2,2,3,3,4,4,5,5-octafluoropentyl methacrylate

Direct observations: clinical cases, poisoning incidents and other

Administrative data

Endpoint:

direct observations: clinical cases, poisoning incidents and other

Remarks:

Skin Irritation

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

23-Jun-2008 to 31-Jul-2008

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

test procedure in accordance with national standard methods with acceptable restrictions

Justification for type of information:

This endpoint study record is part of a Weight of Evidence approach comprising a direct observation from RIPT studies, dermal irritation reported during developmental toxicity studies, irritation reported during an LLNA study and the results of an in vitro dermal adsorption study. The data sources are in agreement regarding dermal irritation and are sufficient to fulfil the information requirements as further explained in the provided endpoint summary.

Cross-reference

Cross-reference 1

Reason / purpose for cross-reference:

reference to other study

Reference

Endpoint:

direct observations: clinical cases, poisoning incidents and other

Remarks:

Skin Irritation

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

23-Jun-2008 to 31-Jul-2008

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

test procedure in accordance with national standard methods with acceptable restrictions

Justification for type of information:

This endpoint study record is part of a Weight of Evidence approach comprising a direct observation from RIPT studies, dermal irritation reported during developmental toxicity studies, irritation reported during an LLNA study and the results of an in vitro dermal adsorption study. The data sources are in agreement regarding dermal irritation and are sufficient to fulfil the information requirements as further explained in the provided endpoint summary.

Reason / purpose for cross-reference:

reference to other study

Reason / purpose for cross-reference:

reference to other study

Reason / purpose for cross-reference:

reference to other study

Reason / purpose for cross-reference:

reference to other study

Reason / purpose for cross-reference:

reference to other study

Reason / purpose for cross-reference:

reference to same study

Study type:

study with volunteers

Endpoint addressed:

skin irritation / corrosion

skin sensitisation

Guideline:

other: Repeated Insult Patch Test

Principles of method if other than guideline:

Two products, AF-2(08-1-14) and AF-3(08-1-23) were evaluated neat to determine its ability to sensitize the skin of volunteer subjects with normal skin using an occlusive repeated insult patch study. Erythema and edema reported during induction phases assessed for skin irritation.

GLP compliance:

no

Specific details on test material used for the study:

Two products containing 2% of test material:
AF-2 (08-1-14) - a hair spray formulation containing 2% OFPMA
AF-3 (08-1-23) - a hair cream formulation containing 2% OFPMA

Type of population:

general

Subjects:

- Number of subjects exposed: 50 subjects
- Sex: males and females
- Age: 18 years of age or older
- Race: any skin type or race, providing the skin pigmentation would allow discernment of erythema (3.4% asian, 25.9% black, 50.0% caucasian, 20.7% hispanic)
- Demographic information: were free of any systemic or dermatological disorder which, in the opinion of the investigative personnel, would have interfered with the study results or increased the risk of adverse events
- Known diseases: in general good health and had completed a medical screening procedure
- Other: Prior to study entry, the subjects were screened to assure that they met the inclusion/exclusion criteria.

Ethical approval:

not specified

Route of exposure:

dermal

Reason of exposure:

intentional

Exposure assessment:

measured

Remarks:

0.2 mL for AF-2(08-1-14), 0.2 g for AF-3(08-1-23)

Details on exposure:

The induction phase consisted of 9 consecutive applications of the study material and subsequent evaluations of the patch sites. Prior to application of the patches, the sites were outlined with a skin marker. Patches were applied on Mondays, Wednesdays and Fridays for 3 consecutive weeks. The subjects were required to remove the patches approximately 24 hours after application. They returned to the facility at 48-hour intervals to have the sites evaluated and identical patches applied to the same sites. Patches applied on Friday were removed by subjects after 24 hours. The sites were evaluated on the following Monday, i.e., 72 hours after patch application. A Monday or Friday holiday resulted in evaluation at 96 hours after patch application.

Following the ninth evaluation, the subjects were dismissed for a rest period of approximately 10-15 days.

Subjects who were absent once during the induction phase received a make-up (MU) patch at the last induction visit. The MU applications were graded 48 hours later at the MU visit, or were recorded as N9G (no ninth grading). Subjects who missed the ninth evaluation but have had 9 patch applications were considered to have completed the induction phase.

The challenge phase was during the sixth week of the study. Identical patches were applied to sites previously unexposed to the study material. The patches were removed by subjects after 24 hours and the sites graded after additional 24-hour and 48-hour periods (i.e., 48 and 72 hours after application). Following a negative induction, a 48/72-hour sequence of “-/+”, “?/+” or “+/+” resulted in an additional reading being performed at the 96-hour interval. Re-challenge was performed whenever there was evidence of possible sensitization.

To be considered a completed case, a subject must have had 9 applications and no fewer than 8 subsequent reading during induction, and a single application and 2 readings during challenge. Only completed cases were used to assess sensitization.

Test material was applied to the patch and the patch was applied to the infrascapular area of the back, either to the right or left of the midline, or to the upper arm.

Examinations:

The subjects returned to the facility at 48-hour intervals to have the sites evaluated and identical patches applied to the same sites during the induction phase. During the challenge phase, the pat ches were removed by subjects after 24 hours and the sites graded after additional 24-hour and 48-h our periods (i.e., 48 and 72 hours after application).

Clinical signs:

Fifty-eight subjects between the ages of 20 and 67 were enrolled and 50 completed the study. There were 3 non-serious adverse events (AEs) reported, which were unrelated or unlikely to be related to the study products.

