sumitomo chemical takeda agro co., ltd. ti-435 february 2004...

Sumitomo Chemical Takeda Agro Co., Ltd. TI-435 February 2004

RCC project no. 852224 of 3

Section A4.1 (01)

Annex Point IIA4.1

Analytical methods for the determination of pure active substance

and, where appropriate, for relevant degradation products, isomers

and impurities of the active substance and additives (e.g. stabilisers)

TI-435 technical grade active ingredient (TGAI)

1 REFERENCE Official

use only

1.1 Reference Kramer, H.T., Telleen, K. (2001): Analytical method for analysis of

TI-435 technical grade active ingredient (TGAI).

Covance, Harrogate, England; unpublished part of report no. 6155-119

1.2 Data protection Yes

1.2.1 Data owner Sumitomo Chemical Takeda Agro Co., Ltd.

1.2.2 Companies with

letter of access

None

1.2.3 Criteria for data

protection

Data on existing a.s. submitted for the first time for entry into Annex I.

2 GUIDELINES AND QUALITY ASSURANCE

2.1 Guideline study Yes

OPPTS 830.1800

2.2 GLP No

2.3 Deviations No

3 MATERIALS AND METHODS

3.1 Preliminary

treatment

3.1.1 Enrichment No enrichment performed. The sample is diluted in methanol and

directly injected on the HPLC.

3.1.2 Cleanup No clean-up performed. The sample is diluted in methanol and directly

injected on the HPLC.

3.2 Detection

3.2.1 Separation method Liquid chromatography (HPLC) using reversed phase conditions

3.2.2 Detector UV detector, wavelength: 265 nm

3.2.3 Standard(s) Internal standard: 3-nitrophenol

3.2.4 Interfering

substance(s)

None for the conditions applied in this study.

3.3 Linearity

3.3.1 Calibration range 53.7 µg/mL to 202 µg/mL

3.3.2 Number of

measurements

Duplicate injections for each of the three standard concentrations

3.3.3 Linearity Correlation coefficient r2 = 1

3.4 Specificity:

interfering

substances

The specificity of the method was demonstrated by examining the

chromatographic peaks of the active ingredient for peak purity by

HPLC-UV DAD. The peak purity indicated that no interferences were

found.

3.5 Recovery rates at

different levels

Five samples of one batch were fortified with known amounts of TI-435

reference substance (ratio 1:1) and analysed. The recoveries ranged



Section A4.1 (01)

Annex Point IIA4.1





from 98.7% to 101.7% and the mean recovery was 100.4% ( 1.13%).

3.5.1 Relative standard

deviation

1.1%

3.6 Limit of

determination

Not determined. It deemed unnecessary for TI-435 technical materials

whose purity is more than 95%.

3.7 Precision

3.7.1 Repeatability Five analysis of one batch were performed on each of two different days

(10 analysis in total). The relative standard deviations were 0.9% on the

first day, 1.7% on the second day and overall, the relative standard

deviation was 1.3%.

3.7.2 Independent

laboratory

validation

Not relevant

4 APPLICANT'S SUMMARY AND CONCLUSION

4.1 Materials and

methods

An analytical method for the analysis of TI-435

was validated according to OPPTS 830.1800. TI-435

was diluted in methanol and analysed directly by liquid chromatography

(HPLC) using reversed phase conditions and UV detection.

Linearity, specificity, accuracy (recovery rates) and repeatability of the

analytical method were determined.

4.2 Conclusion Validity criteria of the analytical method presented can be considered as

fulfilled. Linearity, specificity, accuracy and repeatability of the

analytical method have been demonstrated.

4.2.1 Reliability

4.2.2 Deficiencies

Evaluation by Competent Authorities

Use separate "evaluation boxes" to provide transparency as to the

comments and views submitted

EVALUATION BY RAPPORTEUR MEMBER STATE

Date 08.11.04

Materials and methods

The applicant´s version is acceptable.

Conclusion Applicant´s version is adopted.

Reliability 2

Acceptability acceptable

Remarks

COMMENTS FROM ...

Date Give date of comments submitted



Section A4.1 (01)

Annex Point IIA4.1





Results and discussion Discuss additional relevant discrepancies referring to the (sub)heading numbers

and to applicant´s summary and conclusion.

