Reaction mass of 3,7-dimethyloct-6-en-1-yl 2-methylpropanoate and (2E)-3,7-dimethylocta-2,6-dien-1-yl 2-methylpropanoate and (2Z)-3,7-dimethylocta-2,6-dien-1-yl 2-methylpropanoate

Endpoint summary

Description of key information

Acute oral toxicity of Geranyl Isobutyrate MCS is based on read across from Citronellyl butyrate which was tested in an OECD TG 401 resulting in an LD50 >5000 mg/kg bw

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

Not reported

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Reliability has been presented as 2 because similar to OECD Guideline protocol has been followed but not GLP.

Justification for type of information:

This information is used for read across to Geranyl Isobutyrate MCS.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

yes

Remarks:

no details on test material (purity not indicated), no details on test animals and environmental conditions

GLP compliance:

no

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

not specified

Sex:

not specified

Details on test animals or test system and environmental conditions:

TEST ANIMALS
No details.

ENVIRONMENTAL CONDITIONS
No details.

Route of administration:

oral: unspecified

Vehicle:

not specified

Details on oral exposure:

No details.

Doses:

5000 mg/kg bw

No. of animals per sex per dose:

10 (no sex specified)

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: No data
- Necropsy of survivors performed: No data

Statistics:

Not performed.

Key result

Sex:

not specified

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Based on:

test mat.

Mortality:

Three animals died on day 1.

Clinical signs:

Slow respiration, lethargy and death overnight.

Body weight:

No data.

Dose mg/kg	No. of deaths	Observation day
		1	2	3	4	5	6	7	8	9	10	11	12	13	14
5000	0/10	3	0	0	0	0	0	0	0	0	0	0	0	0	0

Interpretation of results:

other: Not acute harmful

Remarks:

according to EU CLP (EC No. 1272/2008 and its amendments).

Conclusions:

An LD50 of >5000 mg/kg bw was determined in this acute oral toxicity study with rats.

Executive summary:

In an acute oral toxicity study one group of 10 rats was orally exposed to 5000 mg/kg bw of the substance. The rats were observed for signs of toxicity and clinical signs for a period of 14 days. Three animals died on day 1 of the observation period. Slow respiration and lethargy was observed. Based on the results, an LD50 of > 5000 mg/kg bw was determined in the acute oral toxicity study with rats.

Reference 2

Endpoint:

acute toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

2018

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Read-across information.

Justification for type of information:

The read across justification is presented in the Endpoint summary Acute toxicity. The accompanying files are also attached there.

Reason / purpose for cross-reference:

read-across source

Key result

Sex:

not specified

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Based on:

test mat.

Interpretation of results:

other: Not acute harmful

Remarks:

according to EU CLP (EC No. 1272/2008 and its amendments).

Conclusions:

The LD50 value for the substance is >5000 mg/kg bw, based on the results of the source substance.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

The acute oral toxicity result is of sufficient quality and adequate for this dossier.

Additional information

Acute oral toxicity of Geranyl Isobutyrate MCS is based on read-across from Citronellyl butyrate. The executive summary of the Citronelly butyrate is presented below followed by the read-across rationale.

Citronellyl butyrate: Acute oral toxicity, source information:

In an acute oral toxicity study one group of 10 rats was orally exposed to 5000 mg/kg bw of the substance. The rats were observed for signs of toxicity and clinical signs for a period of 14 days. Three animals died on day 1 of the observation period. Slow respiration and lethargy was observed. Based on the results, an LD50 of > 5000 mg/kg bw was determined in the acute oral toxicity study with rats.

The acute toxicity of Geranyl Isobutyrate MCS based on read across from data available for Citronellyl butyrate (CAS #141-16-2)

 

Introduction and hypothesis for the analogue approach

Geranyl Isobutyrate MCS consists of 4 constituents which areIsobutyrate esters of a 3,7-dimethyloctanol chain and can be divided into two subgroups based on the number of unsaturated bonds. The Geranyl-type subgroup consists of two isomers of Geranyl Isobutyrate which have two double bonds in the chain and are present at a total of 70%. The Citronellyl-type subgroup consists of Citronellyl Isobutyrate, which has one double bond in the chain and is present at ca. 25% and a Citronellyl like component without a double bond which is present at <5%.

For Geranyl Isobutyrate MCS there are no acute toxicity data 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 acute oral toxicity of Geranyl Isobutyrate MCS, the analogue approach is selected because for structural analogue, Citronellyl butyrate, acute oral toxicity data is available which can be used for read across.

Hypothesis:The acute toxicity of Geranyl Isobutyrate MCS is the same as for Citronellyl butyrate.

Available information:For Citronellyl butyrate data is available from a study by Moreno (RIFM, 1972). The LD50 in the rat is >5000 mg/kg bw. The data is assigned reliable with restrictions (Klimisch 2).

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 available toxicologicalinformation. Furthermore, a full list of constituents of Geranyl Isobutyrate MCS, including information relevant for read-across, is given in Appendix 1.

Purity / Impurities

The unidentified impurities of Geranyl Isobutyrate MCS are not considered to have a significant influence on the acute oral toxicity.

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.

Analogue selection: For Geranyl Isobutyrate MCS the analogueCitronellyl butyrate was selected because it has the same backbone and functional group and for Citronellyl butyrate acute oral toxicity information is available.

Structural similarities and differences: Geranyl Isobutyrate MCS is similar to Citronellyl butyrate because they have the same 3,7-dimethyloctanol chain and a butyric ester. One difference is that Geranyl Isobutyrate has several constituents with two double bonds while Citronellyl butyrate has only one. The other difference is that the Isobutyrate ester in Geranyl is a straight butyrate ester in Citronellyl butyrate.

