nerol (60/40% reaction mass; Geraniol 60) was tested in a developmental study according to OECD TG 414 (Rel. 1) using the same doses as in the study above: 100, 300 or 1000 mg/kg bw. In this study, the mean body weight gain of the mid and high dose dams was reduced with 13% and 14%, respectively compared to the control group. No test-substance related findings in the value calculated for the post implantation loss, the number of resorptions and viable foetuses were found.Reduced foetal body weights were found at 1000 mg/kg bw/day. Three soft tissue variations were detected, i.e. short innominate, dilated renal pelvis and dilated ureter. The incidences of dilated renal pelvis were statistically significantly increased in the mid- and high-dose groups (300 and 1000 mg/kg bw/d). As these incidences were not related to dose these were considered incidental findings. No other test-item related developmental toxicity effects were found. Based on the reduced foetal body weights at 1000 mg/kg bw and the reduced maternal weights at 1000 and 300 mg/kg bw the NOAELs are 300 and 100 mg/kg bw, respectively. 

Overallthis results in a developmental toxicity NOAEL of 300 mg/kg bw (overruling the result in the OECD TG 421 study) and a NOAEL for systemic toxicity of 100 mg/kg bw based on the OECD TG 414 study too.

Supporting information from ECHA dissemination site: Geraniol (mono constituent) was also tested also in an OECD TG 414 in which no effects were seen in foetuses and dams up to 300 mg/kg bw (EC number: 203-377-1 and CAS number: 106-24-1). Nerol (mono constituent) was tested in a dietary OECD TG 422 in which systemic toxicity NOAEL was set a 191 mg/kg bw, the fertility NOAEL at 720 and the developmental toxicity also at 191 mg/kg bw, respectively. Furthermore in an OECD TG 414 no effects on foetuses and dams were seen up to 750 mg/kg bw.

Target chemical and source chemical

Chemical structures of the target chemical and the source chemical are shown in the data matrix below, including physico-chemical properties and toxicological information, thought relevant for reproduction and developmental toxicity.

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 one impurity known, 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 the two key metabolites, as present as in the product Geraniol / Nerol (60/40%reaction mass; Geraniol 60,) was selected as and analogue because this is a reaction mass too but in a reversed order for which both fertility and developmental toxicity was available. This was given preference over the separate alcohols for which also information is available.

Structural similarities and differences: Neryl acetate multi being the acetates of Nerol and the Geraniol are Z-and E-isomers. These alcohol derivatives are the same isomers but missing the acetate group. The Geraniol Nerol (60/40% reaction mass also called Geraniol 60) has the concentration of the isomers reversed: more Geraniol instead of more Nerol.

Toxico-kinetic: Neryl acetate multi and the Geraniol Nerol (60/40% reaction mass; Geraniol 60) all have a similar high absorption potential based on molecular weights and e.g. log Kows. Metabolism: Nerol acetate multi will be cleaved by carboxyl esterases into its respective alcohols (Toxicological handbooks, Belsito et al., 2008 and Wu et al., 2010). The cleavage of this acetate is experimentally shown for Geranyl acetate as is presented in the IUCLID section 7.1.1. Therefore the systemic exposure will be to Nerol and Geraniol and the metabolic fate thereafter will be very similar and is not affected by isomerisation.

Reproductive Mode of Actions: For Neryl acetate multi the reproductive toxicity can be based on its alcohols. For Geraniol /Nerol reaction mass in the Reproscreen study it showed that the fertility was not affected up to 1000 mg/kg bw. In this study it seemed that the substance affected the developmental toxicity because pup body weight effects were seen with very limited or no maternal toxicity. A follow up OECD TG 414 study was conducted with the Geraniol / Nerol (60/40% reaction mass; Geraniol 60).

In this study maternal body weights were decreased at 1000 and 300 mg/kg bw. At 1000 mg/kg bw also pup body weight were decreased. Therefore the NOAEL for maternal toxicity was set at 100 and the NOAEL for developmental toxicity at 300 mg/kg bw. The body weight decrease is the key effects in dams and foetuses.

The potential cis-trans differences for reproductive toxicity have been accounted for by using the Geraniol/Nerol multi-constituent representing both isomers to a similar extent. In addition, the individual alcohol isomers do not indicate significant species differences: No fertility effects >=750 mg/kg bw; developmental toxicity is >=191 mg/kg bw based on OECD TG 421/422 studies.

Uncertainty of the prediction: Thereare no remaining uncertainties other than those already addressed above.

Data matrix

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

Conclusions on reproduction and developmental toxicity for hazard and risk assessment

For Neryl acetate multi no reproductive toxicity information is available but such information is available for its key metabolites Geraniol / Nerol (60/40% reaction mass; Geraniol 60), which can be used for read across to fill this gap. The current read across document shows that the results are applicable for C&L and/or risk assessment.For Geraniol /Nerol (60/40%reaction mass also called Geraniol 60) a reliable Reproscreen study is available based on which a NOAEL for fertility can be derived of >=1000 mg/kg bw. The developmental toxicity in this study is overruled with a reliable OECD TG 414 for which a NOAEL of 300 mg/kg bw is derived for developmental and 100 mg/kg bw for maternal toxicity based on body weights in both cases. This fertility and developmental toxicity information can be used for read across to Neryl acetate multi. Conversion from the alcohol to the acetate is not needed because the alcohol present a more conservative approach based on lower MW.

