Guidance for Industry

M4S: The CTD — Safety

Appendices

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Drug Evaluation and Research (CDER)

Center for Biologics Evaluation and Research (CBER)

August 2001

ICH
Guidance for Industry

M4S: The CTD — Safety

Appendices

Additional copies are available from:

Office of Training and Communications

Division of Drug Information, HFD-240

Center for Drug Evaluation and Research

Food and Drug Administration

5600 Fishers Lane

Rockville, MD 20857

(Tel) 301-827-4573

(Internet) http://www.fda.gov/cder/guidance/index.htm

or

Office of Communication, Training and

Manufacturers Assistance, HFM-40

Center for Biologics Evaluation and Research

Food and Drug Administration

1401 Rockville Pike, Rockville, MD 20852-1448

Internet: http://www.fda.gov/cber/guidelines.htm.

Fax: 1-888-CBERFAX or 301-827-3844

Mail: the Voice Information System at 800-835-4709 or 301-827-1800

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Drug Evaluation and Research (CDER)

Center for Biologics Evaluation and Research (CBER)

August 2001

ICH
21

APPENDIX A: EXAMPLES OF TABLES AND FIGURES FOR WRITTEN

SUMMARIES

The tables and figures in Appendix A are presented merely as examples. Applicants should provide tables and

figures using a format appropriate to the product.

Study references should be included in the table or text.

Tables should include statistics, if appropriate.
22

Table X: Binding of X and Its Major Metabolites and Comparators to Human X2 and X3 Receptors

Compound X2

Ki1(nM)

X2

Ki2(nM)

X3

Ki1(nM)

X3

Ki2(nM)

1 538 2730 691 4550

2 2699 1050 2.0 181

3 578 14.4 141 10400

4 20 100 10.7 7.9

5 2100 3.1 281 28

6 7.5 8.4 44 2.8

7 3.11 3.76 1.94 1.93

Ki1 and Ki2 represent the high and low affinity binding sites, respectively (Data from Study Number).
23

Figure X: Blood Pressure Following Chronic Dosing With X to SHRa

Blood pressure following chronic dosing with X to SHRa[ref]. Hypotensive effect of saline i.v. infusion over 5 min (s) compared to X, 3 mg/kg i.v.

infusion to SHR pretreated twice daily with saline, 1 mL/kg p.o., for 7 (m) or 14 (p) days or X, 25 mg/kg p.o., for 7 (l) or 14 (n) days. Saline pretreated

statistical significances: p<0.05, all other points after challenge p<0.01. Values represent mean ± s.e.m.

a

SHR= spontaneous hypertensive rat (n=5 per group).
24

Table X: Model Independent Pharmacokinetic Parameters for X in Mice Following Single Oral Doses at 2, 10

and 30 mg/kg [ref]

Parameter

(units)

Parameter value

Sex Males Females

Dose

(mg/kg)

2 10 30 2 10 30

Cmax

(ng/mL)

4.9 20.4 30.7 5.5 12.9 28.6

Tmax (h) 0.8 0.4 0.3 0.4 0.5 0.3

AUC0-t

(ng.h/mL)

21.6 80.5 267 33.3 80 298

AUC0-inf

(ng.h/mL)

28.3 112 297 40.2 90 327

Pharmacokinetic parameters were determined in pooled plasma from three animals

at each time.

Table X: Excretion of Radioactive Material Following Single Doses of [14C]X to Male Mice [ref]

Dose (mg/kg)/ Percentage of administered dose

route Urine* Feces Total+

2.8 i.v. 88.1 ± 7.4 5.5 ± 0.7 93.6 ± 6.9

8.8 p.o. 89.4 ± 4.7 6.9 ± 1.4 95.3 ± 3.4

Excretion was determined over 168 hours after dosing.

Values are means ± S.D. (n= 5 for p.o. and 5 for i.v.)

* - includes radioactivity in cage wash (22.1% after p.o. and 21.7% after i.v.).

+ - includes radioactivity in the carcass.
25

Table X: Concentrations of Radioactive Material in the Tissues of Male Rats After a Single Intravenous

Dose of [14C]X at 1.75 mg/kg [refs]

Tissue Concentration (ng equiv.*/g)

1 h 6 h 24 h 48 h 72 h

Blood 105 96.6 2.34 2.34 3.65

Plasma 142 175 3.12 ND ND

Adrenals 656 49.2 14.3 9.63 ND

Bone

marrow

359 31.5 ND ND ND

Brain 116 9.37 ND ND ND

Eyes 124 28.9 4.69 ND ND

Fat 490 44.0 10.2 6.25 5.47

Heart 105 26.6 ND ND ND

Kidneys 1280 651 21.6 13.3 9.63

Large

intestine

570 2470 39.3 12.0 ND

Liver 875 380 133 87.7 64.6

Lungs 234 59.1 7.55 ND ND

* - ng of X free base equivalent/g.

N= 5 animals/time point.

ND - Not detected.
26

Table X: Excretion of Radioactive Material Following Single Doses of [14C]X to Male Rats [refs]

Dose (mg/kg)/ Percentage of administered dose

route Urine Feces Bile Total

1.75 i.v. 61.3 ± 9.3 30.3 ± 4.1 - 95.2 ± 5.0

1.75 p.o. 57.4 ± 3.8 37.0 ± 3.4 - 95.2 ± 1.5

2 p.o. 72.3 ± 0.8 26.9 ± 1.9 - 99.5 ± 1.1

20 p.o. 23.5 ± 6.3 0.5 ± 0.2 76.0 ± 5.9 100 ± 0.8

220 p.o. 67.1 ± 9.0 24.8 ± 5.0 - 93.3 ± 6.8

Excretion was determined over 168 h period in Wistar rats:Values are means ±

S.D. (n=5); - not assayed; Total includes radioactivity in the carcass and cage

washings.
27

Table X: Comparative Pharmacokinetic Data and Systemic Exposure to X Following Oral Administration to Mice, Rats, Dogs, and

Patients [ref]

Species (formulation) Dose (mg/kg/day) Systemic (plasma) exposure References

Cmax (ng/mL) AUC (ng.h/mL)#

Man (tablet) 0.48$ 36.7 557 X

Mouse (solution) 8.8 68.9 (1.9)* 72.7 (0.2)* Y

21.9 267 (7.3)* 207 (0.5)*

43.8 430 (11.7)* 325 (0.7)*

Rat (solution) 50 479 (13.0)* 1580 (2.8)* Z

Dogs (solution) 1.5 5.58 (0.2)* 15.9 (<0.1)* V

5 24.8 (0.7)* 69.3 (0.1)*

15 184 (5.0)* 511 (0.9)*

Data presented are for male and female animals and are after daily repeated oral administration (at the end of the 60-day mouse study, 14-day rat

study, and 1-year dog study). Data for man are extrapolated from dose normalized data obtained in male and female patients following t.i.d

regimen.

# - AUC0-6 in the mouse, AUC0-t in the rat and in the dog and dose normalized AUC0-τ x 24 in man.

$ - calculated from the total daily dose assuming a body weight of 50 kg for man.

* - Numbers in parentheses represent ratios of exposure in animals to those in patients.
28

Table X: Incidence of Proliferative Interstitial (Leydig) Cell Lesions in Rats [ref]

Dose Groups

Lesion Control 3 mg/kg 30 mg/kg 100 mg/kg

Hyperplasia

(only)

x/50 (%) x/50 (%) x/50 (%) x/50 (%)

Adenoma

(only)

x/50 (%) x/50 (%) x/50 (%) x/50 (%)

Adenoma +

Hyperplasia

x/50 (%) x/50 (%) x/50(%) x/50 (%)

Total* x/50 (%) x/50 (%) x/50 (%) x/50 (%)

* Adenoma and/or Hyperplasia.
29

APPENDIX B: THE NONCLINICAL TABULATED SUMMARIES TEMPLATES

2.6.3 Pharmacology

2.6.3.1 Pharmacology: Overview

2.6.3.2 Primary Pharmacodynamics*

2.6.3.3 Secondary Pharmacodynamics*

2.6.3.4 Safety Pharmacology

2.6.3.5 Pharmacodynamic Drug Interactions*

2.6.5 Pharmacokinetics

2.6.5.1 Pharmacokinetics: Overview

2.6.5.2 Analytical Methods and Validation Reports*

2.6.5.3 Pharmacokinetics: Absorption After a Single Dose

2.6.5.4 Pharmacokinetics: Absorption after Repeated Doses

2.6.5.5 Pharmacokinetics: Organ Distribution

2.6.5.6 Pharmacokinetics: Plasma Protein Binding

2.6.5.7 Pharmacokinetics: Study in Pregnant or Nursing Animals

2.6.5.8 Pharmacokinetics: Other Distribution Study

2.6.5.9 Pharmacokinetics: Metabolism In Vivo

2.6.5.10Pharmacokinetics: Metabolism In Vitro

2.6.5.11Pharmacokinetics: Possible Metabolic Pathways

2.6.5.12Pharmacokinetics: Induction/Inhibition of Drug-Metabolizing Enzymes

2.6.5.13Pharmacokinetics: Excretion

2.6.5.14Pharmacokinetics: Excretion into Bile

2.6.5.15Pharmacokinetics: Drug-Drug Interactions

2.6.5.16Pharmacokinetics: Other

2.6.7 Toxicology

2.6.7.1 Toxicology: Overview

2.6.7.2 Toxicokinetics: Overview of Toxicokinetics Studies

2.6.7.3 Toxicokinetics: Overview of Toxicokinetics Data

2.6.7.4 Toxicology: Drug Substance

2.6.7.5 Single-Dose Toxicity

2.6.7.6 Repeat-Dose Toxicity: Nonpivotal Studies

2.6.7.7 Repeat-Dose Toxicity: Pivotal Studies

2.6.7.8 Genotoxicity: In Vitro

2.6.7.9 Genotoxicity: In Vivo

2.6.7.10Carcinogenicity

2.6.7.11Reproductive and Developmental Toxicity: Nonpivotal Studies

2.6.7.12Reproductive and Developmental Toxicity: Fertility and Early Embryonic Development

to Implantation (Pivotal)

2.6.7.13Reproductive and Developmental Toxicity: Effects on Embryofetal Development

(Pivotal)

2.6.7.14Reproductive and Developmental Toxicity: Effects on Pre- and Postnatal Development,

Including Maternal Function (Pivotol)
30

2.6.7.15Studies in Juvenile Animalsa (template not provided; see footnote a)

2.6.7.16Local Tolerance

2.6.7.17Other Toxicity Studies

* : Tabulated summary is optional. It is preferable to include text tables and figures with the Nonclinical

Written Summary.

a

 : When a juvenile animal study has been conducted, it should be tabulated using the template

appropriate for the type of study and located in Section 2.6.7.15.
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2.6.3.1 Pharmacology Overview Test Article: (1)

Type of Study

Test

System

Method of

Administration

Testing

Facility

Study

Number(4)

 Location

Vol. Page

Primary Pharmacodynamics

 (2)

 (3)

Secondary Pharmacodynamics

Safety Pharmacology

Pharmacodynamic Drug Interactions

Notes: (1) International Nonproprietary Name (INN)

(2) There should be one line for each pharmacology report, in the same order as the CTD. Reports that contain a GLP Compliance

Statement should be identified in a footnote.

(3) The location of the Technical Report in the CTD should be indicated.

(4) Or Report Number (on all tables).
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2.6.3.4 Safety Pharmacology(1) Test Article: (2)

Organ

Systems

Evaluated

Species/

Strain

Method of

Admin.

Dosesa

(mg/kg)

Gender

and No.

per Group Noteworthy Findings

GLP

Compliance

Study

Number(3)

Notes: (1) All safety pharmacology studies should be summarized.

(2) International Nonproprietary Name (INN).

(3) Or Report Number (on all tables).

a - Single dose unless specified otherwise.
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2.6.5.1 Pharmacokinetics Overview Test Article: (1)

Type of Study

Test

System

Method of

Administration

Testing

Facility

Study

Number

 Location

Vol. Page

Absorption

 (2)

 (3)

 Distribution

Metabolism

Excretion

Pharmacokinetic Drug Interactions

Other

Notes: (1) International Nonproprietary Name (INN).

(2) There should be one line for each pharmacokinetics report, in the same order as the CTD. Reports that contain a GLP Compliance

Statement should be identified in a footnote.

(3) The location of the Technical Report in the CTD should be indicated.
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2.6.5.3 Pharmacokinetics: Absorption After a Single Dose Test Article: (1)

Location in CTD: Vol. Page

Study No.

Species __________ __________ __________ __________ _________

Gender (M/F)/Number of animals (4)

Feeding condition

Vehicle/Formulation

Method of Administration

Dose (mg/kg)

Sample (e.g., whole blood, plasma, serum)

Analyte

Assay (2)

PK parameters:

Additional Information: (3)

Notes: (1) International Nonproprietary Name (INN).

(2) For example, HPLC, LSC with 14C-labeled compound.

(3) For example, brief textual results, species differences, gender differences, dose dependency, or special comments.

