Registration Dossier

Administrative data

Description of key information

This endpoint was read across from three structurally similar substances, in a weight of evidence approach. The substances were 1) a mixture of linalool/citronellol (3,7-dimethyloct-6-en-1-ol, CAS 106-22-9 / 3,7-dimethylocta-1,6-dien-3-ol, CAS 78-70-6, 50% each), 2) a mixture of geraniol (3,7-dimethyl-2,6-octadienol) and the isomer (3,7-dimethyl-1,6-octadienol), and 3) citronellyl acetate in a geranyl acetate mixture (71% geranyl acetate (3,7-dimethylocta-2,6-dien-1-yl acetate (E)-, CAS 105-87-3) and 29% citronellyl acetate (3,7-dimethyloct-6-en-1-yl acetate, CAS 150-84-5)).

In a feeding study in rats from secondary literature, a mixture of linalool/citronellol (50% each) were orally administered daily for 90 days, thus giving a daily amount of approx. 50 mg/kg bw/d citronellol (Trubek, 1958). Food intake and body weight gain was reduced in males, however, the authors attributed this effect to be caused by the palatability of the given mixture and considered these effects to be biologically insignificant.

In a limited urine analysis, in haematology, in gross examinations and in liver and kidney weights, no test substance related effects were observed. The NOEL was determined as 51 and 56 mg/kg bw/d (the highest doses tested) citronellol for males and female, respectively.

 

A mixture of geraniol (3,7-dimethyl-2,6-octadienol) and the isomer (3,7-dimethyl-1,6-octadienol) was fed to five male and five female individually housed Osborne-Mendel rats per dose group (Hagan, 1967). Thereby, a concentrations of 1000 ppm (= ca. 55 mg/kg bw/day) was administered for 189-169 days and a concentration of 10000 ppm (= ca. 550 mg/kg bw/day) was given for 112 days. During the study, the food consumption was monitored and blood was collected at the end of study and was subjected analysis of white cell counts, red cell counts and hemoglobin and hematocrit content. Also, animals were necropsied and histopathology was performed. Since no clinical signs, no effects on body weight as well as no histopathological changes were observed, the NOEL could be estimated as 10000 ppm. Thus the NOAEL would be > 550 mg/kg bw/day.

 

Repeated dose toxicity was analyzed in a 13 week oral toxicity study in rats performed by the National Toxicity Program of the US National Institutes of Health (NTP, 1987). In this study, doses of 250, 500, 1000, 2000 and 4000 mg/kg bw/d of food-grade geranyl acetate (71% geranyl acetate (CAS 105-87-3) and 29% citronellyl acetate (CAS 150-84-5)) in corn oil was administered by gavage to ten male and female Fischer 344 rats for 13 weeks. 1/10 female and 2/10 male of the 4000 mg/kg bw/d group died, in addition to one animal accidently killed by gavage error in the 500 mg/kg bw/d group. Besides mortality, the observed substance related toxic effect was a depressed mean body weight of the animals of the 4000 mg/kg bw/d group compared to control (19% for the males, 8% for the females). Three males showed reddened mucosa of the stomach, however no test substance related histopathological changes were observed. Thus, a NOAEL of 2000 mg/kg bw/d of food-grade geranyl acetate has been set, corresponding to 580 mg/kg bw/d citronellyl acetate.

In the same study, also, ten male and female B6C3F1 mice per dose were gavaged by doses of 125, 250, 500, 1000, 2000 mg/kg bw food-grade geranyl acetate in corn oil for the 13 week study.

