1H-Imidazole, 5,5'-[1,1'-biphenyl]-4,4'-diylbis[2-(2S)-2-pyrrolidinyl-, hydrochloride (1:4)

Skin irritation / corrosion

Administrative data

Endpoint:

skin corrosion: in vitro / ex vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

May 21, 2014 to July 10, 2014

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: The study is acceptable as it followed OECD methods and was conducted under GLP conditions.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2014

Report date:

2014

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 435 (In Vitro Membrane Barrier Test Method for Skin Corrosion)

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

2-[(2S)-pyrrolidin-2-yl]-5-(4'-{2-[(2S)-pyrrolidin-2-yl]-1H-imidazol-5-yl}-[1,1'-biphenyl]-4-yl)-1H-imidazole tetrahydrochloride

EC Number:

807-342-7

Cas Number:

1009119-83-8

Molecular formula:

C26H32Cl4N6

IUPAC Name:

2-[(2S)-pyrrolidin-2-yl]-5-(4'-{2-[(2S)-pyrrolidin-2-yl]-1H-imidazol-5-yl}-[1,1'-biphenyl]-4-yl)-1H-imidazole tetrahydrochloride

Test material form:

solid: particulate/powder

Remarks:

migrated information: powder

Details on test material:

Off-white powder stored at room temperature and protected from expsure to light.

Test system

Amount / concentration applied:

Since the test article was a solid (powder), four samples of 500±5 mg were preweighed.
The test article was administered by direct addition to each of the four membrane discs. Due to
the low density of the test article, the pre-weighed samples had large volumes, and only
approximately half of each 500±5 mg sample was able to be applied to the membrane discs.

Details on study design:

The experimental design of this study consisted of a qualification screen with the Chemical Detection System (CDS), a pH determination, a categorization screen, and a definitive Corrositex® assay in the CDS. The Corrositex® assay was evaluated on the basis of a color change in the CDS. The number of minutes elapsed before a color change was observed (if any) was recorded manually and these break through times for the four replicates were used to determine the Packing Group. If a test article break through did not occur, the test article was considered non-corrosive.

A scintillation vial containing the biobarrier matrix powder was placed in a water bath on a stirring hot plate. The entire contents of the biobarrier
diluent vial were added slowly to the matrix powder. The solution was warmed to 64-68ºC to solubilize the biobarrier matrix. Using a repeat pipettor 200 µL of the solubilized matrix solution were pipetted into each membrane disc. The membrane discs were then stored at 2-8ºC in a refrigerator overnight before being used for corrosivity testing.

The positive control used in this study was sodium hydroxide (NaOH) (Sigma, CAS # 1310-73-2, >97% ACS). The negative control used in this study is 10% Citric Acid. A blank vial of CDS was used as a color comparison control. Each assay included a blank (color) control, a negative control and a positive control (tested in a single membrane disc).

Results and discussion

In vitro

Results

Irritation / corrosion parameter:

other: other: corrosive packing group III

Value:

ca. 50

Remarks on result:

other:

Remarks:

Basis: mean Break through time (min:sec). Remarks: pH is 1.5. (migrated information)

In vivo

Irritant / corrosive response data:

Positive control (NaOH) had a mean break through time of 13:56. The results of the positive control, NaOH (Sigma, CAS # 1310-73-2, >97% ACS), fell within two standard deviations of the historical mean (acceptance range: 8:13 to 15:02 min:sec), thereby meeting the acceptance criteria.

Other effects:

A deviation from the protocol occurred during conduct of the assay. On 23 May 2014,
samples of approximately 500 ± 5 mg of the test material were pre-weighed into glass vials;
however, due to the large volume of the test material, each sample was unable to be fully applied
onto the biobarrier membrane discs. Approximately half of the pre-weighed samples were
applied to each membrane disc. Since the results of the assay gave a corrosive classification, it
was demonstrated that an interaction of the test article with the biobarrier was achieved with the
reduced volume. Therefore, this deviation did not have a significant effect on the assay results.

Any other information on results incl. tables

Qualification and pH Screen:

For the qualification screen, 100±1 mg of the test article were added to the CDS

qualification tube. The test article produced an immediate color change in the CDS, and was

therefore qualified for testing in the Corrositex® assay.

Next, 100±1 mg of the test article were added to 1 mL of sterile, deionized water. The

test article dilution was exposed to pH paper (EMD Millipore Corporation) with a 0-14 pH range

in 1 pH unit increments to approximate a narrow pH range. Next, the test article dilution was

exposed to pH paper with a narrower range of 0-6 pH units in 0.5 pH unit increments, to obtain a

more accurate pH value. The pH value obtained from the narrower range pH paper is presented

in Table 3.

Applicant's summary and conclusion

Interpretation of results:

corrosive

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Based on the mean breakthrough time of 50 minutes and 9 seconds, the test article was assigned a corrosive packing group III classification.