REPORT

HYDROLYSIS DETERMINATION OF

TKA 40278 (CGI 827) AT DIFFERENT pH VALUES

Data Requirement / Test Guidelines:

OECD No. 111

EEC Directive 92/69, C.7

Study Director:

Mrs. Alessandra Tognucci

Stud Corn letion Date:

July 16, 2003

Test Fa~

RCC Ltd

Environmental Chemistry & Pharmanalytics

CH-4452 ltingerdSwitzedand

Sponsor:

CIBA SPECIALTY CHEMICALS INC.

CH-4002 Basel/Switzerland

RCC Study Number:

845449

Page 1 of 23

69
RCC Study Number 845449 REPORT Page 2

TKA 40278 (CGI 827)

GLP CERTIFICATE

The Swiss GLP Monitoring Authorlties

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 O~ce of Publla 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

Pharrnanalytlcs

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 Naf~onal 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

the time they were Inspected.

Federal Oft]ce of Public Health

The Director

Bern, March 2003 Prof. Th. Ze]ther

70
RCC Study Number 845449 REPORT Page 3

TKA 402"78 (CG1827)

GOOD LABORATORY PRACTICE

STATEMENT OF COMPLIANCE

RCC Study Number:

Test Item:

Study Director:

Title:

845449

TKA 40278 (CGI 827)

Mrs. Alessandra Tognucci

Hydrolysis Determination of TKA 40278 (CGI 827)

at Different pH Values

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

Laboratory Practice, adopted February 2nd, 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].

Study Director: Ira Tognucci

Date: ~.~

71
RCC Study Number 845449 REPORT Page 4

TKA 40278 (CGI 827)

SIGNATURES

Study Director:

Date:

Tognucci

Management: Dr. JOrn SchreitmOller

Date:

72
RCC Study Number 845449 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:

Study Director:

Title:

845449

TKA 40278 (CGI 827)

Mrs. Alessandra Tognucci

Hydrolysis Determination of TKA 40278 (CGI 827)

at Different pH Values

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, 2002

May 12, 2003 Process based May 12, 2003

(Measurement + Sampling)

July 08/09, 2003 Final report July 09, 2003

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

Quality Assurance: Mrs. M. Richter-Auer

73
RCO Study Number 845449 REPORT Page 6

TKA 40278 ((;(31827)

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:

74
RCC Study Number 845449 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

SUMMARY ....................... i .......................................................................................... 10

1 PURPOSE ........................................................................................................... 11

2 MATERIAL AND METHODS .................................................................. : .............11

2.1 TEST ITEM ................................................................................................. 11

2.2 REAGENTS ................................................................................................ 12

2.3 EQUIPMENT .............................................................................................. 12

2.4 STUDY DESIGN ............................................................................. ; ...........13

2.4.1 Principle of the Test ...................................................................... 13

2.4.2 Performance of the Test ............................................................... 13

2.4,3 Preparation of the Test Solutions (3r’~test) .................................... 13

2.5 ANALYTICAL METHOD ............................................................................. 14

2.5.1 Standard Solutions ........................................................................ 14

2.5.2 HPLC-Conditions .......................................................................... 15

2.6 EVALUATION OF RESULTS ...................................................................... 16

3 RESULTS ............................................................................................................ 17

Table 1 : Results of the Preliminary Test of TKA 40278 (CGI 827) .............................. 18

Table 2: The calibration data of TKA 40278 (CGI 827) ............................................... 23

Figure 1 : Typical HPLC chromatogram of a standard solution of TKA 40278

(CGI 827) (18.714pg/ml) .............................................................................. 19

Figure 2: Typical HPLC chromatogram of a sample solution at ~H 4.0

Conditions: 120 hours in aqueous buffered solution ~H 4.0 at 50°C ............. 20

Figure 3: Typical HPLC chromatogram of a sample solution at ~H 7.0

Conditions: 120 hours in aqueous buffered solution ~H 7.0 at 50°C ............. 21

Figure 4: Typical HPLC chromatogram of a sample solution at ~H 9.0

Conditions: 120 hours in aqueous buffered solution )H 9.0 at 50°C ............. 22

Figure 5: Example of a calibration curve of TKA 40278 (CGI 827) ............................... 23

75
RCC Study Number 845449 REPORT Page 8

TKA 40278 (CGI 827)

PREFACE

GENERAL

Title:

Sponsor:

Monitoring Scientist:

Test Facility:

Hydrolysis Determination of TKA 40278 (CGI 827)

at Different pH Values

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:

Reporting:

Head of RCC Quality Assurance:

Mrs. Alessandra Tognucci

Dr. Ute Schmiedel

Mrs. Manuela Heckel, Mr. Patrick Schanie[

Mrs. Doris Leiminer

Mrs. Iris WLithrich

SCHEDULE

Experimental starting date:

Experimental completion date:

Study completion date:

January27,2003

June 03, 2003

July16,2003/sds

ARCHIVING

RCC Ltd, CH-4452 Itingen/Swltzerland 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.