Seven males and nine females of the 2000 mg/kg bw group died. Also, three females of the lower dose groups died, but this was accidentally due to an error of gavage. No other clinical signs of toxicity were noted during the study. The males of the 2000 mg/kg bw group exhibit a delay in body weight gain. Liver, kidney and myocardium of males and females of the 2000 mg/kg bw group displayed cytoplasmic vacuolization with lipid inclusions indicative of fatty degeneration. Furthermore, stomach lesions including inflammation and edema were reported in this group. Thus, the NOAEL was set at 1000 mg/kg bw/d food-grade geranyl acetate corresponding to 290 mg/kg bw/d citronellyl acetate.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Referenceopen allclose all

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.
Reason / purpose:
reference to same study
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:
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
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
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.
Reason / purpose:
reference to same study
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:
rat
Strain:
Fischer 344
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
Remarks:
Doses / Concentrations:
250, 500, 1000, 2000, 4000 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:
NECROPSY: 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, 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
- 500 mg/kg bw: 1/10 male died, due to error of gavage
- 4000 mg/kg bw: 1/10 female and 2/10 male died
- No signs of toxicity were reported

BODY WEIGHT AND WEIGHT GAIN
The mean body weight of the rats of the 4000 mg/kg bw group was decreased compared to control (19 % for the males, 8 % for the females).

NECROPSY:
- 4000 mg/kg bw: 3 males showed reddened mucosa of the stomach

HISTOPATHOLOGY:
No test substance related effects observed
Dose descriptor:
NOAEL
Effect level:
2 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: = 580 mg/kg bw/day citronellyl acetate
Critical effects observed:
not specified
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
Reason / purpose:
reference to same study
Related information:
Composition 1
Reference:
Composition 0
Composition 0
Composition 0
Composition 0
Qualifier:
no guideline followed
Principles of method if other than guideline:
subchronic to chronic feeding study
GLP compliance:
no
Limit test:
no
Test material information:
Composition 1
Species:
rat
Strain:
Osborne-Mendel
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Housing: individually
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
DIET PREPARATION
- Rate of preparation of diet (frequency): weekly
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
112 days at 10000 ppm; 189-196 days at 1000 ppm
Frequency of treatment:
continuously in diet
Dose / conc.:
550 mg/kg diet
Remarks:
Doses / Concentrations:
1000 or 10000 ppm (ca. 55 or 550 mg/kg/day)
Basis:
nominal in diet
No. of animals per sex per dose:
5 male and 5 female
Control animals:
yes
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: weekly

BODY WEIGHT: Yes
- Time schedule for examinations: weekly


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Time schedule for examinations: weekly


HAEMATOLOGY: Yes
- Time schedule for collection of blood: at termination of study
- Parameters checked: white cell counts, red cell counts, hemoglobin and hematocrits
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes; abdominal and thoracic viscera, and one hind leg, for bone, bone marrow, and muscle

- Organ weights were recorded
- Detailed microscopic examinations were done on 6 or 8 animals evenly divided by sex, in the high dose group and control group, if multiple doses were tested.
- If changes attributable to the test compound were found in the high dose group, additional animals on lower dosage levels were examined
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Dose descriptor:
NOEL
Effect level:
> 10 000 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: not specified
Dose descriptor:
NOEL
Effect level:
> 550 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: not specified
Critical effects observed:
not specified
Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: only secondary source with limited documentation
Reason / purpose:
reference to same study
Related information:
Composition 1
Reference:
Composition 0
Composition 0
Composition 0
Qualifier:
no guideline followed
Principles of method if other than guideline:
Weanling rats were given diets containing equal parts (by weight) of citronellol and linalool for 12 weeks.
GLP compliance:
no
Test material information:
Composition 1
Species:
rat
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Age at study initiation: 27 - 29 days
- Weight at study initiation: 50 - 70 g
- Diet (e.g. ad libitum): ad libitum
Route of administration:
oral: feed
Vehicle:
not specified
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
90 days
Frequency of treatment:
daily
Dose / conc.:
51 mg/kg bw/day (actual dose received)
Remarks:
Doses / Concentrations:
51 mg/kg bw/d (males)
Basis:
actual ingested
Dose / conc.:
56 mg/kg bw/day (actual dose received)
Remarks:
Doses / Concentrations:
56 mg/kg bw/d (females)
Basis:
actual ingested
No. of animals per sex per dose:
10
Control animals:
not specified
Observations and examinations performed and frequency:
Weekly observations were made of growth and food intake. Records were made of physical appearance and behavior. After 12 weeks, urinalysis was conducted on 6 animals (3/sex) and blood hemoglobin levels were determined.
Sacrifice and pathology:
All animals were sacrificed after 90 days and gross necropsy was carried out. Tissues were preserved for possible histological examination at a future date.
Details on results:
Treatment did not influence physical appearance and behaviour.
Weekly measurements revealed slight, but significant reductions in body-weight gain in males after 4 weeks; although these animals recovered, the final body weight and the net body-weight gain were lower than those of controls (approximately 10%).
Food consumption and food use efficiency were also slightly decreased (approximately 5%) in treated males. These parameters were not affected in treated females.

