4-methyl-3-decen-5-ol

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Remarks:

16 Week Study

Type of information:

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

Adequacy of study:

weight of evidence

Study period:

Not reported

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

A valid study is available for the analogous substance geraniol extra, a reaction mass of geraniol and linalool (3,7-Dimethyl-2,6-octadienol and 3,7-Dimethyl-1,6-octadienol). A non-GLP study performed to sound scientific principles with a sufficient level of detail to assess the quality of the submitted data. The read-across is considered to be suitable based on the structural and “mechanistic action” similarities between the target substance (4-methyl-3-decen-5-ol) and source substance (reaction mass of geraniol and linalool) and their similar physico-chemical properties.

Justification for type of information:

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
This read-across is based on the hypothesis that the target substance and 1 source substances have the same expected mode of action and similar physicochemical properties relevant for the read-across endpoints.
The justification of the proposed read-across to geraniol is discussed in the attached RAAF document.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
The target substance (undecavertol) is a mono-constituent substance (EC 279-815-0, CAS 81782-77-6). The typical concentration of the single constituent is 98.0%.
The source substance geraniol (EC 203-377-1, CAS 106-24-1) is a mono-constituent substance. The typical concentration of the mono-constituents is 97.0%.
The target substance and the source substance do not contain any impurities present at ≥ 1%. The purity of the test items within the respective REACH registration dossiers for undecavertol and for geraniol indicates purity > 97.0% with no impurities > 1%.

3. ANALOGUE APPROACH JUSTIFICATION
The structures of the target and source substance are provided in Table 1 (RAAF document). The target substance and the source substance have been characterised in this table using the categories and databases present in the OECD [Q]SAR Toolbox. From the profiling provided (Table 1 - (RAAF document)), it can be seen that the 2 substances share structural similarities and also mechanistic actions which are both general and endpoint specific. This supports the hypothesis that the target and source substances have similar properties as a result of structural similarity and the same expected mode of action.
The OECD toolbox predicts all substances to be of low toxicity according to Cramer classes and both substances show no alerts according to DART Scheme v1.0.
Undecavertol and geraniol are structurally similar substances. The primary route of metabolism for undecavertol is aliphatic c-oxidation followed by either o-glucoronidation or beta oxidation. Geraniol is metabolised via epxoidation foolwed by aliphatic c-oxidation. This is supported by the most probable route of metabolism prediction of TIMES v.2.27.17 (rat in vivo model) as illustrated in the RAAF document..

4. DATA MATRIX
Please see the RAAF document.

Cross-reference

Reference

Endpoint:

sub-chronic toxicity: oral

Remarks:

16 Week Study

Type of information:

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

Adequacy of study:

weight of evidence

Study period:

Not reported

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

A valid study is available for the analogous substance geraniol extra, a reaction mass of geraniol and linalool (3,7-Dimethyl-2,6-octadienol and 3,7-Dimethyl-1,6-octadienol). A non-GLP study performed to sound scientific principles with a sufficient level of detail to assess the quality of the submitted data. The read-across is considered to be suitable based on the structural and “mechanistic action” similarities between the target substance (4-methyl-3-decen-5-ol) and source substance (reaction mass of geraniol and linalool) and their similar physico-chemical properties.

Justification for type of information:

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
This read-across is based on the hypothesis that the target substance and 1 source substances have the same expected mode of action and similar physicochemical properties relevant for the read-across endpoints.
The justification of the proposed read-across to geraniol is discussed in the attached RAAF document.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
The target substance (undecavertol) is a mono-constituent substance (EC 279-815-0, CAS 81782-77-6). The typical concentration of the single constituent is 98.0%.
The source substance geraniol (EC 203-377-1, CAS 106-24-1) is a mono-constituent substance. The typical concentration of the mono-constituents is 97.0%.
The target substance and the source substance do not contain any impurities present at ≥ 1%. The purity of the test items within the respective REACH registration dossiers for undecavertol and for geraniol indicates purity > 97.0% with no impurities > 1%.

