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Toxicological information

Carcinogenicity

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Administrative data

Description of key information

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Referenceopen allclose all

Endpoint:
carcinogenicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
No data
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Remarks:
The study was not conducted according to a guideline and not performed according to GLP. The publication is relatively short, however the design of the study seems proper and the results are described clearly.
Qualifier:
no guideline followed
Principles of method if other than guideline:
Mammary tumors were induced by a single gastric intubation of 65 mg/kg 7,12-dimethylbenz[a]anthracene (DMBA) (in 0.5 mL sesame oil) 101 6-week-old female Sprague-Dawley rats, of which 50 were treated with 1% oxygenated (+/-)-linalool in diet for 20 weeks (start: 2 weeks before tumor induction). Number of tumors and latency were recorded in both groups to determine if linalool inhibited mammary carcinogenesis.
GLP compliance:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
female
Route of administration:
oral: feed
Vehicle:
other: powdered Way Lab Blox diet
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
20 weeks
Frequency of treatment:
Ad libitum
Post exposure period:
Not relevant
Dose / conc.:
1 other: %
Remarks:
Basis: Nominal in diet
No. of animals per sex per dose:
Dose group: 50
Control group: 51
Control animals:
yes, plain diet
Relevance of carcinogenic effects / potential:
The chemopreventive potential of linalool was studied, but the substance was found not to possess this ability. Linalool did not increase the tumor frequency when compared to the untreated control group.

Linalool did not significantly extend tumor latency or reduce the total number of tumors observed when compared to controls. Control group animals had an average number of tumours per rat of 2.3, linalool-treated rats 1.9 tumors per rat.

Conclusions:
Under the conditions of this study, it can be concluded that 20-week exposure to linalool in the diet did not inhibit DMBA induced mammary carcinogenesis.
Executive summary:

This study was conducted to determine if the oxygenated monoterpene (+/-)-Linalool inhibits the mammary carcinogenesis in the rat. Therefore, mammary tumors were induced in 101 female rats, of which 50 were treated with 1% Linalool in the diet shortly before and after induction (total 20 weeks). Number of tumors and tumor latency were recorded in each group.

The results indicate that linalool did not significantly extend tumor latency or reduce the total number of tumors observed when compared to controls. Under the conditions of this study, it was concluded that 20-week exposure to linalool in the diet did not inhibit mammary carcinogenesis and as well did not increase tumor frequency.

Endpoint:
carcinogenicity
Remarks:
intraperitoneal
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
No data
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
Study was not conducted according to OECD guideline 451 and not under GLP conditions, as the study was initiated before introduction of the guideline and GLP. No individual data, but acceptable basic data.
Qualifier:
no guideline followed
Principles of method if other than guideline:
A mouse pulmonary tumor system developed by Andervont and Shimkin in 1940 was used for the testing of a series of food additives (Andervont, H. B., and Shimkin, M. B. Biologic Testing of Carcinogens. II. Pulmonary-Tumor-Induction-Technique. J. Nati. Cancer Inst., I: 225-239, 1940)
GLP compliance:
no
Species:
mouse
Strain:
other: Strain A/He
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Institute for Cancer Research, Philadelphia, National Cancer Institute, Maryland
- Age at study initiation: 6 to 8 weeks
- Weight at study initiation: 18 to 20 gr.
- Housing: In groups of 5 in plastic boxes. Commercial grade sawdust chips were used for bedding.
- Diet: Purina laboratory chow ad libitum
- Water: Ad libitum
Route of administration:
intraperitoneal
Vehicle:
other: Tricaprylin
Details on exposure:
TEST MATERIAL
- Amount applied: 0.1 mL/dose
- Concentration: 0.6 and 3.0 g/kg mouse (total dose)

VEHICLE
- Justification for use and choice of vehicle: No data
- Amount applied: 0.1 mL i.p. injection
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
8 weeks
Frequency of treatment:
3 times weekly for a total of 24 doses
Post exposure period:
16 weeks; the experiments were terminated 24 weeks after the 1st injection.
Dose / conc.:
3 000 mg/kg bw (total dose)
Remarks:
Basis: Actually injected
Dose / conc.:
600 mg/kg bw (total dose)
Remarks:
Basis: Actually injected
No. of animals per sex per dose:
15
Control animals:
yes, concurrent no treatment
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: In a preliminary toxicology test an MTD (maximally tolerated single dose) was determined. In the bioassay 2 dose levels were used, the MTD and a 1:5 dilution of the MTD.
Positive control:
Positive control groups consisting of animals treated with 2 dose levels of urethan (5 or 20 mg/mouse) were also maintained to ensure that the tumor response was comparable to that observed in previous studies with A mice.
Observations and examinations performed and frequency:
BODY WEIGHT: Yes
- Time schedule for examinations: The animals were weighed every 2 weeks during the injection period and at monthly intervals thereafter.
Sacrifice and pathology:
Termination after 24 weeks.

GROSS PATHOLOGY: Yes, macroscopic examination of lungs.

