Loperamide

Skin irritation / corrosion

Administrative data

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2006-06-28 to 2006-07-07

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP study conducted according to OECD Guideline 404 "Acute Dermal Irritation/Corrosion" and Commission Directive 2004/73/EC, B.4. "Acute Toxicity: Dermal Irritation/Corrosion" without deviations.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2006

Report date:

2006

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test material

Test material information

Constituent 1

Reference substance name:

Loperamide

EC Number:

258-416-5

EC Name:

Loperamide

Cas Number:

53179-11-6

Molecular formula:

C29H33ClN2O2

IUPAC Name:

4-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-N,N-dimethyl-2,2-diphenylbutanamide

Details on test material:

- Name of test material (as cited in study report): T001001, 4-(4-chlorophenyl)-4-hydroxy-N,N-dimethyl-alpha, alpha-diphenyl-1-piperidinebutanamide.- Physical state: solid- Analytical purity: 100%- Lot/batch No.: 00456462 RT001001G1B591- Expiration date of the lot/batch: 2011-01-11- Stability under test conditions: no data- Storage condition of test material: at room temperature (range of 20±5 °C), light protected

Test animals

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS- Source: Harlan Netherlands BV, Kreuzelweg 53, NL-5961 NM Horst/ The Netherlands, Postbus 6174, NL-5960 AD Horst/ The Netherlands- Age at study initiation: 12-13 weeks (male), 9-11 weeks (females)- Weight at study initiation: 1795 to 2045 grams- Housing: Individually in stainless steel cages equipped with feed hoppers and drinking water bowls. Wood blocks (RCC Ltd., Fullinsdorf) and haysticks 4642 (batch no. 77/ 05, Provimi Kliba AG) were provided for gnawing.24/06) provided by Provimi Kliba AG, CH-4303 Kaiseraugst.- Water: community tap water from Fullinsdorf, ad libitum - Acclimation period: 2006-06-28 to 2006-07-02 (one female), and 2006-06-28 to 2006-07-03 (one male and one female)ENVIRONMENTAL CONDITIONS- Temperature (deg C): 17-23°C- Humidity (%): 30-70% - Air changes (per hr): 10-15 air changes per hour- Photoperiod (hrs dark / hrs light): 12 hours light/ 12 hours dark- Other: Music was played during the daytime light period.IN-LIFE DATES: From: 2006-07-03 (one female) and 2006-07-04 (one male and one female) To: 2006-07-07

Test system

Type of coverage:

semiocclusive

Preparation of test site:

shaved

Vehicle:

water

Remarks:

water (purified water to moisten)

Controls:

other: Untreated skin areas were used as control.

Amount / concentration applied:

TEST MATERIAL- Amount(s) applied (volume or weight with unit): 0.5 g per animalVEHICLE- Concentration (if solution): 0.5 g was moistened with approximately 0.5 mL of purified water

Duration of treatment / exposure:

4-hour treatment

Observation period:

72 hours (observations made at 1, 24, 48 and 72 hours after removal of the dressing, gauze patch and test item for skin reaction)Observations: Viability/Mortality: Daily from acclimatization of the animals to the termination of test. Clinical Signs: Daily from acclimatization of the animals to the termination of test. Body Weights: At start of acclimatization, on the day of application and at termination of observation.

Number of animals:

three (1 male and 2 females)

Details on study design:

TEST SITE- Area of exposure: The left flank was clipped with an electric clipper, exposing an area of approximately 100 cm² (10 cm x 10 cm). The test substance was applied under a 4 cm X 4 cm surgical gauze patch. The gauze patch was applied to the intact skin of the clipped area. - % coverage: no data- Type of wrap if used: The patch was covered with a semi-occlusive dressing. The dressing was wrapped around the abdomen and anchored with tape. - Other: 0.5 g (per animal) of the test substance was weighed and then moistened with approximately 0.5 mL of purified water before application. The pH of the test substance was measured before the study initiation date. A formulation of a 1% (w/w) solution was prepared. The pH was found to be 5.REMOVAL OF TEST SUBSTANCE- Washing: The skin was flushed with lukewarm tap water to clean the application site. - Time after start of exposure: 4 hoursSCORING SYSTEM: The skin reaction was assessed according to the numerical scoring system listed in the Commission Directive 2004/73/EC, April 29, 2004, (see scoring table in "Any other information on materials and methods" section below) approximately 1, 24, 48, and 72 hours after the removal of the dressing, gauze patch and test substance. If evident, corrosive or staining properties of the test substance were described and recorded.

Results and discussion

In vivo

Results

Results 1

Irritation parameter:

overall irritation score

Basis:

mean

Time point:

other: at approximately 1, 24, 48, and 72 hours

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Results 2

Irritation parameter:

erythema score

Basis:

mean

Remarks:

animal 61

Time point:

other: 24h, 48h, 72h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Remarks on result:

other: male

Results 3

Irritation parameter:

erythema score

Basis:

mean

Remarks:

animal 62

Time point:

other: 24h, 48h, 72h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Remarks on result:

other: female

Results 4

Irritation parameter:

erythema score

Basis:

mean

Remarks:

animal 63

Time point:

other: 24h, 48h, 72h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Remarks on result:

other: female

Results 5

Irritation parameter:

edema score

Basis:

mean

Remarks:

animal 61

Time point:

other: 24h, 48h, 72h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Remarks on result:

other: male

Results 6

Irritation parameter:

edema score

Basis:

mean

Remarks:

animal 62

Time point:

other: 24h, 48h, 72h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Remarks on result:

other: female

Results 7

Irritation parameter:

edema score

Basis:

mean

Remarks:

animal 63

Time point:

other: 24h, 48h, 72h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Remarks on result:

other: female

Irritant / corrosive response data:

The test substance did not elicit any skin reactions at the application site of any animals at any of the observation times (all scores 0). The individual mean score for erythema / eschar and oedema for each of the three animals was therefore 0. Neither alterations of the treated skin were observed nor were corrosive effects evident on the skin.

Other effects:

- Viability/Mortality/ Clinical Signs: No clinical signs of systemic toxicity were observed in the animals during the study and no mortality occurred. - Coloration: No staining produced by the test item of the treated skin was observed.- Body Weight: The body weights of all rabbits were considered to be within the normal range of variability.

Applicant's summary and conclusion

Interpretation of results:

not classified

Remarks:

Migrated informationCriteria used for interpretation of results: EU

Conclusions:

The purpose of this skin irritation study was to assess the possible irritation potential when a single dose of the test substance was placed on the skin of rabbits for approximately four hours. Based upon the referred classification criteria (Commission Directive 2001/59/EC of August 2001), the test substance is considered to be "not irritant" to rabbit skin. Based on the criteria of the CLP regulation, the test substance should not be classified as the mean score over different timepoint for all three animals remains under the cut off value of 2.3.