(4) There should be one column for each study conducted. For comparison, representative information on humans at the maximum

recommended dose should be included.
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2.6.5.4 Pharmacokinetics: Absorption after Repeated Doses Test Article:

[Data can be tabulated as in the format of 2.6.5.3 if applicable.]
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Format A

2.6.5.5 Pharmacokinetics: Organ Distribution Test Article:

Location in CTD: Vol. Page

Study No.

Species:

Gender (M/F)/Number of animals:

Feeding condition:

Vehicle/Formulation:

Method of Administration:

Dose (mg/kg):

Radionuclide:

Specific Activity:

Sampling time:

Concentration (unit)

Tissues/organs T(1) T(2) T(3) T(4) T(5) t1/2?

Additional information:
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Alternate Format B

2.6.5.5 Pharmacokinetics: Organ Distribution Test Article:

Location in CTD: Vol. Page

Study No.

Species:

Gender (M/F)/Number of animals:

Feeding condition:

Vehicle/Formulation:

Method of Administration:

Dose (mg/kg):

Radionuclide:

Specific Activity:

Analyte/Assay (unit):

Sampling time:

Ct Last time point

Tissues/organs conc. T/P1) conc. T/P1) Time AUC t1/2?

Additional information:

1) [Tissue]/[Plasma]
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2.6.5.6 Pharmacokinetics: Plasma Protein Binding Test Article:

Study system:

Target entity, Test system and method:

Species Conc. tested % Bound

Study

 No. 

Location in CTD

Vol. Page

Additional Information:
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2.6.5.7 Pharmacokinetics: Study in Pregnant or Nursing Animals (1) Test Article: (2)

Location in CTD: Vol. Page

Placental transfer Study No.

Species:

Gestation day/Number of animals:

Vehicle/Formulation:

Method of Administration:

Dose (mg/kg):

Analyte:

Assay:

Time (hr) __________ _________ _________ __________ __________

Concentration/Amount (% of dose)

 Dam (3):

 Fetus (3):

Additional Information:

Location in CTD: Vol. Page

Excretion into milk Study No.

Species:

Lactating date/Number of animals:

Feeding condition:

Vehicle/Formulation:

Method of Administration:

Dose (mg/kg):

Analyte:

Assay:

Time [hr] __________ __________ __________ __________ __________

Concentration:

 Milk:

 Plasma:

 Milk/plasma:

 Neonates:

Additional Information:
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Notes for Table 2.6.5.7

(1) Even if the data are obtained in reproduction toxicology studies, they should be presented in this table.

(2) International Nonproprietary Name (INN).

(3) The tissue sampled should be described (e.g., plasma for dams, fetal concentrations).
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2.6.5.8 Pharmacokinetics: Other Distribution Study Test Article:
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2.6.5.9 Pharmacokinetics: Metabolism In Vivo Test Article:

Gender(M/F)/Number of animals:

Feeding condition:

Vehicle/Formulation:

Method of Administration:

Dose (mg/kg):

Radionuclide:

Specific Activity:

 % of Compound in Sample Location in CTD

Species Sample

Sampling Time

 or Period 

% of Dose

in Sample Parent_ M1 M2

Study

 No. Vol Page 

Plasma

Urine

Bile

Feces

Plasma

Urine

Bile

Feces

Plasma

Urine

Bile

Feces

Additional Information:

Note: Human data should be included for comparison if available.
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2.6.5.10 Pharmacokinetics: Metabolism In Vitro Test Article:

Location in CTD: Vol. Page

Study No.

Study system:

Time __________ __________ __________ __________ __________

Concentration:

Compounds

 Parent

 M-1

 M-2

Additional Information:

Note: Human data should be included for comparison if available.
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2.6.5.11 Pharmacokinetics: Possible Metabolic Pathways Test Article:

(Illustrate possible metabolic map indicating species in which metabolic reactions occur.)
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2.6.5.12 Pharmacokinetics: Induction/Inhibition of Drug-Metabolizing Enzymes Test Article:

Location in CTD: Vol. Page

Study No.

Note: Nonclinical studies only.

Type of study:

Method:

Tabulated results:

Additional Information:
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2.6.5.13 Pharmacokinetics: Excretion Test Article: (1)

Species __________ __________ __________ _________

Gender (M/F)/Number of animals (3)

Feeding condition

Vehicle/Formulation

Method of Administration

Dose (mg/kg)

Analyte

Assay

Excretion route (4) Urine Feces Total Urine Feces Total Urine Feces Total Urine Feces Total

 Time

 0 - T hr

Study number

Location in CTD

Additional Information: (2)

Notes: (1) International Nonproprietary Name (INN).

 (2)For example, brief textual results, species differences, gender differences, dose dependency, or special comments.

 (3) There should be one column for each study conducted. For comparison, representative information on humans at the maximum

recommended dose should be included. Can be combined with the Absorption Table if appropriate.

(4) Other routes (e.g., biliary, respiratory) should be added, if performed.
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2.6.5.14 Pharmacokinetics: Excretion into Bile Test Article:

[Data can be tabulated as in the format of 2.6.5.13 if applicable.]
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2.6.5.15 Pharmacokinetics: Drug-Drug Interactions Test Article:

Location in CTD: Vol. Page

Study No.

Type of study:

Method:

Tabulated results:

Additional Information:
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2.6.5.16 Pharmacokinetics: Other Test Article:

Location in CTD: Vol. Page

Study No.

Type of study:

Method:

Tabulated results:

Additional Information:
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2.6.7.1 Toxicology Overview Test Article: (1)

Type of Study

Species and

Strain

Method of

Administration

Duration

of Dosing Doses (mg/kga)

GLP

Compliance

Testing

Facility

Study

Number

Location

Vol. Page

Single-Dose

Toxicity

(2)

(3)

Repeat-Dose

Toxicity

Genotoxicity

Carcinogenicity

Reproductive and

Developmental

Toxicity

Local Tolerance

Other Toxicity

Studies

Notes: (1) International Nonproprietary Name (INN).

(2) There should be one line for each toxicology report, in the same order as the CTD.

(3) The location of the Technical Report in the CTD should be indicated.

a - Unless otherwise specified. For Repeat-Dose Toxicity, the highest No Observed Adverse Effect Level (NOAEL) is underlined.
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2.6.7.2 Toxicokinetics Overview of Toxicokinetics Studies Test Article: (1)

Type of Study

Test

System

Method of

Administration Doses (mg/kg)

GLP

Compliance

Study

Number

 Location

Vol. Page

 (2) (3)

Notes: (1) International Nonproprietary Name (INN).

(2) There should be one line for each toxicokinetics report, in the same order as the CTD (Section 3, Toxicology).

(3) The location of the Technical Report in the CTD should be indicated.
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2.6.7.3 Toxicokinetics Overview of Toxicokinetics Data Test Article: (1)

(2)

Notes: (1) International Nonproprietary Name (INN).

(2) A one- to three-page summary (tables and/or figures) of steady state toxicokinetic data should be prepared in a format that facilitates

comparisons across species, including humans.
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2.6.7.4 Toxicology Drug Substance Test Article: (1)

Batch No. Purity (%) Specified Impurities ( )

Study

Number Type of Study

PROPOSED

 SPECIFICATION:

(2) (3)

Notes: (1) International Nonproprietary Name (INN).

(2) All batches used in the Toxicology studies should be listed in approximate chronological order.

(3) The Toxicology studies in which each batch was used should be identified.
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2.6.7.5 Single-Dose Toxicity (1) Test Article: (2)

Species/

Strain

Method of

Administration

(Vehicle/

Formulation)

Doses

(mg/kg)

Gender

and No.

per Group

Observed

Maximum

Nonlethal Dose

(mg/kg)

Approximate

Lethal

Dose (mg/kg) Noteworthy Findings

Study

Number

Notes: (1) All single-dose toxicity studies should be summarized, in the same order as the CTD. Footnotes should be used to indicate special

features, such as unusual duration, infusion rate, or age of test subjects.

(2) International Nonproprietary Name (INN).
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2.6.7.6 Repeat-Dose Toxicity Nonpivotal Studies (1) Test Article: (2)

Species/

Strain

Method of

Administration

(Vehicle/

Formulation)

Duration

of Dosing Doses

(mg/kg)

Gender

and No.

per Group

NOAELa

(mg/kg) Noteworthy Findings

Study

Number

Notes: (1) All repeat-dose toxicity studies (including all range-finding toxicity studies), other than the definitive GLP studies specified by ICH

Guidance M3 Nonclinical Safety Studies for the Conduct of Human Clinical Trials for Pharmacaeuticals (November 1997), should

be summarized in the same order as the CTD. Footnotes should be used to indicate special features, such as unusual age of test

subjects.

(2) International Nonproprietary Name (INN).

________

a - No Observed Adverse Effect Level.
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2.6.7.7 (1) Repeat-Dose Toxicity (2) Report Title: Test Article: (3)

Species/Strain: Duration of Dosing: Study No.

Initial Age: Duration of Postdose: Location in CTD: Vol. Page

Date of First Dose: Method of Administration:

Vehicle/Formulation: GLP Compliance:

Special Features:

No Observed Adverse Effect Level:

Daily Dose (mg/kg) 0 (Control)

Number of Animals

Toxicokinetics: AUC ( ) (4)

Noteworthy Findings

 Died or Sacrificed Moribund

 Body Weight (%a)

 Food Consumption (%a)

 Water Consumption ( )

 Clinical Observations

 Ophthalmoscopy

 Electrocardiography

M:

(5)

(5)

(5)

F: M: F: M: F: M: F:

- No noteworthy findings. + Mild ++ Moderate +++ Marked (6)

(7) * - p<0.05 ** - p<0.01

a - At end of dosing period. For controls, group means are shown. For treated groups, percent differences from controls are shown. Statistical

significance is based on actual data (not on the percent differences).

(Continued)
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2.6.7.7 (1) Repeat-Dose Toxicity Study No. (Continued)

Daily Dose (mg/kg) 0 (Control)

Number of Animals M: F: M: F: M: F: M: F:

Hematology

Serum Chemistry

Urinalysis

Organ Weightsa (%)

Gross Pathology

Histopathology

Additional Examinations

Postdose Evaluation:

 Number Evaluated

 (8) (9)

- No noteworthy findings.

(7) * - p<0.05 ** - p<0.01

a - Both absolute and relative weights differed from controls in the direction indicated. Number indicates percent difference for the absolute

organ weights.
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Notes for Table 2.6.7.7

(1) The tables should be numbered consecutively (e.g., 2.6.7.7A, 2.6.7.7B, 2.6.7.7C).

(2) There should be one table for each of the repeat-dose toxicity studies specified by ICH Guidance M3 Nonclinical Safety Studies for the

Conduct of Human Clinical Trials for Pharmacaeuticals (November 1997), as well as any other repeat-dose toxicity studies that could be

considered pivotal.

(3) International Nonproprietary Name (INN).

(4) Steady state AUC, Cmax, Css, or other toxicokinetic information supporting the study. If from a separate study, the study number should be

given in a footnote.

(5) ONLY NOTEWORTHY FINDINGS SHOULD BE PRESENTED. If additional parameters (other than those in the template) showed

noteworthy changes, these should be added to the tables. In general, data at end of dosing period can be shown; however, if there were

additional noteworthy findings at earlier timepoints, these should be included. Footnotes should be used as needed to provide additional

information about the tests or the results.

(6) Or other scale, as appropriate.

(7) Methods of statistical analyses should be indicated.

(8) All parameters that still show drug-related changes should be listed. This section should be deleted if the study does not include a postdose

evaluation.

(9) When appropriate, information on animals that were necropsied early should be presented separately.
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2.6.7.8 (1) Genotoxicity: In Vitro Report Title: Test Article: (2)

Test for Induction of: No. of Independent Assays: Study No.

Strains: No. of Replicate Cultures: Location in CTD: Vol. Page

Metabolizing System: No. of Cells Analyzed/Culture:

Vehicles: For Test Article: For Positive Controls: GLP Compliance:

Treatment: Date of Treatment:

Cytotoxic Effects:

Genotoxic Effects:

Metabolic

Activation

Test

Article

Concentration or

Dose Level

( (3) ) _____________ _____________ _____________ ____________ _____________

Without

Activation

(4)

With

Activation

Notes: (1) The tables should be numbered consecutively (e.g.,2.6.7.8A, 2.6.7.8B). Results of replicate assays should be shown on subsequent

pages.

(2) International Nonproprietary Name (INN).

(3) Units should be inserted.

(4) If precipitation is observed, this should be indicated in a footnote.

(5) Methods of statistical analyses should be indicated.

(5) * - p<0.05 ** - p<0.01 
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2.6.7.9 (1) Genotoxicity: In Vivo Report Title: Test Article: (2)

Test for Induction of: Treatment Schedule: Study No.

Species/Strain: Sampling Time: Location in CTD: Vol. Page

Age: Method of Administration:

Cells Evaluated: Vehicle/Formulation: GLP Compliance:

No. of Cells Analyzed/Animal: Date of Dosing:

Special Features:

Toxic/Cytotoxic Effects:

Genotoxic Effects:

Evidence of Exposure:

Test Article

Dose

(mg/kg)

No. of

Animals ______________ ______________ ______________ _____________

Notes: (1) The tables should be numbered consecutively (e.g.,2.6.7.9A, 2.6.7.9B).