HISTOPATHOLOGY: Yes, the milky white nodules on the lung surface were counted and some were taken for histopathological examination. The lungs were also examined microscopically for the presence of other abnormalities, such as inflammatory reactions and adenomatosis. Liver, kidney, spleen, thymus, intestine, and salivary and endocrine glands were examined at autopsy for the presence of abnormalities. Suspicious tissues were examined as to type and cataloged with respect to incidence.
Other examinations:
Not relevant
Statistics:
Mice are classified by the number of survivors with nodules. The data are also expressed as the mean number of nodules and their distribution in the groups. Tumor incidences in treated versus the vehicle control animals were compared by the standard x² test to determine whether the compound was positive.
Clinical signs:
not specified
Mortality:
not specified
Body weight and weight changes:
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
GROSS PATHOLOGY: no effects

HISTOPATHOLOGY: NON-NEOPLASTIC: no effects

HISTOPATHOLOGY: NEOPLASTIC
Only the number of lung tumors in the treatment groups was signficantly different from the control group. All other tumors appeared to be evenly distributed among control and treated animals. They are considered to be "spontaneous" or the background neoplastic "noise" in this species and strain of animals.

HISTORICAL CONTROL DATA: The consistency of the A mouse pulmonary tumor system for carcinogenesis bioassays is reflected in this study. The occurrence of "spontaneous" lung tumors and the response to the reference carcinogen urethan is in accordance with observations reported over the last 33 years.
Relevance of carcinogenic effects / potential:
This study did not reveal any carcinogenic potential of Linalool.

Duration

of experiment

(wk)

No. of

i.p. injections

Total

dose

(g/kg

mouse)

Sex

Survivors/

initial

No. of

mice

with

lung

tumors

No. of

lung

tumors/

mouse

No. of mice according to the no. of lung

tumors/mouse

1

2

3-5

6-10

24

24

3.00

M

9/15

2

0.22 ± 0.07

2

0

0

0

 

 

3.00

F

11/15

3

0.27 ± 0.08

3

0

0

0

 

 

0.60

M

11/15

1

0.09 ± 0.03

1

0

0

0

 

 

0.60

F

9/15

1

0.11± 0.04

1

0

0

0

Conclusions:
Linalool was negative for pulmonary tumor response under the conditions used. It is concluded that Linalool is not capable to induce primary lung tumors in A/He mice.
Executive summary:

Linalool was examined for its ability to induce primary lung tumors in A/He mice. A/He mice were given i.p. injections of Linalool, dissolved in 0.1 mL tricaprylin, 3 times a week for a maximum of 8 weeks. Two dose levels (600 and 3000 mg/kg total dose) and 15 males and 15 females per dose were used. Control groups received 0.1 ml tricaprylin alone or they were untreated. Positive control groups consisted of animals treated with 2 dose levels of urethan (5 or 20 mg/mouse). The animals were killed after of 24 weeks. After fixation of the lungs in Tellyesniczky's fluid, the surface tumors were counted. Response in the treated mice were compared by the x2 test to those in the vehicle controls. Linalool was negative for pulmonary tumor response under the conditions used. This study did not reveal any carcinogenic potential of Linalool.

Endpoint:
carcinogenicity: dermal
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
No data
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
secondary literature
Remarks:
Result is reported in a review publication, and only discussed very shortly. The publication is considered to be of doubtful relevance due to major reporting limitations.
Qualifier:
no guideline followed
Principles of method if other than guideline:
The tumour-promoting effect of essential oils was investigated in mice. Three weeks after initiation of with 9,10-dimethyl-1,2-bezoanthracene by topical application, linalool was applied topically once a week for thirteen weeks.
GLP compliance:
no
Species:
mouse
Strain:
other: 101 (inbred) and stock albino (randombred)
Sex:
not specified
Route of administration:
dermal
Vehicle:
acetone
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
13 weeks (treatment with linalool was started three weeks after topically induction of skin tumour formation with 9,10-dimethyl-1,2-benzanthracene)
Frequency of treatment:
once a week
Post exposure period:
No data
Dose / conc.:
20 other: %
Remarks:
Basis: Nominal concentration
No. of animals per sex per dose:
No data
Relevance of carcinogenic effects / potential:
Linalool as a 20% solution in acetone elicited a weak tumour-promoting response
Key result
Dose descriptor:
other: See "Remarks on result"
Remarks on result:
other: Linalool as a 20% solution in acetone elicited a weak tumour-promoting response
Remarks:
Under the conditions of this study, linalool was identified as a weak tumour promotor

A weak tumour-promoting response is reported, but no detailed data on results are available.

Conclusions:
Under the conditions of this study, linalool was identified as a weak tumour promotor
Executive summary:

The tumour-promoting effect of linalool was studied in mice that were exposed to linalool for thirteen weeks, once a week, after initiation of skin tumour formation with 9,10-dimethyl-1,2-benzanthracene. Linalool was found to elicit a weak tumour-promoting response. However, due to major reporting limitations, the result cannot be evaluated properly.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Justification for classification or non-classification

Based on the available information, linalool does not need to be classified as carcinogenic according to Regulation (EC) No 1272/2008, as amended for fifteenth time in Regulation (EU) No 2020/1182.

Additional information

Some supporting publications are available to the justification statement for the waiving of the carcinogenic bioassay.


- Stoner (1973) described no tumoriogenic potential of linalool in mice. This study was considered most reliable.


- Roe & Field (1965) described an experimental result indicating that linalool elicited a weak tumour-promoting response. However, the publication provides very limited information on the design and result of the experiment. Therefore, the result is regarded to be of doubtful relevance due to major reporting limitations.


- Russin (1989) described that oral administration of linalool for 20 weeks did not increase the number of tumors in rats.


These results and the results from (in vivo) genotoxicity tests (negative) and repeated dose toxicity studies (no pre-neoplastic effects found) indicate that linalool is not a potential carcinogenic substance.