M4S: The CTD -- Safety Appendices

Administrative guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

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

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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.

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Table X: Binding of X and Its Major Metabolites and Comparators to Human X2 and X3 Receptors
Compound 	X2
K i 1(nM)
X2
K i 2(nM)
X3
K i 1(nM)
X3
K i 2(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
Ki 1 and Ki 2 represent the high and low affinity binding sites, respectively (Data from Study Number).

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Figure X: Blood Pressure Following Chronic Dosing With X to SHRa
Blood pressure following chronic dosing with X to SHR a
[ref]. Hypotensive effect of saline i.v. infusion over 5 min () compared to X, 3 mg/kg i.v. infusion
to SHR pretreated twice daily with saline, 1 mL/kg p.o., for 7 () or 14 () days or X, 25 mg/kg p.o., for 7 () or 14 () 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).

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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.

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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.

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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.

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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.

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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.

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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)

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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)
Sex
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 	__________ 	__________ 	__________ 	__________ 	_________
Sex (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 14 C-labeled compound.
(3) For example, brief textual results, species differences, sex 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:
Sex (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:
Sex (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:
Sex (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 	__________ 	__________ 	__________ 	_________
Sex (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, sex 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)
Sex
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)
Sex
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)
Sex
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)

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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

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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.

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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).

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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:
F 0 Males:
F 0 Females:
F 1 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)

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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).

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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).

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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:
F 0 Females:
F 1 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)

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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

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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:
F 0 Females:
F 1 Males:
F 1 Females:
Daily Dose (mg/kg) 	0 (Control)
F 0 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)

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2.6.7.14 (1) Reproductive and Developmental Toxicity 	Study No. 	(Continued)
Daily Dose (mg/kg) 	0 (Control)
F 1 Litters:
(Preweaning)
F 1 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).

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2.6.7.14 (1) Reproductive and Developmental Toxicity 	Study No. 	(Continued)
Daily Dose (mg/kg) 	0 (Control)
F 1 Females:
(Postweaning)
F 2 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).

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2.6.7.14 (1) Reproductive and Developmental Toxicity 	Study No. 	(Continued)
Daily Dose (mg/kg) 	0 (Control)
F 1 Females:
(Postweaning)
F 2 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).

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2.6.7.16 Local Tolerance (1) 	Test Article: (2)
Species/
Strain
Method of
Administration
Doses
(mg/kg)
Sex and
No. per Group 	Noteworthy Findings
Study
Number
Notes: 	(1) All local tolerance studies should be summarized.
(2) International Nonproprietary Name (INN).

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2.6.7.17 Other Toxicity Studies (1) 	Test Article: (2)
Species/
Strain
Method of
Administration
Duration
of Dosing
Doses
(mg/kg)
Sex and
No. per Group 	Noteworthy Findings
Study
Number
Notes: 	(1) All supplementary toxicity studies should be summarized.
(2) International Nonproprietary Name (INN)

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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.

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2.6.3.4 Safety Pharmacology 	Test Article: Curitol Sodium
Organ
Systems
Evaluated
Species/
Strain
Method of
Admin.
Dosesa
(mg/kg)
Sex
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

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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 AZT a 	Rats 	Gavage 	Sponsor Inc. 	94051 	1 	350
a - 	Report contains a GLP Compliance Statement.
EXAMPLE

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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
Sex (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, 14 C
EXAMPLE

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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
Sex (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: 14 C
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
Sex (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, 14 C
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, 14 C
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
Sex (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: 14 C
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
Sex (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, 14 C
EXAMPLE

The Common Technical Document — Safety
86
2.6.5.14 Pharmacokinetics: Excretion into Bile 	Test Article: Curitol Sodium
Species 	Rat 	Rat
Sex (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, 14 C
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/kg a )
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
Repeat-
Dose
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 - G15 b
F: G6 - G18 b
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)
Mice a
M 	F
Rats b
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 , 20 e
68
90
27d , 22 e
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.
AUC
24hr
 (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 Impuritiesa 	Study
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)
Sex
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)
Sex
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, reddish-
stained 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 (x10 6
/mm3 )
MCH
MCHC
Platelet Count (x10 3 /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 Weight b (%)
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
Sex
Toxicokinetics:
AUC on Day 28 (mcg-hr/ml a )
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
60 c
15
44 c
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
13 b
18 a
3
0
3
0
0
0
1
0
3
0
4
0
4
13
1
13
0
24 a
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.
F 0 Males: 100 mg/kg
F 0 Females: 100 mg/kg
F 1 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.
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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:
F 0 Females: 1 mg/kg
F 1 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)
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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
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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:
F 0 Females: 7.5 mg/kg
F 1 Males: 75 mg/kg
F 1 Females: 75 mg/kg
Daily Dose (mg/kg) 	0 (Control) 	7.5 	75 	750
F 0 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)
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113
2.6.7.14 	Reproductive and Developmental Toxicity 	Study No. 95201
(Continued)
Daily Dose (mg/kg) 	0 (Control) 	7.5 	75 	750
F 1 Litters:
(Preweaning)
F 1 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)
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114
2.6.7.14 Reproductive and Developmental Toxicity 	Study No. 95201
(Continued)
Daily Dose (mg/kg) 	0 (Control) 	7.5 	75 	750
F 1 Females:
(Postweaning)
F 2 Litters:
No. Evaluated Postweaning
No. Died or Sacrificed Moribund
Clinical Observations
Necropsy Observations
Premating Body-Weight Change a (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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EXAMPLE
2.6.7.17 Other Toxicity Studies 	Test Article: Curitol Sodium
Species/
Strain
Method of
Administration
Duration
of Dosing
Doses
(mg/kg)
Sex 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 Z-
isomer impurity; toxicologic effects
comparable to MM-180801 without
impurity.
97025