3. ANALOGUE APPROACH JUSTIFICATION
The structures of the target and source substance are provided in Table 1 (RAAF document). The target substance and the source substance have been characterised in this table using the categories and databases present in the OECD [Q]SAR Toolbox. From the profiling provided (Table 1 - (RAAF document)), it can be seen that the 2 substances share structural similarities and also mechanistic actions which are both general and endpoint specific. This supports the hypothesis that the target and source substances have similar properties as a result of structural similarity and the same expected mode of action.
The OECD toolbox predicts all substances to be of low toxicity according to Cramer classes and both substances show no alerts according to DART Scheme v1.0.
Undecavertol and geraniol are structurally similar substances. The primary route of metabolism for undecavertol is aliphatic c-oxidation followed by either o-glucoronidation or beta oxidation. Geraniol is metabolised via epxoidation foolwed by aliphatic c-oxidation. This is supported by the most probable route of metabolism prediction of TIMES v.2.27.17 (rat in vivo model) as illustrated in the RAAF document..

4. DATA MATRIX
Please see the RAAF document.

Qualifier:

no guideline followed

Principles of method if other than guideline:

The subchronic toxicity of the test material to rats was determined in a screening study on 48 food flavourings. Commercially available materials were used, rather than pure chemicals, since the purpose of the study was to evaluate the toxicity of these materials in relation to their use as food additives. Rats were exposed to the test material at 10,000 ppm in their diet over a period of 16 weeks. General condition, bodyweight, food consumption were recorded on a weekly basis. At termination blood samples were collected for haematology examination. Subsequently all rats were sacrificed for gross necropsy and histopathology. A control group was run concurrently.

GLP compliance:

not specified

Limit test:

yes

Species:

rat

Strain:

Osborne-Mendel

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS- Housing: animals were housed individually in wire cages.- Age at study initiation: Weanling rats- Diet: ad libitum.- Water: ad libitum.

Route of administration:

oral: feed

Vehicle:

not specified

Remarks:

assumed to be unchanged

Details on oral exposure:

DIET PREPARATION- Rate of preparation of diet: Fresh diet was prepared and distributed weekly.

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

16 weeks.

Frequency of treatment:

Daily

Dose / conc.:

1 000 mg/kg diet

Remarks:

Doses / Concentrations:10,000 ppmBasis:nominal in diet

No. of animals per sex per dose:

Five animals per sex per dose were treated with the test material. 10 animals per sex were included in the control group.

Control animals:

yes

Details on study design:

- Rationale for animal assignment: Randomised by weight

Observations and examinations performed and frequency:

DETAILED CLINICAL OBSERVATIONS: Yes- Time schedule: weekly.BODY WEIGHT: Yes- Time schedule for examinations: weekly.FOOD CONSUMPTION AND COMPOUND INTAKE: Yes- Food consumption for each animal determined weekly.HAEMATOLOGY: Yes- Time schedule for collection of blood: at termination.- Parameters checked: white blood cell counts, red cell counts, haemoglobin and haematocrit.

Sacrifice and pathology:

GROSS PATHOLOGY: Yes, at termination all rats were sacrificed and exsanguinated and the tissues were examined macroscopically. The viscera were removed and the liver, kidneys, spleen, heart, and testes were weighed.The tissues of rats which died during the study were examined for gross changes and were preserved if autolysis was not advanced. Organs were not weighed but abnormalities and suspected causes of death were recorded.HISTOPATHOLOGY: Yes, the organs listed above and the remaining abdominal and thoracic viscera, the bone, bone marrow and muscle from one hind leg, were all submitted for histopathology. Tissues were preserved in 10% buffered formalin-saline solution. Sections were embedded in paraffin wax and stained with haematoxylin and eosin.Microscopic examinations were performed on 6 or 8 rats, equal numbers of each sex.

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not examined

Details on results:

ANALOGUE APPROACH JUSTIFICATION:- See attached “Justification for read-across” document for full details.- In summary, important considerations for the use of read-across for repeated dose toxicity are: i) 4-methyl-3-decen-5-ol (the target substance) has similar physico-chemical properties to Geraniol Extra (a reaction mass of Geraniol (2E)-3,7-dimethylocta-2,6-dien-1-ol and Linalool 3,7-dimethylocta-4,6-dien-3-ol (the source substance), ii) there are structural similarities between the two chemicals and iii) the OECD QSAR Toolbox assigns an identical toxicity profile to both chemicals. The source substance is therefore considered suitable for classification and labelling and risk assessment purposes using a read-across approach (see Justification for read-across in Section 13).

