Registration Dossier

Administrative data

Description of key information

Key Studies:
Acute dermal irritation in rabbits: Not classified as skin irritant (MB Research Report number MB 10-19293.03; 2010-11-29)


Acute eye irritation in rabbits; Not classified as an eye irritant (MB Research report number MB 10-19293.04; 2010-11-29)

Supporting studies:
Skin irritation:
Non-irritant in the MatTek EpiDerm™ Skin Irritation Test (SIT); (MB Research, Report number MB 11-20527.39; 2012-02-14.)
Non-irritant in humans following 48 hours exposure to 60%, 80% or 100% w/w; (Product Investigations Report number 31078; 2012)
Non-irritant in humans following 48 hours exposure to 10%, 15% or 20% w/w; (Product Investigations Report number 29808; 2012)
Non-irritant in humans following 48 hours exposure to 30%, 40% or 50% w/w; (Product Investigations Report number 30069; 2012)

Eye Irritation:
No reduction in viability in the MatTek EpiOcular MTT viability assay; (MB Research, Report number MB11-20527.19; 2012-02-14)

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records
Reference
Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP, Guideline Study
Qualifier:
according to
Guideline:
EPA OPPTS 870.2500 (Acute Dermal Irritation)
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Covance Research Products Inc., Denver, PA on 06/09/10 & 07/07/10.
- Age at study initiation: The animals were born on 02/20/10 & 03/13/10. Experimental Start date was 8/17/10
- Weight at study initiation: The pretest body weight range was 3.0 - 3.4 kg.
- Housing: The animals were identified by cage notation and a uniquely numbered metal eartag and individually housed in suspended wire bottom cages. Paper bedding was placed beneath the cages and changed at least three times/week. The animal room, reserved exclusively for rabbits on acute tests, was temperature controlled, had a 12 hour light/dark cycle, and was kept clean and vermin free.
- Diet (e.g. ad libitum): Fresh PMI Rabbit Chow (Diet #5321) was provided daily
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: None specified

IN-LIFE DATES: From: 8/17/10 To: 8/24/10
Type of coverage:
semiocclusive
Preparation of test site:
other: The day prior to application of the test article, the dorsal area of the trunk of each animal was clipped free of hair. The prepared site was approximately 10 x 10 cm and remained intact.
Vehicle:
unchanged (no vehicle)
Controls:
not required
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 ml
- Concentration (if solution): Neat

Duration of treatment / exposure:
The test article was kept in contact with the skin for 4 hours at which time the wrappings and patches were removed. Residual test article was removed from the test site by gently washing with distilled water at the end of the exposure period, prior to scoring for dermal reactions.
Observation period:
The test sites were scored for dermal irritation at 60 minutes and at 24, 48 and 72 hours in all animals and on day 7 in one animal following patch removal. Body weights were recorded pretest and at termination.

Animals were observed for toxicological and pharmacological effects at each dermal observation period and observed for mortality daily. All animals were humanely sacrificed using CO2 following study termination.
Number of animals:
3 males
Details on study design:
TEST SITE
-The test article was dosed by volume, 0.5 ml/site. The test article was placed over a 2 x 3 cm gauze patch. Gentle pressure was applied to aid in the distribution of the test article over the prepared site. The patch was secured with non-irritating tape. The torso was covered with a piece of porous dressing (semi-occlusive) large enough to cover the dose site with at least 5 cm square to spare on all sides of the gauze patch. Porous, non-irritating tape was used to encircle the trunk of the animal. The test article was kept in contact with the skin for 4 hours at which time the wrappings and patches were removed. Residual test article was removed from the test site by gently washing with distilled water at the end of the exposure period, prior to scoring for dermal reactions.