(2) International Nonproprietary Name (INN).

(3) Methods of statistical analysis should be indicated.

(3) * - p<0.05 ** - p<0.01).
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2.6.7.10 (1) Carcinogenicity Report Title: Test Article: (2)

Species/Strain: Duration of Dosing: Study No.

Initial Age: Method of Administration: Location in CTD: Vol. Page

Date of First Dose: Vehicle/Formulation:

Treatment of Controls: GLP Compliance:

Basis for High-Dose Selection: (3)

Special Features:

Daily Dose (mg/kg) 0 (Control) 

Gender

Toxicokinetics: AUC ( ) (4)

Number of Animals

 At Start

 Died/Sacrificed Moribund

 Terminal Sacrifice

Survival (%)

Body Weight (%a)

Food Consumption (%a)

M

(5)

F M F M F M F

(6) * - p<0.05 ** - p<0.01

a - At 6 months. For controls, group means are shown. For treated groups, percent differences from controls are shown. Statistical

significance is based on actual data (not on the percent differences). (Continued)
The Common Technical Document — Safety

62

2.6.7.10 (1) Carcinogenicity Study No. (Continued)

Daily Dose (mg/kg) (Control) 0 (Control) 

Number Evaluated

Number of Animals

 with Neoplastic Lesions:

 (7)

Noteworthy Findings:

 Gross Pathology

 Histopathology - Non-Neoplastic

 Lesions

M: F: M: F: M: F: M: F: M: F:

- No noteworthy findings.

* - p<0.05 ** - p<0.01
The Common Technical Document — Safety

63

Notes for Table 2.6.7.10

(1) Tables should be numbered consecutively (e.g., 2.6.7.10A, 2.6.7.10B). There should be one table for each carcinogenicity study.

(2) International Nonproprietary Name (INN).

(3) From ICH Guidance S1C Dose Selection for Carcinogenicity Studies of Pharmaceuticals (March 1995).

(4) Steady state AUC, Cmax, Css, or other toxicokinetic information supporting the study. If the information is from a separate study, the Study

Number should be given in a footnote.

(5) If additional parameters showed drug-related changes, these should be added to the tables. Footnotes should be used as needed to provide

additional information about the tests or the results.

(6) Methods of statistical analysis should be indicated.

(7) Drug-related lesions should be listed first. Then other lesions should be listed by alphabetically ordered organs and/or tissues.
The Common Technical Document — Safety

64

2.6.7.11 Reproductive and Developmental Toxicity Nonpivotal Studies (1) Test Article: (2)

Species/

Strain

Method of

Administration

(Vehicle/

Formulation)

Dosing

Period

Doses

mg/kg No. per Group Noteworthy Findings

Study

Number

Notes: (1) All reproduction toxicity studies (including all relevant range-finding studies), other than the definitive GLP studies specified by M3

Nonclinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals, November 1997, should be summarized in

the same order as the CTD. However, investigative studies should be summarized using a more detailed template.

(2) International Nonproprietary Name (INN).
The Common Technical Document — Safety

65

2.6.7.12 (1) Reproductive and Developmental Toxicity - Report Title: Test Article: (2)

Fertility and Early Embryonic

Development to Implantation (3)

Design similar to ICH 4.1.1? Duration of Dosing:M: Study No.

Species/Strain:Day of Mating: (8)F: Location in CTD: Vol. Page

Initial Age: Day of C-Section:

Date of First Dose: Method of Administration: GLP Compliance:

Special Features: Vehicle/Formulation:

No Observed Adverse Effect Level:

F0 Males:

F0 Females:

F1 Litters:

Daily Dose (mg/kg) 0 (Control)

Males Toxicokinetics: AUC ( ) (4)

No. Evaluated

No. Died or Sacrificed Moribund

Clinical Observations

Necropsy Observations

Body Weight (%a)

Food Consumption (%a)

Mean No. Days Prior to Mating

No. of Males that Mated

No. of Fertile Males (5)

-No noteworthy findings. + Mild ++Moderate +++Marked (6)

(7) *- p<0.05 ** - p<0.01

a - After 4 weeks of dosing. For controls, group means are shown. For treated groups, percent differences from controls are shown.

Statistical significance is based on actual data (not on the percent differences). (Continued)
The Common Technical Document — Safety

66

2.6.7.12 (1) Reproductive and Developmental Toxicity Study No. (Continued)

Daily Dose (mg/kg) 0 (Control)

Females Toxicokinetics: AUC ( ) (4)

No. Evaluated

No. Died or Sacrificed Moribund

Clinical Observations

Necropsy Observations

Premating Body Weight (%a)

Gestation Body Weight (%a)

Premating Food Consumption (%a)

Gestation Food Consumption (%a)

Mean No. Estrous Cycles/14 days

Mean No. Days Prior to Mating

No. of Females Sperm Positive

No. of Pregnant Females

No. Aborted or with Total Resorption of Litter

Mean No. Corpora Lutea

Mean No. Implantations

Mean % Preimplantation Loss

Mean No. Live Conceptuses

Mean No. Resorptions

No. Dead Conceptuses

Mean % Postimplantation Loss

-No noteworthy findings. + Mild ++Moderate +++Marked (6)

(7)* - p<0.05 ** - p<0.01

a - At end of premating or gestation period. For controls, group means are shown. For treated groups, percent differences from controls are

shown. Statistical significance is based on actual data (not on the percent differences).
The Common Technical Document — Safety

67

Notes for Tables 2.6.7.12, 2.6.7.13, and 2.6.7.14

(1) If there are multiple studies of this type, the tables should be numbered consecutively (e.g., 2.6.7.12A, 2.6.7.12B, 2.6.7.13A, 2.6.7.13B).

(2) International Nonproprietary Name (INN).

(3) If a modified study design is used, tables should be modified accordingly.

(4) Steady state AUC, Cmax, or other toxicokinetic information supporting the study. If the information is from a separate study, the study

number should be given in a footnote.

(5) POSSIBLE PRESENTATIONS OF THE RESULTS ARE SHOWN IN THESE TEMPLATES. DATA PRESENTATION SHOULD BE FLEXIBLE

AND APPROPRIATE ACCORDING TO OPTIMAL STATISTICAL ANALYSIS AND THE DESIGN OF THE STUDY. If additional parameters

showed drug-related changes, these should be added to the tables. Footnotes should be used as needed to provide additional information

about the tests or the results.

(6) Or other scale as appropriate.

(7) Methods of statistical analysis should be indicated.

(8) Day of mating should be indicated (e.g., Day 0 or Day 1).
The Common Technical Document — Safety

68

2.6.7.13 (1) Reproductive and Developmental Toxicity - Report Title: Test Article: (2)

Effects on Embryofetal

Development (3)

Design similar to ICH 4.1.3? Duration of Dosing: Study No.

Day of Mating: (8)

Species/Strain: Day of C-Section: Location in CTD: Vol. Page

Initial Age: Method of Administration:

Date of First Dose: Vehicle/Formulation: GLP Compliance:

Special Features:

No Observed Adverse Effect Level:

F0 Females:

F1 Litters:

Daily Dose (mg/kg) 0 (Control)

Dams/Does: Toxicokinetics: AUC () (4)

No. Pregnant

No. Died or Sacrificed Moribund

No. Aborted or with Total Resorption of Litter

Clinical Observations

Necropsy Observations

Body Weight (%a)

Food Consumption (%a)

Mean No. Corpora Lutea

Mean No. Implantations

Mean % Preimplantation Loss

(5)

- No noteworthy findings. + Mild ++Moderate +++Marked (6) G = Gestation day

(7) * - p<0.05 ** - p<0.01

a- At end of dosing period. For controls, group means are shown. For treated groups, percent differences from controls are shown.

Statistical significance is based on actual data (not on the percent differences). (Continued)
The Common Technical Document — Safety

69

2.6.7.13 (1) Reproductive and Developmental Toxicity Study No. (Continued)

Daily Dose (mg/kg) 0 (Control)

Litters: No. Litters Evaluated

No. Live Fetuses

Mean No. Resorptions

No. of Litters with Dead Fetuses

Mean % Postimplantation Loss

Mean Fetal Body Weight (g)

Fetal Sex Ratios

Fetal Anomalies:

 Gross External

 Visceral Anomalies

 Skeletal Anomalies

Total Affected Fetuses (Litters)

- No noteworthy findings.

* - p<0.05 ** - p<0.01
The Common Technical Document — Safety

70

2.6.7.14 (1) Reproductive and Developmental Toxicity - Report Title: Test Article: (2)

Effects on Pre- and Postnatal

Development, Including Maternal Function (3)

Design similar to ICH 4.1.2? Duration of Dosing: Study No.

Day of Mating: (8)

Species/Strain: Method of Administration: Location in CTD: Vol. Page

Initial Age Vehicle/Formulation:

Date of First Dose: Litters Culled/Not Culled: GLP Compliance:

Special Features:

No Observed Adverse Effect Level:

F0 Females:

F1 Males:

F1 Females:

Daily Dose (mg/kg) 0 (Control)

F0 Females: Toxicokinetics: AUC ( ) (4)

No. Pregnant

No. Died or Sacrificed Moribund

No. Aborted or with Total Res. of Litter

Clinical Observations

Necropsy Observations

Gestation Body Weight (%a)

Lactation Body Weight (%a)

Gestation Food Consumption (%a)

Lactation Food Consumption (%a)

Mean Duration of Gestation (days)

Abnormal Parturition

(5)

- No noteworthy findings. + Mild ++Moderate +++Marked (6) G = Gestation day L = Lactation day

(7) * - p<0.05 ** - p<0.01)

a -At end of gestation or lactation. For controls, group means are shown. For treated groups, percent differences from controls are shown.

Statistical significance is based on actual data (not on the percent differences). (Continued)
The Common Technical Document — Safety

71

2.6.7.14 (1) Reproductive and Developmental Toxicity Study No. (Continued)

Daily Dose (mg/kg) 0 (Control)

F1 Litters:

(Preweaning)

F1 Males:

(Postweaning)

No. Litters Evaluated

Mean No. of Implantations

Mean No. Pups/Litter

Mean No. Liveborn Pups/Litter

No. of Litters with Stillborn Pups

Postnatal Survival to Day 4

Postnatal Survival to Weaning

No. of Total Litter Losses

Change in Pup Body Weightsa (g)

Pup Sex Ratios

Pup Clinical Signs

Pup Necropsy Observations

No. Evaluated Postweaning

 Per Litter

No. Died or Sacrificed Moribund

Clinical Observations

Necropsy Observations

Body Weight Changeb (g)

Food Consumption (%c)

Preputial Separation

Sensory Function

Motor Activity

Learning and Memory

Mean No. Days Prior to Mating

No. of Males that Mated

No. of Fertile Males

- No noteworthy findings. + Mild ++Moderate +++Marked (6)

(7)* - p<0.05 ** - p<0.01

a - From birth to weaning.

b - From weaning to mating.

c - At end of postweaning period. For controls, group means are shown. For treated groups, percent differences from controls are shown.

Statistical significance is based on actual data (not on the percent differences).
The Common Technical Document — Safety

72

2.6.7.14 (1) Reproductive and Developmental Toxicity Study No. (Continued)

Daily Dose (mg/kg) 0 (Control)

F1 Females:

(Postweaning)

F2 Litters:

No. Evaluated Postweaning

No. Died or Sacrificed Moribund

Clinical Observations

Necropsy Observations

Premating Body Weight Changea (g)

Gestation Body Weight Change (g)

Premating Food Consumption (%b)

Gestation Food Consumption (%b)

Mean Age of Vaginal Patency (days)

Sensory Function

Motor Activity

Learning and Memory

Mean No. Days Prior to Mating

No. of Females Sperm-Positive

No. of Pregnant Females

Mean No. Corpora Lutea

Mean No. Implantations

Mean % Preimplantation Loss

Mean No. Live Conceptuses/Litter

Mean No. Resorptions

No. of Litter with Dead Conceptuses

No. Dead Conceptuses

Mean % Postimplantation Loss

Fetal Body Weights (g)

Fetal Sex Ratios (% males)

Fetal Anomalies

- No noteworthy findings. + Mild ++Moderate +++Marked (6)

(7)* - p<0.05 ** - p<0.01

a - From weaning to mating

b - At end of premating or gestation period. For controls, group means are shown. For treated groups, percent differences from controls are

shown. Statistical significance is based on actual data (not on the percent differences).
The Common Technical Document — Safety

73

2.6.7.14 (1) Reproductive and Developmental Toxicity Study No. (Continued)

Daily Dose (mg/kg) 0 (Control)

F1 Females:

(Postweaning)

F2 Litters:

No. Evaluated Postweaning

No. Died or Sacrificed Moribund

Clinical Observations

Necropsy Observations

Premating Body Weight Changea (g)

Gestation Body Weight Change (g)

Premating Food Consumption (%b)

Gestation Food Consumption (%ab)

Mean Age of Vaginal Patency (days)

Sensory Function

Motor Activity

Learning and Memory

Mean No. Days Prior to Mating

No. of Females Sperm Positive

No. of Pregnant Females

Mean Duration of Gestation

Abnormal Parturition

No. Litters Evaluated

Mean No. of Implantations

Mean No. Pups/Litter

Mean No. Liveborn Pups/Litter

Mean No. Stillborn Pups/Litter

Postnatal Survival to Day 4

Postnatal Survival to Weaning

Change in Pup Body Weightsa (g)

Pup Sex Ratios

Pup Clinical Signs

Pup Necropsy Observations

Note: Alternate

Format for

Natural

Parturition.

