Phenethyl butyrate

Endpoint summary

Description of key information

The skin sensitization potential of target chemical was assessedin various experimental studies which were conducted on guinea pigs and humans.The predicted data usingDanish QSAR databasehas also been compared with the experimental data.Based on the available key data and supporting studies,it can be concluded thatchemical is unable to cause skin sensitization and considered as not sensitizing. Comparing the above annotations with the criteria of CLP regulation, it can be classified under the category “Not Classified”.

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Reference

Endpoint:

skin sensitisation: in vivo (non-LLNA)

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Justification for type of information:

data is from peer reviewed journals

Qualifier:

equivalent or similar to guideline

Guideline:

other: as mentioned below

Principles of method if other than guideline:

A human maximization assay was conducted to evaluate the sensitization potential of test chemical.

GLP compliance:

not specified

Type of study:

other: Human Maximization test

Justification for non-LLNA method:

Not specified

Species:

human

Strain:

other: not applicable

Sex:

male/female

Details on test animals and environmental conditions:

no data

Route:

epicutaneous, occlusive

Vehicle:

petrolatum

Concentration / amount:

8% (5520µg/cm2)

Day(s)/duration:

5 days

Adequacy of induction:

not specified

No.:

#1

Route:

epicutaneous, occlusive

Vehicle:

petrolatum

Concentration / amount:

8% (5520µg/cm2)

Day(s)/duration:

72 hours

Adequacy of challenge:

not specified

No. of animals per dose:

25 healthy patients

Details on study design:

MAIN STUDY
A. INDUCTION EXPOSURE
- No. of exposures:5
- Exposure period: 48 h
- Test groups: 25 healthy patients
- Control group: no data
- Site: Application was under occlusion to the same site on the forearm or back of all subjects
- Frequency of applications: for five alternate day
- Duration: 5 days
- Concentrations: 8%(5520 µg/cm2) test chemical in petrolatum

B. CHALLENGE EXPOSURE
- No. of exposures: single
- Day(s) of challenge:Following a 10 day rest period
- Exposure period: 48 hours
- Test groups: 25 healthy patients
- Control group: no data
- Site: challenge patches were applied to fresh sites on the back for 48 h under occlusion
- Concentrations: 8%(5520 µg/cm2) in petrolatum
- Evaluation (hr after challenge): The challenge site was evaluated at 48 and 72 h.

Challenge controls:

no data

Positive control substance(s):

not specified

Positive control results:

no data

Reading:

1st reading

Hours after challenge:

48

Group:

test chemical

Dose level:

8% in petrolatum

No. with + reactions:

0

Total no. in group:

25

Clinical observations:

No sensitization reactions were observed.

Remarks on result:

no indication of skin sensitisation

Reading:

2nd reading

Hours after challenge:

72

Group:

test chemical

Dose level:

8%

No. with + reactions:

0

Total no. in group:

25

Clinical observations:

No sensitization reactions were observed.

Remarks on result:

no indication of skin sensitisation

Remarks:

Not sensitizing

No skin reactions were observed on humans.

Interpretation of results:

other: Not sensitizing

Conclusions:

No reaction was observed in any human volunteers during the assay.Hence the test chemical was considered to be not sensitizing to human skin.

Executive summary:

A human maximization assay was conducted to evaluate the sensitization potential of test chemical.

The assay was carried out with 8% (5520µg/cm2) of test chemical in petrolatum on 25 healthy patients. Application was under occlusion to the same site on the forearm or back of all subjects for five alternate day 48 h periods. The patch sites were pretreated for 24 h with 2.5% or 5% aqueous sodium lauryl sulfate (SLS) under occlusion. Following a 10 day rest period, challenge patches were applied to fresh sites on the back for 48 h under occlusion. The challenge site was pretreated for 1 h with 5–10% SLS. The challenge patches were applied to fresh sites on the back for 48 h under occlusion. The challenge site was evaluated at 48 and 72 h.

 

No reaction was observed in any human volunteers during the assay. Therefore the test chemical was considered to be not sensitizing to human skin.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Additional information:

Various studieshas been investigated for the test chemical to observe the potential for skin sensitization to a greater or lesser extent. The studies are based on in vivo experiments in guinea pigs and humans for target chemicaland its structurally similar read across substances.The predicted data usingDanish QSAR databasethe has also been compared with the experimental data and summarized as below;

 

A human maximization assay was conducted to evaluate the sensitization potential of test chemical. The assay was carried out with 8% (5520µg/cm2) of test chemical in petrolatum on 25 healthy patients. Application was under occlusion to the same site on the forearm or back of all subjects for five alternate day 48 h periods. The patch sites were pretreated for 24 h with 2.5% or 5% aqueous sodium lauryl sulfate (SLS) under occlusion. Following a 10 day rest period, challenge patches were applied to fresh sites on the back for 48 h under occlusion. The challenge site was pretreated for 1 h with 5–10% SLS. The challenge patches were applied to fresh sites on the back for 48 h under occlusion. The challenge site was evaluated at 48 and 72 h. No reaction was observed in any human volunteers during the assay. Therefore the test chemical was considered to be not sensitizing to human skin.