The authors attributed the effects in males to reduced palatability of the diet, and considered these effects to be biologically insignificant.

Limited urine analysis and haematology in three rats of each sex per group revealed no differences in concentrations of urinary sugar and albumin and in blood haemoglobin.
At necropsy, gross examination of all animals was performed and weights of liver and kidney were recorded. No differences were found between treated animals and controls.
Key result
Dose descriptor:
NOEL
Effect level:
51 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: not specified
Key result
Dose descriptor:
NOEL
Effect level:
56 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: not specified
Key result
Critical effects observed:
not specified

The NOEL for citronellol was 51 mg/kgbw per day in male rats and 56 mg/kgbw per day in female rats, the highest dose tested

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
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:
rat
Strain:
Fischer 344
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
Remarks:
Doses / Concentrations:
250, 500, 1000, 2000, 4000 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:
NECROPSY: 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, 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
- 500 mg/kg bw: 1/10 male died, due to error of gavage
- 4000 mg/kg bw: 1/10 female and 2/10 male died
- No signs of toxicity were reported

BODY WEIGHT AND WEIGHT GAIN
The mean body weight of the rats of the 4000 mg/kg bw group was decreased compared to control (19 % for the males, 8 % for the females).

NECROPSY:
- 4000 mg/kg bw: 3 males showed reddened mucosa of the stomach

HISTOPATHOLOGY:
No test substance related effects observed
Dose descriptor:
NOAEL
Effect level:
2 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: = 580 mg/kg bw/day citronellyl acetate
Critical effects observed:
not specified
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
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
Composition 0
Composition 0
Composition 0
Qualifier:
no guideline followed
Principles of method if other than guideline:
subchronic to chronic feeding study
GLP compliance:
no
Limit test:
no
Test material information:
Composition 1
Species:
rat
Strain:
Osborne-Mendel
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Housing: individually
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
DIET PREPARATION
- Rate of preparation of diet (frequency): weekly
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
112 days at 10000 ppm; 189-196 days at 1000 ppm
Frequency of treatment:
continuously in diet
Dose / conc.:
550 mg/kg diet
Remarks:
Doses / Concentrations:
1000 or 10000 ppm (ca. 55 or 550 mg/kg/day)
Basis:
nominal in diet
No. of animals per sex per dose:
5 male and 5 female
Control animals:
yes
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: weekly

BODY WEIGHT: Yes
- Time schedule for examinations: weekly


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Time schedule for examinations: weekly


HAEMATOLOGY: Yes
- Time schedule for collection of blood: at termination of study
- Parameters checked: white cell counts, red cell counts, hemoglobin and hematocrits
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes; abdominal and thoracic viscera, and one hind leg, for bone, bone marrow, and muscle