- No noteworthy findings. + Mild ++Moderate +++Marked (6)

(7)* - p<0.05 ** - p<0.01

a - From birth to mating.

b - At end of premating or gestation period. For controls, group means are shown. For treated groups, percent differences from controls are

shown. Statistical significance is based on actual data (not on the percent differences).
The Common Technical Document — Safety

74

2.6.7.16 Local Tolerance (1) Test Article: (2)

Species/

Strain

Method of

Administration

Doses

(mg/kg)

Gender and

No. per Group Noteworthy Findings

Study

Number

Notes: (1) All local tolerance studies should be summarized.

(2) International Nonproprietary Name (INN).
The Common Technical Document — Safety

75

2.6.7.17 Other Toxicity Studies (1) Test Article: (2)

Species/

Strain

Method of

Administration

Duration

of Dosing

Doses

(mg/kg)

Gender and

No. per Group Noteworthy Findings

Study

Number

Notes: (1) All supplementary toxicity studies should be summarized.

(2) International Nonproprietary Name (INN)
The Common Technical Document — Safety

76

APPENDIX C: THE NONCLINICAL TABULALTED SUMMARIES — EXAMPLES

(The following examples correspond to the templates in Appendix B; examples are not provided for the templates Studies in Juvenile

Animals or Local Tolerance)

EXAMPLE

2.6.3.1 Pharmacology Overview Test Article: Curitol Sodium

Type of Study

Test

System

Method of

Administration

Testing

Facility

Study

Number

 Location

Vol. Page

Primary Pharmacodynamics

Antiviral activity vs. VZV

Antiviral activity vs. VZV

Antiviral activity vs. HSV

Antiviral activity vs. CMV

Antiviral activity vs. VZV

Antiviral activity vs. SVV

Human embryonic lung

fibroblasts

Clinical isolates

Human embryonic lung

fibroblasts

Human embryonic lung

fibroblasts

ICR mice

African Green monkeys

In vitro

In vitro

In vitro

In vitro

Gavage

Nasogastric

 Intubation

Sponsor Inc.

Sponsor Inc.

Sponsor Inc.

Sponsor Inc.

Sponsor Inc.

Sponsor Inc.

95401

95402

95406

95408

95411

95420

1

1

1

1

1

1

1

20

30

45

55

100

Secondary Pharmacodynamics

Antimicrobial activity Gram positive and gram

negative bacteria; yeasts

In vitro Sponsor Inc. 95602 1 200

Safety Pharmacology

Effects on central nervous systema

Effects on cardiovascular system

Mice, rats, rabbits, and cats

Dogs

Gavage

Gavage, i.v.

Sponsor Inc.

Sponsor Inc.

95703

95706

2

2

1

75

Pharmacodynamic Drug Interactions

Interactions with anti-HIV activity of AZT Human T lymphocytes In vitro Sponsor Inc. 95425 2 200

a - Report contains a GLP Compliance Statement.
The Common Technical Document — Safety

77

2.6.3.4 Safety Pharmacology Test Article: Curitol Sodium

Organ

Systems

Evaluated

Species/

Strain

Method of

Admin.

Dosesa

(mg/kg)

Gender

and No.

per Group Noteworthy Findings

GLP

Compliance

Study

Number

CNS CD-1

Mice

Gavage 0, 10, 50,

250

10M Slight prolongation of hexobarbital

anesthesia (≥10 mg/kg). No analgesic,

anticonvulsive, or cataleptic properties.

No effects on coordination, traction, or

spontaneous motility.

Yes 92201

Renal, GI, CNS,

and Hemostasis

CD-1

Mice

Gavage 0, 10, 50,

250

6M Slight increases in urinary excretion of

sodium and potassium (≥50 mg/kg). No

effects on GI transit time (charcoal meal),

pupillary diameter, blood coagulation

time, or urine volume.

No 92205

Cardiovascular Mongrel

Dogs

Intravenous 0, 3, 10, 30 3M Dose-related transient decreases in blood

pressure and increases in heart rate and

respiratory rate (all doses). Minor ECG

changes at 30 mg/kg. No effects on

cardiac output, stroke volume, or total

peripheral resistance.

Yes 92210

a - Single dose unless specified otherwise.

EXAMPLE
The Common Technical Document — Safety

78

2.6.5.1 Pharmacokinetics Overview Test Article: Curitol Sodium

Type of Study

Test

System

Method of

Administration

Testing

Facility

Study

Number

 Location

Vol. Page

Absorption

Absorption and excretion

Absorption and excretion

Absorption and excretion

Rats

Dogs

Monkeys

Gavage, i.v.

Gavage, i.v.

Gavage, i.v.

Sponsor Inc.

Sponsor Inc.

Sponsor Inc.

93302

93304

93306

1

1

1

1

25

50

Distribution

Single-dose tissue distribution

Repeat-dose tissue distribution

Plasma protein binding

Plasma protein binding

Rats

Rats

Mice, rats, dogs,

monkeys, Humans,

rats, dogs

Gavage

Gavage

In vitro

Tablets/Gavage/

 Capsules

Sponsor Inc.

Sponsor Inc.

Sponsor Inc.

Sponsor Inc.

93307

93308

93311

93312

1

1

1

1

100

125

150

200

Metabolism

Metabolites in blood, urine, and feces

Metabolites in blood, urine, and feces

Rats

Dogs

Gavage

Gavage

Sponsor Inc.

Sponsor Inc.

93402

93407

1

1

250

300

Excretion

Absorption and excretion

Absorption and excretion

Absorption and excretion

Rats

Dogs

Monkeys

Gavage, i.v.

Gavage, i.v.

Gavage, i.v.

Sponsor Inc.

Sponsor Inc.

Sponsor Inc.

93302

93304

93306

1

1

1

1

25

50

Pharmacokinetic Drug Interactions

Interaction with AZTa Rats Gavage Sponsor Inc. 94051 1 350

a - Report contains a GLP Compliance Statement.

EXAMPLE
The Common Technical Document — Safety

79

2.6.5.3 Pharmacokinetics: Absorption After a Single Dose Test Article: Curitol Sodium

Location in CTD Volume 1, Page 258

Study number 95104

Species Mouse Rat Dog Monkey Human

Gender (M/F)/Number of animals 4M 3M 4F 2M 6M

Feeding condition Fed Fasted Fasted Fed Fasted

Vehicle/Formulation Suspension

10% acacia

Suspension

10% acacia

Capsule Suspension

10% acacia

Tablet

Method of Administration Gavage Gavage Capsule Gavage Oral

Dose (mg/kg) 15 8 5 5 4 mg

Sample (e.g., whole blood, plasma, serum) Plasma Plasma Plasma Plasma Plasma

Analyte TRAa MM-180801 MM-180801 MM-180801 MM-180801

Assay LSC HPLC HPLC HPLC HPLC

PK parameters:

 Tmax (hr) 4.0 1.0 3.3 1.0 6.8

 Cmax (ng/ml or ng-eq/ml) 2,260 609 172 72 8.2

 AUC (ng or ng-eq x hr/ml) 15,201 2,579 1,923 582 135

 (Time for calculation – hr) (0-72) (0-24) (0.5-48) (0-12) (0-24)

 T 1/2 (hr) 10.6 3.3 9.2 3.2 30.9

 (Time for calculation – hr) (7-48) (1-24) (24-96) (1-12) (24-120)

Additional Information:

A single oral dose was well absorbed in mice, rats, dogs, and monkeys.

In a study examining the concentration of compound in the portal vein and inferior vena cava, 30 minutes after a dose to rats, the concentration of

compound was approximately 15-fold higher in the portal circulation compared to systemic circulation. This result indicated extensive metabolism

and/or biliary secretion of compound in the rat.

a - Total radioactivity, 

14C

EXAMPLE
The Common Technical Document — Safety

80

Format A

2.6.5.5 Pharmacokinetics: Organ Distribution Test Article: Curitol Sodium

Location in CTD: Vol.21 Page 1

Study No. 95207

Species: Rat

Gender (M/F)/Number of animals: 3M/each time point

Feeding condition: Fasted

Vehicle/Formulation: Solution/Water

Method of Administration: Oral Gavage

Dose (mg/kg): 10

Radionuclide: 14C

Specific Activity: 2x105 Bq/mg

Sampling time: 0.25, 0.5, 2, 6, 24, 96, and 192 hr

Concentration (mcg/mL)

Tissues/organs 0.25 0.5 2 6 24 t1/2

Blood 9.2 3.7 1.8 0.9 0.1

Plasma 16.5 7.1 3.2 1.6 0.2

Brain 0.3 0.3 0.2 0.1 nd

Lung 9.6 14.1 7.3 2.9 0.1

Liver 73.0 54.5 19.9 12.4 3.2

Kidney 9.6 13.2 4.9 3.8 0.6

Testis 0.3 0.5 0.6 0.5 0.1

Muscle 1.0 1.2 0.8 0.3 nd

Additional information:

Tissues and organs such as the heart, thymus, adrenal, spleen, stomach, intestine.....are examined but not shown.

nd = Not detected.

EXAMPLE
The Common Technical Document — Safety

81

Alternate Format B

2.6.5.5 Pharmacokinetics: Organ Distribution Test Article: Curitol Sodium

Location in CTD: Vol. 21 Page 1

Study No. 95207

Species: Rat

Gender (M/F) / Number of animals: 3M/each time point

Feeding condition: Fed

Vehicle/Formulation: Solution/Saline

Method of Administration: Intravenous

Dose (mg/kg): 1

Radionuclide: Nonlabeled compound

Specific Activity: -

Analyte/Assay: Unchanged compound (mcg/mL)/HPLC

Sampling time: 10 min, 1, 4, 8, 24, 48, 96, and 168 hr

C1hr Last time point

Tissues/organs conc. T/P1) conc. T/P1) Time AUC t1/2

Heart 1.4 0.08 0.44 22 48 57.3 37.3

Liver 4.5 6 1.85 92.5 48 290 51.7

Kidney 2.8 0.20 1.07 53.5 48 126 36.3

Spleen 6.5 8.6 3.5 175 48 410 46.9

Additional information:

1) [Tissue]/[Plasma]

EXAMPLE
The Common Technical Document — Safety

82

2.6.5.6 Pharmacokinetics: Plasma Protein Binding Test Article: Curitol Sodium

Study system: In vitro

Target entity, Test system and method: Plasma, Ultrafiltration

Species Conc. tested % Bound

Study

 No. 

Location in CTD

Vol. Page

Rat 1 - 100uM 82.1 - 85.4 95301 21 150

Dog 1 - 100uM 83.5 - 88.2 95301 21 150

Human 1 - 100uM 75.2 - 79.4 96-103-03 45 1

Additional Information:

EXAMPLE
The Common Technical Document — Safety

83

2.6.5.7 Pharmacokinetics: Study in Pregnant or Nursing Animals Test Article: Curitol Sodium

Location in CTD: Vol. 22 Page 1

Placental transfer Study No. 95702

Species: Rat

Gestation day/Number of animals: 14 and 19 days gestation/3 animals at each time point

Vehicle/Formulation: Solution/Water

Method of Administration: Oral gavage

Dose (mg/kg): 5

Analyte: Total radioactivity, 

14C

Assay: LSC

Time (hr.) 14 days/30 min. 14 days/24 hr. 19 days/30 min. 19 days/24 hr.

Concentration/Amount (% of dose)

Maternal plasma 12.4 0.32 13.9 0.32

Placenta 3.8 0.14 3.3 0.32

Amniotic fluid 0.07 0.04 0.04 0.13

 Whole fetus 0.54 0.03 0.39 0.10

Additional Information:

Maternal blood, liver, kidney, ovary, uterus were also examined but not shown.

Location in CTD: Vol. 22 Page 102

Excretion into milk Study No. 95703

Species: Rat

Lactating date/Number of animals: day 7/3

Feeding condition: Fed

Vehicle/Formulation: Solution/Water

Method of Administration: Oral gavage

Dose (mg/kg): 5

Analyte: Total radioactivity, 

14C

Assay: LSC

Time [hr] 1 2 4 6 8 24

Concentration:

Milk: 0.6 0.8 1.0 1.1 1.3 0.4

Plasma: 1.5 1.4 1.2 0.8 0.6 0.1

Milk/plasma: 0.40 0.57 0.83 1.4 2.2 4.0

Neonates

Additional Information:

EXAMPLE
The Common Technical Document — Safety

84

2.6.5.9 Pharmacokinetics: Metabolism In Vivo Test Article: Curitol Sodium

Gender (M/F)/Number of animals: Rats: 4M Dogs: 3F Humans: 8M

Feeding condition: Fed

Vehicle/Formulation: Rats: Solution/water Dogs: Capsules Humans: 75 mg tablets

Method of Administration: Rats: Gavage* Dogs: Oral Capsule* Humans: Oral Tablet

Dose (mg/kg): Rats: 5 mg/kg Dogs: 5 mg/kg Humans: 75 mg

Radionuclide: 14C

Specific Activity: 2 x 105 Bq/mg

% of Compound in Sample Location in CTD

Species Sample

Sampling Time

or Period

% of Dose

in Sample Parent M1 M2

Study

Number Vol. Page

Rats Plasma

Urine

Bile

Feces

0.5 hr

0-24 hr

0-4 hr

-

-

2.1

28.0

-

87.2

0.6

15.5

-

6.1

n.d.

