Benzeneacetic acid, 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-butyn-1-yl]-.alpha.,.alpha.-dimethyl-

Endpoint summary

Description of key information

Two key skin (OECD 404 and EU method B.4) and eye (OECD 405 and EU method B.5) irritation studies were identified. 
FEXO-07 tested in these studies were not found to be irritating to the skin or eye of rabbits.

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

Study period:

April - July 2003

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP, Guideline study.

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)

Deviations:

no

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

Sex: female.
Number: three animals were required for the complete test.
ldentification: animals were individually idcntified by an ear clip.
Body weight: individuai body weights were taken at the beginning and at the end of the experiment; generally between 2 kg and 3.5 kg at the start of the experiment.
Acclimatisation: for at least 5 days before the treatment, in the area where the experiment took place.
Housing: animals were housed individually in cages of standard size. Excreta was removed by unrolling plasticised brown paper, previously placed under cages. These cages were placed in an air conditioned (17- 21 °C) animal house kept at between 45 % and 65 % relative humidity in which non-recycled filtered air was changed approximately ten times per hour. The artificial day/night cycle was 12 hours light and 12 hours darkness with Iight on at 7.30 a.m.
Feeding: SAFE 112 feed was available ad libitum. The batch used was not quality controlled, therefore no certificate of analysis were available but only a data sheet concerning this feed product was included in report.
Drinking water: potable water was available ad libitum in polycarbonate feeder bottles with a stainless steel nipple. A specimen of water was obtained every 6 months and sent to the Laboratoire Départemental d'Analyse du Cher- 216 rue Louis Mallet, 18014 Bourges Cedex, France- for analysis.
The criteria for acceptable levels of contaminants in the water supply was within the limits of the analytical specifications.

Type of coverage:

semiocclusive

Preparation of test site:

shaved

Vehicle:

other: Each application were sufficiently moistened with distilled watcr or any other appropriate vehicle (generally 0.5 mL).

Controls:

other: Adjacent surfaces of non-treated skin of each animal were serve as a control for the trial.

Amount / concentration applied:

0.5 g of FEX0-07 were applied, as required by the guideline.

Duration of treatment / exposure:

Each animals received one patch for an exposure period of 4 hours; the substance was applied once only.

Observation period:

One hour, 24 hours, 48 hours and 72 hours approximately after removal of the dressing, any skin lesions, which may have developed on the right flank of each animal were evaluated.
With the Sponsor's agreement, additional monitoring may be continued to D8 if signs of initation persist al 72 hours and even D15 if they persist at D8.
(These additional observations were not normally continue for more than 14 days after treatment).

Number of animals:

3

The study were started using three animals. Justification of the number of animals per group: the number of animals per group is the minimum
number crabling an accurate assessment of the studied toxicological effect.

Details on study design:

The aim of the study was to determine in the rabbit irritant properties and/or degree of corrosion caused by FEX0-07 following a single, semi-occluded application to intact skin.
Dermal initation and/or corrosion was evaluated by grading of any skin initation reactions seen, using a predetermined scoring system.

Irritation parameter:

erythema score

Basis:

animal #1

Time point:

other: Mean indices were calculated from results obtained from each rabbit at times 24, 48 and 72 hours

Score:

0

Irritation parameter:

erythema score

Basis:

animal #2

Time point:

other: Mean indices were calculated from results obtained from each rabbit at times 24, 48 and 72 hours

Score:

0

Irritation parameter:

erythema score

Basis:

animal #3

Time point:

other: Mean indices were calculated from results obtained from each rabbit at times 24, 48 and 72 hours

Score:

0

Irritation parameter:

edema score

Basis:

animal #1

Time point:

other: Mean indices were calculated from results obtained from each rabbit at times 24, 48 and 72 hours

Score:

0

Irritation parameter:

edema score

Basis:

animal #2

Time point:

other: Mean indices were calculated from results obtained from each rabbit at times 24, 48 and 72 hours

Score:

0

Irritation parameter:

edema score

Basis:

animal #3

Time point:

other: Mean indices were calculated from results obtained from each rabbit at times 24, 48 and 72 hours

Score:

0

Irritant / corrosive response data:

Mean indices were calculated from results obtained far each rabbit at times 24 hours, 48 hours and 72 hours. For each parameter, the mean of indices for each rabbit for the three times (Mean index per parameter, per animal for the three times = Mi) was noted.
Erythema score: 0 (mean for the three tested animals and three trials)
Edema score: 0 (mean for the three tested animals and three trials).

Other effects:

no data

Interpretation of results:

not irritating

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Under the experimental conditions adopted, FEXO- 07 was found to be non-irritant for the skin of the Rabbit.

