2,6-dimethyloct-7-en-2-yl acetate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

Dihydromyrcenyl acetate has no adverse effects on fertility based on read across from Dihydromyrcenol which was tested via feed in an OECDTG422. The NOAEL >=15000 ppm, representing a mean achieved dose of >=868.7 mg/kg bw/day (taking the lower intake of males as a conservative value).

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

No fertility toxicity data are available for Dihydromyrcenyl acetate. The results of a Repeated dose/Reproscreen study with the analogue Dihydromyrcenol is used for read across for both fertility and developmental toxicity the executive summary of the results with Dihydormyrcenol will be presented below. Thereafter the read across rationale for both reproduction endpoints will be presented.

Dihydromyrcenol Repeat/Reproscreen study

Dihdyromyrcenol is tested in an OECD TG 422 test. The repeated dose toxicity is repeated here and includes the developmental effects to present a complete picture. In the present executive summary the reproductive/developmental toxicity effects are reported following dietary administration. A similarly constituted control group was assigned, and received the vehicle, powdered SDS VRF1 certified diet with corn oil, throughout the same relative treatment period.

Reproductive females were treated daily for three weeks before pairing, throughout pairing, gestation and until Day 6 of lactation. Females were allowed to litter and rear their offspring to weaning and were killed on Day 7 of lactation. The F1 generation were killed on Day 7 of age, but did not directly receive the test substance; any exposure was in utero or via the milk. Toxicity phase males were treated daily for three weeks before pairing up to necropsy after a minimum of five consecutive weeks.

During the study, clinical condition, detailed physical examination and arena observations, sensory reactivity, grip strength, motor activity, body weight, food consumption, ophthalmic examination, haematology (peripheral blood), blood chemistry, urinalysis, oestrous cycles, pre-coital interval, mating performance, fertility, gestation length, organ weight and macroscopic pathology and histopathology investigations were undertaken. The clinical condition, litter size and survival, sex ratio,bodyweightand macropathology for all offspring were also assessed.

Results

Clinical signs: There were no adverse effects observed attributed to treatment on: clinical condition, sensory reaction, grip strength, motor activity, ophthalmic examination and macroscopic pathology.  

Other effects: Minor treatment related effects were observed for body weight, histopathology, blood chemistry and urine analysis. However, the animals showed recovery and, the survival, clinical condition and reproductive performance of the animals was unaffected by treatment, therefore they are considered not to represent an adverse effect of the treatment. In the kidney of male rats, alpha 2u-globulin nephropathy was observed. This is a male-rat-specific finding associated with the binding of xenobiotics to this protein and interference with the normal lysosomal uptake and degradation of the protein, and did not adversly affect the reproductive performance of the animals. Some histological changes were observed in the liver (portal pigment), also these effect were not considered adverse, as no effect on the survival or reproductive performance of the animals was observed and no indication of impaired liver function could be seen from the blood chemistry analyses.

Fertility effects: In the female reproductive tract, all females receiving 15000 ppm were observed to be in diestrus in comparison to the Controls and low and intermediate dosage groups. This was associated with a reduced incidence of luminal dilatation of the uterus, correlating with the stage of oestrous reported in the vagina.  This finding may be related to the test article related bodyweight effects seen in females of this dose group during treatment, but was considered to be of uncertain relationship to treatment since the oestrus cycles prior to pairing, mating performance and fertility of these females had been unaffected by treatment. Overall the reproductive endpoints assessed which were unaffected by treatment included: oestrous cycles, pre-coital interval, mating performance, fertility, gestation length, offspring clinical condition, litter size, survival, sex ratio or external development. The NOAEL for fertility was determined to be >=15000 ppm, representing mean achieved doses of >=868.7 mg/kg bw/day.

Developmental toxicity: Survival, litter size and sex ratio were not adversely affected by parental exposure to 2,6-imethyloct 7-en-2-ol. There was no difference in offspring body weight gain from Day 1-4 of age when compared with Controls; growth thereafter (Day 4-7) was lower in male and female offspring from parents receiving 15000 ppm. This low growth of the offspring was considered not to represent an adverse effect of treatment since the survival, clinical condition and macropathology findings for the offspring were not affected by reatment. There were no changes detected at examination of the offspring dying before or at scheduled termination which indication any effect of the test material.

The study indicates that there were no developmental adverse effects attributed to treatment with 2,6-dimethyloct-7-en-2-ol (dihydromyrcenol) by dietary administration. The NOAEL for developmental toxicity was therefore determined to be the highest dose tested of >=15000 ppm, representing a mean achieved dose of 975.8 mg/kg bw/day via dams during gestation.

Reproduction toxicity of Dihydromyrcenyl acetate (CAS 53767-93-4) using read across from Dihydromyrcenol (CAS 18479-58-8)

 

Introduction and hypothesis for the analogue approach

Dihydromyrcenyl acetate has a C8 alk-1-ene chain with at C2 an acetate ester group and two methyl groups at C3 and C7. For this substance no data on reproduction toxicity 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 toxicity of Dihydromyrcenyl acetate, the analogue approach is selected because for its key metabolite reproductive toxicity information is available which can be used for read across.

