REPORT

DETERMINATION OF THE MELTING POINT / MELTING RANGE OF

TKA 40278 (CGI 827)

Data Requirement / Test Guidelines:

OECD No. 102

EEC Directive 92169, A.I

Study Director’

Mrs. Alessandra Tognucci

Study Completion Date:

April 11, 2003

Test Facility:

RCC Ltd ,

Environmental Chemistry & Pharmanalytics

CH-4452 Itingen/Switzerland

Sponsor;

CIBA SPECIALTY CHEMICALS INC.

CH - 4002 Basel/Switzerland

RCC Study Number:

845417

Page 1 of 12

522
RCC Study Number 845417 REPORT Page 2

TKA 40278 (CGI 827)

GLP CERTIFICATE

The Swiss GLP Monitoring Authorities

~

Swts~ A~ncy for tt~

Env~menL Forests =rid u~ SWISS’metriC

Statement of GLP Compliance

It is hereby confirmed that

dudng the pedod of

the following Test Facilities of

November 18 - 22, 2002

RCC Ltd

4452 Itingen

Switzerland

were inspected by the Federal Office of Public Health, the Swiss Agency for Therapeutic

Products and the Swiss Agency for the Environment, Forests and Landscape with respect to

the compliance with the Swiss legislation on Good Laboratory Practice,

Test Facilities Areas of expertise

Toxicology

Environmental Chemistry and

Pharmanalytics

TOX, ACC, MUT,

OTH (Safety Pharmacology)

ACC, ECT, ENF, EMN, PCT,

RES, OTH (Animal metabolism)

The inspections were performed in agreement with the OECD Guidelines for National GLP

Inspections and Audits. It was found that the aforementioned test facilities were operating In

compliance with the Swiss Ordinance relating to Good Laboratory Practice [RS 813.016.5] at

t~e time they were inspected.

Federal Office of Public Health

The Director

Bern, March 2003 Prof. Th. Zeltner

523
RCC Study Number 845417 REPORT Page 3

TKA 40278 (CGI 827)

GOOD LABORATORY PRACTICE

STATEMENT. OF COMPLIANCE

Rcc Study Number:

Test Item:

Study Director:

Title:

845417

TKA 40278 (CGI 827)

Mrs. Alessandra Tognucci

Determination of the Melting Point / Melting Range

of TKA 40278 (CGI 827)

This study was ~onducted in compliance with the Swiss Ordinance relating to Good

Laboratory Practice, adopted February 2

nd, 2000 [RS 813.016.5]. This Ordinance is based on

the OECD Principles of Good Laboratory Practice, as revised in 1997 and adopted November

26t~, 1997 by decision of the OECD Council [C(97)186/Final].

The purity of the test item is excluded from the statement of compliance (purity available in

Analytical Certifica~5-’~2~-l:,-Ciba Specialty Chemicals Inc.).

Study Director: Mrs. Alessandra Tognucci

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RCC Study Number 845417 REPORT Page 4

TKA 40278 (CGI 827)

SIGNATURES

Study Director:

Management: Dr. JOrn SchreitmQller

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RCC Study Number 845417 REPORT Page 5

TKA 40278 (CGI 827)

QUALITY ASSURANCE UNIT

RC(~ILtd, Environmental Chemistry & Pharmanalytics, CH-4452 Itingen / Switzerland

STATEMENT

Rcc S~udy Number: 845417

Test Item: TKA 40278 (CGI 827)

StudY Director: Mrs. Alessandra Tognucci

Title: Determination of the Melting Point / Melting Range of

TKA 40278 (CGI 827)

The general facilities and activities are inspected periodically and the results are reported to

the responsible person and the management.

Study procedures were periodically inspected. The study plan and this report were audited by

the Quality Assurance Unit. The dates are given below:

Dates and Types of QAU Ih~pections Dates of Reports to the Study

Director and to the Management

January 03, 2003 Study Plan January 03,2003

February 05, 2003 Process based (sample February 05,2003

preparation + measurement

April 08, + 09, 2003 Final report April09,2003

This statement also confirms that this final report reflects the raw data.

Quality Assurance:

526
RCC Study Number 845417 REPORT Page 6

TKA 40278 (CG1827)

CERTIFICATION OF GLP

AND VERIFICATION OF THE REPORT

The statement of Compliance with Good Laboratory Practice found in this report, and signed

by the Study Director is truthful and accurate, and this report as provided by the testing

facility is complete and unaltered.

