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
  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. 

21
  Table X:  Binding of X and Its Major Metabolites and Comparators to Human X2 and X3 Receptors 
Compound  X2  X2  X3  X3 
K1(nM)  K2(nM)  K1(nM)  K2(nM) 
i i i i
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 
K1 and K2 represent the high and low affinity binding sites, respectively (Data from Study Number). 
i i
22
  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 (.) compared to X, 3 mg/kg i.v. 

infusion to SHR pretreated twice daily with saline, 1 mL/kg p.o., for 7 (0) or 14 (0) days or X, 25 mg/kg p.o., for 7 (e) or 14 (I) days. Saline pretreated 

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

aSHR= spontaneous hypertensive rat (n=5 per group). 

23
  Table X:  Model Independent Pharmacokinetic Parameters for X in Mice Following Single Oral Doses at 2, 10 
and 30 mg/kg [ref] 
Parameter  Parameter value 
(units) 
Sex  Males  Females 
Dose  2  10 30 2  10 30 
(mg/kg) 
C 4.9  20.4  30.7  5.5  12.9  28.6
max 
(ng/mL) 
T  (h)  0.8  0.4  0.3  0.4  0.5  0.3 
max
AUC 21.6  80.5  267  33.3  80  298 
0-t 
(ng.h/mL) 
AUC 28.3  112  297  40.2  90  327
0-inf 
(ng.h/mL) 
Pharmacokinetic parameters were determined in pooled plasma from three animals 
at each time. 
14
Table X:  Excretion of Radioactive Material Following Single Doses of [ C]X to Male Mice [ref] 
Dose (mg/kg)/  Percentage of administered dose 
route  *  Feces + 
Urine 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. 

24
  Table X:  Concentrations of Radioactive Material in the Tissues of Male Rats After a Single Intravenous 
14
Dose of [ C]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  359  31.5  ND  ND  ND 
marrow 
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  570  2470  39.3  12.0  ND 
intestine 
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.
 
25
  14
Table X:  Excretion of Radioactive Material Following Single Doses of [ C]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. 
26
  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 
C  (ng/mL) 
max 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-t  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.
 
27
  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  x/50 (%)  x/50 (%)  x/50 (%)  x/50 (%) 
(only) 
Adenoma  x/50 (%)  x/50 (%)  x/50 (%)  x/50 (%) 
(only) 
Adenoma +  x/50 (%)  x/50 (%)  x/50(%)  x/50 (%) 
Hyperplasia 
Total*  x/50 (%)  x/50 (%)  x/50 (%)  x/50 (%) 
* Adenoma and/or Hyperplasia. 
28
  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)
 
29
  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. 
30
  The Common Technical Document  Safety 
2.6.3.1 Pharmacology                                                                       Overview  Test Article: (1) 
Test  Method of  Testing  Study  Location 
Type of Study  System  Administration  Facility  Number(4) Vol.       Page 
Primary Pharmacodynamics        (3) 
                  (2) 
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). 
31
  The Common Technical Document  Safety 
2.6.3.4 Safety Pharmacology(1)  Test Article:  (2) 
Organ  Gender 
Systems  Species/  Method of  Dosesa  and No.  GLP  Study 
Evaluated  Strain  Admin.  (mg/kg)  per Group  Noteworthy Findings  Compliance  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. 
32
  The Common Technical Document  Safety 
2.6.5.1 Pharmacokinetics 	 Overview  Test Article:  (1) 
Test  Method of  Testing  Study   Location 
Type of Study  System  Administration  Facility  Number Vol.       Page 
Absorption     (3)
                       (2) 
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. 
33
  The Common Technical Document  Safety 
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. 
34
  The Common Technical Document  Safety 
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.] 
35
  The Common Technical Document  Safety 
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)  t
1/2?? 
Additional information: 
36
  The Common Technical Document  Safety 
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: 
C Last time point 
t 
Tissues/organs  conc.  T/P1)  conc.  T/P1)  Time  AUC  t
1/2?? 
Additional information: 
1) [Tissue]/[Plasma] 
37
  The Common Technical Document  Safety 
2.6.5.6 Pharmacokinetics: Plasma Protein Binding  Test Article: 
Study system: 
Target entity, Test system and method: 
Study Location in CTD 
Species  Conc. tested  % Bound   No.        Vol.            Page 
Additional Information: 
38
  The Common Technical Document  Safety 
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: 
39
  The Common Technical Document  Safety 
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). 
40
  The Common Technical Document  Safety 
2.6.5.8 Pharmacokinetics: Other Distribution Study  Test Article: 
41
  The Common Technical Document  Safety 
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 
Sampling Time % of Dose  Study
Species  Sample   or Period       in Sample Parent_  M1        M2    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. 
42
  The Common Technical Document  Safety 
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. 
43
  The Common Technical Document  Safety 
2.6.5.11 Pharmacokinetics: Possible Metabolic Pathways  Test Article: 
(Illustrate possible metabolic map indicating species in which metabolic reactions occur.) 
44
  The Common Technical Document  Safety 
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: 
45
  The Common Technical Document  Safety 
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. 
46
  The Common Technical Document  Safety 
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.] 
47
  The Common Technical Document  Safety 
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: 
48
  The Common Technical Document  Safety 
2.6.5.16 Pharmacokinetics: Other  Test Article: 
Location in CTD: Vol.     Page 
Study No. 
Type of study: 
Method: 
Tabulated results: 
Additional Information: 
49
  The Common Technical Document  Safety 
2.6.7.1 Toxicology  Overview  Test Article: (1) 
Species and  Method of  Duration  GLP  Testing  Study  Location 
Type of Study  Strain  Administration  of Dosing  Doses (mg/kga)  Compliance  Facility  Number  Vol.   Page 
Single-Dose  (2) 
(3)
Toxicity 
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. 
50
  The Common Technical Document  Safety 
2.6.7.2 Toxicokinetics  Overview of Toxicokinetics Studies  Test Article: (1) 
Test  Method of  GLP  Study   Location 
Type of Study  System  Administration  Doses (mg/kg)  Compliance  Number 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. 
51
  The Common Technical Document  Safety 
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. 
52
  The Common Technical Document  Safety 
2.6.7.4 Toxicology  Drug Substance  Test Article: (1) 
Study 