 

According to Danish QSAR Database, skin sensitization effects were estimated by four different models i.e, Battery, Leadscope, SciQSAR and CASE Ultra used within Danish QSAR database for the test chemical. Based on estimation, no skin sensitization reactions were observed in guinea pigs and humans. Therefore, the test chemical was considered to be not sensitizing.

 

The above results were further supported by anothermaximization testperformed for similar read across chemical. The test chemical was tested at 4% (2760µg/cm2) in petrolatum on 25 healthy male patients. Application was under occlusion to the same site on the forearms of all subjects for five alternate day, 48 h periods. The patch sites were pretreated for 24 h with 5% aqueous sodium lauryl sulfate (SLS) under occlusion. Following a 10 day rest period, challenge patches were applied to fresh sites on the back for 48 h under occlusion. The challenge site was pretreated for 1 h with 10% SLS. The challenge site was evaluated at 48 and 72 h. No sensitization reactions were observed. Hence, the test chemical can be considered to be not sensitizing to the skin of humans.

The above results were further supported by Buehler test performed for similar read across chemical to determine the allergic reactions caused by the test chemical in guinea pigs. The study was performed according to EPA OPPTS 870.2600 (Skin Sensitisation) Guidelines. 10 healthy male and 10 healthy female Hartley Albino guinea pigs were assigned to test and control groups. The day prior to the first induction application, Site 1 of all animals was clipped free of hair with an electric clipper. The clipped area was approximately 5 x 10 em. Any animal with skin irregularities or irritation was eliminated from the study. The treated sites were reclipped the day prior to each induction application. Thirteen days after the last induction application, a naive site (site 3) on each animal was clipped free of hair. Sites 2 and 4 (right shoulder and hip areas, respectively) were reserved for alternate sites in the event that eschar was noted during the induction phase and/or a re-challenge was required. The day prior to screen dosing, the dorsal area of each animal was clipped free of hair. The clipped area was approximately 10 x 10 cm. Group 1, 100%: Ten males and ten females in Group 1 were dosed with 0.4 ml of the test article. The dose was applied to the left shoulder area (Site 1) using a 25 mm Hilltop Chamber which is designed to keep the test article on a 25 mm area of the site. The chamber contained a cotton pad used to facilitate contact of the liquid test article with the site. The chamber was covered with a strip of rubber dental dam sufficient to cover the treated sites. The torso was wrapped with non-irritating tape to provide occlusion. After 6 hours, the dams were removed. Any residual test article was cleansed from the sites with distilled water and the sites were dried with soft toweling. This procedure was performed once/week on the same day each week for a three week period, a total of 3 six hour insults. Group 2: Five males and five females were untreated for the three week induction period and served as the naive control. Four animals received four concentrations of the test article, one/site as follows: (25, 50, 75, & 90%) and another four animals received three concentrations of the test article, one/site as follows: ( 1 0, 75, 100 & 100% Vehicle Concentration) was placed in a 25 mm Hilltop Chamber, designed to keep the test article on a 25 mm area of the site. The chamber contained a cotton pad which aided in the retention of the liquid sample on the site. The test sites were covered with a strip of rubber dental dam sufficient to cover the treated sites and wrapped with non-irritating tape to provide occlusion. After six hours, the dams and test article were removed, the sites cleansed with distilled water and dried with soft toweling. Fourteen days after the last induction exposure, animals in Groups 1 and 2 were challenged using the same dosing procedure as in the induction phase. Based on the results of the screen, 25% was chosen as the highest non-irritating concentration for the challenge. The doses were applied to a naive site on the left hip area (Site 3). To aid in the analysis of the data, two indices were calculated from the erythema scores: one to evaluate incidence and the other to evaluate severity. The indices were calculated for both the Test Article Group and the Naive Control Group using the 24 and 48 hour scores following challenge patch removal. The Incidence Index is the number of animals with a score of 1 or greater divided by the number of animals examined following challenge. The Severitv Index is the total of all erythema scores following challenge (per time period) divided by the number of scores added. One female died on Day 23; diarrhea in one male of Day 7; soiled anogenital area in 1 male on Days 18-22, 26-27 and in 1 female on Day 30. The incidence and severity ondex for the test groupat 24 and 48 hours post challenge exposure were 0.053 and 0.105 respectively. Hence, the test chemical can be considered to be not sensitizing to skin.

 

Based on the available data for the target chemical, supporting studies and read across substance,it can be concluded thatchemical is unable to cause skin sensitization and considered as not sensitizing. Comparing the above annotations with the criteria of CLP regulation, it can be classified under the category “Not Classified”.

                      

Justification for classification or non-classification

The skin sensitization potential of test substance and its structurally similar read across substancewere observed in various studies. From the results obtained from these studies it is concluded that the chemical is not likely to cause skin sensitization and hence can be classified as non-skin sensitizer.