(-)-3,7-dimethyloct-6-en-1-ol

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable, well documented publication/ study report which meets basic scientific principles.

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Reference

Endpoint:

sub-chronic toxicity: oral

Type of information:

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

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable, well documented publication/ study report which meets basic scientific principles.

Justification for type of information:

ANALOGUE APPROACH

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
This read-across is based on the hypothesis that source substances and target substance have similar physical-chemical properties and (eco)toxicological properties because they are either stereoisomers of the target substance, are hydrolysed to the same substance or their chemical structure differs only by an additional double bond. This prediction is supported by data on the substances themselves.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
The target substance, L-Citronellol, is a mono-constituent substance (EC No. 231-415-7, CAS no. 7540-51-4 consisting of a C8 carbon backbone, methyl substituents at C3 and C7, one double bond and a hydroxyl group. The substance is optically active, comprising a single, pure enantiomeric laevo form.

The source substance, DL-Citronellol, is a mono-constituent substance (EC No. 203-375-0, CAS no. 106-22-9, consisting of a C8 carbon backbone, methyl substituents at C3 and C7, one double bond and a hydroxyl group. The substance is an equimolar mixture of two optical isomers (enantiomers).

The source substance, citronellyl acetate, is a mono-constituent substance (EC No. 205-775-0, CAS no. 150-84-5) consisting of a C8 carbon backbone, methyl substituents at C3 and C7, one double bond and an acetate group.

The source substance, geraniol and it’s isomer, consist of a C8 carbon backbone, methyl substituents at C3 and C7, two double bonds and a hydroxyl group. The only difference between the isomers is the position of the first double bond.

The source substance, geraniol and nerol, is a multi-constituent substance of E/Z isomers (EC No. 906-125-5). The constituents consist of a C8 carbon backbone, methyl substituents at C3 and C7, two double bonds and a hydroxyl group.

The source substance, geraniol, is a mono-constituent substance (EC No. 203-377-1, CAS no. 106-24-1), consisting of a C8 carbon backbone, methyl substituents at C3 and C7, two double bonds and a hydroxyl group. Geraniol is a pure form of the E-isomer.

The source substance, nerol, is a mono-constituent substance (EC No. 203-378-7, CAS no. 106-25-2), consisting of a C8 carbon backbone, methyl substituents at C3 and C7, two double bonds and a hydroxyl group. Nerol is a pure form of the Z-isomer.
The source and target substances are both of high purity with a low concentration of impurities.

3. ANALOGUE APPROACH JUSTIFICATION
The read across hypothesis is based on structural similarity where the source substances only differ in the enantiomeric ratio or an additional double bond. Another source substance is expected to be hydrolysed to the same structure as the target substance.
In a non-chiral environment the target and source chemical DL-Citronellol will have identical properties, but in the chiral environment of living organisms the enantiomers may possess different carcinogenicity and teratogenicity (in a chiral environment, stereoisomers might experience selective absorption, protein binding, transport, enzyme interactions and metabolism, receptor interactions, and DNA binding). All endpoints read-across from DL-Citronellol are considered to be acceptable for this substance assuming that 50% of the target compound is available in the test material.
The source substance citronellyl acetate is read-across from as part of a weight of evidence approach in the repeated dose toxicity endpoint. As this substance is hydrolysed to Citronellol within 2 hours, this read-across endpoint is acceptable in the weight of evidence approach used.
The source substances geraniol, nerol and the reaction mass of geraniol/nerol differ from the target substance only by an additional double bond at C2. These structures are considered to represent a worst case scenario due to the additional potential reactive feature of the second double bond. The genotoxicity, repeated dose and reproductive toxicity endpoints read-across from these substances are therefore acceptable as a worst case assumption.

4. DATA MATRIX
Please refer to the data matrix included in the read-across justification document attached in Section 13.2.