Batch No.  Purity (%)  Specified Impurities ( )  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. 
53
  The Common Technical Document  Safety 
2.6.7.5 Single-Dose Toxicity (1)  Test Article:  (2) 
Method of  Observed 
Administration  Gender  Maximum  Approximate 
Species/  (Vehicle/  Doses  and No.  Nonlethal Dose  Lethal  Study 
Strain  Formulation)  (mg/kg)  per Group  (mg/kg)  Dose (mg/kg)  Number 
Noteworthy Findings 
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). 
54
  The Common Technical Document  Safety 
2.6.7.6 Repeat-Dose Toxicity  Nonpivotal Studies (1)  Test Article:  (2) 
Method of 
Administration  Duration  Gender 
Species/  (Vehicle/  of Dosing  Doses  and No.  NOAELa  Study 
Strain  Formulation)  (mg/kg)  per Group  (mg/kg)  Noteworthy Findings  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. 
55
  The Common Technical Document  Safety 
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  M:  F:  M:  F:  M:  F:  M:  F: 
Toxicokinetics: AUC ( )  (4)  (5) 
Noteworthy Findings
 Died or Sacrificed Moribund
 Body Weight (%a)
 Food Consumption (%a) (5) 
 Water Consumption ( ) (5) 
 Clinical Observations
 Ophthalmoscopy
 Electrocardiography 
- 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) 
56
  The Common Technical Document  Safety 
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. 
57
  The Common Technical Document  Safety 
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. 
58
  The Common Technical Document  Safety 
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:
 
Concentration or 
Metabolic  Test  Dose Level 
Activation  Article  ( (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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  The Common Technical Document  Safety 
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: 
Dose  No. of 
Test Article  (mg/kg)  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). 
60
  The Common Technical Document  Safety 
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  M  F  M  F  M  F  M  F 
Toxicokinetics: AUC ( ) (4) 
Number of Animals
 At Start
 Died/Sacrificed Moribund
 Terminal Sacrifice 
Survival (%)  (5) 
Body Weight (%a) 
Food Consumption (%a) 
(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  M:  F:  M:  F:  M:  F:  M:  F:  M:  F: 
Number of Animals 
   with Neoplastic Lesions: 
                (7) 
Noteworthy Findings:
 Gross Pathology
 Histopathology - Non-Neoplastic
 Lesions 
-      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) 
Method of 
Administration 
Species/  (Vehicle/  Dosing  Doses  Study 
Strain  Formulation)  Period  mg/kg  Noteworthy Findings  Number 
No. per Group 
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  Males:
 
0
F  Females:
 
0
F  Litters:
 
1
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  Females: 
0
F  Litters: 
1
Daily Dose (mg/kg)  0 (Control) 
Dams/Does:  Toxicokinetics: AUC ()  (4) 
No. Pregnant 
No. Died or Sacrificed Moribund  (5) 
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 
-	 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  Females:
 
0
F  Males:
 
1
F  Females:
 
1
Daily Dose (mg/kg)	  0 (Control) 
F  Females:  Toxicokinetics: AUC ( ) (4) 
0
No. Pregnant
 
No. Died or Sacrificed Moribund
 
No. Aborted or with Total Res. of Litter
 
Clinical Observations
 
Necropsy Observations
 
Gestation Body Weight (%a)  (5)
 
Lactation Body Weight (%a)
 
Gestation Food Consumption (%a)
 
Lactation  Food Consumption (%a)
 
Mean Duration of Gestation (days)
 
Abnormal Parturition
 
- 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  Litters:	  No. Litters Evaluated 
1
(Preweaning)	  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

F  Males:   Per Litter
 
1
(Postweaning)  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  Females:	  No. Evaluated Postweaning 
1
(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
 
F  Litters:	  Mean No. Live Conceptuses/Litter
 
2
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  Females:	  No. Evaluated Postweaning 
1
(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) 

Note: Alternate
Sensory Function 
Format for
Motor Activity 
Natural
Learning and Memory 
Parturition.
Mean No. Days Prior to Mating
 