Results of examinations:

Under the conditions employed in this study, there was no evidence of sensitization to AF-2(08-1-14) in 50 out of 50 individuals. Also, during induction there was no dermatologic response to exposure observed in 96% of individuals and in 2% slight to doubtful dermatologic response was seen, and only in 2% (1 individual) a clear erythema (no edema) was observed. Under the conditions employed in this study, there was no evidence of sensitization to AF-3(08-1-23) in 50 out of 50 individuals. During induction there was no dermatologic response to exposure observed in 90% of individuals and in 8% slight to doubtful dermatologic response was seen, and only in 2% (1 individual) a clear erythema (no edema) was observed

Outcome of incidence:

Under the conditions employed in this study, there was no evidence of sensitization to AF-2(08-1-14) and AF-3(08-1-23).

Table 1: Summary of Dermatologic Response Grades – AF-2(08-1-14)
	No reaction (-)	Minimal or doubtful response, slightly / different from surrounding normal skin (?)	Definite erythema, no edema (+)	Total evaluable	Number absent	Number discontinued
Induction Readings
1	54	0	0	54	3	1
2	51	0	0	51	2	5
3	50	1	0	51	2	5
4	49	0	1	50	1	7
5	50	1	0	51	0	7
6	50	1	0	51	0	7
7	49	1	0	50	0	8
8	44	2	0	46	4	8
9	47	1	0	48	2	8
Make Up (MU)	7	0	0	7		8
Challenge phase
48 hours	50	0	0	50	0	8
72 hours	50	0	0	50	0	8

 

Table 2: Maximum elicited response during induction: AF-2(08-1-14)
Response	N(%) subjects
- (no reaction)	48 (96%)
? (minimal or doubtful response, slightly / different from surrounding normal skin)	1 (2%)
+ (definite erythema, no edema)	1 (2%)

 

Table 3: Summary of Dermatologic Response Grades – AF-3(08-1-23)
	No reaction (-)	Minimal or doubtful response, slightly / different from surrounding normal skin (?)	Definite erythema, no edema (+)	Total evaluable	Number absent	Number discontinued
Induction Readings
1	51	3	0	54	3	1
2	48	2	1	51	2	5
3	48	2	1	51	2	5
4	47	2	1	50	1	7
5	48	2	1	51	0	7
6	50	0	1	51	0	7
7	48	1	1	50	0	8
8	45	1	0	46	4	8
9	47	1	0	48	2	8
Make Up (MU)	7	0	0	7
Challenge phase
48 hours	49	1	0	50	0	8
72 hours	50	0	0	50	0	8

 

Table 4: Maximum elicited response during induction: AF-3(08-1-23)
Response	N(%) subjects
- (no reaction)	45 (90%)
? (minimal or doubtful response, slightly / different from surrounding normal skin)	4 (8%)
+ (definite erythema, no edema)	1 (2%)

 

Conclusions:

Under the conditions employed in this study, there was no evidence of sensitization to AF-2(08-1-14) and AF-3(08-1-23). Examination of the data also indicate an absence of irritation reactions.

Executive summary:

Two products containing 2% OFPMA, AF-2(08-1-14) and AF-3(08-1 23), were evaluated neat to determine its ability to sensitize the skin of volunteer subjects with normal skin using an occlusive repeated insult patch study. Fifty subjects completed the study. Under the conditions employed in this study, there was no evidence of sensitization to AF-2(08-1-14) and AF-3(08-1-23). Also, an examination of the data also indicate an absence of irritation reactions.

Cross-reference 2

Reason / purpose for cross-reference:

reference to other study

Reference

Endpoint:

skin irritation: in vivo

Remarks:

Dermal Prenatal Developmental Toxicity Study

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

4 November 2007 to 18 January 2008

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Justification for type of information:

This endpoint study record is part of a Weight of Evidence approach comprising a direct observation from RIPT studies, dermal irritation reported during developmental toxicity studies, irritation reported during an LLNA study and the results of an in vitro dermal adsorption study. The data sources are in agreement regarding dermal irritation and are sufficient to fulfil the information requirements as further explained in the provided endpoint summary.

Reason / purpose for cross-reference:

reference to other study

Reason / purpose for cross-reference:

reference to other study

Reason / purpose for cross-reference:

reference to other study

Reason / purpose for cross-reference:

reference to other study

Reason / purpose for cross-reference:

reference to other study

Reason / purpose for cross-reference:

reference to same study

Guideline:

other: equivalent to: OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Version / remarks:

Only dermal irritation observations reported

Principles of method if other than guideline:

An OECD Guideline 414 (Prenatal Developmental Toxicity Study) dermal exposure equivalent study was completed. The skin irritation observations are reported.

GLP compliance:

no

Remarks:

The study was not commissioned with compliance with REACH as a goal, rather the study was commissioned during early product development.

Specific details on test material used for the study:

Purity: 99%

Species:

rat

Strain:

other: Crl:CD(SD)

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Inc. Portage, Michigan
- Age at study initiation: Approximately 84 to 91 days old upon receipt
- Weight at study initiation: a minimum of 220 g at gestation day 5 (205-308 g on Gestation Day 5)
- Fasting period before study: No
- Housing: Upon arrival and until pairing, all rats were individually housed
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: Prior to the initiation of dose administration, the animals were acclimated to wearing Elizabethan restraint collars. The collars were affixed to each rat on gestation days 4 and 5 for approximately 1 and 3 hours, respectively.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±3°C
- Humidity (%): 50±20%
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12 / 12

IN-LIFE DATES: From: 4 November 2007 (first gestation day 0) To: 27 November 2007 (Last laparohysterectomy)

Type of coverage:

occlusive

Preparation of test site:

clipped

Vehicle:

unchanged (no vehicle)

Amount / concentration applied:

The dosage level was 1300 mg/kg/day administered at a dosage volume of 0.91 mL/kg.

Duration of treatment / exposure:

6-hour exposure period per day for 12 days (gestation days 6-17).

Observation period:

The application site was scored daily (prior to dose administration and following removal of the dressing) for erythema, edema and other dermal findings.

