Final DraftOctober 2002

Part III-3: Standard Formats for Study Summaries (cont'd)

TNsG on Dossier Preparation and Study Evaluation Part III: Standard formats

Final DraftOctober 2002

Company Name / Name of A.S. / Month/Year
Section A6.7
Annex Point IIA6.7 / Carcinogenicity
Specify section no., heading, route and species as appropriate

1Reference

/ Official
use only

1.1Reference

/ Author(s), year, title, laboratory name, laboratory report number, report date (if published, list journal name, volume: pages)
If necessary, copy field and enter other reference(s).

1.2Data protection

/ Yes/No
(indicate if data protection is claimed)

1.2.1Data owner

/ Give name of company

1.2.2Companies with letter of access

/ Give name of company/companies which have the right to use these data on behalf of the data owner (see TNsG in support of AnnexVI)

1.2.3Criteria for data protection

/ Choose one of the following criteria (see also TNsG on Product Evaluation) and delete the others:
Data on new [a.s. / b.p.] for [first entry to Annex I/IA / authorisation]
Data submitted to the MS after 13 May 2000 on existing [a.s. / b.p.] for the purpose of its [entry into Annex I/IA / authorisation]
Data submitted to the MS before 14 May 2000 on existing [a.s. / b.p.] for the purpose of its [entry into Annex I/IA / authorisation]
Data on existing or new [a.s. / b.p.] to [maintain or vary a.s. Annex I/IA entry / vary conditions of a b.p.'s authorisation]
No data protection claimed

2Guidelines and Quality Assurance

2.1Guideline study

/ Yes/No
(If yes, give guidelines; if no, give justification, e.g. "no guidelines available" or "methods used comparable to guidelines xy")

2.2GLP

/ Yes/No
(If no, give justification, e.g. state that GLP was not compulsory at the time the study was performed)

2.3Deviations

/ Yes/No
(If yes, describe deviations from test guidelines or refer to respective field numbers where these are described, e.g. "see 3.x.y")

3MATERIALS AND MethodS

In some fields the values indicated in the EC or OECD test guidelines are given as default values. Adopt, change or delete these default values as appropriate.

3.1Test material

/ As given in section 2
or give name used in study report

3.1.1Lot/Batch number

/ List lot/batch number if available

3.1.2Specification

/ As given in section 2
Deviating from specification given in section 2 as follows
(describe specification under separate subheadings, such as the following; additional subheadings may be appropriate):
3.1.2.1Description
/ If appropriate, give e.g. colour, physical form (e.g. powder, grain size, particle size/distribution)
3.1.2.2Purity
/ Give purity in % active substance
3.1.2.3Stability
/ Describe stability of test material

3.2Test Animals

/ Non-entry field

3.2.1Species

3.2.2Strain

3.2.3Source

3.2.4Sex

3.2.5Age/weight at study initiation

3.2.6Number of animals per group

3.2.6.1at interim sacrifice
/ 10 animals/group/sex or other
3.2.6.2at terminal sacrifice
/ 50 animals/group/sex or other

3.2.7Control animals

/ Yes/No

3.3Administration/Exposure

/ Oral/Inhalation/dermal/intraperitonea/intravenous/intratracheal
Fill in respective route in the following, delete other routes

3.3.1Duration of treatment

/ mice 78 weeks, rats 104 weeks or other

3.3.2Interim sacrifice(s)

/ after 52 weeks or other

3.3.3Final sacrifice

/ after 78 weeks, 104 weeks or other

3.3.4Freqency of exposure

/ 5 days/week, daily or other

3.3.5Postexposure period

/ 14 days, 4 weeks or other
Oral

3.3.6Type

/ Gavage/in food/in drinking water

3.3.7Concentration

/ Gavage.....mg/kg bw
food, drinking water.....ppm + mg/kg bw
food consumption per day .....ad libitum/certain amount per day

3.3.8Vehicle

/ Moistened with water, aqueous solution, corn oil or other

3.3.9Concentration in vehicle

3.3.10Total volume applied

3.3.11Controls

/ Vehicle, plain diet or other
Inhalation

3.3.12Concentrations

/ Nominal concentration ...... [mg/m³]
Analytical concentration ...... [mg/m³]

3.3.13Particle size

/ Only for studies with aerosols
MAAD (mass median aerodynamic diameter) [µm]
+ GSD (geometric standard deviation) [µm]
or other specifications