No. of Females Sperm Positive
 
No. of Pregnant Females
 
Mean Duration of Gestation
 
Abnormal Parturition
 
F  Litters:	  No. Litters Evaluated
 
2
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
 
- 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/  Method of  Doses  Gender and  Study 
Strain  Administration  (mg/kg)  No. per Group  Noteworthy Findings  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/  Method of  Duration  Doses  Gender and  Study 
Strain  Administration  of Dosing  (mg/kg)  No. per Group  Noteworthy Findings  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 
Test  Method of  Testing  Study  Location 
Type of Study  System  Administration  Facility  Number Vol.        Page 
Primary Pharmacodynamics 
Antiviral activity vs. VZV  Human embryonic lung  In vitro  Sponsor Inc.  95401  1  1 
Antiviral activity vs. VZV  fibroblasts  In vitro  Sponsor Inc.  95402  1  20 
Antiviral activity vs. HSV  Clinical isolates  In vitro  Sponsor Inc.  95406  1  30 
Antiviral activity vs. CMV  Human embryonic lung  In vitro  Sponsor Inc.  95408  1  45 
Antiviral activity vs. VZV  fibroblasts  Gavage  Sponsor Inc.  95411  1  55 
Antiviral activity vs. SVV  Human embryonic lung  Nasogastric Sponsor Inc.  95420  1  100 
fibroblasts  Intubation 
ICR mice 
African Green monkeys 
Secondary Pharmacodynamics 
Antimicrobial activity  Gram positive and gram  In vitro  Sponsor Inc.  95602  1  200 
negative bacteria; yeasts 
Safety Pharmacology 
Effects on central nervous systema  Mice, rats, rabbits, and cats  Gavage  Sponsor Inc.  95703  2  1 
Effects on cardiovascular system  Dogs  Gavage, i.v.  Sponsor Inc.  95706  2  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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EXAMPLE
 
2.6.3.4 Safety Pharmacology  Test Article: Curitol Sodium 
Organ  Gender 
Systems  Species/  Method of  Dosesa  and No.  GLP  Study 
Evaluated  Strain  Admin.  (mg/kg)  per Group  Noteworthy Findings  Compliance  Number 
CNS  CD-1  Gavage  0, 10, 50,  10M  Slight prolongation of hexobarbital  Yes  92201 
Mice  250  anesthesia ( 10 mg/kg).  No analgesic, 
anticonvulsive, or cataleptic properties. 
No effects on coordination, traction, or 
spontaneous motility. 
Renal, GI, CNS,  CD-1  Gavage  0, 10, 50,  6M  Slight increases in urinary excretion of  No  92205 
and Hemostasis  Mice  250  sodium and potassium ( 50 mg/kg).  No 
effects on GI transit time (charcoal meal), 
pupillary diameter, blood coagulation 
time, or urine volume. 
Cardiovascular  Mongrel  Intravenous  0, 3, 10, 30  3M  Dose-related transient decreases in blood  Yes  92210 
Dogs  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. 
a  - Single dose unless specified otherwise. 
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EXAMPLE 
2.6.5.1 Pharmacokinetics  Overview  Test Article: Curitol Sodium 
Test  Method of  Testing  Study  Location 
Type of Study  System  Administration  Facility  Number Vol.       Page 
Absorption 
Absorption and excretion  Rats  Gavage, i.v.  Sponsor Inc.  93302  1  1 
Absorption and excretion  Dogs  Gavage, i.v.  Sponsor Inc.  93304  1  25 
Absorption and excretion  Monkeys  Gavage, i.v.  Sponsor Inc.  93306  1  50 
Distribution 
Single-dose tissue distribution  Rats  Gavage  Sponsor Inc.  93307  1  100 
Repeat-dose tissue distribution  Rats  Gavage  Sponsor Inc.  93308  1  125 
Plasma protein binding  Mice, rats, dogs,  In vitro  Sponsor Inc.  93311  1  150 
Plasma protein binding  monkeys, Humans,  Tablets/Gavage/ Sponsor Inc.  93312  1  200 
rats, dogs  Capsules 
Metabolism 
Metabolites in blood, urine, and feces  Rats  Gavage  Sponsor Inc.  93402  1  250 
Metabolites in blood, urine, and feces  Dogs  Gavage  Sponsor Inc.  93407  1  300 
Excretion 
Absorption and excretion  Rats  Gavage, i.v.  Sponsor Inc.  93302  1  1 
Absorption and excretion  Dogs  Gavage, i.v.  Sponsor Inc.  93304  1  25 
Absorption and excretion  Monkeys  Gavage, i.v.  Sponsor Inc.  93306  1  50 
Pharmacokinetic Drug Interactions 
Interaction with AZTa  Rats  Gavage  Sponsor Inc.  94051  1  350 
a  - Report contains a GLP Compliance Statement. 
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EXAMPLE 
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  Suspension  Capsule  Suspension  Tablet 
10% acacia  10% acacia  10% acacia 
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 
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EXAMPLE
 
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  t
1/2 
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. 
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EXAMPLE 
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
 
C Last time point 
1hr 
Tissues/organs  conc.  T/P1)  conc.  T/P1)  Time  AUC  t
1/2 
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] 
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EXAMPLE
 
2.6.5.6 Pharmacokinetics: Plasma Protein Binding  Test Article:  Curitol Sodium 
Study system:  In vitro 
Target entity, Test system and method:  Plasma,  Ultrafiltration 
Study Location in CTD 
Species  Conc. tested  % Bound   No.         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: 
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EXAMPLE
 
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: 
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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 
Sampling Time  % of Dose  Study 
Species  Sample  or Period  in Sample  Parent  M1  M2  Number  Vol.              Page 
Rats  Plasma  0.5 hr  - 87.2  6.1  3.4  95076  26  101 
Urine  0-24 hr  2.1  0.6  n.d.  0.2 
Bile  0-4 hr  28.0  15.5  7.2  5.1 
Feces  - - - - -
Dogs  Plasma  0.5 hr  - 92.8  n.d.  7.2  95082  26  301 
Urine  0-24 hr  6.6  6.4  n.d.  n.d. 
Bile  0-4 hr  32.0  28.5  2.8  n.d. 
Feces  - - - - -
Humans  Plasma  1 hr  - 87.5  trace  12.5  CD-102  42  1 
Urine  0-24 hr  5.5  2.4  2.9  n.d. 
Bile  - - - - -
Feces  - - - - -
Additional Information
 