Number of animals:

25 females per dose

Details on study design:

TEST SITE
- Area of exposure: Back of animals, from the scapula to the wing of the ileum (hipbone) and halfway down the flank of each side of the animal. Doses were evenly applied using a rubber policeman covered glass rod over the clipped, unabraded area. The corners of the application site were marked with indelible ink to allow proper identification of the treated and untreated skin. Elizabethan collars were applied to restrict access to the wrapped dosing site.
- % coverage: The mean areas of coverage were approximately 7.85%.
- Type of wrap if used: The application site for each animal was covered with 8-ply gauze, covered with an occluded non-porous latex bandage and held in place with non-irritating tape.


REMOVAL OF TEST SUBSTANCE
- Washing: Residual material on the skin was visually estimated and recorded, and the test sites were gently washed with a 70:30 isopropanol:water solution and disposable paper towels to remove any residual vehicle or test article.
- Time after start of exposure: After 6-hour exposure period

OBSERVATION TIME POINTS
The application site was scored daily (prior to dose administration and following removal of the dressing) for erythema, edema and other dermal findings

4-STEP GRADING SYSTEM (Draize, 1965)
Erythema and Eschar Formation:
- 0: No erythema
- 1: Very slight erythema (barely perceptible, edges of area not well defined)
- 2: Sight erythema (pale read in colour and edges definable)
- 3: Moderate to severe erythema (definite red in colour and area well defined)
- 4: Severe erythema (beet or crimson red) to slight eschar formation (injuries in depth)
Edema Formation:
- 0: No edema
- 1: Very slight edema (barely perceptible, edges of area not well defined)
- 2: Slight edema (edges of area well defined by definite raising)
- 3: Moderate edema (raised approximately 1 mm)
- 4: Severe edema (raised more than 1 mm and extending beyond area of exposure)


Further study design regarding prenatal development toxicity are discussed elsewhere in this dossier.

Irritation parameter:

overall irritation score

Remarks:

on Day 1 following 6-hour exposure

Basis:

mean

Time point:

24 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Remarks:

no dermal irritation reported at any time point for any animal

Irritation parameter:

erythema score

Basis:

mean

Time point:

24/48/72 h

Remarks on result:

not determinable because of methodological limitations

Irritation parameter:

edema score

Basis:

mean

Time point:

24/48/72 h

Remarks on result:

not determinable because of methodological limitations

Irritant / corrosive response data:

No dermal irritation effects were observed.

Interpretation of results:

study cannot be used for classification

Remarks:

Weight of Evidence classification: GHS criteria not met

Conclusions:

No skin irritation was reported during the daily observations during a rat dermal exposure study equivalent to OECD Guideline 414 (Prenatal Developmental Toxicity Study).

Executive summary:

As part of a weight of evidence approach, the skin irritation observation reported during a rat dermal exposure study equivalent to OECD Guideline 414 (Prenatal Developmental Toxicity Study) were considered. The test article was administered by dermal exposure to clipped dorsum (approximately 8% of total body surface area) to 2 groups of 25 time-mated female Crl:CD(SD) rats once daily from gestation days 6 through 17. The application site for each animal was covered with 8-ply gauze, covered with an occluded non-porous latex bandage and held in place with non-irritating tape. Elizabethan collars were applied to restrict access to the wrapped dosing site. The dosage level was 1300 mg/kg/day administered at a dosage volume of 0.9 mL/kg. A concurrent control group of 25 time-mated females received the vehicle (deionized water) on a comparable regimen at a dosage volume of 1.3 mL/kg. The application site was scored daily (prior to dose administration and following removal of the dressing) for erythema, edema and other dermal findings. The prenatal developmental toxicity study continued to determine potential toxicity as described elsewhere within this dossier.

 

No skin irritation was reported during the daily observations.

Cross-reference 3

Reason / purpose for cross-reference:

reference to other study

Reference

Endpoint:

skin irritation: in vivo

Remarks:

Dermal Prenatal Developmental Toxicity Study

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

3 October 2007 to 18 January 2008

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Justification for type of information:

This endpoint study record is part of a Weight of Evidence approach comprising a direct observation from RIPT studies, dermal irritation reported during developmental toxicity studies, irritation reported during an LLNA study and the results of an in vitro dermal adsorption study. The data sources are in agreement regarding dermal irritation and are sufficient to fulfil the information requirements as further explained in the provided endpoint summary.

Reason / purpose for cross-reference:

other:

Reason / purpose for cross-reference:

reference to other study

Reason / purpose for cross-reference:

reference to other study

Reason / purpose for cross-reference:

reference to other study

Reason / purpose for cross-reference:

reference to other study

Reason / purpose for cross-reference:

reference to same study

Guideline:

other: equivalent to: OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Version / remarks:

Only dermal irritation observations reported

Principles of method if other than guideline:

An OECD Guideline 414 (Prenatal Developmental Toxicity Study) dermal exposure equivalent study was completed. The skin irritation observations are reported.

GLP compliance:

no

Remarks:

The study was not commissioned with compliance with REACH as a goal, rather the study was commissioned during early product development.

Specific details on test material used for the study:

Purity: 99%

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Covance Research Products, Inc., Kalamazoo, Michigan
- Age at study initiation: The animals were approximately 5.5 months old upon receipt.
- Weight at study initiation: Body weight values ranged from 2947 g to 4279 g on gestation day 0.
- Fasting period before study: Not reported
- Housing: housed individually
- Diet: The basal diet was offered in 25 g increments 3 times per day on the day of arrival and in increased amounts over the next few days, until the animals gradually achieved ad libitum status prior to the dose administration period; basal diet was offered ad libitum thereafter.
- Water: ad libitum
- Acclimation period: Prior to the initiation of dose administration, the animals were acclimated to wearing Elizabethan restraint collars. The collars were affixed to each rabbit on gestation days 3, 4, 5 and 6 for approximately 1, 2, 4 and 6 hours, respectively.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19±3°C
- Humidity (%): 50±20%
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12 / 12

IN-LIFE DATES: From: 4 November 2007 (first gestation day 0) To: 27 November 2007 (Last laparohysterectomy)

Type of coverage:

occlusive

Preparation of test site:

clipped

Vehicle:

unchanged (no vehicle)

Amount / concentration applied:

The dosage level was 1300 mg/kg/day administered at a dosage volume of 0.91 mL/kg.

