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Toxicological information

Repeated dose toxicity: dermal

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Administrative data

Endpoint:
sub-chronic toxicity: dermal
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Study period:
30 July 1979 - 04 April 1980
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study was conducted according to methods resembling the OECD guideline 411. However, the study design is reliable and the report is well-documented.
Cross-referenceopen allclose all
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1980
Report Date:
1980

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 411 (Subchronic Dermal Toxicity: 90-Day Study)
Deviations:
no
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Linalool
- Substance type: Essential oil
- Physical state: Liquid
- Storage condition of test material: Room temperature

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Ace Animals, Inc., PO Box 122, Boyertown, Pa. 19512
- Weight at study initiation:
Males: 115-181 g
Females: 110-172 g
- Housing: Standard laboratory conditions
- Diet (e.g. ad libitum): Ad libitum, laboratory rat chow
- Water (e.g. ad libitum): Ad libitum, well water
- Acclimation period: 18 days at test facility

ENVIRONMENTAL CONDITIONS
- Temperature (°C): approx. 21

IN-LIFE DATES:
From: 30 July 1979
To: 28 October 1979

Administration / exposure

Type of coverage:
not specified
Vehicle:
unchanged (no vehicle)
Details on exposure:
TEST SITE
- Area of exposure: Back of the animal
- Time intervals for shavings or clipplings: Weekly (if necessary)

TEST MATERIAL
- Volume applied: Weekly adjusted for body weight
- Amount(s) applied (weight with unit): 250, 1000 and 4000 mg/kg
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
Not relevant
Duration of treatment / exposure:
91 days
Frequency of treatment:
Daily
Doses / concentrations
Remarks:
Doses / Concentrations:
250, 1000 and 4000 mg/kg
Basis:
nominal per unit body weight
No. of animals per sex per dose:
20
Control animals:
other: yes, exposed to 4000 mg/kg saline (n=30)
Details on study design:
No data
Positive control:
Not relevant

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Once daily
- Cage side observations: Signs of toxicity

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Weekly palpation for tumors

DERMAL IRRITATION (if dermal study): Yes (scored according to Draize system)
- Time schedule for examinations: Daily

BODY WEIGHT: Yes
- Time schedule for examinations: Weekly

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes

HAEMATOLOGY: Yes
- Time schedule for collection of blood: At approx. weeks 6 and 13
- Anaesthetic used for blood collection: No data
- Animals fasted: Yes
- How many animals: 5 rats/sex/group
- Parameters checked:
Hematocrit
Hemoglobin
Erythrocytes
Total leucocytes
Differential leucocytes

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: At approx. weeks 6 and 13
- Animals fasted: Yes
- How many animals: 5 rats/sex/group
- Parameters checked:
Alkaline phosphatase
Lactic dehydrogenase
Serum glutamic-oxaloacteic transaminase
Serum glutamic-pyruvic transaminase
Glucose
Cholesterol
Calcium
Phosphorus
Uric acid
Blood urea nitrogen
Total protein
Total bilirubin
Albumin

URINALYSIS: Yes
- Time schedule for collection of urine: At approx. weeks 6 and 13
- Metabolism cages used for collection of urine: No data
- Animals fasted: Yes, overnight
- Parameters checked:
Appearance
pH
Specific gravity
Protein
Ketone glucose
Bilirubin
Occult blood
Microscopic analysis of the sediment
Sacrifice and pathology:
ORGAN WEIGHTS: Yes
Liver
Kidney
Testes
Ovaries
Brain

HISTOPATHOLOGY: Yes
Liver
Spleen
Lung
Adrenals
Kidneys
Urinary bladder
Heart
Thyroid
Testes, or ovaries
Epididymus
Cerebrum
Cerebellum
Cord
Musle and nerve
Pituitary
Skin-untreated
Skin-treated
Bone marrow
Mesenteric lymph node
Parathyroid
Other examinations:
Not relevant
Statistics:
No data

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Dermal irritation:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY
9 females of the highest dosing group died during the study. This high amount strongly suggests a relationship to treatment.
Other deaths were not considered treatment related (males: 1 control, 2 high-dose animals / females: 2 low-dose, 1 mid-dose animals)

Lethargy was noted in females of the high-dose group during week 3.
Rats of the highest dose group had severely depressed motor activity in the evening. This appeared to be an acute effect of the test material, because it was not observed during normal working hours.

No tumors were palpated at any time period.

DERMAL IRRITATION
Slight erythema was observed in all linalool treated groups. In the low-dose group there was no irritation after week 3. In the mid-dose group there was no irritation after week 6. In the high-dose group slight irritation persisted in most rats until week 13.

BODY WEIGHT AND WEIGHT GAIN
Mean body weights in the high-dose group males were lower than control at weeks 2 through 13.

Mean body weight in the mid-dose group females were lower than control at week 4 and 8 through 13. Mean body weight in the high-dose group females were less than control at weeks 2&3 but, after some rats died, the remaining rats maintained weights comparable to control.

FOOD CONSUMPTION
Food consumption was depressed in high-dose males at week 1-3 and 5 and 6.

ORGAN WEIGHTS
In females, terminal body weight of mid-dose group was decreased and the absolute and relative liver and kidney weights in the high-dose group were increased over control. In males, terminal body weight of high dosed males was reduced. This might be the reason for increased relative organ weights as absolute organ weight were comparable to control.

HISTOPATHOLOGY: NON-NEOPLASTIC
Animals that died during the experiment were found to have cardiopulmonary disturbances.

In more than 50% of control rats, the skin showed a grade 1 epithelial hyperplasia. Squamous epithelial hyperplasia ranged from grade 2 to 3 in all animals of the high-dose group.

Effect levels

Dose descriptor:
NOAEL
Effect level:
250 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: see 'Remark'

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Not relevant

Applicant's summary and conclusion

Conclusions:
Under the conditons of this subchronic dermal toxicity study in rats, a No Observed Adverse Effect Level (NOAEL) of 250 mg/kg bw/day was established for linalool based on reduced bw gain at the next higher dose. Based on the criteria outlined in Annex I of 1272/2008/EC and Annex VI of 67/548/EEC, linalool does not need to be classified for dermal repeated dose toxicity.
Executive summary:

Linalool was administered topically to male and female Sprague Dawley rats for 91 consecutive days at doses of 250, 1000 and 4000 mg/kg. Groups of saline treated animals served as the concurrent control.

Mortality apparently related to treatment occurred in females treated with the highest dose of the test material. Depressed activity was the most common and significant toxic sign. Several other deaths occurred during the study but there was no clear relationship to treatment. Slight redness of the skin was noted in all treated groups. It cleared after 3 to 6 weeks at the lower doses but persisted to week 13 at the high dose. Body weights in high-dose group and in mid-dose females were lower than control. Food consumption was depressed in high-dose males early in the test. Hematology, clinical chemistry and urinalysis findings were unremarkable.

Liver weight in males and females of the high-dose group appeared to be greater than controls. Kidney weight in females of the high dose group appeared to be greater than controls. However, histopathologically no changes were seen in these organs. The test material was considered to be responsible for an increase in squamous epithelial hyperplasia from very slight in the controls to slight/moderate in the high dose group.

Under the conditons of this study, a dermal No Observed Adverse Effect Level (NOAEL) of 250 mg/kg bw/day was established for linalool. Based on the criteria outlined in Annex I of 1272/2008/EC and Annex VI of 67/548/EEC, linalool does not need to be classified for dermal repeated dose toxicity.