REPORT

Study Title:

DETERMINATION OF THE RELATIVE DENSITY

OF TKA 40278 (CG| 827)

Data Requirement I Test Guidelines:

OECD No. 109

EEC Directive 92/69, A.3

Study Director:

Mrs, Alessandra Tognucci

~ Date:

April 16, 2003

Test Facllitv:

RCC Ltd

Environmental Chemistry & Pharmanalytics

CH-4452 Itingen/Switzerland

S_9onsor:

CIBA SPECIALTY CHEMICALS INC,

CH - 4002 Basel/Switzerland

RCC Study Number:

845419

Page 1 of 14

153
RCC Study Number 845419 REPORT Page 2

TKA 40278 (CG1827)

GLP CERTIFICATE

The Swiss GLP Monitoring Authorities

SWlS sTnel:].lC ~ut~ F~odu~

Statement GLP Compliance

It is hereby confirmed that

dudng the period of

the following Test Facilities of

November 18 - 22, 2002

RCC Ltd

4452 Itingen

Switzerland

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

Products and the Swiss Agency for the Environment, Forests and Landscape w~th respect to

the complianca with the Swiss tsglslation 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 fo~ National GLP

Inspections and Audits. It was found that the aforementioned test fadlit~es were operating In

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

the Ume they were inspected.

FederalOffice of Publlo Has]th

The Director

Bern, March 2003 Prof. Th. Zeltnet

154
RCC Study Number 845419 REPORT Page 3

TKA 40278 (CG1827)

GOOD LABORATORY PRACTICE

STATEMENT OF COMPLIANCE

RCC Study Number:

Test Item:

Study Director:

Title:

845419

TKA 40278 (CGI 827)

Mrs. Alessandra Tognucci

Determination of the Relative Density of

TKA 40278 (CGI 827)

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

Laboratory Practice. adopted February 2

nd, 2000 [F~S 813.016.5]. This Ordinance is based on

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

26~, 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 Certificate No. 14026512-1; Ciba Specialty Chemicals Inc.).

Study Director: nucci

Date:

155
RCC Study Number 845419 REPORT Page 4

TKA 40278 (CG1827)

SIGNATURES

Study Director: Mrs. Aless = Tognucci

Management: Dr. JOrn Schreitmeller

156
RCC Study Number 845419 REPORT Page 5

TKA 40278 (CGt 827)

QUALITY ASSURANCE UNIT

RCC Ltd, Environmental Chemistry & Pharmanalytics, CH-4452 Itingen / Switzerland

STATEMENT

RCC Study Number:

Test Item:

845419

TKA 40278 (CGI 827)

Study Director:

Title:

Mrs. Alessandra Tognucci

Determination of the Relative Density 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 Inspections Dates of Reports to the Study

Director and to the Management

September 16, 2002 Study Plan September 16, 2003

January 16, 2003 Process based (sample January 16, 2003

preparation + measurement)

April 04, + 09, 2003 Final report April 09, 2003

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

Quality Assurance: ~ Mrs. M. Ric! ~r-Auer

;:;: .............. ........

157
RCC Study Number 845419 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:

158
RCC Study Number 845419 REPORT Page 7

TKA 40278 (CG1827)

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 MATERIALS 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 Test System .................................................................................. 11

2.3.2 Test Item Treatment ..................................................................... 11

2.3.3 General Test Procedure ................................................................ 11

2.3.4 Calibration Procedure ................................................................... 11

2.3.5 Test Item Measurements .............................................................. 11

2.4 DATA HANDLING ................................................................... 12

2,4.1 Definitions ..................................................................................... 12

2.4.2 Calculations .................................................................................. 12

3 RESULTS ............................................................................................................ t3

~able 1: Results of the Calibration ............................................................................ 14

Table 2: Determination of the Density of TKA 40278 (CGI 827) ............................... 14

159
RCC Study Number 845419 REPORT Page 8

TKA 40278 (CG1827)

PREFACE

GENERAL

Title :