Duration of treatment / exposure:

6 hours of exposure per day for 14 days (gestation days 7-20)

Observation period:

The application site was scored daily (prior to dose administration and following removal of the dressing) for erythema, edema and other dermal findings.

Number of animals:

22 females per dose

Details on study design:

TEST SITE
- Area of exposure: The hair was clipped from the back of each animal, from the scapula (shoulder) to the wing of the ileum (hipbone) and halfway down the flank of each side of the animal. Doses were evenly applied using a rubber policeman covered glass rod over the clipped, unabraded area. The corners of the application site were marked with indelible ink to allow proper identification of the treated and untreated skin. Elizabethan collars were applied to restrict access to the wrapped dosing site.
- % coverage: approximately 7.9%
- Type of wrap if used: The application site for each animal was covered with 8-ply gauze, covered with an occluded non-porous latex bandage and held in place with non-irritating tape.

REMOVAL OF TEST SUBSTANCE
- Washing: Residual material on the skin was visually estimated and recorded, and the test sites were gently washed twice (the second wash immediately following the first) with a 70:30 isopropanol:water solution and disposable paper towels to remove any residual vehicle or test article.
- Time after start of exposure: After 6-hour exposure period

OBSERVATION TIME POINTS
The application site was scored daily (prior to dose administration and following removal of the dressing) for erythema, edema and other dermal findings
4-STEP GRADING SYSTEM (Draize, 1965)
Erythema and Eschar Formation:
- 0: No erythema
- 1: Very slight erythema (barely perceptible, edges of area not well defined)
- 2: Sight erythema (pale read in colour and edges definable)
- 3: Moderate to severe erythema (definite red in colour and area well defined)
- 4: Severe erythema (beet or crimson red) to slight eschar formation (injuries in depth)
Edema Formation:
- 0: No edema
- 1: Very slight edema (barely perceptible, edges of area not well defined)
- 2: Slight edema (edges of area well defined by definite raising)
- 3: Moderate edema (raised approximately 1 mm)
- 4: Severe edema (raised more than 1 mm and extending beyond area of exposure)

Further study design regarding prenatal development toxicity are discussed elsewhere in this dossier.

Irritation parameter:

overall irritation score

Remarks:

on day 1 following 6-hour exposure

Basis:

mean

Time point:

24 h

Score:

0

Max. score:

4

Remarks on result:

probability of weak irritation

Remarks:

following repeated exposure

Irritation parameter:

erythema score

Basis:

mean

Time point:

24/48/72 h

Remarks on result:

not determinable because of methodological limitations

Irritation parameter:

edema score

Basis:

mean

Time point:

24/48/72 h

Remarks on result:

not determinable because of methodological limitations

Irritant / corrosive response data:

No dermal irritation effects were observed following single exposure. Very slight erythema was noted in 4 females from 1 to 3 consecutive days during gestiation days 12-14. Due to the absence of this finding in the vehicle control group, these occurrences of very slight erythema were considered to be test article-related; however, because of the transient nature, limited incidence and minimal severity of this finding, it was not considered to be adverse.
In addition, desquamation was noted in 2 and 7 females in the vehicle control and 1300 mg/kg/day group, respectively, prior to dose application; this finding was observed generally beginning as early as gestation day 11 and continuing through gestation day 16. This finding persisted to the time of unwrap (following 6 hours of exposure) in 3 test article-treated females (nos. 52135, 52137 and 52142) during gestation days 14-16.

Interpretation of results:

study cannot be used for classification

Remarks:

Weight of Evidence classification: GHS criteria not met

Conclusions:

Evidence of minimal dermal irritation (very slight erythema) was noted in 4 females from 1 to 3 consecutive days during gestation days 12-14. In addition, desquamation was noted in 2 and 7 females in the vehicle control and 1300 mg/kg/day group, respectively, prior to dose application; this finding was observed generally beginning as early as gestation day 11 and continuing through gestation day 16. This finding persisted to the time of unwrap (following 6 hours of exposure) in 3 test article-treated females (nos. 52135, 52137 and 52142) during gestation days 14-16.

Executive summary:

As part of a weight of evidence approach, the skin irritation observation reported during a rabbit dermal exposure study equivalent to OECD Guideline 414 (Prenatal Developmental Toxicity Study) were considered. The test article was administered by dermal exposure to clipped dorsum (approximately 8% of total body surface area) to 2 groups of 22 time-mated female New Zealand White rabbits once daily, from gestation days 7-20. The application site for each animal was covered with 8-ply gauze, covered with an occluded non-porous latex bandage and held in place with non-irritating tape. Elizabethan collars were applied to restrict access to the wrapped dosing site. The dosage level was 1300 mg/kg/day administered at a dosage volume of 0.91 mL/kg. A concurrent control group of 22 time-mated females received the vehicle (deionized water) on a comparable regimen at a dose volume of 1.3 mL/kg. The application site was scored daily (prior to dose administration and following removal of the dressing) for erythema, edema and other dermal findings. The prenatal developmental toxicity study continued to determine potential toxicity as described elsewhere within this dossier.

 

Minimal dermal irritation (very slight erythema) was noted in 4 females from 1 to 3 consecutive days during gestation days 12-14.

In addition, desquamation was noted in 2 and 7 females in the vehicle control and 1300 mg/kg/day group, respectively, prior to dose application; this finding was observed generally beginning as early as gestation day 11 and continuing through gestation day 16. This finding persisted to the time of unwrap (following 6 hours of exposure) in 3 test article-treated females (nos. 52135, 52137 and 52142) during gestation days 14-16.