- Organ weights were recorded
- Detailed microscopic examinations were done on 6 or 8 animals evenly divided by sex, in the high dose group and control group, if multiple doses were tested.
- If changes attributable to the test compound were found in the high dose group, additional animals on lower dosage levels were examined
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Dose descriptor:
NOEL
Effect level:
> 10 000 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: not specified
Dose descriptor:
NOEL
Effect level:
> 550 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: not specified
Critical effects observed:
not specified
Endpoint:
sub-chronic toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: only secondary source with limited documentation
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
Composition 0
Composition 0
Qualifier:
no guideline followed
Principles of method if other than guideline:
Weanling rats were given diets containing equal parts (by weight) of citronellol and linalool for 12 weeks.
GLP compliance:
no
Test material information:
Composition 1
Species:
rat
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Age at study initiation: 27 - 29 days
- Weight at study initiation: 50 - 70 g
- Diet (e.g. ad libitum): ad libitum
Route of administration:
oral: feed
Vehicle:
not specified
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
90 days
Frequency of treatment:
daily
Dose / conc.:
51 mg/kg bw/day (actual dose received)
Remarks:
Doses / Concentrations:
51 mg/kg bw/d (males)
Basis:
actual ingested
Dose / conc.:
56 mg/kg bw/day (actual dose received)
Remarks:
Doses / Concentrations:
56 mg/kg bw/d (females)
Basis:
actual ingested
No. of animals per sex per dose:
10
Control animals:
not specified
Observations and examinations performed and frequency:
Weekly observations were made of growth and food intake. Records were made of physical appearance and behavior. After 12 weeks, urinalysis was conducted on 6 animals (3/sex) and blood hemoglobin levels were determined.
Sacrifice and pathology:
All animals were sacrificed after 90 days and gross necropsy was carried out. Tissues were preserved for possible histological examination at a future date.
Details on results:
Treatment did not influence physical appearance and behaviour.
Weekly measurements revealed slight, but significant reductions in body-weight gain in males after 4 weeks; although these animals recovered, the final body weight and the net body-weight gain were lower than those of controls (approximately 10%).
Food consumption and food use efficiency were also slightly decreased (approximately 5%) in treated males. These parameters were not affected in treated females.

The authors attributed the effects in males to reduced palatability of the diet, and considered these effects to be biologically insignificant.

Limited urine analysis and haematology in three rats of each sex per group revealed no differences in concentrations of urinary sugar and albumin and in blood haemoglobin.
At necropsy, gross examination of all animals was performed and weights of liver and kidney were recorded. No differences were found between treated animals and controls.
Key result
Dose descriptor:
NOEL
Effect level:
51 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
body weight and weight gain
food consumption and compound intake
Key result
Dose descriptor:
NOEL
Effect level:
56 mg/kg bw/day (actual dose received)
Sex:
female
Basis for effect level:
other: not specified
Key result
Critical effects observed:
not specified

The NOEL for citronellol was 51 mg/kgbw per day in male rats and 56 mg/kgbw per day in female rats, the highest dose tested

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
300 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
Read across from 3 test items:
a mixture of linalool/citronellol (3,7-dimethyloct-6-en-1-ol, CAS 106-22-9 / 3,7-dimethylocta-1,6-dien-3-ol, CAS 78-70-6, 50% each),
a mixture of geraniol (3,7-dimethyl-2,6-octadienol) and the isomer (3,7-dimethyl-1,6-octadienol),
geranyl acetate mixture (71% geranyl acetate (3,7-dimethylocta-2,6-dien-1-yl acetate (E)-, CAS 105-87-3) and 29% citronellyl acetate (3,7-dimethyloct-6-en-1-yl acetate, CAS 150-84-5))

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Mode of Action Analysis / Human Relevance Framework

Additional information

Justification for classification or non-classification

Specific target organ toxicity - repeated exposure

No valid key study on oral repeated dose toxicity is available for citronellol. However oral repeated dose toxicity data from literature with citronellol in a mixture or with structurally and metabolically related test substances are taken for assessment in a weight of evidence.

 In a feeding study in rats from secondary literature, a mixture of linalool/citronellol (50% each) were orally administered daily for 90 days, thus giving a daily amount of approx. 50 mg/kg bw/d citronellol (Trubek, 1958). Food intake and body weight gain was reduced in males, however, the authors attributed this effect to be caused by the palatability of the given mixture and considered these effects to be biologically insignificant.

In a limited urine analysis, in haematology, in gross examinations and in liver and kidney weights, no test substance related effects were observed. The NOEL was determined as 51 and 56 mg/kg bw/d citronellol for males and female, respectively.