Sponsor:

Monitoring Scientist:

Test Facility:

De~rmination ofthe Rela~ve Densi~ of

TKA40278(CGI827)

ClBA 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 Coordinators:

Head of Quality Assurance:

Mrs. Alessandra Tognucci

Dr. Ute Schmiedel

Mrs. Barbara FI0kiger, Mrs. Manuela Heckel

Mrs. Iris W0thrich

SCHEDULE

Experimental starting date:

Experimental completion date:

Study completion date:

January 20,2003

January 31,2003

Apri116,2003/w~

ARCHIVlNG

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.

160
RCC Study Number 845419 REPORT Page 9

TKA 40278 (CGI 827)

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.3 "Relative density", EEC Publication No. L383, December 1992.

OECD Guideline for Testing of Chemicals, No. 109, "Density of Liquids and Solids", adopted

July 27, 1995.

SUMMARY OF STUDY PLAN AMENDMENTS

First Amendment to Study Plan:

Concerning:

Alteration:

Reason:

Schedule

New experimental starting and completion date

Delay in study

161
RCC Study Number 845419 REPORT Page 10

TKA 40278 (CG1827)

1 PURPOSE

The purpose of the study was to determine the relative density of the test item at a specific

temperature by means of a gas comparison pycnometer.

2 MATERIALS AND METHODS

2.1 TEST ITEM

Data of test item as supplied 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

A sample cell of known volume will be partly filled with an accurately weighed amount of the

dried test item. An inert gas will be allowed to penetrate into the interstices of the test item

particles at ambient pressure, A reference cell of known volume will be pressurized with the

inert gas and the pressure will be recorded. The two cells will then be connected and after

equilibration the pressure will be recorded again.

The powder volume will be calculated from the two pressure readings, assuming that the inert

gas exhibits ideal gas behaviour. The density of the test item will then be calculated from the

mass and the volume of the test item.

162
RCC Study Number 845419 REPORT Page 11

TKA 40278 (CG1827)

2.3 PERFORMANCE OF THE TEST

2.3.1 Test System

Test system:

Weighings:

Calibration ball:

Gas:

Conditions:

Gas comparison pycnometer (Multi-Pycnometer,

Syosset, N.Y., USA).

Analytical balance with an accuracy of 1 rag.

Mettler Toledo PM 100

Chrome plated ball with a calibrated known volume

(Vca~ = 56.559 cm3).

Helium 46

All manipulations were performed at 19.7 °C ± 0.3 °C.

Quantachrome,

2.3.2 Test Item Treatment

The test item was dried in a desiccator over silica gel for 260 hours before use.

2.3.3 General Test Procedure

A reference cell of a defined volume (Vref) is pressurised with helium to a pressure of not

more than 20 psi (1.406 kg/cm3) and the pressure is read. Subsequently, the volume of the

sample cell (being filled with helium at ambient pressure) is added to the pressure system,

resulting in a lower pressure, which is read, too.

During the performance of the test, the temperature is kept constant and measured.

2.3.4 Calibration Procedure

The volume calibration of the reference cell and the sample cell was based on a chrome

plated calibration ball (VcaI) with a calibrated volume. The test procedure as outlined above

was performed with an empty sample cell, resulting in pressure readings Pl and P2, for the

upper and lower pressure readings, respectively. The same procedure was performed with

the sample cell containing the calibrated ball (pressure readings P3 and P4 for the upper and

lower pressure values, respectively).

From these four pressure readings, the volume of the reference cell and the volume of the

sample cell was calculated as outlined under item 2.4.

Both procedures were performed in triplicate.

2.3.5 Test Item Measurements

The sample celt was weighed, filled with the test item and placed in the Multi-Pycnometer.

Then, the test was performed as outlined above, resulting in pressure readings PKsarnp[e) and

P2(sarnple) for the upper and the lower pressure reading, respectively. From these pressure

readings, the volume of the test item was calculated as outlined under item 2.4.