Cross-reference 4

Reason / purpose for cross-reference:

reference to other study

Reference

Endpoint:

skin irritation: in vitro / ex vivo

Remarks:

In Vitro Percutaneous Absorption

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

08 April 2010 to 05 May 2010

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Justification for type of information:

This endpoint study record is part of a Weight of Evidence approach comprising a direct observation from RIPT studies, dermal irritation reported during developmental toxicity studies, irritation reported during an LLNA study and the results of an in vitro dermal adsorption study. The data sources are in agreement regarding dermal irritation and are sufficient to fulfil the information requirements as further explained in the provided endpoint summary.

Reason / purpose for cross-reference:

reference to other study

Reason / purpose for cross-reference:

reference to other study

Reason / purpose for cross-reference:

reference to other study

Reason / purpose for cross-reference:

reference to other study

Reason / purpose for cross-reference:

reference to other study

Reason / purpose for cross-reference:

reference to same study

Guideline:

other: OECD Guideline 428 (Skin Absorption: In Vitro Method)

Version / remarks:

Dermal irritation observations reported

Principles of method if other than guideline:

An OECD Guideline 428 (Skin Absorption: In Vitro Method) study was conducted. The dermal irritation observations are reported.

GLP compliance:

yes

Specific details on test material used for the study:

Specific details on test material used for the study
- Radiolabelling: yes
- Source and lot/batch No.of test material: American Radiolabelled Chemicals Inc, batch no. 090109
- Radiochemical purity: 93.6%
- Specific activity: 5 mCi/mmol
- Locations of the label: carbonyl carbon

Test system:

human skin model

Details on animal used as source of test system:

Six samples of full-thickness human skin (4 abdomen and 2 breast) were obtained from female patients aged 19 to 63 years old attending St. John’s Hospital, NHS Lothian, Livingston, UK. On arrival at Charles River, these samples were cleaned of subcutaneous fat and connective tissue using a scalpel blade. The skin samples were washed in cold running water and dried using tissue paper.

The skin samples were then cut into smaller pieces (where appropriate), wrapped in aluminium foil, put into self sealing plastic bags and stored at -20°C until they were used in the study.

Vehicle:

other: leave-on hair styling cream

Amount/concentration applied:

The leave-on hair styling cream containing 2% (w/v) radiolabelled test substance (concentration by radioactivity 2.11% w/v) was applied, at an application rate of about 20 mg/cm² (469 μg equiv. OFPMA/cm²)

Duration of treatment / exposure:

24 hours (single exposure)

Number of replicates:

24 human split thickness skin membranes (12 occluded and 12 unoccluded)

Type of coverage:

other: occluded and unoccluded skin were assessed

Vehicle:

other: leave-on hair styling cream

Details on study design:

SKIN PREPARATION
- Source of skin: female patients aged 19 to 63 years old attending St. John’s Hospital, NHS Lothian, Livingston, UK
- Type of skin: breast or abdomen
- Preparative technique: Split-thickness membranes were prepared by pinning the full-thickness skin, stratum corneum uppermost, onto a raised cork board and cutting at a setting equivalent to 200-400 μm depth using a Zimmer® electric dermatome.
- Thickness of skin (in mm): full-thickness 1430 to 2130 μm; split-thickness 400 μm
- Membrane integrity check: A tritiated water barrier integrity test was performed and any human skin sample exhibiting absorption greater than 0.6% of the applied dose was excluded from subsequent absorption measurements.
- Storage conditions: The split-thickness membranes were stored at about -20°C.

PRINCIPLES OF ASSAY
- Diffusion cell: automated flow-through diffusion cell apparatus
- Receptor fluid: Phosphate buffered saline containing polyoxyethylene 20-oleyl ether (PEG, about 6%, w/v), sodium azide (about 0.01%), streptomycin (about 0.1 mg/mL) and penicillin G (about 100 units/mL)
- Solubility od test substance in receptor fluid: solubility of OFPMA in phosphate buffered saline is 900 mg/L
- Flow-through system: flow rate 1.451 to 1.571 mL/h
- Test temperature: 31.9 to 32.8 °C
- Occlusion: For twelve of the cells (Test Group 1), the donor chambers were occluded with an occlusive trap containing carbon filters. For the other twelve cells (Test Group 2), the donor chamber was left open to the atmosphere and the system was used inside a fume hood.

Remarks on result:

not measured/tested

Other effects / acceptance of results:

Following topical application of [14C]-OFPMA in the test preparation (2%, w/v) to occluded skin, the absorbed dose and dermal delivery of [14C]-OFPMA were 1.18% (5.52 μg equiv./cm2) and 1.53% (7.18 μg equiv./cm2), respectively. There was no report of damage to the stratum corneum.

Interpretation of results:

study cannot be used for classification

Remarks:

Weight of Evidence classification: GHS criteria not met

Conclusions:

Following topical application of [14C]-OFPMA in the test preparation (2%, w/v) to occluded skin, the absorbed dose and dermal delivery of [14C]-OFPMA were 1.18% (5.52 μg equiv./cm2) and 1.53% (7.18 μg equiv./cm2), respectively.  There was no report of damage to the stratum corneum.

Executive summary:

The stratum corneum was observed during a skin irritation observation during a OECD Guideline 428 (Skin Absorption: In Vitro Method) and considered as part of the overall weight of evidence for skin irritation. The in vitro dermal absorption of OFPMA was determined according to OECD Guideline 428 and the accompanying OECD Guidance Document No. 28. Split-thickness human skin membranes were mounted into flow-through diffusion cells. The test preparation containing [14C]-OFPMA (2%, w/v) was applied, at an application rate of about 20 mg/cm² (469 μg equiv. OFPMA/cm²), to 24 human split-thickness skin membranes mounted into flow through diffusion cells in vitro. Immediately after dosing, the donor chamber of 12 cells was covered with an occlusive trap containing carbon filters in an attempt to collect any volatile OFPMA. The remaining 12 cells remained unoccluded and so were open to the atmosphere, simulating the intended consumer use. The integrity of the stratum corneum was observed prior to assessment of the absorbed dose. The Percutaneous absorption study continued to determine dermal adsorption as described elsewhere within this dossier.