Final conclusion:For Neryl acetate multi the NOAEL for fertility and developmental toxicity is >=1000 and 300 mg/kg bw, respectively. The maternal NOAEL can be set to 100 mg/kg bw.

Data matrix supporting the read across to Neryl acetate multi from Geraniol (Nerol) for reproductive toxicity

Common name	Neryl acetate multi Z and E-isomer	Neryl acetate mono Z-isomer	Geranyl Acetate (E-isomer)	Geraniol / Nerol (60/40 % reaction mas; Geraniol 60)
	Target	Target                 Major constituent	Target Minor constituent	Source
Chemical name	Multi-constituent	2,6-Octadien-1-ol, 3,7-dimethyl-, (Z)-	2,6-Octadien-1-ol, 3,7-dimethyl-, (E)	Reaction mass of 2,6-Octadien-1-ol, 3,7-dimethyl-, (E) and 2,6-Octadien-1-ol, 3,7-dimethyl-, (Z)-
Chemical structure	Not applicable			(Geraniol)
% in product	>80%	55-65	35-45	60/40
CAS#	16409-44-2	141-12-8	105-87-3	106-24-1 / 106-25-2
EC#	240-458-0	205-459-2	203-341-5	906-125-5
Empirical formula	(C12H20O2)	C12H20O2	C12H20O2	C10H18O
MW	(196)	196	196	154
Phys-chem *
Appearance	Liquid	Liquid	Liquid	Liquid
Ws (mg/L)	28.8 (exp.)	18.2	18.2	>1000
log Kow	4.6 (exp.)	4.5	4.5	3.5
Human health-Reproductive toxicity
Fertility toxicity Parental toxicity NOAEL in mg/kg bw	≥ 1000 (Read across)	≥ 1000	≥ 1000	≥ 1000 300 (OECD TG 421)
Developmental toxicity Maternal toxicity NOAEL in mg/kg bw	Not used for read across			100 300 (OECD TG 421)
Developmental toxicity Maternal toxicity NOAEL mg/kg bw	300 100 (Read across)			300 100 (OECD TG 414)

* Physico-chemical properties are calculated with EpiSuite unless stated otherwise i.e. ‘(exp.), ECHA site visited May 2018.

Effects on developmental toxicity

Description of key information

Development toxicity based on read-across from Geraniol 60 (Geraniol 60/Nerol 40%) tested in an OECD TG 414 with a NOAEL of 300 mg/kg bw/d and systemic toxicity with a NOAEL of 100 mg/kg bw.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

300 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

The study used for read across is considered reliable (Klimisch 1 study).

Additional information

The development toxicity is assessed based on read-across from Geraniol 60 (Geraniol 60%/Nerol 40%), which was tested in an OECD TG 421. For developmental toxicity effects were seen in the OECD TG 421 below the systemic effects 100 and 300 mg/kg bw, respectively. Therefore also a developmental toxicity test was performed according to OECD TG 414, which resulted in a developmental NOAEL of 300 mg/kg bw and a systemic NOAEL of 100 mg/kg bw. Both studies are presented in the developmental toxicity section. The read across rationale is presented in the section 'Effects on fertility - Additional information'.

Geraniol / Nerol (reaction mass; Geraniol 60) and its developmental toxicity in the OECD TG 421

The number of live born pups was statistically significantly decreased in high-dose females, resulting from a lower number of pups delivered total and a higher number of stillborn pups. Furthermore, the viability index indicating pup mortality during early lactation (PND 0 - 4) was reduced in the high and mid dose group. Fetal weights were reduced in the high dose group. Based on these effects the NOAEL for development was considered to be 100 mg/kg bw/day, based on decreased pup viability in the group exposed to 300 mg/kg bw/day in absence of maternal toxicity. Body weight effects were seen on pups and therefore the developmental toxicity in this study at 100 mg/kg bw, which were further investigated in an OECD TG 414 study, which is presented below, overruling the foetus effects in this study.

Geraniol / Nerol (60/40 reaction mass; Geraniol 60) and its developmental toxicity in the 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, the same doses were used as in the screening study (100, 300 or 1000 mg/kg bw/day, test item in corn oil). In this study, the mean body weight gain of the mid and high dose rats was 13% and 14% below the control group and resulting in a maternal NOAEL of 100 mg/kg bw. No test-substance related findings in the value calculated for the post implantation loss, the number of resorptions and viable foetuses were found. Reduced fetal body weights were found at 1000 mg/kg bw/day. Three soft tissue variations were detected, i.e. short innominate, dilated renal pelvis and dilated ureter. The incidences of dilated renal pelvis were statistically significantly increased in the mid- and high-dose groups (300 and 1000 mg/kg bw/d). As these incidences were not related to dose, they may well be incidental findings. No other test-item related embryotoxic/teratogenic effects were found. Based on the reduced fetal body weights at 1000 mg/kg bw/day, the NOAEL for development based on this study was concluded to be 300 mg/kg bw/day. The maternal toxicity was set at 100 mg/kg bw based on reduced body weight at the high and mid dose.

Justification for classification or non-classification

For Neryl acetate multi the NOAEL for fertility is concluded to be 1000 mg/kg bw/day, based on read-across from Geraniol 60. The NOAEL for developmental effects is concluded to be 300 mg/kg bw/day, based on read-across from Geraniol 60. No classification is needed for this endpoint according to EU CLP (EC No. 1272/2008 and its amendments).