Discuss if deviating from view of rapporteur member state

Conclusion Discuss if deviating from view of rapporteur member state

Reliability Discuss if deviating from view of rapporteur member state

Acceptability Discuss if deviating from view of rapporteur member state

Remarks


RCC project no. 852224 Page 1 of 2

Section A4.1/02

Annex Point IIA4.1




TI-435 technical grade active ingredient (TGAI) and impurities

1 REFERENCE Official

use only

1.1 Reference Kramer, H.T., Telleen, K. (2001b): Preliminary analysis of TI-435

technical grade active ingredient (TGAI).

Covance, Harrogate, England; unpublished revised report no. 6155-119,

January 10, 2001, amended on January 15, 2002 and January 17, 2003


1.2.1 Data owner


letter of access


protection


2.1 Guideline study Yes

US EPA OPPTS 830.1700

2.2 GLP Yes

2.3 Deviations None


The identity and analysis of TI-435 technical grade active ingredient and

impurities are confidential information.


The identity and analysis of TI-435 technical grade active ingredient and

impurities are confidential information.

4.1 Conclusion Validity criteria of the analytical method can be considered as fulfilled.

4.1.1 Reliability 1

4.1.2 Deficiencies No





Date 21.10.04


The applicant’s version is acceptable.

Conclusion Applicant´s version is adopted

Reliability 1



Section A4.1/02

Annex Point IIA4.1




TI-435 technical grade active ingredient (TGAI) and impurities


Remarks Please find the information in the confidential part of the CA-report: Confidential

data and information; Doc. III; Doc. III-A; III-A_02_01_cloth

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Remarks



Section A4.2 (01) Annex Point IIA4.2

Analytical methods including recovery rates and the

limits of determination for the active substance, and for

residues thereof, and where relevant in/on the following:

(a) Soil

1 REFERENCE

Official

use only

1.1 Reference Schramel, O. (2000): Residue analytical method 00540 (MR-654/98) for

determination of TI-435 and the metabolites TZNG and MNG in soil by

Liquid Chromatography with electrospray MS/MS-detection.

Bayer AG, unpublished report no. MR-654/98


1.2.1 Data owner Sumitomo Chemical Takeda Agro Co., Ltd. and Bayer CropScience


letter of access

None


protection

Data on existing a.s. submitted for the first time for entry into Annex I.


2.1 Guideline study No

2.2 GLP Yes

2.3 Deviations Not relevant


3.1 Preliminary

treatment

3.1.1 Enrichment Mixing of 20 g of soil with 4 g hydromatrix

Transfer of soil/hydromatrix-mixture into a stainless steel cartridge of

an ASE extractor

Extraction at 80°C with approx. 50 mL acetonitrile/ water/ acetic acid

(200 : 800 : 0.8, v/v/v) for 5 min.

Addition of 1 ml internal standard (d3 -TI-435, 13

C,15

N- TZNG, and

d3 -MNG)

Adjustment to 50 mL with acetonitrile/ water (1:4, v/v)

3.1.2 Cleanup No purification of the soil extract was performed.

3.2 Detection

3.2.1 Separation method HPLC

3.2.2 Detector Electrospray MS/MS-detection in the Multiple Reaction Monitoring

mode

3.2.3 Standard(s) Isotopically labelled internal standard (d3 -TI-435, 13

C,15

N- TZNG, and

d3 -MNG) to compensate for possible matrix effects in the MS/MS

detector

3.2.4 Interfering

substance(s)

None

3.3 Linearity







(a) Soil

3.3.1 Calibration range TI-435: 1.07 - 534.1 µg/L

TZNG: 1.11 - 494.8 µg/L

MNG: 1.07 - 533.5 µg/L

3.3.2 Number of

measurements

9 levels measured

3.3.3 Linearity TI-435: R² = 0.9999

TZNG: R² = 0.9997

MNG: R² = 0.9995

3.4 Specifity:

interfering

substances

Since the HPLC MS/MS determination is highly specific, a

confirmatory method is not required. This was confirmed by well

resolved peaks which were obtained at both fortification levels.

