Registration Dossier

Administrative data

Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP, guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2009
Report Date:
2009

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
EPA OPPTS 870.1200 (Acute Dermal Toxicity)
GLP compliance:
yes
Test type:
fixed dose procedure
Limit test:
yes

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): trans-beta-farnesene
-CAS 18794-84-8

Test animals

Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Covance Research Products, Inc., Denver, PA
- Age at study initiation: 17 weeks
- Weight at study initiation: The pretest body weight range was 2.4 - 2.7 kg for males and 2.7 - 2.9 kg for females.
- Fasting period before study: No
- Housing: housed 1/cage in suspended wire cages. Paper bedding was placed beneath the cages and changed at least three times/week.
- Diet (e.g. ad libitum): Fresh PMI Rabbit Chow (Diet #5321) was provided daily
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 14.72 – 22.94 °C
- Humidity (%): 0-27%
- Air changes (per hr): Not specified
- Photoperiod (hrs dark / hrs light): 12 hour light/dark cycle

IN-LIFE DATES: From: 1/6/09 To: 1/20/09

Administration / exposure

Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: 10 cm x 15 cm
- % coverage: 10%
- Type of wrap if used: 4 ply gauze dressing. The torso was wrapped with plastic sheeting in a semi-occlusive manner, which was secured with non-irritating tape.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Residual test article was removed by gently washing with distilled water
- Time after start of exposure: 24 hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 5000 mg/kg dose
- Concentration (if solution): neat
- Constant volume or concentration used: yes/no
- For solids, paste formed: Not aplicable

VEHICLE - none
Duration of exposure:
24 hours
Doses:
5000 mg/kg
No. of animals per sex per dose:
5 males and 5 females
Control animals:
not required
Details on study design:
Dermal responses were recorded at 24 hours postdose and on days 7 and 14. Animals were observed for toxicity and pharmacological effects at 1, 2 and 4 hours postdose and once daily for 14 days. All animals were observed twice a day for mortality. Body weights were recorded pretest, weekly and at termination. All animals were examined for gross pathology. Abnormal tissues were preserved in 10% neutral buffered formalin for possible future histological examination.

Results and discussion

Preliminary study:
Not applicable
Effect levelsopen allclose all
Sex:
female
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Based on:
test mat.
Sex:
male
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Based on:
test mat.
Mortality:
None observed
Clinical signs:
No systemic observations noted during study.
Body weight:
An. # Sex Dose (cc) Day 0 Day 7 Day 14
H2126 M 16.3 2.7 2.6 2.9
H2118 M 15.1 2.5 2.4 2.6
H2121 M 14.4 2.4 2.3 2.4
H2122 M 15.7 2.6 2.5 2.7
H2125 M 16.3 2.7 2.6 2.8
MEAN 2.6 2.5 2.7
S.D. 0.1 0.1 0.2
# 5 5 5

H2149 F 17.5 2.9 2.7 2.9
H2151 F 16.9 2.8 2.8 2.9
H2153 F 17.5 2.9 2.7 2.9
H2154 F 17.5 2.9 2.8 3.0
H2155 F 16.3 2.7 2.8 2.9
MEAN 2.8 2.8 2.9
S.D. 0.1 0.1 0.0
# 5 5 5
Gross pathology:
An. # Sex 24 hours Day 7 Day 14
Erythema Edema Erythema Edema Erythema Edema
H2126 M 1 0 1p 0 1e 0
H2118 M 1 0 2 2 1ef 1
H2121 M 0 0 1 2 1ef 0
H2122 M 0 0 1 2 1ef 0
H2125 M 1 0 1 2 1ef 1
H2149 F 1 0 1 1 1ef2 0
H2151 F 0 0 1p 1 1ef2 1
H2153 F 1 0 2p 2 1ef2 1
H2154 F 1 0 1 1 1ef2 0
H2155 F 0 0 1 1 1ef 0

f = flaking skin e = alopecia surrounding dose site 2 = alopecia extended down both sides and completely across the abdomen p = pale areas
Other findings:
Upon necropsy, skin abnormalities at treatment sites were noted in all animals.

Applicant's summary and conclusion

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Rabbit 24 hour dermal LD50 > 5000 mg/kg
Executive summary:

The acute dermal toxicity of farnesene was investigated in rabbits. The test material was applied to the shaved dorsal skin of 5 male and 5 female rabbits at 5000 mg/kg of body weight, under an occlsive dressing. The test article was kept in contact with the skin for 24 hours. Dermal responses were recorded at 24 hours postdose and on days 7 and 14. Animals were observed for toxicity and pharmacological effects at 1, 2 and 4 hours postdose and once daily for 14 days. All animals were observed twice a day for mortality.

Body weights were recorded pretest, weekly and at termination. All animals were examined for gross pathology. Abnormal tissues were preserved in 10% neutral buffered formalin for possible future histological examination.

There were no deaths during the study and all animals survived the 5000 mg/kg dermal application in good health. Dermal responses were absent to very slight at 24 hours, very slight to well defined on day 7 and very slight on day 14. Additionally, pale areas, flaking skin and areas of poor hair regrowth were noted during the study. Slight body weight loss was noted on day 7 in 8/10 animals, but all returned to normal by day 14. Treated skin abnormalities were the only abnormality noted at necropsy.

The dermal LD50 of trans-ß-farnesene, in the rabbit is greater than 5000 mg/kg of body weight.