SCORING SYSTEM:

Erythema & Eschar
No erythema 0
Very slight erythema (barely perceptible) 1
Well defined erythema 2
Moderate to severe erythema 3
Severe erythema (beet redness) to slight eschar formation (injuries in depth) 4


Edema
No edema 0
Very slight edema (barely perceptible) 1
Slight edema (edges of area well-defined by definite raising) 2
Moderate edema (raised approximately 1.0 mm) 3
Severe edema (raised more than 1.0 mm, extending beyond the area of exposure) 4
Irritation parameter:
erythema score
Basis:
animal #1
Remarks:
Mean
Time point:
24/48/72 h
Score:
0.33
Max. score:
1
Reversibility:
fully reversible within: 48 hours
Irritation parameter:
edema score
Basis:
animal #1
Remarks:
Mean
Time point:
24/48/72 h
Score:
0
Max. score:
1
Reversibility:
other: not applicable
Irritation parameter:
erythema score
Basis:
animal #2
Remarks:
Mean
Time point:
24/48/72 h
Score:
1.4
Max. score:
2
Reversibility:
fully reversible within: 7 days
Irritation parameter:
edema score
Basis:
animal #2
Remarks:
Mean
Time point:
24/48/72 h
Score:
0.33
Max. score:
1
Reversibility:
fully reversible within: 48 hours
Irritation parameter:
erythema score
Basis:
animal #3
Remarks:
Mean
Time point:
24/48/72 h
Score:
1
Max. score:
2
Reversibility:
fully reversible within: 72 hours
Irritation parameter:
edema score
Basis:
animal #3
Remarks:
Mean
Time point:
24/48/72 h
Score:
0
Max. score:
0
Reversibility:
other: not applicable
Irritant / corrosive response data:
At one hour following the 4 hour exposure, erythema was very slight to well defined and edema was very slight. At 24 hours, erythema was very slight to well defined and edema was absent to very slight. At 48 hours, erythema was absent to very slight and edema was absent. At 72 hours, erythema was absent to very slight (one animal) and edema was absent. Animal #H3487/M was extended to day 7. No erythema or edema was noted.



Dermal Observations, Body Weights and Systemic Observations
===============================================================================
Rabbit Eartag: H3490 H3427 H3487
Sex: M M M
Pretest Body Weight - kg: 3.4 3.0 3.1
Terminal Body Weight Day 7 - kg: 3.4 3.1 3.2

Time after patch removal Erythema & Eschar Formation

60 minutes 1 2 2
24 hours 1 2 2
48 hours 0 1 1
72 hours 0 1 0
7 days N/A 0 N/A
Edema

60 minutes 1 1 1
24 hours 0 1 0
48 hours 0 0 0
72 hours 0 0 0
7 days N/A 0 N/A
Systemic Observations

60 minutes A A A
24 hours A A A
48 hours A A A
72 hours A A A


N = Normal; N/A = Not applicable
Other effects:
There were no abnormal physical signs noted during the observation period.

All body weight changes were normal
Interpretation of results:
other: Not classified
Remarks:
Criteria used for interpretation of results: EU
Conclusions:
Test material was not irritating per the EU CLP criteria
Executive summary:

Objective: To determine the irritant or corrosive effects, if any, of test article when applied dermally. This study was designed to comply with the standards set forth in EPA Health Effects Testing Guidelines, OPPTS Series 870.2500, final guideline, August 1998.

Method Synopsis: Since the test article was not expected to produce severe irritation or corrosion, three healthy New Zealand White rabbits (males) were dosed dermally with farnesane.

The test article (0.5ml) was applied dermally to one intact site/rabbit. The test article was kept in contact with the skin for 4 hours at which time the wrappings were removed. Erythema and edema were scored at 60 minutes and at 24, 48 and 72 hours in all animals and on day 7 in one animal (H3487/M) following patch removal. The skin was also evaluated for ulceration and necrosis or any evidence of tissue destruction at these time periods. Animals were observed for toxicological and pharmacological effects at each dermal observation period and observed for mortality daily. Body weights were recorded pretest and at termination. 

Summary: At one hour following the 4 hour exposure, erythema was very slight to well defined and edema was very slight. At 24 hours, erythema was very slight to well defined and edema was absent to very slight. At 48 hours, erythema was absent to very slight and edema was absent. At 72 hours, erythema was absent to very slight (one animal) and edema was absent. Animal #H3487/M was extended to day 7. No erythema or edema was noted.

There were no abnormal physical signs noted during the observation period. All body weight changes were normal.

Conclusion: Farnesane is not classfied as a dermal irritant according to CLP criteria. 