 

There was no report of damage to the stratum corneum.

Cross-reference 5

Reason / purpose for cross-reference:

reference to other study

Reference

Endpoint:

skin irritation: in vivo

Remarks:

skin irritation reported in LLNA study

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

10 May 2007 to 11 January 2008

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Justification for type of information:

This endpoint study record is part of a Weight of Evidence approach comprising a direct observation from RIPT studies, dermal irritation reported during developmental toxicity studies, irritation reported during an LLNA study and the results of an in vitro dermal adsorption study. The data sources are in agreement regarding dermal irritation and are sufficient to fulfil the information requirements as further explained in the provided endpoint summary.

Reason / purpose for cross-reference:

reference to other study

Reason / purpose for cross-reference:

reference to other study

Reason / purpose for cross-reference:

reference to other study

Reason / purpose for cross-reference:

reference to other study

Reason / purpose for cross-reference:

reference to other study

Reason / purpose for cross-reference:

reference to same study

Guideline:

other: equivalent to: OECD Guideline 429 (Skin Sensitisation: Local Lymph Node Assay)

Version / remarks:

Skin irritation observations reported

Principles of method if other than guideline:

A study equivalent to OECD Guideline 429 (Skin Sensitisation: Local Lymph Node Assay) with no deviations was conducted. Application sight was observed for signs of irritation.

GLP compliance:

no

Remarks:

The study was not commissioned with compliance with REACH as a goal, rather the study was commissioned during early product development.

Specific details on test material used for the study:

Purity: 98%

Species:

mouse

Strain:

CBA

Remarks:

CBA:J

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: The Jackson Laboratory, Bar Harbor, ME.
- Females nulliparous and non-pregnant: not specified
- Microbiological status of animals, when known: Animals were examined to ensure good health and suitability as test subjects for use in the study.
- Age at study initiation: appromixately 7-8 weeks
- Weight at study initiation: 17-21g
- Housing: housed individually
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 1 week
- Indication of any skin lesions: Animals were examined to ensure good health and suitability as test subjects for use in the study.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-25°C
- Humidity (%): 37-61%
- Air changes (per hr): Not reported
- Photoperiod (hrs dark / hrs light): 12 / 12

- IN-LIFE DATES: From: 07 June 2007 To: 11 June 2007

Type of coverage:

not specified

Preparation of test site:

not specified

Vehicle:

other: acetone/olive oil (4:1 v/v)

Amount / concentration applied:

11.3, 22.5, 33.8 and 45% in an acetone:olive oil (4:1) vehicle.
Highest concentration tested was 45% which was considered as the solubility limit in an acetone:olive oil 4:1 mixture.

Number of animals:

5 females/dose

Details on study design:

Five mice per group were dosed with the test substance at concentrations of 11.3, 22.5, 33.8 and 45% in an acetone:olive oil (4:1) vehicle. The mice were dosed once daily at approximately the same time for three consecutive days. All mice were observed twice daily on dosing days immediately prior to and approximately 4-6 hours after dosing, then once daily for moribundity, mortality, and any signs of toxicity and skin reactions.

Further study design relating to the investigation for skin sensitization is reported elsewhere within this dossier.

Irritation parameter:

other: irritation observation

Basis:

animal: all animals

Time point:

24 h

Remarks on result:

no indication of irritation

Irritation parameter:

erythema score

Basis:

mean

Time point:

24/48/72 h

Remarks on result:

not determinable because of methodological limitations

Irritation parameter:

edema score

Basis:

mean

Time point:

24/48/72 h

Remarks on result:

not determinable because of methodological limitations

Irritant / corrosive response data:

There were no mortalities and no signs of systemic toxicity or irritation noted for the test and control animals.

Interpretation of results:

study cannot be used for classification

Remarks:

Weight of Evidence classification: GHS criteria not met

Conclusions:

No skin irritation was reported during the daily observations during a study equivalent to OECD Guideline 429 (Skin Sensitisation: Local Lymph Node Assay).

Executive summary:

As part of a weight of evidence approach, the skin irritation observation reported during a study equivalent to OECD Guideline 429 (Skin Sensitisation: Local Lymph Node Assay) with no deviations were considered. Five mice per group were dosed with the test substance at concentrations of 11.3, 22.5, 33.8 and 45% in an acetone:olive oil (4:1) vehicle following 1 week of acclimation period. The mice were dosed once daily at approximately the same time for three consecutive days. All mice were observed twice daily on dosing days immediately prior to and approximately 4-6 hours after dosing, then once daily for moribundity, mortality, and any signs of toxicity and skin reactions. The skin sensitization study continued to determine skin sensitization potential as described elsewhere within this dossier.

There were no mortalities and no signs of systemic toxicity or irritation noted for the test and control animals.

Cross-reference 6

Reason / purpose for cross-reference:

reference to same study

Reference

Endpoint:

sensitisation data (humans)

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

23-Jun-2008 to 31-Jul-2008

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Reason / purpose for cross-reference:

reference to same study

Type of sensitisation studied:

skin

Study type:

study with volunteers

Guideline:

other: Repeated Insult Patch Test

Principles of method if other than guideline:

Two products, AF-1(08-1-7) and AF-4(08-1-32) were evaluated neat to determine its ability to sensitize the skin of volunteer subjects with normal skin using an occlusive repeated insult patch study.