7.2

-

3.4

0.2

5.1

-

95076 26 101

Dogs Plasma

Urine

Bile

Feces

0.5 hr

0-24 hr

0-4 hr

-

-

6.6

32.0

-

92.8

6.4

28.5

-

n.d.

n.d.

2.8

-

7.2

n.d.

n.d.

-

95082 26 301

Humans Plasma

Urine

Bile

Feces

1 hr

0-24 hr

-

-

-

5.5

-

-

87.5

2.4

-

-

trace

2.9

-

-

12.5

n.d.

-

-

CD-102 42 1

Additional Information

* - Intraduodenal administration for collection of bile.

n.d. - None detected.

EXAMPLE
The Common Technical Document — Safety

85

2.6.5.13 Pharmacokinetics: Excretion Test Article: Curitol Sodium

Species Rat Rat Dog Dog

Gender (M/F)/Number of animals 4M 4M 3M 3M

Feeding condition Fasted Fasted Fasted Fasted

Vehicle/Formulation Solution

Water

Solution

Saline

Capsule Solution

Saline

Method of Administration Oral Intravenous Oral Intravenous

Dose (mg/kg) 10 5 10 5

Analyte TRAa TRAa TRAa TRAa

Assay LSC LSC LSC LSC

Excretion route Urine Feces Total Urine Feces Total Urine Feces Total Urine Feces Total

Time

0 - 24 hr

0 - 48 hr

0 - 72 hr

0 - 96 hr

26

30

31

31

57

65

65

67

83

95

97

98

22

27

28

29

63

69

70

70

85

96

98

99

20

25

26

26

29

65

73

74

49

90

99

100

23

28

29

29

42

78

72

73

65

96

101

102

Study number 95102 95156

Location in CTD Volume 20, Page 75 Volume 20, Page 150

Additional Information:

a - Total radioactivity; percent recovery, 14C

EXAMPLE
The Common Technical Document — Safety

86

2.6.5.14 Pharmacokinetics: Excretion into Bile Test Article: Curitol Sodium

Species Rat Rat

Gender (M/F) / Number of animals 4M 4M

Feeding condition Fasted Fasted

Vehicle/Formulation Solution

Water

Solution

Saline

Method of Administration Oral Intravenous

Dose (mg/kg) 10 5

Analyte TRAa TRAa

Assay LSC LSC

Excretion route Bile Urine Total Bile Urine Total

 Time

 0 - 2 hr

0 - 4 hr

0 - 8 hr

0 - 24 hr

0 - 48 hr

37

50

62

79

83

-

-

-

9

10

37

50

62

86

93

75

82

86

87

88

-

-

-

11

11

75

82

86

98

99

Study number 95106

Location in CTD Volume 20, Page 150

a - Total radioactivity; percent recovery, 14C

EXAMPLE
The Common Technical Document — Safety

87

2.6.7.1 Toxicology Overview Test Article: Curitol Sodium

Type of Study

Species and

Strain

Method of

Administration

Duration

of Dosing Doses (mg/kga)

GLP

Compliance

Testing

Facility

Study

Number

 Location

Vol. Page

Single-Dose

Toxicity

CD-1 Mice

Wistar Rats

Gavage

Intravenous

Gavage

Intravenous

-

-

-

-

0, 1000, 2000, 5000

0, 100, 250, 500

0, 1000, 2000, 5000

0, 100, 250, 500

Yes

Yes

Yes

Yes

Sponsor Inc.

CRO Co.

Sponsor Inc.

CRO Co.

96046

96047

96050

96051

1

1

1

1

1

100

200

300

RepeatDose

Toxicity

CD-1 Mice

Wistar Rats

Beagle Dogs

Cynomolgus

Monkeys

Diet

Diet

Gavage

Gavage

Gavage

Capsules

Capsules

Gavage

3 Months

2 Weeks

2 Weeks

3 Months

6 Months

1 Month

9 Months

5 Days

0, 62.5, 250, 1000,

4000, 7000

0, 1000, 2000, 4000

0, 500, 1000, 2000

0, 200, 600, 1800

0, 100, 300, 900

0, 10, 40, 100

0, 5, 20, 50

0, 500, 1000

Yes

No

No

Yes

Yes

Yes

Yes

No

CRO Co.

Sponsor Inc.

Sponsor Inc.

Sponsor Inc.

Sponsor Inc.

Sponsor Inc.

Sponsor Inc.

CRO Co.

94018

94019

94007

94214

95001

94020

96041

94008

2

3

3

4

5

6

7

8

1

1

200

1

1

1

1

1

Genotoxicity S. typhimurium

and E. coli

Human

Lymphocytes

Wistar Rats

In Vitro

In Vitro

Gavage

-

-

3 Days

0, 500, 1000, 2500,

and/or

5000 mcg/plate

0, 2.5, 5, 10, 20, and

40 mcg/ml

0, 1000, 2000

Yes

Yes

Yes

Sponsor Inc.

CRO Co.

Sponsor Inc.

96718

97634

96037

9

9

9

1

100

200

a - Unless otherwise specified. For Single-Dose Toxicity and Repeat-Dose Toxicity, the highest No Observed Adverse Effect Level (NOAEL)

is underlined.

 (Continued)

EXAMPLE
The Common Technical Document — Safety

88

2.6.7.1 Toxicology Overview (Continued) Test Article: Curitol Sodium

Type of Study

Species and

Strain

Method of

Administration

Duration

of Dosing Doses (mg/kg)

GLP

Compliance

Testing

Facility

Study

Number

 Location

Vol. Page

Carcinogenicity CD-1 Mice

Wistar Rats

Diet

Gavage

21 Months

24 Months

0, 0, 25, 100, 400

0, 0, 25, 100, 400

Yes

Yes

CRO Co.

Sponsor Inc.

95012

95013

10

12

1

1

 Reproduction

Toxicity

Wistar Rats

Wistar Rats

NZW Rabbits

Wistar Rats

Gavage

Gavage

Gavage

Gavage

a

F: G6 - G15b

F: G6 - G18b

F: G6 - L21b

0, 5, 30, 180

0, 10, 100, 1000

0, 1, 5, 25

0, 7.5, 75, 750

Yes

Yes

Yes

Yes

CRO Co.

Sponsor Inc.

CRO Co.

Sponsor Inc.

96208

94211

97028

95201

14

15

16

17

1

1

1

1

 Local

Tolerance

NZW Rabbits Dermal 1 Hour 0, 15 mg No Sponsor Inc. 95015 18 1

Other

 Toxicity Studies

 Antigenicity Guinea Pigs Subcutaneous Weekly for 3

weeks

0, 5 mg No CRO Co. 97012 18 20

 Impurities Wistar Rats Gavage 2 Weeks 0, 1000, 2000 Yes Sponsor Inc. 97025 18 200

________

a - Males: 4 weeks prior to mating. Females - 2 weeks prior to mating through Gestation Day 7.

b - G = Gestation Day L = Lactation Day

EXAMPLE
The Common Technical Document — Safety

89

EXAMPLE

2.6.7.2 Toxicokinetics Overview of Toxicokinetics Studies Test Article: Curitol Sodium

Type of Study

Test

System

Method of

Administration Doses (mg/kg)

GLP

Compliance

Study

Number

 Location

Vol. Page

Three-month range-finding study

Two-week toxicity study

Six-month toxicity study

One-month toxicity study

Nine-month toxicity study

Carcinogenicity study

Carcinogenicity study

Toxicokinetics study

Mice

Rats

Rats

Dogs

Dogs

Mice

Rats

Rabbits

Diet

Gavage

Gavage

Capsules

Capsules

Diet

Gavage

Gavage

62.5, 250, 1000, 4000, 7000

500, 1000, 2000

100, 300, 900

10, 40, 100

5, 20, 50

25, 100, 400

25, 100, 400

1, 5, 25

Yes

No

Yes

Yes

Yes

Yes

Yes

No

94018

94007

95001

94020

96041

95012

95013

97231

 2

 3

 5

 6

 7

10

12

16

1

200

1

1

1

1

1

1
The Common Technical Document — Safety

90

2.6.7.3 Toxicokinetics Overview of Toxicokinetics Data Test Article: Curitol Sodium

 Steady State AUC (mcg-hr/ml)

Daily Dose

 (mg/kg)

 Micea

 M F

 Ratsb

 M F Dogsc

Female

Rabbitsb Humansf

 1

 5

 10

 20

 25

 40

 10 12 6 8

 3

 4

10

10

 9

 25

273

 3

 50

62.5

 100

 250

 300

 400

 35

 40

 120

 815

 40

 48

 135

 570

 25d, 20e

 68

 90

 27d, 22e

 72

 85

12

40

 500

 900

1000

2000

4000

7000

2,103

4,975

8,241

1,870

3,987

7,680

 125

 200

 250

 327

 120

 190

 240

 321

__________

a - In diet.

b - By gavage.

c - In capsules. Males and females combined.

d - Six-month toxicity study.

e - Carcinogenicity study.

f - Protocol 147-007.

EXAMPLE
The Common Technical Document — Safety

91

EXAMPLE

2.6.7.3 Toxicokinetics Overview of Toxicokinetics Data Test Article : Curitol Sodium

0.1

1

10

100

1000

0.01 0.1 1 10 100

Dose (mg/kg)

Humans

Male Mice

Female Mice

Male Rats

Female Rats

Dogs

Steady state AUC24hr values of unchanged MM-180801 in humans after repeated oral administration of 1, 2.5, and 5 mg OD, in comparison with

those in mice in the carcinogenicity study, rats in the 6-month toxicity study, and dogs in the 9-month toxicity study.

AUC24hr (ug x hr/ml)
The Common Technical Document — Safety

92

2.6.7.4 Toxicology Drug Substance Test Article: Curitol Sodium

Batch No. Purity (%)

Specified ImpuritiesaStudy

Number Type of Study

 A B C

PROPOSED

 SPECIFICATION: >95 ≤ 0.1 ≤ 0.2 ≤ 0.3 - -

LN125 98.2 0.1 0.1 0.2 94007

94008

96718

Two-Week Oral Range-Finding Study in Rats

Five-Day Oral Range-Finding Study in Monkeys

Ames Test

94NA103 99.1 0.2 0.1 0.2 96046

96050

94214

94020

97634

Single-Dose Oral Study in Mice

Single-Dose Oral Study in Rats

Three-Month Oral Study in Rats

One-Month Oral Study in Dogs

Human Lymphocytes Assay In Vitro

95NA215 97.3 0.1 0.3 0.1 96047

96051

96037

94211

97028

Single-Dose Intravenous Study in Mice

Single-Dose Intravenous Study in Rats

Micronucleus Test in Rats

Embryofetal Development Study in Rats

Embryofetal Development Study in Rabbits

95NB003 94.6 0.2 0.3 0.4 94019

97012

Two-Week Palatability Study in Rats

Antigenicity Study in Hamsters

96NB101 99.0 0.4 0.1 0.0 94018

95001

95002

95012

95013

96208

95015

Three-Month Dietary Range-Finding Study in Mice

Six-Month Oral Study in Rats

One-Year Oral Study in Dogs

Dietary Carcinogenicity Study in Mice

Oral Carcinogenicity Study in Rats

Fertility and Early Embryonic Development Study in Rats

Dermal Irritation Study in Rabbits

a - Area percent.

EXAMPLE
The Common Technical Document — Safety

93

2.6.7.5 Single-Dose Toxicity Test Article: Curitol Sodium

Species/

Strain

Method of

Administration

(Vehicle/

Formulation)

Doses

(mg/kg)

Gender

and No.

per Group

Observed

Maximum

Nonlethal Dose

(mg/kg)

Approximate

Lethal

Dose (mg/kg) Noteworthy Findings

Study

Number

CD-1

Mice

Gavage

(Water)

Intravenous

(Saline)

0,

1000,

2000,

5000

0,

100,

250,

500

10M

10F

10M

10F

≥5000

≥5000

250

250

>5000

>250

<500

≥2000: Transient body weight losses.

5000: Decreased activity,

convulsions, collapse.

≥250: Body-weight losses.

500: 3M and 2F died.

96046

96047

Wistar

Rats

Gavage

(CMC

Suspension)

Intravenous

(5% Dextrose)

0,

1000,

2000,

5000

0,

100,

250,

500

5M

5F

5M

5F

2000

≥5000

250

≥500

>2000

<5000

>250

<500

≥2000: Transient body weight losses;

inactivity;

chromorhinorrhea.