*      - Intraduodenal administration for collection of bile.
 
n.d.  - None detected. 
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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  Solution  Capsule  Solution 
Water  Saline  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  26  57  83  22  63  85  20  29  49  23  42  65 
0 - 48 hr  30  65  95  27  69  96  25  65  90  28  78  96 
0 - 72 hr  31  65  97  28  70  98  26  73  99  29  72  101 
0 - 96 hr  31  67  98  29  70  99  26  74  100  29  73  102 
Study number  95102  95156 
Location in CTD  Volume 20, Page 75  Volume 20, Page 150 
Additional Information: 
a  - Total radioactivity; percent recovery, 14C 
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EXAMPLE 
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  Solution 
Water  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  37  - 37  75  - 75 
0 -  4 hr  50  - 50  82  - 82 
0 -  8 hr  62  - 62  86  - 86 
0 - 24 hr  79  9  86  87  11  98 
0 - 48 hr  83  10  93  88  11  99 
Study number  95106 
Location in CTD  Volume 20, Page 150 
a  - Total radioactivity; percent recovery, 14C 
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2.6.7.1 Toxicology                                                                         Overview  Test Article: Curitol Sodium 
Species and  Method of  Duration  GLP  Testing  Study   Location 
Type of Study  Strain  Administration  of Dosing  Doses (mg/kga)  Compliance  Facility  Number Vol.   Page 
Single-Dose  CD-1 Mice  Gavage  - 0, 1000, 2000, 5000  Yes  Sponsor Inc.  96046  1  1 
Toxicity  Intravenous  - 0, 100, 250, 500  Yes  CRO Co.  96047  1  100 
Wistar Rats  Gavage  - 0, 1000, 2000, 5000  Yes  Sponsor Inc.  96050  1  200 
Intravenous  - 0, 100, 250, 500  Yes  CRO Co.  96051  1  300 
Repeat- CD-1 Mice  Diet  3 Months  0, 62.5, 250, 1000,  Yes  CRO Co.  94018  2  1 
Dose  4000, 7000 
Toxicity 
Wistar Rats  Diet  2 Weeks  0, 1000, 2000, 4000  No  Sponsor Inc.  94019  3  1 
Gavage  2 Weeks  0, 500, 1000, 2000  No  Sponsor Inc.  94007  3  200 
Gavage  3 Months  0, 200, 600, 1800  Yes  Sponsor Inc.  94214  4  1 
Gavage  6 Months  0, 100, 300, 900  Yes  Sponsor Inc.  95001  5  1 
Beagle Dogs  Capsules  1 Month  0, 10, 40, 100  Yes  Sponsor Inc.  94020  6  1 
Capsules  9 Months  0, 5, 20, 50  Yes  Sponsor Inc.  96041  7  1 
Cynomolgus  Gavage  5 Days  0, 500, 1000  No  CRO Co.  94008  8  1 
Monkeys 
Genotoxicity  S. typhimurium  In Vitro  - 0, 500, 1000, 2500,  Yes  Sponsor Inc.  96718  9  1 
and E. coli  and/or 
5000 mcg/plate 
Human  In Vitro  - 0, 2.5, 5, 10, 20, and  Yes  CRO Co.  97634  9  100 
Lymphocytes  40 mcg/ml 
Wistar Rats  Gavage  3 Days  0, 1000, 2000  Yes  Sponsor Inc.  96037  9  200 
a  - Unless otherwise specified.  For Single-Dose Toxicity and Repeat-Dose Toxicity, the highest No Observed Adverse Effect Level (NOAEL) 
is underlined.
 (Continued) 
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2.6.7.1 Toxicology                                                                     Overview (Continued)  Test Article: Curitol Sodium 
Species and  Method of  Duration  GLP  Testing  Study  Location 
Type of Study  Strain  Administration  of Dosing  Doses (mg/kg)  Compliance  Facility  Number Vol.   Page 
Carcinogenicity  CD-1 Mice  Diet  21 Months  0, 0, 25, 100, 400  Yes  CRO Co.  95012  10  1 
Wistar Rats  Gavage  24 Months  0, 0, 25, 100, 400  Yes  Sponsor Inc.  95013  12  1
 Reproduction  Wistar Rats  Gavage  a  0, 5, 30, 180  Yes  CRO Co.  96208  14  1 
Toxicity  Wistar Rats  Gavage  F: G6 - G15b  0, 10, 100, 1000  Yes  Sponsor Inc.  94211  15  1 
NZW Rabbits  Gavage  F: G6 - G18b  0, 1, 5, 25  Yes  CRO Co.  97028  16  1 
Wistar Rats  Gavage  F: G6 - L21b  0, 7.5, 75, 750  Yes  Sponsor Inc.  95201  17  1
 Local  NZW Rabbits  Dermal  1 Hour  0, 15 mg  No  Sponsor Inc.  95015  18  1 
Tolerance 
Other
 Toxicity Studies
 Antigenicity  Guinea Pigs  Subcutaneous  Weekly for 3  0, 5 mg  No  CRO Co.  97012  18  20
weeks 
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 
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2.6.7.2 Toxicokinetics  Overview of Toxicokinetics Studies  Test Article: Curitol Sodium 
Test  Method of  GLP  Study  Location 