3.3.14Type or preparation of particles

/ For studies with particles

3.3.15Type of exposure

/ Whole body or nose/head only

3.3.16Vehicle

3.3.17Concentration in vehicle

3.3.18Duration of exposure/day

/ 4h or other

3.3.19Controls

/ sham exposure or other
Dermal

3.3.20Area covered

/ 10 % of body surface or other

3.3.21Occlusion

/ semiocclusive or other

3.3.22Vehicle

3.3.23Concentration in vehicle

3.3.24Total volume applied

3.3.25Duration of exposure

/ 6 h or other

3.3.26Removal of test substance

/ water or solvent
give solvent, detergent

3.3.27Controls

/ solvent or other
Intraperitoneal/Intravenous/Intratracheal instillation

3.3.28Vehicle

3.3.29Concentration in vehicle

3.3.30Total volume applied

3.3.31Controls

/ Vehicle or other

3.4Examinations

3.4.1Body weight

/ Yes/No

3.4.2Food consumption

/ Yes/No

3.4.3Water consumption

/ Yes/No

3.4.4Clinical signs

/ Yes/No

3.4.5Makroskopic investigations

/ Palpable masses, skin tumours

3.4.6Ophthalmoscopic examination

/ Yes/No

3.4.7Haematology

/ Yes/No
Number of animals: / all animals, 10 animals/sex/group or other
Time points: / After 3, 6, 12, 18, 24 months of treatment, end of study or other
Parameters: / Haematocrit, haemoglobin concentration, erythrocyte count, total and differential leukocyte count, platelet count, clotting time, prothrombin time, thromboplastin time
Other:

3.4.8Clinical Chemistry

/ Yes/No
Number of animals: / All animals, 10 animals/sex/group or other
Time points: / After 3, 6, 12, 18, 24 months of treatment, end of study or other
Parameters: / Sodium, potassium, glucose, total cholesterol, urea, blood urea nitrogen, total bilirubin, creatinine, total protein and albumin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma glutamyl transpeptidase, sorbitol dehydrogenase, methaemoglobin, lipids, hormone (specify hormones), acid/base balance, cholinesterase inhibition.
Other

3.4.9Urinalysis

/ Yes/No
Number of animals: / All animals, 10 animals/sex/group or other
Time points: / After 3, 6, 12, 18, 24 months of treatment, end of study or other
Parameters: / Appearance, volume, osmolality, specific gravity, pH, protein, glucose, blood
Other

3.4.10Pathology

/ Yes/No
3.4.10.1Organ Weights
/ Yes/No
from: / all surviving animals, at interim sacrifice, at terminal sacrifice
Organs: / Liver, kidneys, adrenals, testes, epididymides, uterus, ovaries, thymus, spleen, brain, heart
Other

3.4.11Histopathology

/ Yes/No
from: / all dose groups
high dose group and controls
other dose groups, if any effect
from: / all surviving animals
at interim sacrifice
at terminal sacrifice
Organs: / Brain, spinal cord, pituitary, thyroid, parathyroid, thymus, oesophagus, salivary glands, stomach, small and large intestines, liver, pancreas, kidneys, adrenals, spleen, heart, trachea, lungs, aorta, gonads, uterus, female mammary gland, prostate, urinary bladder, gall bladder (mouse), lymph node, peripheral nerve, bone marrow, skin, eyes
Other

3.4.12Other examinations

/ E.g. enzyme induction, cell proliferation, reversibility of effects

3.5Statistics

3.6Further remarks

4Results and Discussion

Describe findings. If appropriate, include table. Sample tables are given below.

4.1Body weight

/ No effects / describe significant effects referring to data in results table

4.2Food consumption

/ No effects / describe significant effects referring to data in results table

4.3Water consumption

/ No effects / describe significant effects referring to data in results table

4.4Clinical signs

/ No effects / describe significant effects referring to data in results table

4.5Macroscopic investigations

/ No effects / describe significant effects referring to data in results table

4.6Ophthalmoscopic examination

/ No effects / describe significant effects referring to data in results table

4.7Haematology

/ No effects / describe significant effects referring to data in results table

4.8Clinical Chemistry

/ No effects / describe significant effects referring to data in results table

4.9Urinalysis

/ No effects / describe significant effects referring to data in results table

4.10Pathology

/ No effects / describe significant effects referring to data in results table

4.11Organ Weights

/ No effects / describe significant effects referring to data in results table

4.12Histopathology

/ No effects / describe significant effects referring to data in results table

4.13Other examinations

/ No effects / describe significant effects referring to data in results table

4.14Time to tumours

/ For dermal route and skin tumours: give mean time until appearance of tumour or time until appearance of first tumour or other measure

4.15Other

/ Describe any other significant effects

5Applicant's Summary and conclusion

5.1Materials and methods

/ Give concise description of method; give test guidelines no. and discuss relevant deviations from test guidelines

5.2Results and discussion

/ Summarize relevant results; discuss dose-response relationship.