Executive summary:

Any irritant properties and/or degree of corrosion of FEXO-07 were evaluated in the Rabbit following a single semi-occluded application to intact skin, in compliance with requirements of OECD Guideline N. 404 and Method B4 of Council Directive N. 67/548/EEC and subsequent amendments.

3 animals were used for the study. 0.5 g of FEXO-07 was applied on the skin. Adjacent surfaces of untreated skin served as a control for the t:rial. Semi-occlusive dressings held the test substance in piace 4 hours on the skin of the three animals. Any cutaneous lesions were evaluated approximately one hour, 24, 48 and 72 hours, after removal of the dressing. The application of the test substance did not induce coloration of the application site and did not interfere with grading of any skin lesions. Mean indices were calculated from results obtained from each rabbit at times 24, 48 and 72 hours.

Results obtained were: Mean index (Mi) for Erythema and Oedema for each animal tested was 0.00.

Under the experimental conditions adopted, FEXO- 07 (batch 1/03) was found to be non-irritant for the skin of the Rabbit.

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

Study period:

Mar - xxx 2006

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP, Guideline study.

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)

Deviations:

no

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

Sex: female.
Identification: animals were individually identified by an ear clip.
Body weight: individual body weights were taken at the beginning and at the end of the experiment: it was between 2.8 kg and 3.4 kg at the start of the experiment.
Age: between 12 and 16 weeks at the start of the experiment.

Acclimatisation: for at least 5 days before the treatment, in the area where the experiment took place.
Housing: animals were housed individually in cages of standard size. Excreta were removed by unrolling plasticised brown paper, previously placed under cages. These cages were placed in an air conditioned (17- 21 °C) animal house kept at between 45% and 65 % relative humidity (except during the cleaning slot) in which non-recycled filtered air was changed approximately ten times per hour.
The artificial day/night cycle was 12 hours light and 12 hours darkness with light on at 7.30 a.m.

Feeding: SDS/DIETEX STANRAB (P) SQC feed was distributed daily at fixed times. The criteria for acceptable levels of contaminants in the feed supplied were within the limits of the analytical specifications established by the dit manufacturer.
Drinking water: Drinking water was available ad libitum in polycarbonate feeder bottles with a stainless steel nipple. A specimen of water is sent every 6 months to the Laboratoire Départemental d' Analyse du Cher- 216 rue Louis Mallet, 18014 Bourges Cedex, France- for analysis. The criteria for acceptable levels of contaminants in the water supplied were within the lirnits of the analytical specifications.

Vehicle:

unchanged (no vehicle)

Remarks:

FEX0-07 was applied to the eye as supplied by the Study Monitor.

Controls:

other: The untreated right eye served as a control.

Amount / concentration applied:

0.1 g of FEX0-07 was introduced into the conjunctival sac of the left eye of each of the animals.

Duration of treatment / exposure:

FEX0-07 was instilled once only.
Eyelids were held closed for approximately 1 second in arder to avoid any loss of FEX0-07.
The eye may be washed 24 hours after instillation if this is deemed appropriate.

Observation period (in vivo):

1 hour, 24, 48 and 72 hours approximately after the instillation of FEX0-07.

The day of instillation will be taken as the first study day D1.

Number of animals or in vitro replicates:

3

Justification of the number of animals per group: the number of animals per group was the minimum number enabling an accurate assessment of the studied toxicological effect.

Details on study design:

The aim of the study was to determine any irritant property of FEX0-07 following a single ocular instillation in the rabbit.
Ocular irritation and/or corrosion following instillation of FEX0-07 in the eye of the rabbit were evaluated by grading of any ocular irritation reaction seen, using a predetermined scoring system.
Three animals were required for the complete test.
Animals were selected on the basis of their general conditions. In addition, both eyes of each animal selected far testing were examined immediately before testing starts.

Irritation parameter:

chemosis score

Basis:

mean

Time point:

other: 1 hour

Score:

0

Irritation parameter:

chemosis score

Basis:

mean

Time point:

other: Mean indices calculated from results obtained for each rabbit at times 24, 48 and 72 hours

Score:

0

Irritation parameter:

iris score

Basis:

mean

Time point:

other: 1 hour

Score:

0

Irritation parameter:

iris score

Basis:

mean

Time point:

other: Mean indices calculated from results obtained for each rabbit at times 24, 48 and 72 hours

Score:

0

Irritation parameter:

cornea opacity score

Basis:

mean

Time point:

other: 1 hour

Score:

0

Irritation parameter:

cornea opacity score

Basis:

mean

Time point:

other: Mean indices calculated from results obtained for each rabbit at times 24, 48 and 72 hours