Type of Study  System  Administration  Doses (mg/kg)  Compliance  Number Vol.      Page 
Three-month range-finding study  Mice  Diet  62.5, 250, 1000, 4000, 7000  Yes  94018  2 1 
Two-week toxicity study  Rats  Gavage  500, 1000, 2000  No  94007  3 200 
Six-month toxicity study  Rats  Gavage  100, 300, 900  Yes  95001  5 1 
One-month toxicity study  Dogs  Capsules  10, 40, 100  Yes  94020  6 1 
Nine-month toxicity study  Dogs  Capsules  5, 20, 50  Yes  96041  7  1 
Carcinogenicity study  Mice  Diet  25, 100, 400  Yes  95012  10  1 
Carcinogenicity study  Rats  Gavage  25, 100, 400  Yes  95013  12  1 
Toxicokinetics study  Rabbits  Gavage  1, 5, 25  No  97231 16  1 
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2.6.7.3 Toxicokinetics  Overview of Toxicokinetics Data  Test Article: Curitol Sodium 
                                                   Steady State AUC (mcg-hr/ml) 
Daily Dose            Micea Ratsb Female 
  (mg/kg)  M          F  M          F  Dogsc  Rabbitsb  Humansf
 1  9  3
 5  3  25 
10  4 
20 10 
25  10  12  6  8 273
 40 10
 50  12 
62.5  35  40
 100  40  48  25d, 20e  27d, 22e 40
 250  120  135
 300  68  72
 400  815  570  90  85 
500  125  120
 900  200  190
1000  2,103  1,870  250  240
2000  327  321 
4000  4,975  3,987 
7000  8,241  7,680
__________ 
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. 
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2.6.7.3  Toxicokinetics  Overview of Toxicokinetics Data  Test Article : Curitol Sodium 
1000 
100 
)  Humans 
ml
r/ Male Mice 
h
x  Female Mice 
g  10 
u Male Rats 
(
 hr Female Rats 
4
2
C Dogs 
U
A
1 
0.1 
0.01  0.1  1  10  100 
Dose (mg/kg) 
Steady state AUC  values of unchanged MM-180801 in humans after repeated oral administration of 1, 2.5, and 5 mg OD, in comparison with 
24hr
those in mice in the carcinogenicity study, rats in the 6-month toxicity study, and dogs in the 9-month toxicity study. 
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2.6.7.4 Toxicology  Drug Substance  Test Article: Curitol Sodium 
Specified Impuritiesa  Study 
Batch No.  Purity (%)  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  Two-Week Oral Range-Finding Study in Rats 
94008  Five-Day Oral Range-Finding Study in Monkeys 
96718  Ames Test 
94NA103  99.1  0.2  0.1  0.2  96046  Single-Dose Oral Study in Mice 
96050  Single-Dose Oral Study in Rats 
94214  Three-Month Oral Study in Rats 
94020  One-Month Oral Study in Dogs 
97634  Human Lymphocytes Assay In Vitro 
95NA215  97.3  0.1  0.3  0.1  96047  Single-Dose Intravenous Study in Mice 
96051  Single-Dose Intravenous Study in Rats 
96037  Micronucleus Test in Rats 
94211  Embryofetal Development Study in Rats 
97028  Embryofetal Development Study in Rabbits 
95NB003  94.6  0.2  0.3  0.4  94019  Two-Week Palatability Study in Rats 
97012  Antigenicity Study in Hamsters 
96NB101  99.0  0.4  0.1  0.0  94018  Three-Month Dietary Range-Finding Study in Mice 
95001  Six-Month Oral Study in Rats 
95002  One-Year Oral Study in Dogs 
95012  Dietary Carcinogenicity Study in Mice 
95013  Oral Carcinogenicity Study in Rats 
96208  Fertility and Early Embryonic Development Study in Rats 
95015  Dermal Irritation Study in Rabbits 
a  - Area percent. 
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EXAMPLE 
2.6.7.5 Single-Dose Toxicity  Test Article: Curitol Sodium 
Method of  Observed 
Administration  Gender  Maximum  Approximate 
Species/  (Vehicle/  Doses  and No.  Nonlethal Dose  Lethal  Study 
Strain  Formulation)  (mg/kg)  per Group  (mg/kg)  Dose (mg/kg)  Noteworthy Findings  Number 
CD-1  Gavage  0,  10M   5000  >5000   2000: Transient body weight losses.  96046 
Mice  (Water)  1000,  10F   5000 
2000,  5000: Decreased activity, 
5000  convulsions, collapse. 
 250: Body-weight losses. 
Intravenous  0,  10M  250  >250  500: 3M and 2F died. 
96047 
(Saline)  100,  10F  250  <500 
250, 
500 
Wistar  Gavage  0,  5M  2000  >2000   2000: Transient body weight losses;  96050 
Rats  (CMC  1000,  5F   5000  <5000  inactivity; 
Suspension)  2000,  chromorhinorrhea. 
5000  5000: 2M died. 
Intravenous  0,  5M  250  >250   250: Body weight losses in  96051 
(5% Dextrose)  100,  5F   500  <500  males. 
250,  500: 3M died. 
500 
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EXAMPLE 