5.3Conclusion

5.3.1Reliability

/ Based on the assessment of materials and methods include appropriate reliability indicator 0, 1, 2, 3, or 4

5.3.2Deficiencies

/ No/Yes
(If yes, discuss the impact of deficiencies and implications on results. If relevant, justify acceptability of study.)
Evaluation by Competent Authorities
Use separate "evaluation boxes" to provide transparency as to the comments and views submitted

Evaluation by Rapporteur Member State

Date

/ Give date of action

Materials and Methods

/ State if the applicants version is acceptable or indicate relevant discrepancies referring to the (sub) heading numbers and to applicant’s summary and conclusion.

Results and discussion

/ Adopt applicant's version or include revised version. If necessary, discuss relevant deviations from applicant's view referring to the (sub)heading numbers

Conclusion

/ Other conclusions:
(Adopt applicant's version or include revised version)

Reliability

/ Based on the assessment of materials and methods include appropriate reliability indicator

Acceptability

/ acceptable / not acceptable
(give reasons if necessary, e.g. if a study is considered acceptable despite a poor reliability indicator. Discuss the relevance of deficiencies and indicate if repeat is necessary.)

Remarks

Comments from ...

Date

/ Give date of comments submitted

Materials and Methods

/ 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

Results and discussion

/ 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

Table A6_7-1.Table for Clinical Chemistry, Haematology and Urinalysis (modify if necessary)
Use this table, if relevant effects occur and if time sequence is important. Symbols for increases or decreases ( / ) will be sufficient. Give figures or percentages if in doubt.
affected / unit / Controls / low dose / medium dose / high dose
sex / parameter / weeks after start of treatment
m
f
* p < 0,05
Give only those parameters which are changed in at least one dose group compared to control,
usually only statistically significant effects.
Depending on number of parameters changed use separate tables for Haematology, Clinical Chemistry and Urinalysis
Table A6_7-2.Results of Carcinogenicity study
Parameter / control data / low dose / medium dose / high dose / dose-response + /
historical / study
m / f / m / f / m / f / m / f / m / f / m / f
If differing numbers of animals are examined, give number affected/number of animals examined for each individual finding.
Number of animals examined
Mortality
clinical signs
body weight gain
food consumption
clinical chemistry
haematology
urinalysis
Overall tumour incidence:
No. of animals with neoplasms
No. of animals with benign neoplasms
No. of animals with malignant neoplasms
No. of animals with > 1 neoplasm
Organ a
tumour a*
tumour x*
non-neoplastic changes
Organ b
tumour b*
tumour x*
non-neoplastic changes

*:specify tumour type

TNsG on Dossier Preparation and Study Evaluation Part III: Standard formatsPage 1

Final DraftOctober 2002

Company Name / Name of A.S. / Month/Year
Section A6.8.1
Annex Point IIA6.8.1 / Teratogenicity Study
Specify section no., heading, route and species as appropriate

1Reference

/ Official
use only

1.1Reference

/ Author(s), year, title, laboratory name, laboratory report number, report date (if published, list journal name, volume: pages)
If necessary, copy field and enter other reference(s).

1.2Data protection

/ Yes/No
(indicate if data protection is claimed)

1.2.1Data owner

/ Give name of company

1.2.2Companies with letter of access

/ Give name of company/companies which have the right to use these data on behalf of the data owner (see TNsG in support of AnnexVI)

1.2.3Criteria for data protection

/ Choose one of the following criteria (see also TNsG on Product Evaluation in support of AnnexVI) and delete the others:
Data on new [a.s. / b.p.] for [first entry to Annex I/IA / authorisation]
Data submitted to the MS after 13 May 2000 on existing [a.s. / b.p.] for the purpose of its [entry into Annex I/IA / authorisation]
Data submitted to the MS before 14 May 2000 on existing [a.s. / b.p.] for the purpose of its [entry into Annex I/IA / authorisation]
Data on existing or new [a.s. / b.p.] to [maintain or vary a.s. Annex I/IA entry / vary conditions of a b.p.'s authorisation]
No data protection claimed