Signature of the Sponsor:

Date:

527
RCC Study Number 845417 REPORT Page 7

TKA 40278 (CGI 827)

CONTENTS

GLP CERTIFICATE ........................................................................................................ 2

STATEMENT OF COMPLIANCE ..................~ ................................................................. 3

SIGNATURES ................................................................................................................ 4

QUALITY ASSURANCE UNIT ........................................................................................ 5

CERTIFICATION OF GLP AND VERIFICATION OF THE REPORT .............................. 6

CONTENTS .................................................................................................................... 7

PREFACE....................................................................................................................... 8

DATA REQUIREMENT / TEST GUIDELINES ................................................................9

SUMMARY OF STUDY PLAN AMENDMENTS ...........................................................~.. 9

1 PURPOSE ......................................................................... ~ ................................. 10

2 MATERIAL AND METHODS ................................................................................ 10

2.1 TEST ITEM ................................................................................................. 10

2.2 PRINCIPLE OF THE TEST .................~ ...................................................... 10

2.3 PERFORMANCE OF THE TEST ................................................................ 11

2.3.1 Thermal Analysis .......................................................................... 11

2.3.2 Preliminary Test ............................................................................ 11

2.3.3 Main Study .................................................................................... 11

2.4 DATA HANDLING ...................................................................................... 11

3 RESULTS .................................. : ......................................................................... i2

Table: Determination of the melting point of TKA 40278 (CGI 827) (summary) ..... 12

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RCC Study Number 845417 REPORT Page 8

TKA 40278 (CGI 827)

PREFACE

GENERAL

Title:

Sponsor:

Monitoring Scientist:

Test Facility:

Determination of the Melting Point / Melting Range of

TKA 40278 (CGI 827)

CIBA SPECIALTY CHEMICALS INC.

CH-4002 Basel/Switzerland

Dr. Moung Sook Lee

RCC Ltd

Environmental Chemistry & Pharmanalytics

Zelgliweg 1

CH-4452 Itingen/Switzerland

RESPONSIBILITIES

Study Director:

Deputy Study Director:

Technical Coordinator:

Head of RCC Quality Assurance:

Mrs. Alessandra Tognucci

Dr. Ute Schmledel

Mr. Christoph Wild

Mrs. Iris W0thrich

SCHEDULE

Experimental starting date:

Experimental completion date:

Study completion date:

Janua~ 02,2003

January 02,2003

April11,2003

ARCHIVING

RCC Ltd, CH-4452 Itingen/Switzerland will retain the study plan, raw data, a sample of test

item and the final report of the present study for at least ten years.

No data will be discarded without the sponsor’s consent.

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RCC Study Number 845417 REPORT Page 9

TKA 40278 (CG1827)

DATA REQUIREMENT / TEST GUIDELINES

This study followed the procedures indicated by the following internationally accepted

guidelines and recommendations:

EEC Directive 92/69, Part A, Methods for the determination of physico-chemical properties,

A.1 "Melting/Freezing temperature", EEC Publication No. L383, December 1992.

OECD Guideline for Testing of Chemicals No. 102, "Melting Point / Melting Range", adopted

July 27, 1995.

SUMMARY OF STUDY PLAN AMENDMENTS

First Amendment to Study Plan:

Concernin_g; Schedule

Alteration: New experimental starting and completion date

Reason: Delay in study

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RCC Study Number 845417 REPORT Page 10

TKA 40278 (CGI 827)

1 PURPOSE

The ~l~urpose of the study was to evaluate the melting point / melting range of the test item.

2 MATERIAL AND METHODS

2.t TESTITEM

Data as provided by the sponsor.

Identity:

Product Name:

Batch:

Purity:

Appearance:

Expiration date:

Storage:

TKA 40278

CGI 827

KL 01/02

See Analytical Certificate, Study No. 14026512-1

’Ciba Specialty Chemicals Inc.

Solid, slightly yellow

August 30, 2004

At room temperature at about 20 ~C.

The test item is light sensitive.

2.2 PRINCIPLE OF THE TEST

The above mentioned guidelines contain several different methods for the determination of

the melting point ! melting range. These are, between others, thermal analysis using a

calorimeter and the capillary method, where the melting resp. freezing temperature is

measured. In the present study the capillary method was applied.