2.6.7.6 Repeat-Dose Toxicity  Nonpivotal Studies   Test Article: Curitol Sodium 
Method of 
Administration  Gender 
Species/  (Vehicle/  Duration  Doses  and No.  NOAELa  Study 
Strain  Formulation)  of Dosing  (mg/kg)  per Group  (mg/kg)  Noteworthy Findings  Number 
CD-1  Diet  3 Months  0, 62.5,  10M, 10F  M:4000   4000: Lower body weights; gastric  94018 
Mice  250, 1000,  F: 1000  erosions/ulcers in some mice. 
4000, and  7000: 4M and 6F died/ sacrificed; 
7000  lower body weights; single-cell necrosis 
in liver. 
Wistar  Diet  2 Weeks  0, 1000,  5M, 5F  1000   2000: Lower body weights.  94019 
Rats  2000, and  4000: 2M and 1F sacrificed moribund. 
4000 
Gavage  2 Weeks  0, 500,  5M, 5F  1000  2000: Lower body weights; single-cell  94007 
(Water)  1000, and  necrosis in liver. 
2000 
Beagle  Gavage  5 Days  0, 500,  1M, 1F  <500   500: Weight losses, inappetence.  94008 
Dogs  (CMC  and 1000 
Suspension) 
________ 
a  - No Observed Adverse Effect Level. 
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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  M:30  F:30  M:20  F:20  M:20  F:20  M:30  F:30 
Toxicokinetics: AUC (mcg-hr/ml):
 Day 1 - - 30  28  130  125  328  302 
Day 28 - - 52  47  145  140  400  380 
Day 90  - - 50 51 160 148 511 475
Noteworthy Findings
 Died or Sacrificed Moribund 0  0  0  0  0  0  0  0
 Body Weight (%a) 394 g  244 g  0  -1  -10*  -11*  -25**  -45**
 Food Consumption (%a) 20.4 g  17.2 g  0  -1  -1  -8*  -30**  -50** 
Clinical Observations
 Hyperactivity - -    +   ++ 
Chromorhinorrhea, reddish-
stained coat, white feces - -     ++ ++ 
Emaciated, piloerection, stilted gait - -      ++
 Ophthalmoscopy  - -      
-      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) 
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2.6.7.7A Repeat-Dose Toxicity  Study No. 94214 (Continued) 
Daily Dose (mg/kg)  0 (Control)  200  600  1800 
Number of Animals  M:30  F:30  M:20  F:20  M:20  F:20  M:30  F:30 
Hematology
 Hemoglobin (g/dl) 15.8  15.0  15.7  14.9  15.8  14.6  14.0*  13.1* 
 Erythrocyte Count (x106/mm3)  8.1  - 7.9  - 8.1  - 7.4*  -
 MCH - 22  - 21  - 22  - 19* 
MCHC - 34  - 34  - 34  - 30* 
 Platelet Count  (x103/mm3)  846  799  825  814  914  856  931*  911* 
Serum Chemistry
 Creatinine (IU/L) 0.7  0.7  0.7  0.7  0.7  0.7  1.1*  1.1* 
 Proteins g/dl) - 6.7  - 6.6  - 6.6  - 5.0** 
 Cholesterol (mg/dl) 96  - 86  - 90  - 105*  -
 ALT (IU/L) 67  56  60*  52  55*  47*  53*  58 
 AST (IU/L) 88  92  96  90  87*  84*  85*  93 
 Bilirubin (mg/dl) 0.18  0.20  0.17  0.20  0.18  0.20  0.22**  0.26** 
 Calcium (mEq/L) - 10.7  - 10.8  - 10.8  - 9.8** 
 Phosphorus (mEq/L)  9.3  - 9.3  - 9.3  - 8.2*  -
Urinalysis
 Protein Conc. (mg/dl) 260  49  102  34  123  54  126*  22* 
pH 7.5  - 7.5  - 7.2  - 6.3**  -
 Glucose (mg/dl) - 0  - 0  - 20  - 98** 
 Urine Volume (ml)  - 18  - 18  - 16  - 12* 
-      No noteworthy findings. 

Dunnett's Test:     *- p<0.05          **- p<0.01
 
(Continued)
 
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2.6.7.7A Repeat-Dose Toxicity  Study No. 94214 (Continued) 
Daily Dose (mg/kg)  0 (Control)  200  600  1800 
Number of Animals  M:30  F:30  M:20  F:20  M:20  F:20  M:30  F:30 
Organ Weightsb (%)
 Kidney 3.01 g  1.75 g  0  +5*  +1  +8**  +12**  +20** 
Liver  15.9 g  8.01 g  0  +1  +10*  +12*  +12*  +20** 
Gross Pathology
 Number examined 20  20  20  20  20  20  20  20 
Kidneys: Pallor 0  0  0  0  0  5  1  2 
Glandular Stomach: Discoloration  0  0  0  0  0  1  1  4 
Histopathology
 Number examined 20  20  20  20  20  20  20  20 
Kidneys: Tubular dilatation 0  0  0  0  0  6  3  4 
Mild 0  0  0  0  0  6  1  0 
Moderate 0  0  0  0  0  0  2  4 
Glandular Stomach: Erosions  0  0  0  0  0  2  2  9 
Additional Examinations  - - - - - - - -
Postdose Evaluation:
 Number Evaluated 10  10  0  0  0  0  10  10 
Body Weight a (%) 422 g  265 g  -1  -2  -3  -4  -10*  -20** 
 Kidney Weightb (%)  3.24 g  1.81 g  0  -1  -1  0  +8*  +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. 
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EXAMPLE #2
 