Reason / purpose for cross-reference:

read-across source

Qualifier:

equivalent or similar to guideline

Guideline:

other: Specifications for the Conduct of Studies to Evaluate the Toxic and Carcinogenic Potential of Chemical, Biological, and Physical Agents in Laboratory Animals for the National Toxicology Program (NTP)

GLP compliance:

not specified

Limit test:

no

Species:

mouse

Strain:

B6C3F1

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan Industries, Indianapolis, IN
- Age at study initiation: 6 weeks
- Housing: 5/cage
- Diet and water: ad libitum
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 - 23
- Humidity (%): 40 - 60
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

corn oil

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

13 weeks

Frequency of treatment:

once daily, 5 days per week

Dose / conc.:

125 mg/kg bw/day (actual dose received)

Remarks:

Doses / Concentrations:
125, 250, 500, 1000, 2000 mg/kg bw/day
Basis:
actual ingested

Dose / conc.:

250 mg/kg bw/day (actual dose received)

Remarks:

Doses / Concentrations:
125, 250, 500, 1000, 2000 mg/kg bw/day
Basis:
actual ingested

Dose / conc.:

500 mg/kg bw/day (actual dose received)

Remarks:

Doses / Concentrations:
125, 250, 500, 1000, 2000 mg/kg bw/day
Basis:
actual ingested

Dose / conc.:

1 000 mg/kg bw/day (actual dose received)

Remarks:

Doses / Concentrations:
125, 250, 500, 1000, 2000 mg/kg bw/day
Basis:
actual ingested

Dose / conc.:

2 000 mg/kg bw/day (actual dose received)

Remarks:

Doses / Concentrations:
125, 250, 500, 1000, 2000 mg/kg bw/day
Basis:
actual ingested

No. of animals per sex per dose:

10

Control animals:

yes, concurrent vehicle

Observations and examinations performed and frequency:

CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly (including palpation for tissue masses or swelling)

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

OBSERVATION OF MORTALITY AND MORBIDITY: YES
- Time schedule: twice daily

Sacrifice and pathology:

GROSS PATHOLOGY: Yes (all animals, unless precluded in whole or in part by autolysis or cannibalization)

HISTOPATHOLOGY: Yes (control and high-dose group animals)
- gross lesions, tissue masses, abnormal lymph nodes, skin, mandibular lymph nodes, mammary gland, salivary gland, thigh muscle, sciatic nerve, bone marrow, thymus, larynx, trachea, lungs and bronchi, heart, thyroid, parathyroid, esophagus, stomach, duode- num, jejunum, ileum, colon, mesenteric lymph nodes, liver, gallbladder, pancreas, spleen, kidneys, adrenals, urinary bladder, seminal vesicles/ prostate/ testes or ovaries/ uterus, brain, pituitary, and spinal cord
- Tissues were preserved in 10% neutral buffered formalin, embedded in paraffin, sectioned, and stained with hematoxylin and eosin.

Details on results:

CLINICAL SIGNS AND MORTALITY
- 2000 mg/kg bw/d: 7/10 males and 9/10 females died
- 0, 250, 500 mg/kg bw/d: 1 female per given dose group died due to error of gavage
- No other signs of toxicity were reported

BODY WEIGHT AND WEIGHT GAIN
- 2000 mg/kg bw: gain of weight of males slightly delayed

HISTOPATHOLOGY: NON-NEOPLASTIC
2000 mg/kg bw:
- liver, kidney and myocardium showed cytoplasmic vacuolization with lipid inclusions.
Liver: 7/10 m; 8/9 f
Kidney: 2/10 m; 4/9 f
Myocardium: 2/10m; 1/9f

- Stomach leasions including inflammation and edema
Stomach: 2/10m; 6/10f

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: = 290 mg/kg bw/day (nominal) citronellyl acetate

Key result

Critical effects observed:

not specified

Data source

Reference

Reference Type:

publication

Title:

Carciogenesis Studies of Food Grade Geranyl Acetate (71% Geranyl Acetate, 29% Citronellyl Acetate) (CAS No. 105-87-3) in F344/N Rats and B6C3F1 Mice (Gavage Studies)

Author:

US National Institutes of Health

Year:

1987

Bibliographic source:

National Toxicology Program - Technical Report Series No. 252

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

other: Specifications for the Conduct of Studies to Evaluate the Toxic and Carcinogenic Potential of Chemical, Biological, and Physical Agents in Laboratory Animals for the National Toxicology Program (NTP)

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Citronellyl acetate

EC Number:

205-775-0

EC Name:

Citronellyl acetate

Cas Number:

150-84-5

IUPAC Name:

3,7-dimethyloct-6-en-1-yl acetate

Constituent 2

Reference substance name:

Geranyl acetate

EC Number:

203-341-5

EC Name:

Geranyl acetate

Cas Number:

105-87-3

Molecular formula:

C12H20O2

IUPAC Name:

3,7-dimethylocta-2,6-dien-1-yl acetate

Test material form:

other: liquid

Details on test material:

- Name of test material (as cited in study report): food-grade geranyl acetate
- Composition of test material: 71% geranyl acetate (CAS 105-87-3) and 29% citronellyl acetate (CAS 150-84-5) was reported for the lot used for chronic studies. No accurate determination of the content of these two components was made for the lot used in the subacute and subchronic studies.
- Lot No.: 70201 (Elan Chemical Co, Newark, NJ)
- Impurities: approx. 1%
- Storage condition of test material: in the dark at 5°C

Test animals

Species:

mouse

Strain:

B6C3F1

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan Industries, Indianapolis, IN
- Age at study initiation: 6 weeks
- Housing: 5/cage
- Diet and water: ad libitum
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 - 23
- Humidity (%): 40 - 60
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

13 weeks

Frequency of treatment:

once daily, 5 days per week

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

125 mg/kg bw/day (actual dose received)

Remarks:

Basis:
actual ingested

Doses / concentrations 2

Dose / conc.:

250 mg/kg bw/day (actual dose received)

Remarks:

Basis:
actual ingested

Doses / concentrations 3

Dose / conc.:

500 mg/kg bw/day (actual dose received)

Remarks:

Basis:
actual ingested

Doses / concentrations 4

Dose / conc.:

1 000 mg/kg bw/day (actual dose received)

Remarks:

Basis:
actual ingested

Doses / concentrations 5

Dose / conc.:

2 000 mg/kg bw/day (actual dose received)

Remarks:

Basis:
actual ingested

No. of animals per sex per dose:

10

Control animals:

yes, concurrent vehicle

Examinations

Observations and examinations performed and frequency:

CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly (including palpation for tissue masses or swelling)

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

OBSERVATION OF MORTALITY AND MORBIDITY: YES
- Time schedule: twice daily

Sacrifice and pathology:

GROSS PATHOLOGY: Yes (all animals, unless precluded in whole or in part by autolysis or cannibalization)

HISTOPATHOLOGY: Yes (control and high-dose group animals)
- gross lesions, tissue masses, abnormal lymph nodes, skin, mandibular lymph nodes, mammary gland, salivary gland, thigh muscle, sciatic nerve, bone marrow, thymus, larynx, trachea, lungs and bronchi, heart, thyroid, parathyroid, esophagus, stomach, duode- num, jejunum, ileum, colon, mesenteric lymph nodes, liver, gallbladder, pancreas, spleen, kidneys, adrenals, urinary bladder, seminal vesicles/ prostate/ testes or ovaries/ uterus, brain, pituitary, and spinal cord
- Tissues were preserved in 10% neutral buffered formalin, embedded in paraffin, sectioned, and stained with hematoxylin and eosin.

Results and discussion

Results of examinations

Details on results:

CLINICAL SIGNS AND MORTALITY
- 2000 mg/kg bw/d: 7/10 males and 9/10 females died
- 0, 250, 500 mg/kg bw/d: 1 female per given dose group died due to error of gavage
- No other signs of toxicity were reported

BODY WEIGHT AND WEIGHT GAIN
- 2000 mg/kg bw: gain of weight of males slightly delayed

HISTOPATHOLOGY: NON-NEOPLASTIC
2000 mg/kg bw:
- liver, kidney and myocardium showed cytoplasmic vacuolization with lipid inclusions.
Liver: 7/10 m; 8/9 f
Kidney: 2/10 m; 4/9 f
Myocardium: 2/10m; 1/9f

- Stomach leasions including inflammation and edema
Stomach: 2/10m; 6/10f

Effect levels

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: = 290 mg/kg bw/day (nominal) citronellyl acetate

Target system / organ toxicity

Key result

Critical effects observed:

not specified