The sample in the capillary tube is heated automatically in a heating chamber. A beam of

light is directed through the test item to a precisely calibrated photocell. The optical properties

of most substances change to transparency during melting. The intensity of light reaching the

photocell increases and sends a stop signal to the digital indicator reading out the

temperature of the heating chamber. In the present study, a transmission of 40 % was

defined as end point of melting.

This method is not suitable for some highly coloured substances, where the melting point /

melting range should be determined visually.

531
RCC Study Number 845417 REPORT Page 11

TKA 40278 (CG1827)

2.3 PERFORMANCE OF THE TEST

2,3.1 Thermal Analysis

Test System:

Instrument:

Detection:

Capillary tube:

Test conditions:

BOCHI Melting Point Tester, B-545

40 % transmission using a photocell

Glass; (Fa. Bechi; Art. No.: 017590)

The test was performed in an air atmosphere.

2,3.2 Preliminary Test

The finely ground test item is placed 4 mm to 6 mm high in a capillary tube and packed

tightly. During the experiment three of the filled capillary tubes were measured together. The

samples were heated up from 45 °C to about 100 °C at a rate of 5 K/min.

2.3.3 Main Study

The finely ground test item is placed 4 mm to 6 mm high in a capillary tube and packed

tightly. During the experiment six samples were measured in 2 runs. The samples were

heated up from 45 °C to 75 °C with a heating rate of 3 K/min and from 75 °C to 95 °C with a

rate of 1 K/min. Any unexpected changes in sample appearance are also described in the

raw data.

2.4 DATA HANDLING

The melting point is defined as the temperature at which phase transition from solid to liquid

state at normal atmospheric pressure takes place. This temperature ideally corresponds to

the temperature at the solidification point or the freezing point. As the phase transition of

many substances takes place over a large temperature range, it is often described as the

melting range.

Using the capillary method, the temperature of the final stage of melting usually is taken as

the melting temperature*. If this is not suitable or applicable, the temperature at the beginning

and at the final stage of melting or the temperature of decomposition will be stated. Results

will be given in degrees centigrade and in Kelvin.

Conversion of units (K to ° C):

with

t = T- 273.2

t = Celsius temperature, degrees Centigrade [°C]

T = Thermodynamic temperature, Kelvin [K]

* For many substances, this corresponds quite well with a light transmission of 40 %, which is used as end point

during automatical detection, 532
RCO Study Number 845417 REPORT Page 12

TKA 40278 (CGI 827)

3 RESULTS

The de!ermination of the melting point / melting range of the test item was performed

accctrding to the EEC Directive 92/69, A.1 "Melting/Freezing temperature", December 1992

and~o the OECD Guideline No. 102: " Melting point / melting range", adopted July 27, 1995

using the capillary method.

The results of the individual main test measureraents are summarized in the attached table.

Three filled capillary tubes were placed in the heating chamber and heated up from 45 °C

with a rate of 5 K/min. The melting point of the test item was observed visually at 77 °C. After

the experiment, the samples were melted and slightly yellow but not completely transparent.

In order to determine the melting point more precisely, further tests were performed using the

capillary tester. A total of 6 samples were heated with a heating rate of 3 K/rain (from 45 °C

to 75 °C) and with 1 K/min. (from 75 °C to 95 °C). All samples were completely molten

between 83.7 °C ahd 84.9 °C. After the measurement the samples were slightly yellow but

not completely transparent.

In conclusion, the mean melting point of TKA 40278 (CGI 827) was determined to be

which is equal to

---84.3~C~J: 0;5 ~ .......

357.5 K + 0.5 K

Table: Determination of the melting point of TKA 40278 (CGI 827) (summary)

Test Temperature Heating rate in the Temperature Temperature

range relevant [°C] [K]

[°C] temperature range

[K/min]

83.8 357.0

Preliminary Test 45-100 5 83.9 357.1

83.7 356.9

91.4" 364.6

Main Test 45 -95 84.7 357.9

84.9 358.1

83.9 357.1

2n~ Main Test 45-95 1 83.7 356.9

84.5 357.7

Mean melting point: 84.3 357.5

Standard deviation: (+) 0.5 0.5

The mean melting point was calculated from the bold values.

* outlier (not used for calculation)

533