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Toxicological information

Repeated dose toxicity: oral

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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:
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:
read-across source
Related information:
Composition 1
Reference:
Composition 0
Qualifier:
equivalent or similar to
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 information:
Composition 1
Species:
mouse
Strain:
B6C3F1
Sex:
male/female
Details on test animals 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:
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

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
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 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 / concentrationsopen allclose all
Dose / conc.:
125 mg/kg bw/day (actual dose received)
Remarks:
Basis:
actual ingested
Dose / conc.:
250 mg/kg bw/day (actual dose received)
Remarks:
Basis:
actual ingested
Dose / conc.:
500 mg/kg bw/day (actual dose received)
Remarks:
Basis:
actual ingested
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
Remarks:
Basis:
actual ingested
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

Applicant's summary and conclusion