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  M:3  F:3  M:3  F:3  M:3  F:3  M:3  F:3 
Toxicokinetics: AUC (mcg-hr/ml):
 Day 1 - - 5  6  10  12  40  48 
Day 28  - - 4  5  8  11  35  45 
Noteworthy Findings
 No. Died or Sacrificed Moribund
 Body Weight (%a) 0  0  0  0  0  0  0  0 
Clinical Observations: 9.8 kg  9.2 kg  0  0  -1  -19**  0  -18** 
Hypoactivity (after dosing)
 Ophthalmoscopy - - - - - - +  ++ 
Electrocardiography - - - - - - - -
Hematology - - - - - - - -
Serum Chemistry - - - - - - - -
  ALT (IU/L): Week 2 
                     Week 4  22  25  24  27  21  24  48*  69** 
25  27  26  25  23  25  54*  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) 
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2.6.7.7B Repeat-Dose Toxicity  Study No. 94020 (Continued)
 
Daily Dose (mg/kg)  0 (Control)  10  40  100
 
Number of Animals  M:3  F:3  M:3  F:3  M:3  F:3  M:3  F:3 
Organ Weightsa (%)
 Liver  339 g  337 g  +1  -1  +17** +16** +23** +21**
Gross Pathology  - - - -    -
Histopathology
 Number Examined 3  3  3  3  3  3  3  3
 Liver: Centrilobular hypertrophy  0  0  0  0  0  0  2  3
Additional Examinations
 Hepatic Enzyme Induction  - - - -    
-      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. 
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EXAMPLE #1
 
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. 
Assay #1 
Metabolic  Test  Dose Level 
Revertant Colony Counts (Mean SD) 
Activation  Article  (mcg/plate) 
TA 98  TA 100  TA 1535  TA 1537  WP2 uvrA 
Without  DMSO  100 mcl/plate  24  9  129  4  15  4  4  2  17  3 
Activation  MM-180801  312.5  24  6  128  11  12  4  4  2  14  2 
625  32  9  153  9  9  2  8  2  17  5 
1250  30  4  152  12  9  3  9  2  18  4 
2500  27  5  140  6  9  3  5  1  19  1 
5000a  30  3  137  21  15  1  7  2  13 4 
2-Nitrofluorene  2  696 
Sodium azide  1  542  468 
9-Aminoacridine  100  515 
MMS  2.5 mcl/plate  573 
With  DMSO  100 mcl/plate  27  6  161  12  12  5  5  1  21  8 
Activation  MM-180801  312.5  31  4  142  8  12  5  4  2  17  3 
625  30  1  156  15  17  2  9  5  23  3 
1250  33  2  153  13  13  3  8  2  18  3 
2500  35  8  160  4  10  2  8  2  19  5 
5000a  31  4  153  5  9  4  7  1  17 4 
2-Aminoanthracene  2.5  1552  1487  214  61 
10  366 
a  - Precipitation. 
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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 g/ml, and with S9 at 50 and 200 g/ml. 
Metabolic  Test  Concentration  Cytotoxicitya  Aberrant Cells  Total polyploid 
Activation  Article  (mcg/ml)  (% of control)  Mean %  Abs/Cell  cells 
Without  DMSO  - 100  2.0  0.02  4 
Activation 
MM-180801  2.5  78  3.0  0.03  3 
5  59  4.0  0.05  4 
10  36  16.5**  0.20  2 
20  32  35.0**  0.55  3 
Mitomycin  0.10  52  38.5**  0.64  5 
With  DMSO  - 100  4.0  0.04  3 
Activation 
MM-180801  2.5  91  4.5  0.05  3 
10  88  4.5  0.05  2 
50  80  9.5*  0.10  4 
200  43  34.0**  0.66  3 
Cyclophosphamide  4  68  36.5**  0.63  6 
Dunnett's Test:     * - p<0.05          ** - p<0.01 
a - Based on mitotic indices. 
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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.
 
Dose  No. of  Mean % PCEs Mean % MN-PCEs
Test Article  (mg/kg)  Animals       (SD)          (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 
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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.
 
Dose  No. of  Time Nuclear  Cytoplasm  NG  % IR  NGIR 
Test Article  (mg/kg)  Animals  hrs.  Mean  SD  Mean  SD  Mean  SD  Mean  SD  Mean  SD 
Vehicle 	 0  3M  16  3.5  0.2  7.3  0.3  -3.8  0.4  0  0  
MM-180801	  2  3M  2  3.0  1.1  5.5  1.4  -2.6  0.4  0  0  
2  3M  16 4.1  0.5  6.5  0.8  -2.4  0.2  0  0  
20  3M  2  3.9  0.2  6.9  0.3  -3.0  0.1  1  0  5.7  0.4 
20  3M  16 3.6  0.3  6.3  0.4  -2.7  0.2  0  0  
200  3M  2  4.2  0.2  7.5  0.3  -3.4  0.2  0  0  
200  3M  16 3.1  0.3  5.3  0.3  -2.2  0.1  0  0  
2000  3M  2  4.8  0.4  8.2  0.7  -3.4  0.4  0  0  
2000  3M 16  2.7  0.1  4.8  0.3  -2.1  0.3  0  0  
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.
 
