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

For Citronellyl Acetate Multi, the fertility and development toxicity is assessed based on read-across from Geraniol 60 (Geraniol 60%/Nerol 40%), which was tested bin an OECD TG 421. For fertility no adverse effects was observed on fertility and the NOAEL was >= 1000 mg/kg bw/d. For developmental toxicity effects were seen in the OECD TG 421 below the sysemic 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. The latter study is presented in the developmental toxicity section.

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 Citronellyl Acetate Multi using read-across from 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 saturated hydrocarbon backbone. For Citronellyl Acetate Multi no reproduction 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 in vitro tests, QSARs, grouping and read-across. For assessing the reproduction and developmental toxicity of Citronellyl Acetate Multi the analogue approach is selected because for a close structural related metabolite, Geraniol/Nerol (60/40%, Geraniol 60), information is available which can be used for read-across.

Hypothesis: Citronellyl Acetate Multi has similar reproductive and developmental toxicity, resulting in the same NOAEL as Geraniol/Nerol (Geraniol 60) based on the metabolisation of Citronellyl Acetate Multi into similar metabolites as Geraniol.

Available information:Screening study for reproductive/ developmental toxicity: For Geraniol (Geraniol/Nerol (60/40%, Geraniol 60), data is available from a study according to OECD TG 421 and in compliance with GLP criteria. In this study, rats 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 dosed 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 for the reaction mass of geraniol and Nerol, whereas the NOAEL for systemic effects is lower. 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/day, based on decreased pup viability in the group exposed to 300 mg/kg bw/day in absence of maternal toxicity. Further work was done on the developmental toxicity in view of the lower NOAEL for developmental toxicity compared to maternal toxicity.

Available information, Prenatal developmental toxicity study: For 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 Reproscreening study, OECD TG 421 (100, 300 or 1000 mg/kg bw/day, test item in corn oil).

Maternal toxicity: In this study, the mean body weight gain of the mid and high dose dams were 13% and 14% below the control group and considered adverse. The NOAEL for maternal toxicity was considered 100 mg/kg bw.

Developmental toxicity: 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). As these incidences were not related to dose, they may well be incidental findings. No other test-item related developmental toxicity was found. Based on the reduced fetal body weights at 1000 mg/kg bw/day, the NOAEL for development was concluded to be 300 mg/kg bw/day.

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 reproduction and developmental toxicity, of all substances.

Purity / Impurities

The purity and impurities of the target chemical do not indicate reproductive/developmental 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 acetate ester groups of all the constituents of Citronellyl Acetate Multi are expected to be rapidly metabolised(see section toxico-kinetic) under formation ofthe corresponding alcohols and acetic acid. Geraniol/Nerol is a structurally related to these alcohols of Citronellyl Acetate Multi constituents.

Structural similarities and differences: All constituents of Citronellyl Acetate Multi, including Citronellyl Acetate mono, are 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. Geraniol 60 consists for ca 60% of geraniol (‘trans-geraniol’) and 40% nerol (‘cis-geraniol’), both sharing a common hydrocarbon backbone with the target chemical but with one or two additional double bonds. The acetate functionality in Citronellyl Acetate Multi is not present and is a primary alcohol in the analogue Geraniol 60.

Toxico-kinetic, systemic exposure: The source chemical and the target chemical indicate similar absorption based on the similarity in chemical backbone structure and metabolites.Metabolism: The ester bond present in the acetate ester of all components of Citronellyl Acetate Multi will behydrolysed into the respective alcohol and acetic acid due to activity of carboxylases in the gut and liver. For Geranyl Acetate this has been experimentally shown (see toxico-kinetic record). This further shows that there will be no acetate in the systemic circulation. Geraniol has some more and more reactive metabolites as predicted by the OECD Toolbox, See Annex 1 and 2).

Toxico-dynamics: The effects of Citronellyl Acetate Multi are maternal body weight (gain) decrease > 100 mg/kg bw, fetal and pup body weight at doses >=300 mg/kg bw as is found for Geraniol. The acetic acid formed is a natural constituent of the body and is not anticipated to induce an adverse effect on reproduction and development under normal conditions and does not needs to be considered. The additional and sometimes somewhat more reactive metabolites of Geraniol may indicate a conservative approach when used for read across to Citronellyl Acetate Multi.

Uncertainty of the prediction: There are no other 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 Citronellyl Acetate Multi as such no reproductive toxicity (fertility and developmental) toxicity is available. For a structurally related metabolite Geraniol 60 (Geraniol-trans/Nerol-cis form) such information is available which can be used for read across and can be adequately and reliably be documented. For Geraniol reliable reproduction and developmental toxicity data is available from studies according to OECD TG 421 and a follow up study to distinguish maternal and developmental toxicity an OECD TG 414 was performed. From these studies, the NOAEL values for systemic toxicity was 100 mg/kg bw (OECD TG 414), for fertility it was > 1000 mg/kg bw/day (OECD TG 421) and the NOAEL for development was found to be 300 mg/kg bw/day (OECD TG 414).

Final conclusion:For Citronellyl Acetate Multi the NOAEL for systemic toxicity is 100, for fertility it is > 1000 and for developmental toxicity it is 100 mg/kg bw, respectively.

Data matrix presenting the information relevant for read across to Citronellyl Acetate Multi from Geraniol for reproductive toxicity

Substance	Citronellyl Acetate Multi	Citronellyl Acetate mono constituent	Dihydro-Citronellyl Acetate constituent	Geraniol/Nerol (trade name: Geraniol 60)
Read-across	Target	Target	Target	Source
Structure *	See constituents
% in product		60-75	10-20	Ca 60/40
CAS	See constituents	150-84-5	20780-49-8	106-24-1 /106-25-2
EC	904-114-0	205-775-0	244-034-6	906-125-5
MW	See constituents	198	200	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)	3.5 (ECHA site)
Ws (mg/L)	12.1 (exp)	5.7(ECHA site)	4.7 (ECHA site)	>1000 (ECHA site)
Vp (Pa)	2.6 (exp)	7.0 (ECHA site)	12.9 (ECHA site)	2.12 (ECHA site)
Human health
Repeated dose Mg/kg bw	100			300 (OECD TG 421); 100 (OECD TG 414)
Fertility toxicity NOAEL mg/kg bw	≥ 1000 (RA, Geraniol 60)	See Multi	See Multi	≥ 1000 (OECD TG 421)
Developmental toxicity NOAEL	100 (RA, Geraniol 60)	See Multi	See Multi	100 (OECD TG 421); 300 (OECD TG 414)

RA = read-across.

 

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

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 Citronellyl 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/d, 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).