 

 

 

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records
Reference
Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP, Guideline study
Qualifier:
according to
Guideline:
EPA OPPTS 870.2400 (Acute Eye Irritation)
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Covance Research Products, Inc., Denver, PA on 07/07/10 & 08/04/10
- Age at study initiation: The animals were born on 03/13/10 & 04/17/10. Study Initiation on 08/24/10
- Weight at study initiation: The pretest body weight range was 2.4 - 3.2 kg.
- Housing: The animals were identified by cage notation and a uniquely numbered metal eartag. The animals were housed 1/cage in suspended 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: Minimum of 5 days

ENVIRONMENTAL CONDITIONS: The animal room, reserved exclusively for rabbits on acute tests, was temperature controlled, had a 12-hour light/dark cycle, and was kept clean and vermin free.

IN-LIFE DATES: From: 8/24/10 To: 8/27/10
Vehicle:
unchanged (no vehicle)
Controls:
other: Contralateral, untreated eye served as control
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 ml
- Concentration (if solution): neat


Duration of treatment / exposure:
The test article (0.1 ml) was placed by syringe into the conjunctival sac that was formed by gently pulling the lower eyelid away from the eye. After instillation, the lids were held together for approximately one second to insure adequate distribution of the test article. One eye of each rabbit was dosed. The contralateral eye served as a control.

Observation period (in vivo):
Type and Frequency of Observations
The treated and control eye of each rabbit was examined for irritation of the cornea, iris and conjunctiva at 1, 24, 48 and 72 hours. A Mini-Maglite® flashlight equipped with a high intensity bulb was used to aid in scoring. Sodium fluorescein dye procedures were used at the 24-hour observation interval in the treated eyes. The eyes were examined with the aid of an ultraviolet light source. Ocular reactions were graded according to the numerical Draize technique.

Body weights were recorded pretest.

Observations for mortality, toxicity and pharmacological effects were recorded at each ocular observation period. All animals were humanely sacrificed using CO2 following study termination.
Number of animals or in vitro replicates:
Three rabbits (males), free from evidence of ocular irritation or abnormalities, were assigned to this study without conscious bias. Prior to being selected for this study, both eyes of each animal were examined for any evidence of irritation or abnormalities of the cornea, iris and/or conjunctiva. A Mini-Maglite® flashlight equipped with a high intensity bulb was used to aid in the examination. Only animals in apparent good health were made available for study assignment.
Details on study design:
REMOVAL OF TEST SUBSTANCE: No removal
SCORING SYSTEM: Ocular reactions were graded according to the numerical Draize technique, summarized below.

SCALE FOR SCORING OCULAR LESIONS (Draize, J. H. et al. J. Pharm. Exp. Ther. 82:377-390, 1944).
(1) CORNEA:
(A) Opacity: Degree of density (area most dense taken for reading):
No ulceration or opacity 0
Scattered or diffuse areas of opacity (other than slight dulling of normal luster),details of iris clearly visible 1(*)
Easily discernible translucent area, details of iris slightly obscured 2(*)
Opalescent areas, no details of iris visible, size of pupil barely discernible 3(*)
Opaque cornea, iris not discernible through the opacity 4(*)
(B) Area of cornea Involved:
One quarter (or less) but not zero 1
Greater than one-quarter, but less than one-half 2
Greater than one-half, but less than three-quarters 3
Greater than three quarters up to whole area 4
SCORE EQUALS A x B x 5 Maximum Total 80

(2) IRIS:
(A) Normal 0
Folds above normal, congestion, swelling, circumcorneal injection (any or all of these or combination
of any thereof), iris still reacting to light (sluggish reaction is positive) 1(*)
No reaction to light, hemorrhage, gross destruction (any or all of these) 2(*)
SCORE EQUALS A x 5 Maximum Total 10

(3) CONJUNCTIVAE:
(A) REDNESS (refers to palpebral and bulbar conjunctivae excluding cornea & iris):
Blood vessels normal 0
Some blood vessels definitely hyperemic (injected) 1
More diffuse, deeper crimson red, individual vessels not easily discernible 2(*)
Diffuse beefy red 3(*)
(B) CHEMOSIS
No swelling 0
Any swelling above normal (includes nictitating membranes) 1
Obvious swelling with partial eversion of lids 2(*)
Swelling with lids about half closed 3(*)
Swelling with lids more than half closed 4(*)
(C) DISCHARGE
No Discharge 0
Any amount different from normal (does not include small amounts observed in
inner canthus of normal animals) 1
Discharge with moistening of the lids and hairs just adjacent to lids 2
Discharge with moistening of the lids and hairs and considerable area around the eye 3
SCORE EQUALS (A+B+C)x2 Maximum Total 20