76
RCC Study Number 845449 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:

OECD Guideline for Testing of Chemicals No. 111, "Hydrolysis as a Function of pH"; adopted

May 12, 1981. (only at pH 4.0, pH 7.0 and pH 9.0)

EEC Directive 92/69, Section C.7, "Abiotic Degradation: Hydrolysis as a Function of pH",

L383 A, December 1992,

SUMMARY OF STUDY PLAN AMENDMENTS

First amendment to study plan;

1) Concerning: Schedule

Alteration:

Reason:

Change of experimental starting, completion date and date of draft

report

- Delay in study

- Technical reason

2) Concerning:

Alteration:

Reason:

Test Item

Purity

Information given by the sponsor

77
RCC Study Number 845449 REPORT Page 10

TKA 40278 (CGI 827)

SUMMARY

The hydrolysis determination of TKA 40278 (CGI 827) at different pH values was based on

the OECD Guideline No. 111, "Hydrolysis as a Function of pH"; adopted May 12, 1981 and

on the EEC Directive 92/69, Section C.7, "Abiotic Degradation: Hydrolysis as a Function of

pH", L383 A, December 1992.

The results of pH 4.0, pH 7.0 and pH 9.0 showed no significant degradation of TKA 40278

(CGI 827) at 50°C. The degradation of TKA 40278 (CGI 827) was less than 10 % after 5

days. These results were summarised in the table below.

pH Hydrolysis after 5 days, 50°C

[%]

4.0 <1o

7.o <1o

9.0 <1o

According to the EEC Directive 92/69, Section C.7 it can be concluded, that the estimated

half-life time is higher than one year under representative environmental conditions (25°C).

Therefore, TKA 40278 (CGI 827) was considered to be hydrolytically stable, and no further

testing was necessary.

78
RCC Study Number 845449 REPORT Page 11

TKA 40278 (OGI 827)

1 PURPOSE

The purpose of this study was to determine the hydrolysis behavlour of TKA 40278 (CGI 827)

in aqueous buffered solutions adjusted to pH 4.0, pH 7.0 and pH 9.0.

Hydrolysis is one of the most common reactions controlling abiotic degradation in the

environment. This reaction is particularly relevant for substances with low biodegradability.

2 MATERIAL AND METHODS

2.1 TEST ITEM

Data as provided by the sponsor.

Identity:

Product Name:

Batch:

Purity:

Appearance:

Expiration date:

Storage:

TKA 40278

CGI 827

KL 01/02

94.1%

Solid, slightly yellow

August 30, 2004

At room temperature at about 20 °C.

The test item is light sensitive.

79
RCO Study Number 845449 REPORT Page 12 TKA 40278 (CG1827)

2.2 REAGENTS

Buffer pH 4, Biphthalate Baker

Buffer pH 7, Phosphate Baker

Buffer pH 9, Borate/Potassium chloride/NaOH Baker

Art. No. 5657

Art. No. 5656

Art. No. 7145

Water RCC from Milli-Q supply

Acetonitrile Baker Art. No. 9017

Tetrahydrofuran Baker Art. Nr. 9441

The buffer solutions were sterilized for 25 minutes in an autoclave prior to first use. Nitrogen

was passed through the buffer solutions for 15 minutes except when freshly sterilized.

2.3 EQUIPMENT

Glassware:

All glassware, which must be inert in the pH range applied, was rinsed with sterile buffer. The

hydrolysis was carried out in flasks, which were stoppered or sealed with an inert material (e.

g. PTFE).

The test vessels were labelled with the following information: RCC study number and the

additional information necessary to assure unmistakable identification.

Water Baths:

Thermostatically controlled water bath Haake SWB 25

80
RCC Study Number 845449 REPORT Page 13

TKA 40278 (CG1827)

2.4 STUDY DESIGN

2.4.1 Principle of the Test

The study was conducted as described in the guidelines and in accordance with the RCC Ltd

Standard Operating Procedures.