 

In this weight of evidence, data from a study performed with geraniol (3,7-dimethyl-2,6-octadien-1-ol) were also taken into account. Inclusion of geraniol into this assessment is justified by the structural similarity with citronellol (3,7-dimethyloct-6-en-1-ol). These structures are identical except for an additional double bond found in geraniol. The structure of geraniol is considered to represent a worst case when compared to citronellol based on this second double bond as possible additional reactive feature. Furthermore, relevant physicochemical parameters show comparability between geraniol and citronellol (molecular weight of 154.2 and 156.3 ; log Pow at 2.6 and 3.41; vapour pressure of 1 and 8.6 Pa; water solubility of 769 and 307 mg/l respectively).

A mixture of geraniol (3,7-dimethyl-2,6-octadienol) and the isomer (3,7-dimethyl-1,6-octadienol) was fed to five male and five female individually housed Osborne-Mendel rats per dose group (Hagan, 1967). Thereby, a concentrations of 1000 ppm (= ca. 55 mg/kg bw/day) was administered for 189-169 days and a concentration of 10000 ppm (= ca. 550 mg/kg bw/day) was given for 112 days. During the study, the food consumption was monitored and blood was collected at the end of study and was subjected analysis of white cell counts, red cell counts and hemoglobin and hematocrit content. Also, animals were necropsied and histopathology was performed. Since no clinical signs, no effects on body weight as well as no histopathological changes were observed, the NOEL could be estimated as 10000 ppm. Thus the NOAEL would be > 550 mg/kg bw/day.

 

Furthermore, data from the metabolically related acetates of citronellol and geraniol; i.e. citronellyl acetate (CAS 150-84-5) and geranyl acetate (CAS 105-87-3), are taken into account for further assessment. These acetates are expected to hydrolyze to geraniol or citronellol and acetic acid. In animals, hydrolysis of aliphatic esters are catalyzed by classes of enzymes recognized as carboxylesterases or esterase. Citronellyl acetate has been reported to be completely hydrolyzed within 2 hours by simulated intestinal fluid containing pancreatin at pH 7.5.

 

Repeated dose toxicity was analyzed in a 13 week oral toxicity study in rats performed by the National Toxicity Program of the US National Institutes of Health (NTP, 1987). In this study, doses of 250, 500, 1000, 2000 and 4000 mg/kg bw/d of food-grade geranyl acetate (71% geranyl acetate (CAS 105-87-3) and 29% citronellyl acetate (CAS 150-84-5)) in corn oil was administered by gavage to ten male and female Fischer 344 rats for 13 weeks. 1/10 female and 2/10 male of the 4000 mg/kg bw/d group died, in addition to one animal accidently killed by gavage error in the 500 mg/kg bw/d group. Besides mortality, the observed substance related toxic effect was a depressed mean body weight of the animals of the 4000 mg/kg bw/d group compared to control (19% for the males, 8% for the females). Three males showed reddened mucosa of the stomach, however no test substance related histopathological changes were observed. Thus, a NOAEL of 2000 mg/kg bw/d of food-grade geranyl acetate has been set, corresponding to 580 mg/kg bw/d citronellyl acetate.

In the same study, also, ten male and female B6C3F1 per dose were gavaged by doses of 125, 250, 500, 1000, 2000 mg/kg bw food-grade geranyl acetate in corn oil for the 13 week study.

Seven males and nine females of the 2000 mg/kg bw group died. Also, three females of the lower dose groups died, but this was accidentally due to an error of gavage. No other clinical signs of toxicity were noted during the study. The males of the 2000 mg/kg bw group exhibit a delay in body weight gain. Liver, kidney and myocardium of males and females of the 2000 mg/kg bw group displayed cytoplasmic vacuolization with lipid inclusions indicative of fatty degeneration. Furthermore, stomach lesions including inflammation and edema were reported in this group. Thus, the NOAEL was set at 1000 mg/kg bw/d food-grade geranyl acetate corresponding to 290 mg/kg bw/d citronellyl acetate.

 

 

No significant/adverse toxic effects were therefore observed within the classification guidance value ranges in the CLP regulation for specific target organ toxicity-repeated exposure (Category 2) based on a 90-day exposure.i. e. no significant/adverse toxic effects were seen at or below a dose of 100 mg/kg bw/day.

Based on these results, the substance is not classified for specific target organ toxicity-repeated exposure.