The maximum total score is the sum of all scores obtained for the cornea, iris and conjunctivae.
4.
(*)Indicates a positive response

ULTRAVIOLET FLUORESCEIN SCAN SCORING CODE:

0 = Negative
1 = Positive with an area 1/4 or less
2 = Positive with an area >1/4 but <1/2
3 = Positive with an area >1/2, but <3/4
4 = Positive with an area >3/4, up to entire area




TOOL USED TO ASSESS SCORE: To screen for any evidence of irritation or abnormalities of the cornea, iris and/or conjunctiva prior to start of test, A Mini-Maglite® flashlight equipped with a high intensity bulb was used to aid in scoring. The treated and control eye of each rabbit was examined for irritation of the cornea, iris and conjunctiva at 1, 24, 48 and 72 hours. A Mini-Maglite® flashlight equipped with a high intensity bulb was used to aid in scoring. Sodium fluorescein dye procedures were used at the 24-hour observation interval in the treated eyes. The eyes were examined with the aid of an ultraviolet light source. Ocular reactions were graded according to the numerical Draize technique.
Irritation parameter:
cornea opacity score
Basis:
animal: Mean of animals 1, 2, & 3
Time point:
24/48/72 h
Score:
0
Remarks on result:
no indication of irritation
Irritation parameter:
iris score
Basis:
animal: Mean of animals 1, 2, & 3
Time point:
24/48/72 h
Score:
0
Remarks on result:
no indication of irritation
Irritation parameter:
conjunctivae score
Basis:
animal: Mean of animals 1, 2, & 3
Time point:
24/48/72 h
Score:
0
Remarks on result:
no indication of irritation
Irritation parameter:
chemosis score
Basis:
animal: Mean of animals 1, 2, & 3
Time point:
24/48/72 h
Score:
0
Remarks on result:
no indication of irritation
Irritation parameter:
overall irritation score
Basis:
mean
Time point:
other: 1, 24, 48, and 72 hours
Score:
0
Remarks on result:
other: See "any other information on results incl. tables" for complete data summary
Irritant / corrosive response data:
There was no corneal opacity, iritis or conjunctival irritation noted at any observation period.
The control eyes appeared normal at all observation periods.
Systemic Observations: There were no abnormal physical signs noted during the observation period.

Other effects:
None observed

Ocular Findings, Systemic Observations, and Body Weights

Animal/Sex

Item

Tissue

Reading

1 hour

24 hour

48 hour

72 hour

H3492/M

A

Cornea

Opacity

0

0

0

0

 

B

Area

0

0

0

0

 

1.      

0

0

0

0

 

C

Iris

 

0

0

0

0

 

2.       = (C x 5)

 

0

0

0

0

 

D

Conjunctiva

Redness

0

0

0

0

 

E

 

Chemosis

0

0

0

0

 

F

 

Discharge

0

0

0

0

 

3.      

 

0

0

0

0

 

      Total 1 + 2+ 3

 

0

0

0

0

 

Systemic Observations

 

A

A

A

A

 

Sodium Fluorescein

 

 

0

NA

NA

 

Pretest Body Weight : 3.2 Kg

 

 

 

 

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Animal/Sex

Item

Tissue

Reading

1 hour

24 hour

48 hour

72 hour

H3555/M

A

Cornea

Opacity

0

0

0

0

 

B

 

Area

0

0

0

0

 

1.      

0

0

0

0

 

C

Iris

 

0

0

0

0

 

2.       = (C x 5)

 

0

0

0

0

 

D

Conjunctiva

Redness

0

0

0

0

 

E

 

Chemosis

0

0

0

0

 

F

 

Discharge

0

0

0

0

 

3.      

0

0

0

0

 

 

      Total 1 + 2+ 3

 

0

0

0

0

 

Systemic Observations

 

A

A

A

A

 

Sodium Fluorescein

 

 

0

NA

NA

 

Pretest Body Weight : 2.4 Kg

 

 

 

 

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Animal/Sex

Item

Tissue

Reading

1 hour

24 hour

48 hour

72 hour

H3539/M

A

Cornea

Opacity

0

0

0

0

 

B

 

Area

0

0

0

0

 

1.      