2Guidelines and Quality Assurance

2.1Guideline study

/ Yes/No
(If yes, give guidelines; if no, give justification, e.g. "no guidelines available" or "methods used comparable to guidelines xy")

2.2GLP

/ Yes/No
(If no, give justification, e.g. state that GLP was not compulsory at the time the study was performed)

2.3Deviations

/ Yes/No
(If yes, describe deviations from test guidelines or refer to respective field numbers where these are described, e.g. "see 3.x.y")

3MATERIALS AND MethodS

In some fields the values indicated in the EC or OECD test guidelines are given as default values. Adopt, change or delete these default values as appropriate.

3.1Test material

/ As given in section 2
or give name used in study report

3.1.1Lot/Batch number

/ List lot/batch number if available

3.1.2Specification

/ As given in section 2
Deviating from specification given in section 2 as follows
(describe specification under separate subheadings, such as the following; additional subheadings may be appropriate):
3.1.2.1Description
/ If appropriate, give e.g. colour, physical form (e.g. powder, grain size, particle size/distribution)
3.1.2.2Purity
/ Give purity in % active substance
3.1.2.3Stability
/ Describe stability of test material

3.2Test Animals

/ Non-entry field

3.2.1Species

/ rabbit, rat or other

3.2.2Strain

3.2.3Source

3.2.4Sex

3.2.5Age/weight at study initiation

3.2.6Number of animals per group

/ 20 or other
Give number, specify, if there are differences for example for treatment and recovery groups

3.2.7Control animals

/ Yes/No

3.2.8Mating period

/ 14 days or other

3.3Administration/Exposure

/ Oral/Inhalation/ intraperitonea
Fill in respective route in the following, delete other routes

3.3.1Duration of exposure

rat/mouse: / day 6-15 / post mating
hamster: / day 6-14 / post mating
rabbit: / day 6-18 / post mating
or other

3.3.2Postexposure period

/ 14 days, 4 weeks or other
Oral

3.3.3Type

/ Gavage/in food/in drinking water

3.3.4Concentration

/ Gavage.....mg/kg bw
food, drinking water.....ppm + mg/kg bw
food consumption per day .....ad libitum/certain amount per day

3.3.5Vehicle

/ Moistened with water, aqueous solution, corn oil or other

3.3.6Concentration in vehicle

3.3.7Total volume applied

3.3.8Controls

/ Vehicle, plain diet or other
Inhalation

3.3.9Concentrations

/ Nominal concentration ...... [mg/m³]
Analytical concentration ...... [mg/m³]

3.3.10Particle size

/ Only for studies with aerosols
MAAD (mass median aerodynamic diameter) [µm]
+ GSD (geometric standard deviation) [µm]
or other specifications

3.3.11Type or preparation of particles

/ For studies with particles

3.3.12Type of exposure

/ Whole body or nose/head only

3.3.13Vehicle

3.3.14Concentration in vehicle

3.3.15Exposure period / day

3.3.16Controls

/ sham exposure or other
Intraperitoneal

3.3.17Vehicle

3.3.18Concentration in vehicle

3.3.19Total volume applied

3.3.20Controls

/ Vehicle or other

3.4Examinations

3.4.1Body weight

/ Yes/No

3.4.2Food consumption

/ Yes/No

3.4.3Clinical signs

/ Yes/No

3.4.4Examination of uterine content

/ Gravid uterine weight
Number of corpora lutea
Number of implantations
Or other

3.4.5Examination of foetuses

/ No entry field
3.4.5.1General
/ Litter Size, Nr. of dead Foetuses, Foetal Weight, Sex Ratio Or Other
3.4.5.2Skelet
/ Yes/No
3.4.5.3Soft tissue
/ Yes/No

3.5Further remarks

4Results and Discussion

Describe findings. If appropriate, include table. Sample tables are given below.

4.1Maternal toxic Effects

/ No effects / describe significant effects referring to data in results table; give concentrations of test substance resulting in toxic effects if any

4.2Teratogenic / embryotoxic effects

/ No effects / describe significant effects referring to data in results table

4.3Other effects

/ Describe any other significant effects

5Applicant's Summary and conclusion

5.1Materials and methods

/ Give concise description of method; give test guidelines no. and discuss relevant deviations from test guidelines

5.2Results and discussion

/ Summarize relevant results; discuss dose-response relationship.

