(3R,6S)-1-benzyl-6-methylpiperidin-3-amine acetyl-L-leucinate [1:1]

Skin irritation / corrosion

Administrative data

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

6th April 2020 to 4th June 2020

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2020

Report date:

2020

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Test guideline 2

Qualifier:

according to guideline

Guideline:

other: EC No 440/2008, part B: "Acute Toxicity: Dermal Irritation/Corrosion".

Test guideline 3

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.2500 (Acute Dermal Irritation)

Test guideline 4

Qualifier:

according to guideline

Guideline:

other: JMAFF Guidelines (2000), including the most recent revisions.

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

(3R,6S)-1-benzyl-6-methylpiperidin-3-amine acetyl-L-leucinate [1:1]

EC Number:

840-203-9

Cas Number:

2295746-51-7

Molecular formula:

C21H35N3O3

IUPAC Name:

(3R,6S)-1-benzyl-6-methylpiperidin-3-amine acetyl-L-leucinate [1:1]

Test material form:

solid: particulate/powder

Test animals

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River France, L’Arbresle, France
- Age at study initiation: approximately 13-14 weeks old
- Weight at study initiation: 2913 to 3451 g.
- Housing: On arrival and following assignment to the study, animals were housed individually in labeled cages with perforated floors equipped with water bottles. The room in which the animals were kept were documented in the study records. Each cage was clearly labeled.
- Diet: Pelleted diet for rabbits KLIBA NAFAG Rabbit Diet 3409 maintenance and breeding, from Granovit AG, Kaiseraugst, Swizerland) was provided once daily throughout the study. In addition, hay (TecniLab-BMI BV, Someren, The Netherlands) was available during the study period.
- Water: Municipal tap-water ad libitum
- Acclimation period: The animals were allowed to acclimate to the Test Facility toxicology accommodation for at least 5 days before the commencement of dosing.

ENVIRONMENTAL CONDITIONS
- Temperature: 19°C, daily mean
- Humidity: 52 - 68%
- Air changes: Ten or greater air changes per hour with 100% fresh air (no air recirculation)
were maintained in the animal rooms.
- Photoperiod: 12 hrs dark / 12 hrs light

Test system

Type of coverage:

semiocclusive

Preparation of test site:

clipped

Vehicle:

other: 0.7 mL watery ethanol (50% v/v)

Controls:

yes, concurrent no treatment

Amount / concentration applied:

TEST MATERIAL
- Amount applied: 0.5 grams of the test item.

VEHICLE
- Amount applied: The test item was moistened with 0.7 mL watery ethanol (50% v/v)

Duration of treatment / exposure:

4 hours

Observation period:

72 hours

Number of animals:

Three

Details on study design:

TEST SITE
Approximately 24 hours before dosing, the dorsal fur was clipped with an electric clipper, exposing an area of approximately 150 square centimeters (10x15 cm). To facilitate scoring, treated skin areas were re-clipped at least three hours before the observations.
Each animal was treated by dermal application of 0.5 grams of the test item. The test item was moistened with 0.7 mL watery ethanol (50% v/v) and applied to the skin of one flank, using a metalline patch of 2x3 cm. The patch was mounted on Micropore tape, which was wrapped around the abdomen and secured with Coban elastic bandage.

REMOVAL OF TEST SUBSTANCE
Four hours after the application, the dressing was removed, and the skin cleaned of residual test item using tap water.

OBSERVATION TIME POINTS
1, 24, 48 and 72 hours

SCORING SYSTEM:
The irritation was assessed according to the following numerical scoring system. At each observation, the highest scores given were recorded:
Erythema and eschar formation:
No erythema 0
Very slight erythema (barely perceptible) 1
Well-defined erythema 2
Moderate to severe erythema 3
Severe erythema (beef redness) * 4
*. Where signs of necrosis or corrosion (injuries in depth) prevent erythema scoring, the maximum grade for erythema (= 4) is given.
Oedema formation:
No oedema 0
Very slight oedema (barely perceptible) 1
Slight oedema (edges of area well-defined by definite raising) 2
Moderate oedema (raised approximately 1 millimeter) 3
Severe oedema (raised more than 1 millimeter and extending beyond the area of exposure) 4

Results and discussion

In vivo

Results

Results 1

Irritation parameter:

edema score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Remarks on result:

no indication of irritation

Results 2

Irritation parameter:

edema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Remarks on result:

no indication of irritation

Results 3

Irritation parameter:

edema score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Remarks on result:

no indication of irritation

Results 4

Irritation parameter:

erythema score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Remarks on result:

no indication of irritation

Results 5

Irritation parameter:

erythema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Remarks on result:

no indication of irritation

Results 6

Irritation parameter:

erythema score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Remarks on result:

no indication of irritation

Other effects:

Toxicity / Mortality
No signs of systemic toxicity were observed in the animals during the test period and no mortality occurred.

Coloration / Remnants
No staining of the treated skin by the test item was observed.

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

Based on these results PF-07202371-S7 does not have to be classified and has no obligatory
labelling requirement for skin irritation according to the Globally Harmonized System of
Classification and Labelling of Chemicals (GHS) of the United Nations (2017) (including all
amendments) and Regulation (EC) No 1272/2008 on classification, labelling and packaging
of items and mixtures (including all amendments).

Executive summary:

The objective of this primary skin irritation study was to assess the possible irritation or corrosion potential of a single dose of PF-07202371-S7 when administered to the intact skin of rabbits. 
Three rabbits were exposed to 0.5 grams of PF-07202371-S7, moistened with 50% watery ethanol by application onto clipped skin for 4 hours using asemi-occlusivedressing. Skin reactions were assessed 1, 24, 48 and 72 hours after exposure.
No skin irritation was caused by four hours exposure to PF-07202371-S7.
Based on these results PF-07202371-S7 does not have to be classified and has no obligatory labelling requirement for skin irritation according to the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2017) (including all amendments) and Regulation (EC) No 1272/2008 on classification, labelling and packaging of items and mixtures (including all amendments).