GLP compliance:

no

Specific details on test material used for the study:

Two products containing 2% of test material:
AF-1 (08-1-7) - a hair spray formulation containing 2% OFPMA
AF-4 (08-1-32) - a hair cream formulation containing 2% OFPMA

Type of population:

general

Ethical approval:

not specified

Subjects:

- Number of subjects exposed: 50 subjects
- Sex: males and females
- Age: 18 years of age or older
- Race: any skin type or race, providing the skin pigmentation would allow discernment of erythema (1.7% asian, 34.5% black, 56.9% caucasian, 5.2% hispanic, 1.7% other)
- Demographic information: were free of any systemic or dermatological disorder which, in the opinion of the investigative personnel, would have interfered with the study results or increased the risk of adverse events
- Known diseases: in general good health and had completed a medical screening procedure
- Other: Prior to study entry, the subjects were screened to assure that they met the inclusion/exclusion criteria.

Clinical history:

Individuals excluded from participation in the study were those who:
1. had any visible skin disease at the study site which, in the opinion of the investigative personnel, would have interfered with the evaluation;
2. were receiving systemic or topical drugs or medication which, in the opinion of the investigative personnel, would have interfered with the study results;
3. had psoriasis and/or active atopic dermatitis/eczema;
4. were females who were pregnant, planning to become pregnant during the study, or breastfeeding; and/or
5. had a known sensitivity to cosmetics, skin care products, or topical drugs as related to the material being evaluated.

Controls:

None

Route of administration:

dermal

Details on study design:

TYPE OF TEST(S) USED: patch test (epicutaneous test)

ADMINISTRATION
- Type of application: occlusive
- Description of patch: 2 cm x 2 cm Webril pad attached to a non-porous, plastic film adhesive bandage (3M medical tape).
- Volume applied: 0.2 mL for AF-1(08-1-7) and 0.2 g for AF-4(08-1-32)

EXAMINATIONS
- Grading/Scoring system: The symbols found in this scoring scales below were used to express the response observed at the time of examination:
- = no reaction
? = minimal or doubtful response, slightly different from surrounding normal skin
+ = definite erythema, no edema
++ = definite erythema, definite edema
+++ = definite erythema, definite edema and vesiculation
- Statistical analysis: In the absence of any sensitization reactions in this sample size (50 evaluable subjects), a 95% upper confidence bound on the population rate of sensitization would be 4.9%.

Results of examinations:

SYMPTOMS
- Frequency, level, duration of symptoms observed: There were no adverse events reported.

Number enrolled: 58
Number discontinued: 8
Reasons for discontinuation: Lost to follow-up (6); protocol violation -exclusionary meds (2)
Number completed: 50

Table 1: Summary of Dermatologic Response Grades – AF-1(08-1-7)
	No reaction (-)	Total evaluable	Number absent	Number discontinued
Induction Readings
1	54	54	3	1
2	51	51	4	3
3	51	51	4	3
4	52	52	3	3
5	52	52	2	4
6	53	53	0	5
7	52	52	1	5
8	50	50	1	7
9	49	49	2	7
Make Up (MU)	15	15
Challenge phase
48 hours	50	50	0	8
72 hours	50	50	0	8

 

Table 2: Maximum elicited response during induction: AF-1(08-1-7)
Response	N(%) subjects
- (no reaction)	51 (100%)

 

 

Table 2: Summary of Dermatologic Response Grades – AF-4(08-1-32)
	No reaction (-)	Minimal or doubtful response, slightly / different from surrounding normal skin (?)	Total evaluable	Number absent	Number discontinued
Induction Readings
1	54	0	54	3	1
2	51	0	51	4	3
3	51	0	51	4	3
4	51	1	52	3	3
5	50	2	52	2	4
6	51	2	53	0	5
7	50	2	52	1	5
8	49	1	50	1	7
9	19	0	49	2	7
Make Up (MU)	15	0	15
Challenge phase
48 hours	50	0	50	0	8
72 hours	50	0	50	0	8

 

Table 4: Maximum elicited response during induction: AF-4(08-1-32)
Response	N(%) subjects
- (no reaction)	49 (96.1%)
? (minimal or doubtful response, slightly / different from surrounding normal skin)	2 (3.9%)

Conclusions:

Under the conditions employed in this study, there was no evidence of sensitization to AF-1(08-1-7) and AF-4(08-1-32).

Executive summary:

The test substances AF-1(08-1-7) and AF-4(08-1-32), both containing 2% of 2,2,3,3,4,4,5,5-octafluoropentyl methacrylate, were evaluated to determine their ability to sensitize the skin of volunteer subjects with normal skin using an occlusive repeated insult patch study. Fifty subjects completed the study. Under the conditions employed in this study, there was no evidence of sensitization to the test substances assessed.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2008

Report date:

2008

Materials and methods

Study type:

study with volunteers

Endpoint addressed:

skin irritation / corrosion

skin sensitisation

Test guideline

Guideline:

other: Repeated Insult Patch Test

Principles of method if other than guideline:

Two products, AF-1(08-1-7) and AF-4(08-1-32) were evaluated neat to determine its ability to sensitize the skin of volunteer subjects with normal skin using an occlusive repeated insult patch study. Erythema and edema reported during induction phases assessed for skin irritation.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

2,2,3,3,4,4,5,5-octafluoropentyl methacrylate

EC Number:

206-596-0

EC Name:

2,2,3,3,4,4,5,5-octafluoropentyl methacrylate

Cas Number:

355-93-1

Molecular formula:

C9H8F8O2

IUPAC Name:

2,2,3,3,4,4,5,5-octafluoropentyl 2-methylprop-2-enoate

Test material form:

liquid

Specific details on test material used for the study:

Two products containing 2% of test material:
AF-1 (08-1-7) - a hair spray formulation containing 2% OFPMA
AF-4 (08-1-32) - a hair cream formulation containing 2% OFPMA

Method

Type of population:

general

Subjects:

- Number of subjects exposed: 50 subjects
- Sex: males and females
- Age: 18 years of age or older
- Race: any skin type or race, providing the skin pigmentation would allow discernment of erythema (1.7% asian, 34.5% black, 56.9% caucasian, 5.2% hispanic, 1.7% other)
- Demographic information: were free of any systemic or dermatological disorder which, in the opinion of the investigative personnel, would have interfered with the study results or increased the risk of adverse events
- Known diseases: in general good health and had completed a medical screening procedure
- Other: Prior to study entry, the subjects were screened to assure that they met the inclusion/exclusion criteria.