The procedure was repeated until reproducible results were obtained (repeatability of

< ± 0.02 g/cm3). The sample cell containing the test item was reweighed to determine the

mass of the tested material.

163
RCC Study Number 845419 REPORT Page 12

TKA 40278 (CG1827)

2.4 DATA HANDLING

2,4.1 Definitions

The density (p) of a substance is the quotient of the mass (m) and the volume (V) of that

substance at a specific temperature.

SI unit is in [kg/m3]. 1 [g/cm3] corresponds with 1000 [kg/m3]

The relative density D~° of solids or liquids is the ratio between the mass of a volume of

substance to be examined, determined at 20 °C and the mass of the same volume of water,

determined at 4 °C. The density of water at 4 °C is 1.0000 g/cm3. The relative density has no

dimension.

2.4.2 Calculations

Vc~l (1) Reference cell volume (cm=):

Vr~, = Ip~ p~)

Sample cell volume (cm3) (2)

Test item volume (cm=): (3)

Density (g/cm3): P = m ~,=p~.___~ (4)

where:

Vsample:

Vcell:

Mref:

V~l:

msample:

Pl, P2:

P3, P4:

Pl(sarnple), P2(sample):

p:

Volume of the test item [cm=]

Volume of the sample cell [cm~]

Volume of the reference cell [cm3]

Volume of the calibrated ball [cm3]

Amount of test item [g]

Pressure readings after pressudsing the calibration cell without

calibrated ball [psi]

Pressure readings in the calibration procedure with calibrated ball [psi]

Pressure readings after pressurising the sample cell filled with a defined

amount of test item [psi]

Density of the test item [g/cm3]

Since the test is performed at 20 °C + 1 °C, the relative density (D~°) is given.

164
RCC Study Number 845419 REPORT Page 13

TKA 40278 (CG1827)

3 RESULTS

The determination of the relative density of the test item was performed in accordance with

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

properties, A.3 "Relative density" and the OECD Guideline for Testing of Chemicals, No. 109,

"Density of Liquids and Solids" using a gas comparison pycnometer.

The test was performed at a temperature of 19.7 °C :1:0.3 °C.

The calibration procedure was performed in triplicate. The individual measurements and the

results are shown in Table 1.

The determination of the relative density of the test item was performed with two independent

test item samples each at least measured in triplicate. The individual measurements are

summarised in Table 2.

The tabulated values in Tables 1 and 2 represent rounded results, which were obtained by

calculation using the exact raw data.

The density of the test item TKA 40278 (CGI 827) was determined to be 1.195 g/cm~

(= 1.195  ̄ 10~ kg/m~) at 19.7 °C + 0.3 °C using a gas comparison pycnometer,

In conclusion, the relative density of TKA 40278 (CGI 827) was determined to be

1.195.

165
RCC Study Number 845419 REPORT Page 14

TKA 40278 (CG1827)

Table 1: Results of the Calibration

Calibration volume (Vcal):56.559 cm~

Gas: Helium

Measurement pl p2 p3 V ref V cell

[psi] [psi] [psi] [psi] [cm3] [cm~]

1 17.119 5.249 17.145 7.014 69.229 156.553

2 17.320 5.311 17.249 7.057 69.235 156.551

3 17.558 5.384 17,703 7.243 69.228 156.535

mean: 69.231 156.546

Table 2: Determination of the Density Of TKA 40278 (CGI 827)

Sampte Sample Measumment pl p2 V

Density

no. weight (sample) (sample) (sample)

[g] [psi] [psi] [cm~] [g/cm3]

1 15.130 5.067 19.055 1.195

1 22.762 2 t5.145 5.072 19,054 1.195 1.194

3 15.141 5.071 19.068 1.194

1 15.155 5.095 19.851 1.191

2 23.640 2 15.037 5.052 19.716 1.199 1.195

3 15.117 5.080 19~761 1.196

mean: 1.195

standa~ deviation[± g~m~: 0.003

166