Hypothesis: Dihydromyrcenyl acetate has the same reproduction and developmental toxicity compared to Dihydromyrcenol its key alcohol.

Available information:For Dihydromyrcenol a Repeated dose /Reproscreen study according to OECD guideline 422 is available. Animals were exposed to 1500, 5000 and 15000 ppm of the test item via feed. Based on the results of this study it is concluded that the No-observed-adverse-effect-level (NOAEL) for reproductive/developmental effects was 15000 ppm (975.8 mg/kg bw/day, using the lowest substance intake of females).

Target chemical and source chemical(s)

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

Purity / Impurities

The purity and impurities of the target chemical do not indicate repeated dose 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: For Dihydromyrcenyl acetate Dihydromyrcenol was selected, because the acetic ester will be cleaved into Dihydromyrcenol and systemic exposure will be to the same substance e.g. Wu et al (2010).

Structural similarities and differences: Dihydromyrcenyl acetate is the acetic ester derivative of Dihydromyrcenol. The acetic acid part is not present in the source substance.

Toxico-kinetics, Absorption: Dihydromyrcenyl acetate and the source substance Dihydromyrcenol have similar absorption characteristics based on similarities in molecular weights (198 and 156, respectively). The somewhat higher log Kow for the acetate 4.9 compared to 3.25 for the alcohol will still present the same oral absorption but may present somewhat lower dermal absorption.

Metabolism:The substance will metabolise fast into Dihydromyrcenol and acetic acid via all routes because carboxyl esterases are present in all tissues. This metabolism has been experimentally shown in the gut and in the liver for Geranyl acetate (as is presented in IUCLID section 7.1.1). The acetic acid is a normal constituent of the body and will not affect the reproductive toxicity.

Toxico-dynamics:Dihydromyrcenyl acetate has the same reproductive toxicity as Dihydromyrcenol because the systemic exposure will be to Dihydromyrcenol. The acetic acid will not influence this reproductive toxicity.

Conversion of the NOAEL: A conversion based on molecular weight to Dihydromyrcenyl acetate from Dihydromyrcenol is not considered necessary because the Dihydromyrcenol presents a conservative value having the lower molecular weight.

Uncertainty of the prediction: There are no other uncertainties which are not already addressed above.

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

Conclusions for reproductive toxicity:

For Dihydromyrcenyl acetate no reproductive toxicity is available. For its key metabolite Dihydromyrcenol such information is present, which can be used for read across.When using read across the result derived should be applicable for C&L and/or risk assessment, cover an exposure period duration comparable or longer than the corresponding method and be presented with adequate and reliable documentation. This documentation is presented in the current document. For Dihydromyrcenol a Repeated dose/Reproscreen study according to OECD guideline 422 (Rel. 1) is available and a NOAEL of >= 975.8 mg/kg bw (based on female intake of the substance) for both fertility and developmental toxicity was found. These NOAELs can be applied to Dihydromyrcenyl acetate.

Final conclusion on reproductive toxicity: Dihydromyrcenyl acetate is considered to have a NOAEL for fertility and development toxicity of at least 975.8 mg/kg bw/day.

Data matrix for the read across from Dihydromyrcenol to Dihydromyrcenyl Acetate

NAME	Dihydromyrcenyl acetate	Dihydromyrcenol
	Target	Source
Chemical structure
CAS	53767-93-4	18479-58-8
EC no	258-751-7	242-362-4
REACH registered	2018	Registered
Chemical formula	C12H22O2	C10H20O
Molecular weight	198.0	156.3
Physico-chemical data
Physical state	Liquid	Liquid
Vapour pressure, Pa	14.4 Pa at 24°C (IFF, 1999)	20 Pa at 25°C ( ECHA dissemination site)
Water solubility, mg/l	6.1 mg/L at 24°C (IFF, 1999)	939 mg/L at 20°C ( ECHA dissemination site)
Log Kow	Log Pow: 4.9 (IFF, 2017)	Log Pow: 3.25 ( ECHA dissemination site)
Human health
Acute oral toxicity in mg/kg bw	LD50: >5000 (OECD TG 401 )	LD50: 3600 (OECD TG 401)
Repeated dose toxicity in mg/kg bw	868.7 (male intake) (OECD TG 422)	868.7 (male intake) (OECD TG 422)
Fertility and developmental toxicity in mg/kg bw	>=975.8 (Read across)	>=975.8 (female intake) (OECD TG 422)

 

Effects on developmental toxicity

Description of key information

Dihydromyrcenyl acetate has no adverse effects on developmental toxicity based on read across from Dihydromyrcenol which was tested via feed in an OECDTG422. The NOAEL >=15000 ppm, representing a mean achieved dose of >=868.7 mg/kg bw/day (taking the lower intake of males as a conservative value).

Effect on developmental toxicity: 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 developmental toxicity assessment is included in the fertility section above.

Justification for classification or non-classification

Based on the current data-set the substance does not need to be classified for toxicity on reproduction and development according to EU CLP (EC No. 1272/2008 and its amendments).