5000: 2M died.

≥250: Body weight losses in

males.

500: 3M died.

96050

96051

EXAMPLE
The Common Technical Document — Safety

94

2.6.7.6 Repeat-Dose Toxicity Nonpivotal Studies Test Article: Curitol Sodium

Species/

Strain

Method of

Administration

(Vehicle/

Formulation)

Duration

of Dosing

Doses

(mg/kg)

Gender

and No.

per Group

NOAELa

(mg/kg) Noteworthy Findings

Study

Number

CD-1

Mice

Diet 3 Months 0, 62.5,

250, 1000,

4000, and

7000

10M, 10F M:4000

F: 1000

≥4000: Lower body weights; gastric

erosions/ulcers in some mice.

7000: 4M and 6F died/ sacrificed;

lower body weights; single-cell necrosis

in liver.

94018

Wistar

Rats

Diet

Gavage

(Water)

2 Weeks

2 Weeks

0, 1000,

2000, and

4000

0, 500,

1000, and

2000

5M, 5F

5M, 5F

1000

1000

≥2000: Lower body weights.

4000: 2M and 1F sacrificed moribund.

2000: Lower body weights; single-cell

necrosis in liver.

94019

94007

Beagle

Dogs

Gavage

(CMC

Suspension)

5 Days 0, 500,

and 1000

1M, 1F <500 ≥500: Weight losses, inappetence. 94008

________

a - No Observed Adverse Effect Level.

EXAMPLE
The Common Technical Document — Safety

95

2.6.7.7A Repeat-Dose Toxicity Report Title: MM-180801: Three--Month Oral Toxicity Study in Rats Test Article: Curitol Sodium

Species/Strain: Wistar Rats Duration of Dosing: 3 Months Study No. 94214

Initial Age: 5 Weeks Duration of Postdose: 1 Month Location in CTD: Vol. 4 Page 1

Date of First Dose: 15 Jan 94 Method of Administration: Gavage

Vehicle/Formulation: Aqueous Solution GLP Compliance: Yes

Special Features: None

No Observed Adverse Effect Level: 200 mg/kg

Daily Dose (mg/kg) 0 (Control) 200 600 1800

Number of Animals

Toxicokinetics: AUC (mcg-hr/ml):

 Day 1

 Day 28

 Day 90

Noteworthy Findings

 Died or Sacrificed Moribund

 Body Weight (%a)

 Food Consumption (%a)

 Clinical Observations

 Hyperactivity

 Chromorhinorrhea, reddishstained coat, white feces

 Emaciated, piloerection, stilted gait

 Ophthalmoscopy

M:30

-

-

-

0

394 g

20.4 g

-

-

-

-

F:30

-

-

-

0

244 g

17.2 g

-

-

-

-

M:20

30

52

50

 0

 0

 0

 -

 -

 -

 -

F:20

28

47

51

 0

 -1

 -1

 -

 -

 -

 -

M:20

130

145

160

 0

 -10*

 -1

 -

 -

 -

 -

F:20

125

140

148

 0

 -11*

 -8*

 +

 -

 -

 -

M:30

328

400

511

 0

 -25**

 -30**

 -

 ++

 -

 -

F:30

302

380

475

 0

 -45**

 -50**

++

++

++

 -

- No noteworthy findings. + Mild ++ Moderate +++ Marked

Dunnett's Test: *- p<0.05 ** - p<0.01

a - At end of dosing period. For controls, group means are shown. For treated groups, percent differences from controls are shown. Statistical

significance is based on actual data (not on the percent differences).

(Continued)

EXAMPLE #1
The Common Technical Document — Safety

96

2.6.7.7A Repeat-Dose Toxicity Study No. 94214 (Continued)

Daily Dose (mg/kg) 0 (Control) 200 600 1800

Number of Animals

Hematology

 Hemoglobin (g/dl)

 Erythrocyte Count (x106/mm3)

MCH

 MCHC

 Platelet Count (x103/mm3)

Serum Chemistry

 Creatinine (IU/L)

 Proteins g/dl)

 Cholesterol (mg/dl)

 ALT (IU/L)

 AST (IU/L)

 Bilirubin (mg/dl)

 Calcium (mEq/L)

 Phosphorus (mEq/L)

Urinalysis

 Protein Conc. (mg/dl)

 pH

 Glucose (mg/dl)

 Urine Volume (ml)

M:30

15.8

8.1

-

-

846

0.7

-

96

67

88

0.18

-

9.3

260

7.5

-

-

F:30

15.0

-

22

34

799

0.7

6.7

-

56

92

0.20

10.7

-

49

-

0

18

M:20

15.7

7.9

-

-

825

0.7

-

86

60*

96

0.17

-

9.3

102

7.5

-

-

F:20

14.9

-

21

34

814

0.7

6.6

-

52

90

0.20

10.8

-

34

-

0

18

M:20

15.8

8.1

-

-

914

0.7

-

90

55*

87*

0.18

-

9.3

123

7.2

-

-

F:20

14.6

-

22

34

856

0.7

6.6

-

47*

84*

0.20

10.8

-

54

-

20

16

M:30

14.0*

7.4*

-

-

931*

1.1*

-

105*

53*

85*

0.22**

-

8.2*

126*

6.3**

-

-

F:30

13.1*

-

19*

30*

911*

1.1*

5.0**

-

58

93

0.26**

9.8**

-

22*

-

98**

12*

- No noteworthy findings.

Dunnett's Test: *- p<0.05 **- p<0.01

(Continued)

EXAMPLE #1
The Common Technical Document — Safety

97

2.6.7.7A Repeat-Dose Toxicity Study No. 94214 (Continued)

Daily Dose (mg/kg) 0 (Control) 200 600 1800

Number of Animals

Organ Weightsb (%)

 Kidney

 Liver

Gross Pathology

 Number examined

 Kidneys: Pallor

 Glandular Stomach: Discoloration

Histopathology

 Number examined

 Kidneys: Tubular dilatation

 Mild

 Moderate

 Glandular Stomach: Erosions

Additional Examinations

Postdose Evaluation:

 Number Evaluated

 Body Weight a (%)

 Kidney Weightb

 (%)

M:30

3.01 g

15.9 g

20

0

0

20

0

0

0

0

-

10

422 g

3.24 g

F:30

1.75 g

8.01 g

20

0

0

20

0

0

0

0

-

10

265 g

1.81 g

M:20

0

0

20

0

0

20

0

0

0

0

-

0

-1

0

F:20

+5*

+1

20

0

0

20

0

0

0

0

-

0

-2

-1

M:20

+1

+10*

20

0

0

20

0

0

0

0

-

0

-3

-1

F:20

+8**

+12*

20

5

1

20

6

6

0

2

-

0

-4

0

M:30

+12**

+12*

20

1

1

20

3

1

2

2

-

10

-10*

+8*

F:30

+20**

+20**

20

2

4

20

4

0

4

9

-

 10

-20**

+10

- No noteworthy findings.

Dunnett's Test: * - p<0.05 **- p<0.01

a - At end of postdose recovery period. For controls, group means are shown. For treated groups, percent differences from controls are shown.

Statistical significance is based on actual data (not on the percent differences).

b - Both absolute and relative weights differed from controls in the direction indicated. Number indicates percent difference for the absolute

organ weights.

EXAMPLE #1
The Common Technical Document — Safety

98

2.6.7.7B Repeat-Dose Toxicity Report Title: MM-180801: One-Month Oral Toxicity Study in Dogs Test Article: Curitol Sodium

Species/Strain: Beagle Dogs Duration of Dosing: 1 Month Study No. 94020

Initial Age: 5-6 Months Duration of Postdose: None Location in CTD: Vol. 6 Page 1

Date of First Dose: 2 Feb 94 Method of Administration: Oral

Vehicle/Formulation: Gelatin Capsules GLP Compliance: Yes

Special Features: Hepatic enzyme induction evaluated at termination.

No Observed Adverse Effect Level: 10 mg/kg

Daily Dose (mg/kg) 0 (Control) 10 40 100

Number of Animals

Toxicokinetics: AUC (mcg-hr/ml):

 Day 1

 Day 28

Noteworthy Findings

 No. Died or Sacrificed Moribund

 Body Weight (%a)

 Clinical Observations:

 Hypoactivity (after dosing)

 Ophthalmoscopy

 Electrocardiography

 Hematology

 Serum Chemistry

 ALT (IU/L): Week 2

 Week 4

M:3

-

-

0

9.8 kg

-

-

-

-

22

25

F:3

-

-

0

9.2 kg

-

-

-

-

25

27

M:3

5

4

0

0

-

-

-

-

24

26

F:3

6

5

0

0

-

-

-

-

27

25

M:3

10

8

0

-1

-

-

-

-

21

23

F:3

12

11

0

-19**

-

-

-

-

24

25

M:3

40

35

0

0

+

-

-

-

48*

54*

F:3

48

45

0

-18**

++

-

-

-

69**

84**

- No noteworthy findings. + Mild ++ Moderate +++ Marked

Dunnett's Test: * - p<0.05 ** - p<0.01

a - At end of dosing period. For controls, group means are shown. For treated groups, percent differences from controls are shown. Statistical

significance is based on actual data (not on the percent differences). (Continued)

EXAMPLE #2
The Common Technical Document — Safety

99

2.6.7.7B Repeat-Dose Toxicity Study No. 94020 (Continued)

Daily Dose (mg/kg) 0 (Control) 10 40 100

Number of Animals

Organ Weightsa (%)

 Liver

Gross Pathology

Histopathology

 Number Examined

 Liver: Centrilobular hypertrophy

Additional Examinations

 Hepatic Enzyme Induction

M:3

339 g

-

3

0

-

F:3

337 g

-

3

0

-

M:3

+1

-

3

0

-

F:3

-1

-

3

0

-

M:3

+17**

 -

 3

 0

 -

F:3

+16**

 -

 3

 0

 -

M:3

+23**

 -

 3

 2

 -

F:3

+21**

 -

 3

 3

 -

- No noteworthy findings.

Dunnett's Test: * - p<0.05 ** - p<0.01

a - Both absolute and relative weights differed from controls in the direction indicated. Number indicates percent difference for the absolute

organ weights.

EXAMPLE #2
The Common Technical Document — Safety

100

2.6.7.8A Genotoxicity: In Vitro Report Title: MM-180801: Ames Reverse Mutation Study in Test Article: Curitol Sodium

 Salmonella and E. Coli

Test for Induction of: Reverse mutation in bacterial cells No. of Independent Assays: 2 Study No. 96669

Strains: S. typhimurium and E. coli No. of Replicate Cultures: 3 Location in CTD: Vol. 10 Page211

Metabolizing System: Aroclor-induced rat liver S9, 7.1% No. of Cells Analyzed/Culture: -

Vehicles: Test Article: DMSO Positive Controls: DMSO GLP Compliance: Yes

Treatment: Plate incorporation for 48 hr. Date of Treatment: Feb. 1996

Cytotoxic Effects: None.

Genotoxic Effects: None.

Metabolic

Activation

Test

Article

Dose Level

(mcg/plate)

Assay #1

Revertant Colony Counts (Mean ±SD)

TA 98 TA 100 TA 1535 TA 1537 WP2 uvrA

Without

Activation

DMSO

MM-180801

2-Nitrofluorene

Sodium azide

9-Aminoacridine

MMS

100 mcl/plate

312.5

625

1250

2500

5000a

2

1

100

2.5 mcl/plate

24 ± 9

24 ± 6

32 ± 9

30 ± 4

27 ± 5

30 ± 3

696

129 ± 4

128 ± 11

153 ± 9

152 ± 12

140 ± 6

137 ± 21

542

15 ± 4

12 ± 4

9 ± 2

9 ± 3

9 ± 3

15 ± 1

468

4 ± 2

4 ± 2

8 ± 2

9 ± 2

5 ± 1

7 ± 2

515

17 ± 3

14 ± 2

17 ± 5

18 ± 4

19 ± 1

13 ±4

573

With

Activation

DMSO

MM-180801

2-Aminoanthracene

100 mcl/plate

312.5

625

1250

2500

5000a

2.5

10

27 ± 6

31 ± 4

30 ± 1

33 ± 2

35 ± 8

31 ± 4

1552

161 ± 12

142 ± 8

156 ± 15

153 ± 13

160 ± 4

153 ± 5

1487

12 ± 5

12 ± 5

17 ± 2

13 ± 3

10 ± 2

9 ± 4

214

5 ± 1

4 ± 2

9 ± 5

8 ± 2

8 ± 2

7 ± 1

61

21 ± 8

17 ± 3

23 3

18 ± 3

19 ± 5

17 ±4

366

a - Precipitation.