3.5 Recovery rates at

different levels

The method was validated in two different soils:

1. BBA 2.2: weak loamy sand/loamy sand*, pH (CaCl2): 6.3,

CEC: 10 meq/100 g, 4.3% org. matter, 7.2% clay

2. Hoefchen: heavy loamy silt/silty loam*, pH (CaCl2): 6.7,

CEC: 13 meq/100 g, 1.6% org. matter, 19% clay

* classifications according to DIN / USDA

Soil samples were fortified at and above the limit of quantitation

(0.005 mg/kg and 0.05 mg/kg) prior to the extraction procedure. The

recoveries are detailed in Table A4_2_01-1.

3.5.1 Relative standard

deviation

3.6 Limit of

determination

Control samples were amended with a standard solution of TI-435,

TZNG and MNG to achieve fortification levels of 0.005 mg/kg and

0.05 mg/kg. The lowest fortification level experimentally tested at

which acceptable recovery data have been obtained was 0.005 mg/kg for

TI-435 and its metabolites. Accordingly, this level corresponds (per

definition) to the limit of quantitation (LOQ).

LOQ = 0.005 mg/kg TI-435, TZNG and MNG

The limit of detection was 0.002 mg/kg for TI-435 and its metabolites.

3.7 Precision

3.7.1 Repeatability The repeatability was determined by 10 measurements of the standard

solution of 0.1 mg/L. The intensity ratios of TI-435 to d3 -TI-435,

TZNG to 13

C,15

N-TZNG and MNG to d3 -MNG were determined. The

relative standard deviations of the intensity rations were 2.5% for TI-

435, 2.9% for TZNG and 2.1% for MNG.

3.7.2 Independent

laboratory

validation

Not relevant







(a) Soil


4.1 Materials and

methods

A method for the residue analysis of TI-435

was presented and validated. After extraction of

fortified soil samples, TI-435 in the soil extracts were

analysed directly by HPLC with Electrospray MS/MS-detection.

d3 -TI-435, 13

C,15

N- TZNG, and

d3 –MNG)

Linearity, specificity, recovery rates, limit of determination and

quantitation (LOD and LOQ) and repeatability of the analytical method

were determined.

4.2 Conclusion The analytical method presented permits the determination of residues

of TI-435 in soil with satisfactory

accuracy and precision. Therefore, the method is considered valid for

the determination of residues of TI-435 in soil.

4.2.1 Reliability 1






Date 2004-12-02


Applicant's version is adopted with exception of points 3.4 Specifity and 4.2.2

Deficiencies. A confirmation of positive results without a second analytical

method is possible only, if at least two product ions were monitored with LC-

MS/MS.

Conclusion The method is considered valid for the determination of residues of TI-435,

TZNG and MNG in soil as primary method.

Reliability 1


Remarks

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Remarks



Table A4_2_01-1: Recovery in %

Fortification level 0.005 mg/kg wet soil 0.05 mg/kg wet soil

n mean range rel. SD mean range rel. SD overall

TI-435

BBA 2.2 5 108 103-112 3.5 100 95 -104 3.1

Hoefchen 5 103 97 -111 5.3 101 96 -107 4.6

mean : 103

rel. SD : 4.9

TZNG

BBA 2.2 5 99 85 -112 10.6 104 95 -109 5.2

Hoefchen 5 96 85 -106 10.1 101 94 -109 5.3

mean : 100

rel. SD : 7.9

MNG

BBA 2.2 5 107 100-112 4.4 94 92 - 96 2.2

Hoefchen 5 101 91 -110 7.2 94 87 - 99 5.2

mean : 99

rel. SD : 7.3



Analytical methods including recovery rates and the limits of determination for the active substance, and for residues thereof, and where relevant in/on the following:

(a) Soil

1 REFERENCE Officialuse only

1.1 Reference (2001):


1.2.1 Data owner

1.2.2 Companies with letter of access

1.2.3 Criteria for data protection



2.2 GLP Yes



3.1 Preliminary treatment

3.1.1 Enrichment

3.1.2 Cleanup

3.2 Detection

3.2.1 Separation method

3.2.2 Detector

3.2.3 Standard(s)

3.2.4 Interfering substance(s)

3.3 Linearity





(a) Soil

3.3.1 Calibration range

3.3.2 Number of measurements

3.3.3 Linearity

3.4 Specifity: interfering substances

3.5 Recovery rates at different levels

3.5.1 Relative standard deviation

3.6 Limit of determination

3.7 Precision

3.7.1 Repeatability

3.7.2 Independent laboratory validation


4.1 Materials and methods

A method for the residue analysis of TI-435 in soil was presented and validated. After extraction of fortified soil samples, TI-435 in soil extracts were analysed directly by HPLC with UV detection.