Dose descriptor:

NOEL

Effect level:

10 000 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No effects on growth, haematology, macroscopic or microscopic changes in tissue were noted in any of the exposed animals.

Critical effects observed:

not specified

Conclusions:

Under the conditions of the test, no treatment related effects on growth, haematology, macroscopic or microscopic changes in tissue were noted in any of the exposed animals at 10,000 ppm. Therefore the NOEL can be said to be the maximum concentration tested, 10,000 ppm (equivalent to 10,000 mg/kg diet).

Executive summary:

The subchronic toxicity of the test material to rats was determined in a screening study on 48 food flavourings. Commercially available materials were used, rather than pure chemicals, since the purpose of the study was to evaluate the toxicity of these materials in relation to their use as food additives. Rats were exposed to the test material at 10,000 ppm in their diet over a period of 16 weeks. General condition, bodyweight and food consumption were recorded on a weekly basis. At termination blood samples were collected for haematology examination. Subsequently all rats were sacrificed for gross necropsy and histopathology. A vehicle control group was run concurrently.

Under the conditions of the test, no treatment related effects on growth, haematology and macroscopic or microscopic changes in tissue were noted in any of the exposed animals. Therefore the NOEL can be said to be the maximum concentration tested, 10,000 ppm (equivalent to 10,000 mg/kg diet).

Important considerations for the use of read-across for repeated dose toxicity are: i) 4-methyl-3-decen-5-ol (the target substance) has similar physico-chemical properties to Geraniol Extra (a reaction mass of Geraniol (2E)-3,7-dimethylocta-2,6-dien-1-ol and Linalool 3,7-dimethylocta-4,6-dien-3-ol (the source substance), ii) there are structural similarities between the two chemicals and iii) the OECD QSAR Toolbox assigns an identical toxicity profile to both chemicals. The source substance is therefore considered suitable for classification and labelling and risk assessment purposes using a read-across approach (see Justification for read-across in Section 13).

Data source

Reference

Reference Type:

publication

Title:

Food Flavourings and Compounds of Related Structure. II. Subacute and Chronic Toxicity

Author:

Hagna EC, Hansen WH, Fitzhugh OG, Jenner PM, Jones WI, Taylor JM, Long EL, Nelson AA & Brouwer JB

Year:

1996

Bibliographic source:

Food and Cosmetics Toxicology. Volume 5, pp. 141-157, Pergamon Press 1967

Report date:

1996

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

The subchronic toxicity of the test material to rats was determined in a screening study on 48 food flavourings. Commercially available materials were used, rather than pure chemicals, since the purpose of the study was to evaluate the toxicity of these materials in relation to their use as food additives. Rats were exposed to the test material at 10,000 ppm in their diet over a period of 16 weeks. General condition, bodyweight, food consumption were recorded on a weekly basis. At termination blood samples were collected for haematology examination. Subsequently all rats were sacrificed for gross necropsy and histopathology. A control group was run concurrently.

GLP compliance:

not specified

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

Geraniol extra, the reaction mass of geraniol and linalool (3,7-Dimethyl-2,6-octadienol and 3,7-Dimethyl-1,6-octadienol)

IUPAC Name:

Geraniol extra, the reaction mass of geraniol and linalool (3,7-Dimethyl-2,6-octadienol and 3,7-Dimethyl-1,6-octadienol)

Test material form:

not specified

Test animals

Species:

rat

Strain:

Osborne-Mendel

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS- Housing: animals were housed individually in wire cages.- Age at study initiation: Weanling rats- Diet: ad libitum.- Water: ad libitum.

Administration / exposure

Route of administration:

oral: feed

Vehicle:

not specified

Remarks:

assumed to be unchanged

Details on oral exposure:

DIET PREPARATION- Rate of preparation of diet: Fresh diet was prepared and distributed weekly.

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

16 weeks.

Frequency of treatment:

Daily

Doses / concentrations

Dose / conc.:

1 000 mg/kg diet

Remarks:

Doses / Concentrations:10,000 ppmBasis:nominal in diet

No. of animals per sex per dose:

Five animals per sex per dose were treated with the test material. 10 animals per sex were included in the control group.