Ethical approval:

not specified

Route of exposure:

dermal

Reason of exposure:

intentional

Exposure assessment:

measured

Remarks:

0.2 mL for AF-1(08-1-7) and 0.2 g for AF-4(08-1-32)

Details on exposure:

The induction phase consisted of 9 consecutive applications of the study material and subsequent evaluations of the patch sites. Prior to application of the patches, the sites were outlined with a skin marker. Patches were applied on Mondays, Wednesdays and Fridays for 3 consecutive weeks. The subjects were required to remove the patches approximately 24 hours after application. They returned to the facility at 48-hour intervals to have the sites evaluated and identical patches applied to the same sites. Patches applied on Friday were removed by subjects after 24 hours. The sites were evaluated on the following Monday, i.e., 72 hours after patch application. A Monday or Friday holiday resulted in evaluation at 96 hours after patch application.

Following the ninth evaluation, the subjects were dismissed for a rest period of approximately 10-15 days.

Subjects who were absent once during the induction phase received a make-up (MU) patch at the last induction visit. The MU applications were graded 48 hours later at the MU visit, or were recorded as N9G (no ninth grading). Subjects who missed the ninth evaluation but have had 9 patch applications were considered to have completed the induction phase.

The challenge phase was during the sixth week of the study. Identical patches were applied to sites previously unexposed to the study material. The patches were removed by subjects after 24 hours and the sites graded after additional 24-hour and 48-hour periods (i.e., 48 and 72 hours after application). Following a negative induction, a 48/72-hour sequence of “-/+”, “?/+” or “+/+” resulted in an additional reading being performed at the 96-hour interval. Re-challenge was performed whenever there was evidence of possible sensitization.

To be considered a completed case, a subject must have had 9 applications and no fewer than 8 subsequent reading during induction, and a single application and 2 readings during challenge. Only completed cases were used to assess sensitization.

Test material was applied under occlusive patch conditions. The patch was applied to the infrascapular area of the back, either to the right or left of the midline, or to the upper arm.

Examinations:

The subjects returned to the facility at 48-hour intervals to have the sites evaluated and identical patches applied to the same sites during the induction phase. During the challenge phase, the patches were removed by subjects after 24 hours and the sites graded after additional 24-hour and 48-hour periods (i.e., 48 and 72 hours after application).

Results and discussion

Clinical signs:

Fifty-eight (58) subjects between ages of 20 and 69 were enrolled and 50 completed the study. There were two protocol violations. This did not affect the validity of the study. There were no adverse events reported.

Results of examinations:

Under the conditions employed in this study, there was no evidence of sensitization to AF-1(08-1-7) in 50 out of 50 individuals. Also, during induction there was no dermatologic response to exposure observed.
Under the conditions employed in this study, there was no evidence of sensitization to AF-4(08-1-32) in 50 out of 50 individuals. Also, during induction there was no dermatologic response to exposure observed in 96% of individuals and in 4% slight to doubtful dermatologic response was seen.

Outcome of incidence:

Under the conditions employed in this study, there was no evidence of sensitization to AF-1(08-1-7) and AF-4(08-1-32).

Any other information on results incl. tables

Table 1: Summary of Dermatologic Response Grades – AF-1(08-1-7)
	No reaction (-)	Total evaluable	Number absent	Number discontinued
Induction Readings
1	54	54	3	1
2	51	51	4	3
3	51	51	4	3
4	52	52	3	3
5	52	52	2	4
6	53	53	0	5
7	52	52	1	5
8	50	50	1	7
9	49	49	2	7
Make Up (MU)	15	15
Challenge phase
48 hours	50	50	0	8
72 hours	50	50	0	8

Table 2: Maximum elicited response during induction: AF-1(08-1-7)
Response	N(%) subjects
- (no reaction)	51 (100%)

Table 3: Summary of Dermatologic Response Grades – AF-4(08-1-32)
	No reaction (-)	Minimal or doubtful response, slightly / different from surrounding normal skin (?)	Total evaluable	Number absent	Number discontinued
Induction Readings
1	54	0	54	3	1
2	51	0	51	4	3
3	51	0	51	4	3
4	51	1	52	3	3
5	50	2	52	2	4
6	51	2	53	0	5
7	50	2	52	1	5
8	49	1	50	1	7
9	19	0	49	2	7
Make Up (MU)	15	0	15
Challenge phase
48 hours	50	0	50	0	8
72 hours	50	0	50	0	8

Table 4: Maximum elicited response during induction: AF-4(08-1-32)
Response	N(%) subjects
- (no reaction)	49 (96.1%)
? (minimal or doubtful response, slightly / different from surrounding normal skin)	2 (3.9%)

Applicant's summary and conclusion

Conclusions:

Under the conditions employed in this study, there was no evidence of sensitization to AF-1(08-1-7) and AF-4(08-1-32). Examination of the data also indicate an absence of irritation reactions.

Executive summary:

The test substances AF-1(08-1-7) and AF-4(08-1-32), both containing 2% of 2,2,3,3,4,4,5,5-octafluoropentyl methacrylate, were evaluated to determine their ability to sensitize the skin of volunteer subjects with normal skin using an occlusive repeated insult patch study. Fifty subjects completed the study. Under the conditions employed in this study, there was no evidence of sensitization to the test substances assessed. Also, an examination of the data indicated an absence of irritation reactions.