EXAMPLE #1
The Common Technical Document — Safety

101

2.6.7.8B Genotoxicity: In Vitro Report Title: MM-180801: Cytogenetics Study in Primary Test Article: Curitol Sodium

 Human Lymphocytes

Test for Induction of: Chromosome aberrations No. of Independent Assays: 1 Study No. 96668

Strains: Primary human lymphocytes No. of Replicate Cultures: 2 Location in CTD: Vol. 10 Page245

Metabolizing System: Aroclor-induced rat liver S9, 5% No. of Cells Analyzed/Culture: 100

Vehicles: Test Article: DMSO Positive Controls: DMSO GLP Compliance: Yes

Treatment: Continuous treatment for 24 hrs. without S9; pulse treatment 5 hrs. Date of Treatment: Aug. 1996

and recovery time 24 hrs. with and without S9.

Cytotoxic Effects: Dose-related decreases in mitotic indices.

Genotoxic Effects: Chromosome aberrations without S9 at 10 and 20 μg/ml, and with S9 at 50 and 200 μg/ml.

Metabolic

Activation

Test

Article

Concentration

(mcg/ml)

Cytotoxicitya

(% of control)

Aberrant Cells

Mean % Abs/Cell

Total polyploid

cells

Without

Activation

DMSO

MM-180801

Mitomycin

-

2.5

5

10

20

0.10

100

78

59

36

32

52

2.0

3.0

4.0

16.5**

35.0**

38.5**

0.02

0.03

0.05

0.20

0.55

0.64

4

3

4

2

3

5

With

Activation

DMSO

MM-180801

Cyclophosphamide

-

2.5

10

50

200

4

100

91

88

80

43

68

4.0

4.5

4.5

9.5*

34.0**

36.5**

0.04

0.05

0.05

0.10

0.66

0.63

3

3

2

4

3

6

Dunnett's Test: * - p<0.05 ** - p<0.01

a - Based on mitotic indices.

EXAMPLE #2
The Common Technical Document — Safety

102

2.6.7.9A Genotoxicity: In Vivo Report Title: MM-180801: Oral Micronucleus Study in Rats Test Article: Curitol Solution

Test for Induction of: Bone marrow micronuclei Treatment Schedule: Three daily doses. Study No: 96683

Species/Strain: Wistar Rats Sampling Time: 24 hrs. after last dose. Location in CTD: Vol. 10 Page502

Age: 5 Weeks Method of Administration: Gavage.

Cells Evaluated: Polychromatic erythrocytes Vehicle/Formulation: Aqueous solution. GLP Compliance: Yes

No. of Cells Analyzed/Animal: 2000 Date of Dosing: July 1996

Special Features: None.

Toxic/Cytotoxic Effects: At 2000 mg/kg, clinical signs, two deaths, and decreases in bone marrow PCEs.

Genotoxic Effects: None.

Evidence of Exposure: Overt toxicity at 2000 mg/kg.

Test Article

Dose

(mg/kg)

No. of

Animals

Mean % PCEs

 (±SD)

Mean % MN-PCEs

 (±SD)

Vehicle 0 5M 52 ± 1.9 0.20 ± 0.12

MM-180801 2 5M 54 ± 3.7 0.25 ± 0.16

20 5M 49 ± 3.1 0.20 ± 0.07

200 5M 50 ± 2.1 0.26 ± 0.08

2000 3M 31 ± 2.5 0.12 ± 0.03

Cyclophosphamide 7 5M 51 ± 2.3 2.49 ± 0.30**

Dunnett's Test: * - p<0.05 ** - p<0.01

EXAMPLE #1
The Common Technical Document — Safety

103

2.6.7.9B Genotoxicity: In Vivo Report Title: MM-180801: Oral DNA Repair Study in Rats Test Article: Curitol Solution

Test for Induction of: Unscheduled DNA synthesis Treatment Schedule: Single dose. Study No: 51970

Species/Strain: Wistar Rats Sampling Time: 2 and 16 hr. Location in CTD: Vol. 11 Page 2

Age: 5 Weeks Method of Administration: Gavage.

Cells Evaluated: Hepatocytes. Vehicle/Formulation: Aqueous solution. GLP Compliance: Yes

No. of Cells Analyzed/Animal: 100 Date of Dosing: Jan. 1997

Special Features: None.

Toxic/Cytotoxic Effects: None.

Genotoxic Effects: None.

Evidence of Exposure: Toxicokinetics - See Study No. 94007, Two-Week Oral Toxicity Study in Rats.

Test Article

Dose

(mg/kg)

No. of

Animals

Time

 hrs.

Nuclear

Mean ± SD

Cytoplasm

Mean ± SD

NG

Mean ± SD

% IR

Mean ± SD

NGIR

Mean ± SD

Vehicle 0 3M 16 3.5 ± 0.2 7.3 ± 0.3 -3.8 ± 0.4 0 ± 0 -

MM-180801 2

2

20

20

200

200

2000

2000

3M

3M

3M

3M

3M

3M

3M

3M

 2

16

 2

16

 2

16

 2

16

3.0 ± 1.1

4.1 ± 0.5

3.9 ± 0.2

3.6 ± 0.3

4.2 ± 0.2

3.1 ± 0.3

4.8 ± 0.4

2.7 ± 0.1

5.5 ± 1.4

6.5 ± 0.8

6.9 ± 0.3

6.3 ± 0.4

7.5 ± 0.3

5.3 ± 0.3

8.2 ± 0.7

4.8 0.3

-2.6 ± 0.4

-2.4 ± 0.2

-3.0 ± 0.1

-2.7 ± 0.2

-3.4 ± 0.2

-2.2 ± 0.1

-3.4 ± 0.4

-2.1 ± 0.3

0 ± 0

0 ± 0

1 ± 0

0 ± 0

0 ± 0

0 ± 0

0 ± 0

0 ± 0

-

-

5.7 ± 0.4

-

-

-

-

-

DMN 10 3M 2 10.7 ± 3.0 5.8 ± 1.0 4.9 ± 2.1 41 ±15 11.4 ± 0.4

Nuclear = Nuclear grain count; the number of grains over the nucleus.

Cytoplasm = Cytoplasmic grain count; the highest grain count from 2 nuclear-sized areas adjacent to the nucleus.

NG = Net grains/nucleus; the nuclear count minus the cytoplasmic count.

% IR = Percentage of cells with at least 5 NG.

NGIR = Average net grains/nucleus of cells in repair.

EXAMPLE #2
The Common Technical Document — Safety

104

2.6.7.10 Carcinogenicity Report Title: MM-180801: Dietary Carcinogenicity Study in Mice Test Article: Curitol Sodium

Species/Strain: CD-1 Mice Duration of Dosing: 21 months Study No. 95012

Initial Age: 6 Weeks Method of Administration: Diet Location in CTD: Vol. 4 Page 1

Date of First Dose: 20 Sep 95 Vehicle/Formulation: In Diet

Treatment of Controls: Drug-Free Diet GLP Compliance: Yes

Basis for High-Dose Selection: Toxicity-based endpoint.

Special Features: 12 additional males and 12 additional females per drug-treated group bled at 6 months for toxicokinetic monitoring and then

removed from the study.

Daily Dose (mg/kg) 0 (Control) 25 100 400

Gender

Toxicokinetics:

 AUC on Day 28 (mcg-hr/mla)

 Css on Day 180 (mcg/ml)

Number of Animals:

 At Start

 Died/Sacrificed Moribund

 Terminal Sacrifice

 M

-

-

60

16

44

 F

-

-

60

16

44

 M

10

0.4

60c

15

44c

 F

12

0.5

60

13

47

 M

40

1.7

60

18

42

 F

48

0.3

60

20

40

 M

815

 34

 60

 27

 33

 F

570

 24

 60

 25

 35

Survival (%) 67 73 75 80 71 68 56 59

Body Weight (%b) 33g 31g 0 0 -7* 0 -13** -19**

Food consumption (%b) 6g/day 5g/day 0 0 -9* -8* -17** -15**

Dunnett's Test: * - p<0.05 ** - p<0.01

a - From Study No. 95013.

b - At 6 months. For controls, group means are shown. For treated groups, percent differences from controls are shown. Statistical

significance is based on actual data (not on the percent differences)

c - One missing mouse could not be evaluated.

(Continued)

EXAMPLE
The Common Technical Document — Safety

105

2.6.7.10 Carcinogenicity Study No. 95012 (Continued)

Daily Dose (mg/kg) 0 (Control) 25 100 400

Number Evaluated M: 60 F: 60 M: 59 F: 60 M: 60 F: 60 M: 60 F: 60

Number of Animals

 with Neoplastic Lesions:

 Skin: Hemangioma

 Hemangiosarcoma

 Adrenal: Adrenocortical adenoma

Adrenocortical adenocarcinoma

 Adenoma + Adenocarcinoma

 Pheochromocytoma

 Bone: Osteochondrosarcoma

 Osteoma

 Epididymis: Sarcoma, undifferentiated

 Gallbladder: Adenoma

 Harderian gland: Adenoma

Kidney: Renal cell adenoma

 Liver:Hepatocellular adenoma

Hepatocellular carcinoma

 Hepatocellular adenoma + carcinoma

 Lung: Alveolar/bronchiolar adenoma

 Alveolar/bronchiolar carcinoma

 Adenoma + carcinoma

0

1

4

0

4

0

0

0

0

0

4

1

3

2

3

13

4

15

1

3

1

0

1

0

1

1

0

0

2

2

1

1

2

10

0

10

1

2

2

0

2

0

0

0

1

1

3

0

4

1

4

11

1

11

0

2

0

0

0

0

1

0

0

0

1

0

2

2

3

11

1

12

6

b

9

4

0

4

1

0

0

0

0

3

2

3

3

5

14

2

15

 1

11

 3

 1

 3

 1

 0

 0

 0

 0

 4

 0

 1

 1

 2

 7

 2

9

13b

18a

3

0

3

0

0

0

1

0

3

0

4

0

4

13

1

13

0

24a

1

0

1

1

0

0

0

0

1

0

1

1

1

4

1

5

a - Trend analysis, p<0.005

b - Trend analysis, p<0.025

(Continued)

EXAMPLE
The Common Technical Document — Safety

106

2.6.7.10 Carcinogenicity Study No. 95012 (Continued)

Daily Dose (mg/kg) 0 (Control) 25 100 400

Number Evaluated

 Mediastinum: Sarcoma, undifferentiated

 Oviduct: Adenoma

 Pancreas: Islet cell adenoma

 Peritoneum: Osteosarcoma

 Seminal vesicle: Adenoma

 Stomach: Osteochondrosarcoma

 Thymus: Thymoma

 Thyroid: Follicular cell adenoma

 Uterus: Papillary cystadenoma

 Whole animal: Lymphosarcoma

 Whole animal: Histiocytic sarcoma

M: 60

0

1

1

0

0

0

0

6

1

F: 60

1

1

0

0

0

1

1

1

13

0

M: 59

0

0

0

1

0

0

0

4

0

F: 60

0

1

0

0

1

0

0

0

11

0

M: 60

0

0

1

0

0

0

0

3

0

F: 60

1

0

0

0

0

0

1

2

12

1

M: 60

0

0

0

0

0

0

0

5

0

F: 60

0

0

0

1

0

0

0

0

11

0

Noteworthy Findings:

 Gross Pathology - - - - - - - -

 Histopathology - Non-Neoplastic

 Lesions

 Liver: Hepatocellular hypertrophy

 Testes: Hypospermatogenesis

4

1

2 3

2

2 4

15*

1 40**

30**

45**

- No noteworthy findings.

Fisher Exact Test: * - p<0.05 ** - p<0.01

EXAMPLE
The Common Technical Document — Safety

107

2.6.7.11 Reproductive and Developmental Toxicity Nonpivotal Studies Test Article: Curitol Sodium

Species/

Strain

Method of

Administration

(Vehicle/

Formulation)

Dosing

Period

Doses

mg/kg No. per Group Noteworthy Findings

Study

Number

Wistar Rats Gavage

(Water)

G6 through

 G15

0, 500, 1000,

2000

8 Pregnant

 Females

≥1000: Deaths; weight losses; decreased

food consumption; clinical signs;

resorptions.

94201

NZW

Rabbits

Gavage

(CMC

Suspension)

13 Days 0, 5,15, 45 6 Nonpregnant

 Females

≥15: Decreased weight gain and food

consumption.

45: Four does died.

97020

G – Gestation day

EXAMPLE
The Common Technical Document — Safety

108

2.6.7.12 Reproductive and Developmental Toxicity Report Title: MM-180801: Oral Study of Effects on Fertility Test Article: Curitol Sodium

Fertility and Early Embryonic and Early Embryonic Development in Rats

Development to Implantation

Design similar to ICH 4.1.1? Yes Duration of Dosing: M: 4 weeks prior to mating Study No. 97072

Species/Strain: Wistar Rats F: 2 weeks prior to mating, Location in CTD: Vol. 6 Page 1

Initial Age: 10 Weeks through day 7 of gestation

Day of Mating: Day 0

Date of First Dose: 3 Mar 97 Day of C-Section: Day 16 of gestation GLP Compliance: Yes

Special Features: None Method of Administration: Gavage

No Observed Adverse Effect Level: Vehicle/Formulation: Aqueous solution.