 

0

0

 

 

 

C

Iris

 

0

0

0

0

 

2.       = (C x 5)

 

0

0

0

0

 

D

Conjunctiva

Redness

0

0

0

0

 

E

 

Chemosis

0

0

0

0

 

F

 

Discharge

0

0

0

0

 

3.      

 

0

0

0

0

 

      Total 1 + 2+ 3

 

0

0

0

0

 

Systemic Observations

 

A

A

A

A

 

Sodium Fluorescein

 

 

0

NA

NA

 

Pretest Body Weight : 2.5 Kg

 

 

 

 

A = Normal; NA = Not applicable

Interpretation of results:
other: Not irritating
Remarks:
Criteria used for interpretation of results: EU
Conclusions:
Ocular administration of Farnesane CAS# 3891-98-3 did not produce irritation.
Executive summary:

Objective: To determine the irritant and/or corrosive effects, if any, of a test article when instilled into the rabbit eye. This study was designed to comply with the standards set forth in EPA Health Effects Testing Guidelines, OPPTS Series 870.2400, final guideline, August 1998.

 

Method Synopsis: Three healthy New Zealand White rabbits (males), free from evidence of ocular irritation and corneal abnormalities, were dosed with Farnesane CAS# 3891-98-3.  The test article (0.1 ml) was placed into the conjunctival sac of one eye of each rabbit. The contralateral eye served as a control. The eyes were examined and scored by the Draize technique at 1,24, 48 and 72 hours. The control eyes were examined at the same time periods. Sodium fluorescein dye procedures were used at the 24-hour observation interval. Observations for mortality, toxicity and pharmacological effects were recorded at each ocular observation period. Body weights were recorded pretest.

 

Summary: 

 

There was no corneal opacity, iritis or conjunctival irritation noted at any observation period.

 

The control eyes appeared normal at all observation periods.

 

There were no abnormal physical signs noted during the observation period.

 

Conclusion: Ocular administration of Farnesane CAS# 3891-98-3 did not produce irritation.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Skin Irritation:

In the key study for skin irritation, all animals showed slight to well defined erythema from 60 minutes to 24 hours post exposure, thereafter the reaction subsided with only 2 animals showing slight erythema at 48 hours and 1 animal showing slight erythema at 72 hours. This resolved by 7 days post exposure. Only 1 animal showed slight edema at 24 hours post exposure, which had resolved by 48 hours.

A supporting in vitro skin irritation test (MatTek Epiderm) was performed according to test guideline 439. The mean tissue viability scored in the test was 96.4%, indicating that the substance is non-irritant.

Further clinical studies have been performed to ascertain the irritant potential of the substance: In the first study volunteers were exposed to concentrations of 60%, 80% and 100% for 24 or 48 hours. A maximal Global irritation index of 0.075 was observed for 48 hours exposure to 100% farnesane. This value is indicative of a non-irritant.

Two further studies exposing human volunteers to concentrations of farnesane between 10% and 50% for 24 hours or 48 hours demonstrated that the substance is non-irritant with global irritation indices of 0 for all concentrations at each exposure time.

Eye Irritation:

The key study for eye irritation indicates farnesane is not an eye irritant; a guideline in vivo study was performed in rabbits, there were no adverse effects for any of the parameters at any time point. The resulting MMAS is 0.

In a supporting non-guideline in vitro study (MatTek Epiocular) there was no reduction in viability of the tissues; the ET50 is >256 minutes indicating that the farnesane is not an eye irritant.


Justification for selection of skin irritation / corrosion endpoint:
GLP animal data study, Klimish score of 1. Supporting studies ( one in-vitro evaluation and 3 in-vivo human patch tests) confirm the lack of dermal response.

Justification for selection of eye irritation endpoint:
GLP animal data study, Klimish score of 1. Lack of occular response correlates with results of an in-vitro supporting study

Justification for classification or non-classification

Skin irritation: All scores < 2.3, therefore not classified as skin irritant. Supporting in vitro skin irritation test confirms lack of dermal irritation.

Eye irritation: All scores of 0 and eyes appeared normal. Supporting in-vitro study confirms lack of occular irritation.