5.3Conclusion

5.3.1LO(A)EL maternal toxic effects

/ Give critical effect and dose/concentration

5.3.2NO(A)EL maternal toxic effects

/ Give dose/concentration, if necessary separately for males and females

5.3.3LO(A)EL embryotoxic / teratogenic effects

/ Give critical effect and dose/concentration

5.3.4NO(A)EL embryotoxic / teratogenic effects

/ Give dose/concentration

5.3.5Reliability

/ Based on the assessment of materials and methods include appropriate reliability indicator 0, 1, 2, 3, or 4

5.3.6Deficiencies

/ No/Yes
(If yes, discuss the impact of deficiencies and implications on results. If relevant, justify acceptability of study.)
Evaluation by Competent Authorities
Use separate "evaluation boxes" to provide transparency as to the comments and views submitted

Evaluation by Rapporteur Member State

Date

/ Give date of action

Materials and Methods

/ State if the applicants version is acceptable or indicate relevant discrepancies referring to the (sub) heading numbers and to applicant’s summary and conclusion.

Results and discussion

/ Adopt applicant's version or include revised version. If necessary, discuss relevant deviations from applicant's view referring to the (sub)heading numbers

Conclusion

/
Other conclusions:
(Adopt applicant's version or include revised version)

Reliability

/ Based on the assessment of materials and methods include appropriate reliability indicator

Acceptability

/ acceptable / not acceptable
(give reasons if necessary, e.g. if a study is considered acceptable despite a poor reliability indicator. Discuss the relevance of deficiencies and indicate if repeat is necessary.)

Remarks

Comments from ...

Date

/ Give date of comments submitted

Materials and Methods

/ 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

Results and discussion

/ 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

Table A6_8-1.Table for Teratogenic effects (separate data for all dosage groups)
Maternal effects
Modify if necessary and give historical data if available
Parameter / controldata / low dose / medium dose / high dose / dose-response
+ / -
historical / study
Number of dams examined
Clinical findings during application of test substance
Mortality of dams
state %
Abortions
Body weight gain
day 0-x, day 0-y, day x-y, day 0-end of test,
Food consumption
Water consumption
if test substance is applied with drinking water
Pregnancies
pregnancy rate or %
Necropsy findings in dams dead before end of test
Table A6_8-2.Table for Teratogenic effects (separate data for all dosage groups)
Litter response (Caesarean section data)
Modify if necessary and give historical data if available
Parameter / controldata / low dose / medium dose / high dose / dose-response
+ / -
historical / study
Corpora lutea
state total/number of dams
Implantations
state total/number of dams
Resorptions
state total/number of dams
total number of fetuses
pre-implantation loss
state %
post-implantation loss
state %
total number of litters
fetuses / litter
live fetuses / litter
state ratio
dead fetuses / litter
state ratio
fetus weight (mean)
[g]
placenta weight (mean)
[g]
crown-rump length (mean)
[mm]
Fetal sex ratio
[state ratio m/f]
Table A6_8-3.Table for Teratogenic effects (separate data for all dosage groups)
Examination of the fetuses
Modify if necessary and give historical data if available
Parameter / controldata / low dose / medium dose / high dose / dose-response
+ / -
historical / study
External malformations*
[%]
External anomalies*
[%]
Skeletal malformations*
[%]
Skeletal anomalies*
[%]
Skeletal variants*
[%]
Visceral malformations*
[%]
Visceral anomalies*
[%]
Variants visceral*
[%]

TNsG on Dossier Preparation and Study Evaluation Part III: Standard formatsPage 1

Final DraftOctober 2002

Company Name / Name of A.S. / Month/Year
Section A6.8.2
Annex Point IIA6.8.2 / Multigeneration Reproduction Toxicity Study
Specify section no., heading, route and species as appropriate

1Reference

/ Official
use only

1.1Reference

/ Author(s), year, title, laboratory name, laboratory report number, report date (if published, list journal name, volume: pages)
If necessary, copy field and enter other reference(s).

1.2Data protection

/ Yes/No
(indicate if data protection is claimed)

1.2.1Data owner

/ Give name of company

1.2.2Companies with letter of access