The test item was dissolved in the buffer solutions and incubated at 50°C with the water bath

kept constant at ± 0.1°C, usually. The concentration of the test item was determined as a

function of time at each pH.

2.4.2 Performance of the Test

Three preliminary tests were performed at 50°C ± 0.5°C at each of pH 4.0, pH 7.0 and pH

9.0.

Aliquots of each test solution were analysed in time intervals using the analytical method as

described later in this report. Analysis was performed before incubation, after 2.4 hours and

after 120 hours.

The first and the second test were performed under normal daylight. Probably due to the light

sensitivity of the test item, the content of test item found in the sample solutions showed high

differences. Therefore, a third preliminary test was performed under red-light. The first and

the second preliminary test are not reported but part of the raw data.

A main study was not performed, as the test item was found to be stable according to the

criteria given in the guideline.

2.4,3 Preparation of the Test Solutions (3rd test)

pH 4.0

13.96 mg of TKA 40278 (CGI 827) were dissolved in 100 mt buffer solution (pH 4.0)

containing 2 % acetonitrile as solubilizer. This mixture was ultrasonified for 10 minutes and

submitted to a 0.2 pm filtration. To obtain a test solution of not more than half the water

solubility, the solution was diluted 1:1 with the respective buffer. Two allquots of this test

solution of approximately 50 ml each were transferred into 50 ml Erienmeyer flasks in order

to perform a duplicate test.

pH 7.0

13.93 mg of TKA 40278 (CGI 827) were dissolved in 100 ml buffer solution (pH 7.0)

containing 2 % acetonitrile as solubilizer. This mixture was ultrasonified for 10 minutes and

submitted to a 0.2 pm filtration. To obtain a test solution of not more than half the water

solubility, the solution was diluted 1:1 with the respective buffer. Two aliquots of this test

solution of approximately 50 ml each were transferred into 50 ml Erlenmeyer flasks in order

to perform a duplicate test.

81
RCC Study Number 845449 REPORT Page 14

TKA 40278 (CG1827)

pH 9.0

13.45 mg of TKA 40278 (CGI 827) were dissolved in 100 ml buffer solution (pH 9.0)

containing 2 % acetonitrile as solubilizer, This mixture was ultrasonified for 10 minutes and

submitted to a 0.2 pm filtration. To obtain a test solution of not more than half the water

solubility, the solution was diluted 1:1 with the respective buffer. Two aliquots of this test

solution of approximately 50 ml each were transferred into 50 ml Erlenmeyer flasks in order

to perform a duplicate test.

2.5 ANALYTICAL METHOD

2.5.1 Standard Solutions

Analytical standards were prepared from stock solutions created by combining the test item

with appropriate solvent.

31.19 mg of TKA 40278 (CGI 827) were dissolved in 100 ml of a mixture of acetonitdle/water

(50:50, v:v) to prepare a stock solution of 311.9 pg/ml TKA 40278 (CGI 827). Calculated

volumes of this stock solution were diluted with the same mixture to obtain six standard

solutions in the range from 4.679 pg/ml to 109.165 ,ug/ml TKA 40278 (CGI 827). These

solutions were used to calibrate the HPLC-system.

A second stock solution was prepared: 31.31 mg test item were weighed and diluted to obtain

three solutions with concentrations in the range from 9.393 pg/ml to 78.275 pg/ml TKA 40278

(CGI 827). These solutions were measured in respective to the calibration curve to verify the

HPLC-system during the test.

Sample Preparation

After incubation 5 pl aliquots of the test solutions at each pH value were analysed without

dilution by measuring the UV/VIS signal of TKA 40278 (CGI 827) after HPLC separation of

the injected sample solution.

82
RCC Study Number 845449 REPORT Page 15

TKA 40278 (CGI 827)

2.5.2 HPLC-Conditions

Apparatus: Merck Workstation D-7000

Merck-Hitachi Pump L-7100

Merck-Hitachi Autoaampler L-7200

Merck-Hitachi Detector DAD L-7450

Merck-Hitachi Column Oven L-7300

Column: LiChrosphere RP 18e, 5,um, 250 mm  ̄ 4 mm

Mobile Phase: Eluent A: Water

Eluent B: Acetonitrile

Eluent C: Tetrahydrofuran

Gradient:

Time A B C

0 - 3 min 7O % 15% 15%

3 - 20 o% 85 % 15%

20 - 25 min 0% 85 % 15%

25 - 26 m]n 70 % 15% 15%

26 -35 min 70 % 15 % 15 %

Detection: 260 nm

Temperature: Room temperature ( 23 °C)

Injection Volume: 5

Flow: 0.7 ml/min

The retention time of TKA 40278 (CGI 827) was at about 14.5 minutes.