Linearity, specificity, recovery rates, limit of determination and quantitation (LOD and LOQ) and repeatability of the analytical method were determined.

A second HPLC column of different polarity was used for confirmation analysis.

4.2 Conclusion The analytical method presented permits the determination of residues of TI-435 in soil with satisfactory accuracy and precision. Therefore, the method is considered valid for the determination of residues of TI-435 in soil.

4.2.1 Reliability 1







(a) Soil

Evaluation by Competent Authorities Use separate "evaluation boxes" to provide transparency as to the



Date


Conclusion

Reliability

Acceptability

Remarks

COMMENTS FROM ...


Results and discussion Discuss additional relevant discrepancies referring to the (sub)heading numbers and to applicant´s summary and conclusion. Discuss if deviating from view of rapporteur member state




Remarks

Sumitomo Chemical Takeda Agro Co., Ltd. TI-435 April 2005



(a) Soil

1 REFERENCE Officialuse only


1.2 Data protection

1.2.1 Data owner





2.2 GLP Yes




3.1.1 Enrichment

3.1.2 Cleanup

3.2 Detection


3.2.2 Detector

3.2.3 Standard(s)






(a) Soil

3.3 Linearity



3.3.3 Linearity





3.7 Precision

3.7.1 Repeatability

3.7.2 Independent laboratory





(a) Soil

validation



A method for the residue analysis of TI-435 in soil was presented and validated. After

extraction of fortified soil samples, TI-435, in the soil extracts were analysed directly by HPLC with

Electrospray MS/MS-detection.

Linearity, specificity, recovery rates, limit of determination and quantitation (LOD and LOQ) and repeatability of the analytical method were determined.

4.2 Conclusion The analytical method presented permits the determination of residues of TI-435 in soil with satisfactory accuracy and precision. Therefore, the method is considered valid for the determination of residues of TI-435,

in soil.

4.2.1 Reliability 1





Date


Conclusion

Reliability

Acceptability

Remarks

COMMENTS FROM ...

Date

Results and discussion

Conclusion

Reliability

Acceptability





(a) Soil

Remarks





(b) Air

1 REFERENCE

Officialuse only


1.2 Data protection

1.2.1 Data owner




2.1 Guideline study Yes Commission Directive 96/46EC of July 16, 1996 Directive 91/414/EEC – guideline on residue analytical method Document 8064/VI/97 rev. 4 (15/12/1998)

2.2 GLP Yes

2.3 Deviations No



3.1.1 Sampling

3.1.2 Enrichment

3.1.3 Cleanup

3.2 Detection


3.2.2 Detector

3.2.3 Standard(s)


3.3 Linearity



3.3.3 Linearity





(b) Air





3.7 Precision

3.7.1 Repeatability






(b) Air



A method for residue analysis of TI-435 in air was described and validated. The required limit of quantification was defined based on toxicological parameters . Approximately 1/10 and a 5-fold of this concentration were analysed. The method is based on the guidance documents Commission Directive 96/46EC and Directive 91/414/EEC – guideline on residue analytical method Document 8064/VI/97 rev. 4 (15/12/1998).

Linearity, specificity, recovery rates, limit of determination and quantification (LOD and LOQ) and repeatability of the analytical method were determined.

4.2 Conclusion The analytical method presented permits the determination of residues of TI-435 in air with satisfactory accuracy and precision. Therefore, the method is considered valid for the determination of residues of TI-435 in air. The results obtained by the confirmatory method (HPLC-UV using a CN phase) were in good agreement with the results obtained by the HPLC-UV method using a reversed phase.

4.2.1 Reliability 1





Date


Conclusion

Reliability

Acceptability

Remarks

COMMENTS FROM ...