Control animals:

yes

Details on study design:

- Rationale for animal assignment: Randomised by weight

Examinations

Observations and examinations performed and frequency:

DETAILED CLINICAL OBSERVATIONS: Yes- Time schedule: weekly.BODY WEIGHT: Yes- Time schedule for examinations: weekly.FOOD CONSUMPTION AND COMPOUND INTAKE: Yes- Food consumption for each animal determined weekly.HAEMATOLOGY: Yes- Time schedule for collection of blood: at termination.- Parameters checked: white blood cell counts, red cell counts, haemoglobin and haematocrit.

Sacrifice and pathology:

GROSS PATHOLOGY: Yes, at termination all rats were sacrificed and exsanguinated and the tissues were examined macroscopically. The viscera were removed and the liver, kidneys, spleen, heart, and testes were weighed.The tissues of rats which died during the study were examined for gross changes and were preserved if autolysis was not advanced. Organs were not weighed but abnormalities and suspected causes of death were recorded.HISTOPATHOLOGY: Yes, the organs listed above and the remaining abdominal and thoracic viscera, the bone, bone marrow and muscle from one hind leg, were all submitted for histopathology. Tissues were preserved in 10% buffered formalin-saline solution. Sections were embedded in paraffin wax and stained with haematoxylin and eosin.Microscopic examinations were performed on 6 or 8 rats, equal numbers of each sex.

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not examined

Details on results:

ANALOGUE APPROACH JUSTIFICATION:- See attached “Justification for read-across” document for full details.- In summary, important considerations for the use of read-across for repeated dose toxicity are: i) 4-methyl-3-decen-5-ol (the target substance) has similar physico-chemical properties to Geraniol Extra (a reaction mass of Geraniol (2E)-3,7-dimethylocta-2,6-dien-1-ol and Linalool 3,7-dimethylocta-4,6-dien-3-ol (the source substance), ii) there are structural similarities between the two chemicals and iii) the OECD QSAR Toolbox assigns an identical toxicity profile to both chemicals. The source substance is therefore considered suitable for classification and labelling and risk assessment purposes using a read-across approach (see Justification for read-across in Section 13).

Effect levels

Dose descriptor:

NOEL

Effect level:

10 000 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No effects on growth, haematology, macroscopic or microscopic changes in tissue were noted in any of the exposed animals.

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

Under the conditions of the test, no treatment related effects on growth, haematology, macroscopic or microscopic changes in tissue were noted in any of the exposed animals at 10,000 ppm. Therefore the NOEL can be said to be the maximum concentration tested, 10,000 ppm (equivalent to 10,000 mg/kg diet).

Executive summary:

The subchronic toxicity of the test material to rats was determined in a screening study on 48 food flavourings. Commercially available materials were used, rather than pure chemicals, since the purpose of the study was to evaluate the toxicity of these materials in relation to their use as food additives. Rats were exposed to the test material at 10,000 ppm in their diet over a period of 16 weeks. General condition, bodyweight and food consumption were recorded on a weekly basis. At termination blood samples were collected for haematology examination. Subsequently all rats were sacrificed for gross necropsy and histopathology. A vehicle control group was run concurrently.

Under the conditions of the test, no treatment related effects on growth, haematology and macroscopic or microscopic changes in tissue were noted in any of the exposed animals. Therefore the NOEL can be said to be the maximum concentration tested, 10,000 ppm (equivalent to 10,000 mg/kg diet).

Important considerations for the use of read-across for repeated dose toxicity are: i) 4-methyl-3-decen-5-ol (the target substance) has similar physico-chemical properties to Geraniol Extra (a reaction mass of Geraniol (2E)-3,7-dimethylocta-2,6-dien-1-ol and Linalool 3,7-dimethylocta-4,6-dien-3-ol (the source substance), ii) there are structural similarities between the two chemicals and iii) the OECD QSAR Toolbox assigns an identical toxicity profile to both chemicals. The source substance is therefore considered suitable for classification and labelling and risk assessment purposes using a read-across approach (see Justification for read-across in Section 13).