Score:

0

Irritation parameter:

other: redness

Basis:

mean

Time point:

other: 1 hour

Score:

0

Irritation parameter:

other: redness

Basis:

mean

Time point:

other: Mean indices calculated from results obtained for each rabbit at times 24, 48 and 72 hours

Score:

0

Irritant / corrosive response data:

No ocular irritation reaction was seen in the animals up to the end of the observation period.
Chemosis score: 0 (mean for the three tested animals and three trials)
Redness score: 0 (mean for the three tested animals and three trials)
Iris score: 0 (mean for the three tested animals and three trials)
Cornea score: 0 (mean for the three tested animals and three trials)

The application of the test item did not induce colouring of the application site and did not interfere with grading of any eye lesion.

The surface area of corneal opacity and the lacrimation were not taken into account in the calculation of mean index.

The results related to area of corneal opacity are

- 1 h (mean for the three animals): 0

- 24 h (mean for the three animals): 0

- 48 h (mean for the three animals): 0

- 72 h (mean for the three animals): 0

The results related to lacrimation are

- 1 h (mean for the three animals): 0

- 24 h (mean for the three animals): 0

- 48 h (mean for the three animals): 0

- 72 h (mean for the three animals): 0

Interpretation of results:

not irritating

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Under the experimental conditions adopted, FEX0-07 (batch 0511049) was found to be non-irritant for the eye of the rabbit.

Executive summary:

Any irritant property and/or degree of corrosion of the test item FEX0-07 (batch 0511049) was evaluated following a single ocular instillation in the rabbit in accordance with the General Requirements of OECD Guideline N. 405 and method B5 of Commission Directive N. 92/69/EEC adapting to technical progress for the 17th time Council Directive N. 67/548/EEC and subsequent arrendments. Three animals were used far the study 0.1 g of FEX0-07 was introduced into the conjunctival sac of the left eye of each of the anirnals. The untreated right eye served as a control. The application of the test itern did not induce colouring of the application site and did not interfere with grading of any eye lesion. Any conjunctival, iris and corneal lesion was evaluated approximately one hour, 24 hours, 48 hours and 72 hours after instillation of FEX0-07. Mean indices were calculated from results obtained for each rabbit at times 24, 48 and 72 hours.

Results obtained were: Mean index (Mi) for chemosis, redness, iris and cornea for each animal tested was 0.00.

Under the experimental conditions adopted, FEX0-07 (batch 0511049) was found to be non-irritant for the eye of the rabbit.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Skin irritation

One key study (Klimisch score=1) was identified, in which FEXO-07 were tested for skin irritation in the rabbit using a method according to OECD 404 and EU method B.4.

0.5 g of substance was applied following following a single semi-occluded application (placed for 4 hours) on the skin of the three animals. Any cutaneous lesions were evaluated approximately one hour, 24, 48 and 72 hours, after removal of the dressing. Mean indices were calculated from results obtained from each rabbit at times 24, 48 and 72 hours:

For all the animals the results were:

Mean index erithema: 0.00

Mean index oedema: 0.00

Eye irritation

One key study (Klimisch score=1) was identified, in which FEXO-07 were tested for eye irritation in the rabbit using a method according to OECD 405 and EU method B.5.

FEXO-07 was tested for primary eye irritation in the rabbit.

0.1 g of substance was applied following a single ocular instillation into the conjunctival sac of the left eye of each of three animals.

Any conjunctival, iris and corneal lesion was evaluated approximately one hour, 24 hours, 48 hours and 72 hours after instillation of FEX0-07.

Mean indices were calculated from results obtained from each rabbit at times 24, 48 and 72 hours:

For all the animals the results expressed as Mean Index for the assessed end-point were:

(i) chemosis: 0.00, (ii) redness: 0.00, (iii) iris: 0.00 and (iv) cornea: 0.00.

Justification for selection of skin irritation / corrosion endpoint:
Only one end-point was available for the selection. However, it was judged as reliable because the test was performed in accordance with validated guidelines

Justification for selection of eye irritation endpoint:
Only one end-point was available for the selection. However, it was judged as reliable because the test was performed in accordance with validated guidelines

Justification for classification or non-classification

Based on evaluation of the skin irritation data discussed above, FEXO-07 was found to be non-irritant for the skin of the rabbit so it does not meet the criteria for classification and labelling under both the CLP Regulation and the Directive 67/548/EEC.

Based on evaluation of the eye irritation data discussed above, FEXO-07 was found to be non-irritant for the eye of the rabbit so it does not meet the criteria for classification and labelling under both the CLP Regulation and the Directive 67/548/EEC.