(b) Air

Remarks





(c) Water

1 REFERENCE

Official use only


1.2 Data protection

1.2.1 Data owner




2.1 Guideline study SANCO/825/00 rev. 6 of 20/06/00 of the European Commission

2.2 GLP Yes

2.3 Deviations No



3.1.1 Enrichment

3.1.2 Cleanup

3.2 Detection


3.2.2 Detector

3.2.3 Standard(s)


3.3 Linearity



3.3.3 Linearity






(c) Water




3.7 Precision

3.7.1 Repeatability


3.8 Confirmation analysis



A method for residue analysis of TI-435 in drinking and surface water was presented and validated.

-435 was analysed directly by HPLC with UV detection. The method is based on guidance document SANCO/825/00 rev. 6 of 20/06/00 of the European Commission.

Linearity, specificity, recovery rates, limit of determination and quantification (LOD and LOQ) and repeatability of the analytical method were determined.

4.2 Conclusion The analytical method presented permits the determination of residues of TI-435 in drinking and surface water with satisfactory accuracy and precision. Therefore, the method is considered valid for the determination of residues of TI-435 in drinking and surface water.

4.2.1 Reliability 1






(c) Water


Use separate "evaluation boxes" to provide transparency as to the comments and views submitted


Date


Conclusion

Reliability

Acceptability

Remarks

COMMENTS FROM ...






Remarks


Section A4.3/01 Annex Point IIIA IV.1

Analytical methods including recovery rates and the limits of determination for residues in/on food or feedstuffs and other products where relevant

1 REFERENCE

Officialuse only

1.1 Reference (2000c):

1.2 Data protection

1.2.1 Data owner




2.1 Guideline study Yes SANCO/825/00 rev. 6 of 20/06/00 of the European Commission and BBA Guideline: Residue Analytical Methods for Post-Registration Control Purposes of July 21, 1998

2.2 GLP Yes

2.3 Deviations No



3.1.1 Enrichment

3.1.2 Cleanup

3.2 Detection


3.2.2 Detector

3.2.3 Column

3.2.4 Standard(s)






3.3 Linearity



3.3.3 Linearity





3.7 Precision

3.7.1 Repeatability









A method for the determination of the residue of TI-435 in plant material is presented and validated. Specimens of apple, wheat, sugar-beet and oil seed rape were extracted with acetone / water .

the samples were analysed by HPLC. The method is based on SANCO/825/00 rev. 6 of 20/06/00 of the European Commission. Linearity, specificity, recovery rates, limit of determination and quantitation (LOD and LOQ) and repeatability of the analytical method were determined.

4.2 Conclusion The analytical method presented permits the determination of residues of TI-435 in tested matrices with satisfactory accuracy and precision. Therefore, the method is considered valid for the determination of residues of TI-435 in plant material.

4.2.1 Reliability 1





Date


Conclusion

Reliability

Acceptability

Remarks

COMMENTS FROM ...










1 REFERENCE

Officialuse only


1.2 Data protection

1.2.1 Data owner




2.1 Guideline study Yes SANCO/825/00 rev. 6 of 20/06/00 of the European Commission and BBA Guideline: Residue Analytical Methods for Post-Registration Control Purposes of July 21, 1998

2.2 GLP Yes

2.3 Deviations No



3.1.1 Enrichment

3.1.2 Cleanup

3.2 Detection


3.2.2 Detector





3.2.3 Column

3.2.4 Standard(s)


3.3 Linearity



3.3.3 Linearity





3.7 Precision

3.7.1 Repeatability









An analytical method is presented that describes the additional validation of method

for determination of the active substance in plant material. The method is based on SANCO/825/00 rev. 6 of 20/06/00 of the European Commission. Linearity, specificity, recovery rates, limit of determination and quantitation (LOD and LOQ) and repeatability of the analytical method were determined.

4.2 Conclusion The analytical method presented permits the determination of residues of TI-435 in tested matrices with satisfactory accuracy and precision down to a limit of quantitation of Therefore, the method is considered valid for the determination of residues of TI-435 in plant material.

4.2.1 Reliability 1





Date


Conclusion

Reliability

Acceptability

Remarks

COMMENTS FROM ...






Remarks


sumitomo chemical takeda agro co., ltd. ti-435 february 2004...

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