F0 Males: 100 mg/kg

F0 Females: 100 mg/kg

F1 Litters: 1000 mg/kg

Daily Dose (mg/kg) 0 (Control) 10 100 1000

Males Toxicokinetics: AUCb (mcg-hr/ml)

No. Evaluated

No. Died or Sacrificed Moribund

Clinical Observations:

Salivation

Necropsy Observations

Body Weight (%a)

Mean No. Days Prior to Mating

No. of Males that Mated

No. of Fertile Males

-

22

0

-

-

452 g

2.7

22

21

1.8

22

0

-

-

0

2.5

21

21

25

22

0

+

-

0

2.3

22

21

320

22

0

++

-

-12*

2.8

22

21

- No noteworthy findings. + Mild ++Moderate +++Marked

Dunnett's Test * - p<0.05 ** - p<0.01

a -After 4 weeks of dosing. For controls, group means are shown. For treated groups, percent differences from controls are shown.

Statistical significance is based on actual data (not on the percent differences).

b -From Study No. 94220. (Continued)

EXAMPLE
The Common Technical Document — Safety

109

2.6.7.12 Reproductive and Developmental Toxicity Study No. 97072

(Continued)

Daily Dose (mg/kg) 0 (Control) 10 100 1000

Females Toxicokinetics: AUCb (mcg-hr/ml)

No. Evaluated

No. Died or Sacrificed Moribund

Clinical Observations

Salivation

Necropsy Observations

Premating Body Weight (%a)

Gestation Body Weight (%a)

Premating Food Consumption (%a)

Gestation Food Consumption (%a)

Mean No. Estrous Cycles/14 days

Mean No. Days Prior to Mating

No. of Females Sperm Positive

No. of Pregnant Females

Mean No. Corpora Lutea

Mean No. Implantations

Mean % Preimplantation Loss

Mean No. Live Conceptuses

Mean No. Resorptions

No. Dead Conceptuses

Mean % Postimplantation Loss

-

22

0

-

-

175 g

225 g

14 g

15 g

3.9

2.1

21

21

15.9

14.5

8.8

13.3

1.2

0

8.3

2.1

22

1

-

-

0

0

0

0

3.8

2.3

22

21

15.8

14.0

11.4

13.3

0.7

0

5.0

27

22

0

-

-

0

0

0

0

3.8

2.5

22

22

16.8

15.3

8.9

14.3

1.0

0

6.5

310

22

0

+

-

-5*

-12**

-6*

-15**

3.9

2.2

21

20

15.3

13.8

9.8

12.8

1.0

0

7.2

- No noteworthy findings. + Mild ++Moderate +++Marked

Dunnett's Test * - p<0.05 ** - p<0.01

a - At end of premating or gestation period. For controls, group means are shown. For treated groups, percent differences from controls are

shown. Statistical significance is based on actual data (not on the percent differences).

b - From Study No. 94220.

EXAMPLE
The Common Technical Document — Safety

110

2.6.7.13 Reproductive and Developmental Toxicity - Report Title: MM-180801: Oral Study of Effects on Test Article: Curitol Sodium

Effects on Embryofetal Embryofetal Development in Rabbits

Development

Design similar to ICH 4.1.3? Yes Duration of Dosing: G6-G18 Study No. 97028

Day of Mating: Day 0

Species/Strain: NZW Rabbits Day of C-Section: G29 Location in CTD: Vol. 6 Page 200

Initial Age: 5 months Method of Administration: Gavage

Date of First Dose: 7 Aug 97 Vehicle/Formulation: Aqueous Solution GLP Compliance: Yes

Special Features: None.

No Observed Adverse Effect Level:

F0 Females: 1 mg/kg

F1 Litters: 5 mg/kg

Daily Dose (mg/kg) 0 (Control) 1 5 25

Dams/Does: Toxicokinetics: AUCb (mcg-hr/ml)

No. Pregnant

No. Died or Sacrificed Moribund

No. Aborted or with Total Resorption of Litter

Clinical Observations

Necropsy Observations

Body Weight (%a)

Food Consumption (%a)

Mean No. Corpora Lutea

Mean No. Implantations

Mean % Preimplantation Loss

-

20

0

0

-

-

3.2 kg

60 g/day

9.4

7.9

15.8

2.6

19

1

0

-

-

0

0

9.3

8.1

13.1

31

20

1

0

-

-

-15*

-9*

9.4

9.1

4.0

345

20

 0

 3

++

-

 -20**

 -16**

 10.4

 9.4

 8.9

- No noteworthy findings. + Mild ++Moderate +++Marked G = Gestation day

Dunnett's Test * - p<0.05 ** - p<0.01

a - At end of dosing period. For controls, group means are shown. For treated groups, percent differences from controls are shown. Statistical

significance is based on actual data (not on the percent differences).

b - From Study No. 97231. (Continued)

EXAMPLE
The Common Technical Document — Safety

111

2.6.7.13 Reproductive and Developmental Toxicity Study No. 97028 

(Continued)

Daily Dose (mg/kg) 0 (Control) 1 5 25

Litters: No. Litters Evaluated

No. Live Fetuses

Mean No. Resorptions

No. Dead Fetuses

Mean % Postimplantation Loss

Mean Fetal Body Weight (g)

Fetal Sex Ratios (% males)

Fetal Anomalies:

Gross External

Lower jaw: Short

No. Fetuses (%)

No. Litters (%)

Visceral Anomalies

Tongue: Absent

No. Fetuses (%)

No. Litters (%)

Skeletal Anomalies

Mandible: Cleft

No. Fetuses (%)

No. Litters (%)

Ribs: Cervical

No. Fetuses (%)

No. Litters (%)

Sternebrae: Misshapen

No. Fetuses (%)

No. Litters (%)

Total Affected Fetuses (Litters)

18

140

0.2

1

4.3

44.82

46.3

0

0

0

0

0

0

2 (1.4)

1 (5.6)

2 (1.4)

2 (11.1)

2 (2)

16

126

0.3

0

2.8

42.44

57.7

0

0

0

0

0

0

0

0

1 (0.8)

1 (6.3)

1 (1)

17

148

0.4

0

5.4

42.14

57.4

0

0

0

0

0

0

1 (0.7)

1 (5.9)

0

0

0

18

86*

4.7**

0

49.0**

42.39

52.8

7 (8.0)*

5 (27.8)**

6 (6.9)*

6 (33.3)**

10 (11.5)**

8 (44.4)**

0

0

1 (1.2)

1 (5.6)

15 (10)

- No noteworthy findings.

Fisher Exact Test * - p<0.05 ** - p<0.01

EXAMPLE
The Common Technical Document — Safety

112

2.6.7.14 Reproductive and Developmental Toxicity - Report Title: MM-180801: Oral Study of Effects on Test Article: Curitol Sodium

Effects on Pre- and Postnatal Pre- and Postnatal Development in Rats

Development, Including Maternal Function

 Design similar to ICH 4.1.2? Yes Duration of Dosing: G6 - L21 Study No. 95201

Day of Mating: Day 0

Species/Strain: Wistar Rats Method of Administration: Gavage Location in CTD: Vol. 10 Page 1

Initial Age: 9-10 Weeks Vehicle/Formulation: Water

Date of First Dose: 8 Oct 95 Litters Culled/Not Culled: Culled to 4/sex/litter GLP Compliance: Yes

Special Features: None

No Observed AdverseEffect Level:

F0 Females: 7.5 mg/kg

F1 Males: 75 mg/kg

F1 Females: 75 mg/kg

Daily Dose (mg/kg) 0 (Control) 7.5 75 750

F0 Females: Toxicokinetics: AUCb (mcg-hr/ml)

No. Pregnant

No. Died or Sacrificed Moribund

Clinical Observations

Necropsy Observations

Gestation Body Weight (%a)

Lactation Body Weight (%a)

Gestation Food Consumption (%a)

Lactation Food Consumption (%a)

Mean Duration of Gestation (days)

Abnormal Parturition

-

23

0

-

-

225 g

210 g

15 g

16 g

22.1

-

2.4

21

0

-

-

0

0

0

0

22.2

-

21

22

0

++

-

0

0

0

0

22.1

-

150

23

8

+++

-

-25**

0

-12*

0

23.5+

-

- No noteworthy findings. + Mild ++Moderate +++Marked G = Gestation day

Dunnett's Test * - p<0.05 ** - p<0.01 L = Lactation day

Kruskal-Wallis with Dunn's procedure + - p<0.05

a -At end of gestation or lactation. For controls, group means are shown. For treated groups, percent differences from controls are shown.

Statistical significance is based on actual data (not on the percent differences).

b -From Study No. 97227 (Continued)

EXAMPLE
The Common Technical Document — Safety

113

2.6.7.14 Reproductive and Developmental Toxicity Study No. 95201

(Continued)

Daily Dose (mg/kg) 0 (Control) 7.5 75 750

F1 Litters:

(Preweaning)

F1

 Males:

(Postweaning)

No. Litters Evaluated

Mean No. Pups/Litter

Mean No. Liveborn Pups/Litter

Mean No. Stillborn Pups/Litter

Postnatal Survival to Day 4

Postnatal Survival to Weaning

Change in Pup Body Weightsa (g)

Pup Sex Ratios (% males)

Pup Clinical Signs

Pup Necropsy Observations

No. Evaluated Postweaning

No. Died or Sacrificed Moribund

Clinical Observations

Necropsy Observations

Body Weight Changeb (g)

Food Consumption (%b)

Preputial Separation

Sensory Function

Motor Activity

Learning and Memory

Mean No. Days Prior to Mating

No. of Males that Mated

No. of Fertile Males

23

13.6

13.5

0.1

-

-

60

51

-

-

23

-

-

-

200

15 g

-

-

-

-

2.4

23

23

21

13.8

13.8

0.0

-

-

58

53

-

-

21

-

-

-

195

0

-

-

-

-

3.3

21

21

22

14.9

14.6

0.3

-

-

62

49

-

-

22

-

-

-

195

0

-

-

-

-

2.9

21

19

15

11.2++

9.4++

1.8+

-

-

53*

51

-

-

15

-

-

-

186*

-11*

-

-

-

-

3.5

23

20

- No noteworthy findings. + Mild ++Moderate +++Marked

Dunnett's Test * - p<0.05 ** - p<0.01

Kruskal-Wallis with Dunn's procedure + - p<0.05 ++ - p<0.01

a - From birth to weaning.

b - From weaning to mating. For controls, group means are shown. For treated groups, percent differences from controls are shown.

Statistical significance is based on actual data (not on the percent differences) (Continued)

EXAMPLE
The Common Technical Document — Safety

114

2.6.7.14 Reproductive and Developmental Toxicity Study No. 95201

(Continued)

Daily Dose (mg/kg) 0 (Control) 7.5 75 750

F1 Females:

(Postweaning)

F2 Litters:

No. Evaluated Postweaning

No. Died or Sacrificed Moribund

Clinical Observations

Necropsy Observations

Premating Body-Weight Changea (g)

Gestation Body-Weight Change (g)

Premating Food Consumption (%b)

Gestation Food Consumption (%b)

Mean Age of Vaginal Patency (days)

Sensory Function

Motor Activity

Learning and Memory

Mean No. Days Prior to Mating

No. of Females Sperm Positive

No. of Pregnant Females

Mean No. Corpora Lutea

Mean No. Implantations

Mean % Preimplantation Loss

Mean No. Live Conceptuses/Litter

Mean No. Resorptions

No. Dead Conceptuses

Mean % Postimplantation Loss

Fetal Body Weights (g)

Fetal Sex Ratios (% males)

Fetal Anomalies

23

0

-

-

226

153

15 g

16 g

-

-

-

-

2.4

23

23

16.4

15.8

3.8

15.0

0.8

0

5.1

3.69

53

-

21

1

-

-

230

160

0

0

-

-

-

-

3.3

21

21

16.2

15.2

6.3

14.9

0.3

0

2.2

3.65

49

-

22

0

-

-

235

144

0

0

-

-

-

-

3.1

21

20

15.8

14.4

12.3

13.6

0.8

0

5.2

3.75

54

-

23

0

-

-

196*

158

-13*

0

-

-

-

-

3.5

23

21

15.5

14.9

3.7

14.4

0.5

0

3.4

3.81

54

-

-No noteworthy findings. + Mild ++Moderate +++Marked

Dunnett's Test * - p<0.05 ** - p<0.01

a - From weaning to mating.

b - During postweaning period. For controls, group means are shown. For treated groups, percent differences from controls are shown. Statistical

significance is based on actual data (not on the percent differences).

EXAMPLE
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115

EXAMPLE

2.6.7.17 Other Toxicity Studies Test Article: Curitol Sodium

Species/

Strain

Method of

Administration

Duration

of Dosing

Doses

(mg/kg)

Gender and

No. per Group Noteworthy Findings

Study

Number

Antigenicity

Guinea

Pigs

Subcutaneous Weekly

for

3 weeks;

challenge

1 week

later.

0, 5 mg 5M, 5F Mildly positive delayed hypersensitivity

reaction. No evidence of passive

cutaneous anaphylaxis or systemic

anaphylaxis.

97012

Impurities

WISTAR

Rats

Gavage 2 Weeks 0, 1000,

2000

10M, 10F MM-180801 fortified with 2% of the Zisomer impurity; toxicologic effects

comparable to MM-180801 without

impurity.

97025