Toxico-kinetic: The oral absorption will be the same for both Geranyl Iso- and Citronellyl butyrate because the molecular weight is the same and these substances have similar (estimated) water solubility and Log K_ow,which is still in the favourable range for uptake.Metabolism: Geranyl Isobutyrate MCS and Citronellyl butyrate are both enzymatically hydrolysed rapidly in the intestine before absorption and/or the liver after absorption (Longland, 1977), resulting in 3,7-dimethyloctanol with a varying number of double bonds. These terpene-type alcohols formed, such as Geraniol and Citronellol, and their unsaturated analogues exhibit similar pathways of metabolism in animals resulting in participation in normal fatty acid metabolism and excretion in the urine, as such or as glucuronic acid conjugates (EFSA, 2008). The corresponding butyric and Isobutyric acid formed are also produced when dietary fibre is fermented in the colon and are not anticipated to influence the acute oral toxicity to a significant extent.

Toxico-dynamics: The reactive site in Geranyl Isobutyrate MCS and Citronellyl butyrate is the alkyl ester group which is present in bot substances and all constituents. As presented in the kinetic section the additional double bond in the Geraniol-type will not cause additional toxicity.

Uncertainty of the prediction: Geranyl Isobutyrate MCS constituents which have a conjugated double bond with the ester may cleave slightly faster, because the ester becomes more electronegative. The cleavage of the ester bond will be complete in the intestines and therefore the rated of this cleavage will not affect the acute oral toxicity. Besides this, there are no other remaining uncertainties.

Data matrix

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

Conclusions per endpoint for hazard and risk assessment

For Geranyl Isobutyrate MCS there is no acute oral toxicity information available. The information is derived from read across of Citronellyl butyrate. When using read across the result derived should be applicable for C&L and/or risk assessment and be presented with adequate and reliable documentation. The documentation is present in the current read across document. For Citronellyl butyrate a well conducted acute oral toxicity test (Reliability 2) with a LD50 of > 5000 mg/kg bw is available. Based on the reasoning above for Geranyl Isobutyrate MCS an LD50 of > 5000mg/kg bw can be derived for the endpoint acute oral toxicity.

Final conclusion on hazard and risk assessment:

Geranyl Isobutyrate MCS has an LD50 of > 5000 mg/kg bw.

 

Data matrix for the read across of Geranyl Isobutyrate MCS from Citronellyl butyrate

Common name	Geranyl Isobutyrate MCS	Citronellyl butyrate
Chemical name	n.a.	3,7-dimethyloct-6-en-1-yl butanoate
	Target	Source
Chemical structures	For a full list of constituents, see Appendix 1.
REACH	2018	Registered
CAS #	--	141-16-2
EC #	905-357-4	205-463-4
Empirical formula	n.a.	C14H26O2
SMILES	n.a.	CCCC(=O)OCCC(C)CCC=C(C)C
Physico-chemical data
Molecular weight	n.a.	226
Physical state	Liquid	Liquid
Log Kow	5.7 (exp.)	5.54 (est.)
Ws (mg/L)	17.4 (exp.)	1.63 (est.)
Vp (Pa)	1.2 (exp.)	6.2 (est.)
Human health endpoints
Acute oral	Read across: LD50 >5000 mg/kg bw	LD50 >5000 mg/kg bw (OECD TG 423)

 

References:

EFSA, 2000, Scientific Opinion of the Panel on Food Additives, Flavourings, Processing Aids and Materials in contact with Food (AFC) on a request from the Commission Flavouring Group Evaluation 6, Revision 1 (FGE.06Rev 1): Flavouring Group Evaluation 6, Revision 1 (FGE.06Rev1): Straight- and branched-chain aliphatic unsaturated primary alcohols, aldehydes, carboxylic acids, and esters from chemical groups 1 and 4 (Commission Regulation (EC) No 1565/2000 of 18 July 2000). The EFSA Journal (2008) 616, 1-74.

 

Longland, R.C., Shilling, W.H. & Gangolli, S.D. (1977) The hydrolysis of flavouring esters by artificial gastrointestinal juices and rat tissue preparations. Toxicology, 8, 197–204.

 

Appendix 1. Data matrix for the constituents of Geranyl isobutyrate MCS and Citronellyl butyrate

Common names	Geranyl isobutyrate MCS				Citronellyl butyrate
Constituent	1	2	3	4
Constituents	3,7-dimethyloctyl 2-methylpropanoate	3,7-dimethyloct-6-en-1-yl 2-methylpropanoate	(2Z)-3,7-dimethylocta-2,6-dien-1-yl 2-methylpropanoate	(2E)-3,7-dimethylocta-2,6-dien-1-yl 2-methylpropanoate	3,7-dimethyloct-6-en-1-yl butanoate
Chemical structures
CAS no	71662-25-4	97-89-2	2345-24-6	2345-26-8	141-16-2
Concentration range	3.7	25	14	56
Empirical formula	C14H28O2	C14H26O2	C14H24O2	C14H24O2	C14H26O2
Molecular weight	228	226	224	224	226
Physico-chemical data*
Water solubility, mg/l	0.56	0.68	0.82	0.82	0.59
Log Kow	5.6	5.5	5.4	5.4	5.5

* Episuite v4.11

 

 

Justification for classification or non-classification

Based on the results, the substance does not need to be classified for acute oral toxicity according to EU CLP (EC No. 1272/2008 and its amendments).