83
RCC Study Number 845449 REPORT Page 16

TKA 40278 (CGI 827)

2.6 EVALUATION OF RESULTS

Injected samples were quantified by peak area with reference to the calibration curve. The

latter was obtained by correlation of the peak area of the analytical standards with their

corresponding concentration. The correlation was performed using a least squares fit of the

function given below.

From this curve the concentration x of TKA 40278 (CGI 827) was calculated by the following

equation:

Y=b.x+a ~ x=(Y-a)/b

where

Y = peak area of injected sample solutions (counts)

x = concentration of injected sample solution (,ug/ml)

b = slope

a = y-axis intercept

84
RCC Study Number 845449 REPORT Page 17 TKA 40278 (CGI 827)

3 RESULTS

The hydrolysis determination of TKA 40278 (CGI 827) at different pH values was based on

the OECD Guideline No. 111, "Hydrolysis as a Function of pH"; adopted May 12, 1981 and

on the EEC Directive 92/69, Section C.7, "Abiotic Degradation: Hydrolysis as a Function of

pH", L383 A, December 1992.

The results of the individual measurements are summarised in the attached table. The

tabulated values represent rounded results obtained by calculation used the exact raw data,

The results of pH 4.0, pH 7.0 and pH 9.0 showed no significant degradation of TKA 40278

(CGI 827) at 50°C. The degradation of TKA 40278 (CGI 827) was less than 10 % after 5

days. According to the EEC Directive 92/69, Section C.7, it can be concluded, that the

estimated half-life time is higher than one year under representative environmental conditions

(25°C). Therefore, TKA 40278 (CGI 827) was considered to be hydrolytically stable, and no

further testing was necessary.

A typical chromatogram of a standard solution is given in Figure 1. Typical chromatograms of

the test’solutions after an incubation time of 5 days are given in the Figures 2 to 4. The

linearity of the analytical method was proved in the concentration range from 4.679 pg/ml to

109.165 pg/mL An example of a calibration curve of TKA 40278 (CGI 827) is shown in Figure

5. The calibration data are given in Table 2.

85
RCC Study Number 845449 REPORT Page 18 TKA 40278 (CGI 827)

Table 1: Results of the Preliminary Test of TKA 40278 (CGI 827)

Initial Concentration Concentration

concentration measured after measured after

measured 2.4 hours 5 days

incubation incubation

[,ug/ml] [,ug/ml]

20.47 pH 4.0 19.38 20.99

19.67 17.92 21.38

10.79 11.18 pH 7.0 10.29

10.68 10.2.7 11.80

20.36 20.87 pH 9.0 19.51

19,36 20.59 19.73

Based on the measured concentrations it can be stated, that the test item is stable under the

conditions of the test.

86
RCC Study Number 845449 REPORT Page 19

TKA 40278 (CGI 827)

Figure 1: Typical HPLC chromatogram of a standard solution of TKA 40278 (CGI 827)

(18,714 pg/ml)

D-7000 HSM: 845449 Series: 0005 Report: modified System: Sys 1

D-7000 HPLC System Manager Report

Analyzed: 03.06.03 13:32 Reported: 04.06.03 07:20

Data Path: C:\Win32App\HSM\845449\DATA\0005\

Processing Method: TKA 40278A

System(acquisition): Sys 1

Application: 845449

S~le Name: E 4 18.714

Injection from this vial: 1 of 1

Sample Description:

Processed: 04.06.03 07:19

Serles:0005

Vial Number: 3

Vial Type: UNK

Volume: 5,0 ul

845&45

Chrom Type: Fixed WL Chromatogram, 260 nm

Acquisition Method: TKA 40278A

Colu~m Type: kelne

Pump A Type: L-7100

Solvent A:

Solvent C:

Method Description: Discovery C 18

Developed by: FRJ

Solvent B:

ChromType: FixedWL Chromatogram, 260 nm

Peak Quantitation: AREA

Calculation Method: AREA%

Me. RT Name Area : Area %

1 14,49 859330 i00,000

859330 i00,000

Peak rejection level: i000

87
RCC Study Number 845449 REPORT TKA 40278 (¢GI 827) Page 20

Figure 2: Typical HPLC chromatogram of a sample solution at pH 4.0

Conditions: 120 hours in aqueous buffered solution pH 4.0 at 50°C

D.7000 HSM: 845449 Scdes: 0004 Report: modified Sys~m: SFs

D-7000 IIPLC System Manager Report

Analyzed: 27.05.03 20:32 Reported: 02.06.03 14:21

Data Path: C:\Win32App\MSM\845449\DATA\0004\

Processing Method: T~A 40278A

System(acquisition) : Sys 1

Application: 845449

Sample Name: p 19-4 120h

Injection from this vlal: 1 ~f 1

Sample Description:

Processed: 02.06.03 14:21

Series:0004

Chrom Type: Fixed WL Chromatogram, 260 nm

2,5 -

Acquisition Method: TKA 40278A

Coloa%nType: kelne

Pump A Type: L-7100

Solvent A:

Solvent C:

Method D~scription: Discovery C 18

Developed byt FRJ

Solvent B:

Chrom %~ype: Fixed WL Chromatogram, 260 nm

Peak Quantitation: AREA

Calculation Method: AREA%

No. RT Name Area Area %

1 14,50 950150  ̄ 100,000

950150 100,000

Peak rejection level: i000

88
RCC Study Number 845449 REPORT TKA 40278 (CG1827) Page 21

Figure 3: Typical HPLC chromatogram of a sample solution at pH 7.0 Conditions: 120 hours in aqueous buffered solution pH 7.0 at 50°C

D-7000 HSM: g45449 Sed~s: 0004 RepoM: modified System: s~ 1

D-7000 HPLC System Manager Report

Analyzed: 27.05,03 22:22 Reported: 02.06.03 11:34

Processed: 02.06.03 ii:33 Data Path: C: \WIn32App\MSM\845449\DATA\0004\

Processing Method: TKA 40278A

System(acquisitlon) : Sys 1 Series:0004 Application: 845449 Vial Number: 9 Sample Name: p 21-7 120h Vial Type: DNK Injection from this vlal: i ~f i Volume: 5,0 ul Sample Description:

Chrom Type: Fixed WL Chromatogram, 260 run

Developed by: FRJ

Acquisition Method: TKA 40278A

Column Type: keine

Pump A Type: L-7100

Solvent A:

Solvent C:

Method Description: Discovery C 18

Solvent B:

Cb/om Type: Fixed WL Chromatogram, 260 nm

Peak Quantitation: AREA

Calculation Method: AREA%

NO. RT Name Area Area %

1 14,49 455520 100,000

455520 i00,000

Peak rejection level : 1000

89
RCC Study Number 845449 REPORT TKA 40278 (CGI 827) Page 22

Figure 4: Typical HPLC chromatogram of a sample solution at pH 9.0 Conditions: 120 hours in aqueous buffered solution pH 9.0 at 50°C

D-7000 HSM: 845~49 Series: 0~04 Report: modified

D-7000 HPLC System Manager Report

Analyzed: 28.05.03 00:49 Reported: 02.06.03 ii:34

Data Path: C:\WIn32App\HSM\845449\DATA\0004\ Processed: 02.06.03 11:33

Processing Method: TKA 40278A

System(acq~isitlon): Sys 1

Application: 845449

Sample Name: p 24-9 120h

Injection from this vial: 1 of 1

Sample Description:

Series:0004

Volume: 5,0 ul

Chrom Type: Fixed WL Chromatogram, 260 nm

0,20

Acquisition Method: TKA 40278A

Column Type: kelne

Pump A T~rpe: L-7100

Solvent A:

Solvent C:

Method Descriptlon: Discovery C 18

Developed by: FRJ

Solvent B:

Chrom Type: Fixed WL Chromatogram, 260 rum

Peak Quantltatlon: AREA

Calculation Method: AREA%

No. RT Ma~e Area Area %

1 14,48 891730 i00,000

891730 i00,000

Peak rejection level: I000

9O
RCC Study Number 845449 REPORT TKA 40278 (CG1827) Page 23

Figure 5: Example of a calibration curve of TKA 40278 (CGI 827)

Unear Regression

0 10 20 30 40 50 60 70 80

Concentration

Y=b.x+a with y = Area Counts

x = concentration (.ug/ml) b = 46213.3 (slope)

a = -20027.6 (y-axis intercept)

r2 = 0.9999

Table 2: The calibration data of TKA 40278 (CGI 827)

Concentration Area Counts

[,ug/ml] Deviation

in%

(x) (¥)

4.6785 214680 8.6

46.785 2125650 -0.8

10.9165 470860 -2,7

18.714 845955 0.1

77.975 3593820 0.3

91