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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  M  F  M  F  M  F  M  F 
Toxicokinetics:
 AUC on Day 28 (mcg-hr/mla) - - 10  12  40  48  815 570
 Css on Day 180 (mcg/ml)  - - 0.4  0.5  1.7  0.3  34  24
Number of Animals:
 At Start 60  60  60c  60  60  60  60  60
 Died/Sacrificed Moribund 16  16  15  13  18  20  27  25
 Terminal Sacrifice 44 44 44c 47 42 40  33  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) 
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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 0 1 1 0 6b  1 13b 0 
 Hemangiosarcoma 1 3 2 2 9 11
 18a  24a
  Adrenal: Adrenocortical adenoma  4 1 2 0 4 3
 3 1
Adrenocortical adenocarcinoma 0  0  0  0  0
   1
 0  0 
Adenoma + Adenocarcinoma 4 1 2 0  4 3
 3 1
 Pheochromocytoma 0 0 0 0  1  1
 0 1
 Bone: Osteochondrosarcoma 0 1 0 1  0  0
 0 0
 Osteoma 0 1 0 0  0  0
 0 0
 Epididymis: Sarcoma, undifferentiated 0 0 1 0  0  0
 1 0
 Gallbladder: Adenoma 0 0 1 0  0  0
 0 0
 Harderian gland: Adenoma  4 2 3 1  3  4
 3 1
Kidney: Renal cell adenoma 1 2 0 0  2  0
 0 0
  Liver:Hepatocellular adenoma  3 1 4 2  3  1
 4 1
Hepatocellular carcinoma 2 1 1 2  3  1
 0 1
 Hepatocellular adenoma + carcinoma 3
  2
  4
  3  5
   2
 4
  1
Lung: Alveolar/bronchiolar adenoma 13  10 11  11
  14  7 13
  4

Alveolar/bronchiolar carcinoma 4 0 1 1 2 2
 1
 1
Adenoma + carcinoma  15  10  11  12 15  9
 13
  5

a  - Trend analysis, p<0.005
b  - Trend analysis, p<0.025 
(Continued) 
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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 
Mediastinum: Sarcoma, undifferentiated
 Oviduct: Adenoma 0  1  0  0  0  1  0  0 
Pancreas: Islet cell adenoma 1  1  0  0 
Peritoneum: Osteosarcoma 1  0  0  0  0  0  0  0 
Seminal vesicle: Adenoma 1  0  0  0  1  0  0  1 
Stomach: Osteochondrosarcoma 0  1  0  0 
Thymus: Thymoma 0  0  0  1  0  0  0  0 
Thyroid: Follicular cell adenoma 0  1  0  0  0  0  0  0 
Uterus: Papillary cystadenoma 0  1  0  0  0  1  0  0 
Whole animal: Lymphosarcoma 1  0  2  0 
Whole animal: Histiocytic sarcoma  6  13  4  11  3  12  5  11 
1  0  0  0  0  1  0  0 
Noteworthy Findings:
 Gross Pathology  - - - - - - - -
Histopathology - Non-Neoplastic
 Lesions
 Liver: Hepatocellular hypertrophy 4  2  3  2  4  1  40**  45** 
Testes: Hypospermatogenesis  1  2  15*  30** 
-      No noteworthy findings. 

Fisher Exact Test:  *  - p<0.05         ** - p<0.01
 
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2.6.7.11 Reproductive and Developmental Toxicity                   Nonpivotal Studies   Test Article: Curitol Sodium 
Method of 
Administration 
Species/  (Vehicle/  Dosing  Doses  Study 
Strain  Formulation)  Period  mg/kg  No. per Group  Noteworthy Findings  Number 
Wistar Rats  Gavage  G6 through 0, 500, 1000,  8 Pregnant  1000: Deaths; weight losses; decreased  94201 
(Water)   G15  2000   Females  food consumption; clinical signs; 
resorptions. 
NZW  Gavage  13 Days  0, 5,15, 45  6 Nonpregnant  15: Decreased weight gain and food  97020 
Rabbits  (CMC   Females  consumption. 
Suspension)  45: Four does died. 
G  Gestation day 
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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  Males: 100 mg/kg
 
0
F  Females: 100 mg/kg
 
0
F  Litters: 1000 mg/kg
 
1
Daily Dose (mg/kg)  0 (Control)  10  100  1000 
Males  Toxicokinetics: AUCb (mcg-hr/ml)  - 1.8  25  320 
No. Evaluated  22  22  22  22 
No. Died or Sacrificed Moribund  0  0  0  0 
Clinical Observations: 
Salivation  - - +  ++ 
Necropsy Observations  - - - 
Body Weight (%a)  452 g  0  0  -12* 
Mean No. Days Prior to Mating  2.7  2.5  2.3  2.8 
No. of Males that Mated  22  21  22  22 
No. of Fertile Males  21  21  21  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)
 
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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)  - 2.1  27  310 
No. Evaluated  22  22  22  22 
No. Died or Sacrificed Moribund  0  1  0  0 
Clinical Observations 
Salivation  - - - + 
Necropsy Observations  - - - -
Premating Body Weight (%a)  175 g  0  0  -5* 
Gestation Body Weight (%a)  225 g  0  0  -12** 
Premating Food Consumption (%a)  14 g  0  0  -6* 
Gestation Food Consumption (%a)  15 g  0  0  -15** 
Mean No. Estrous Cycles/14 days  3.9  3.8  3.8  3.9 
Mean No. Days Prior to Mating  2.1  2.3  2.5  2.2 
No. of Females Sperm Positive  21  22  22  21 
No. of Pregnant Females  21  21  22  20 
Mean No. Corpora Lutea  15.9  15.8  16.8  15.3 
Mean No. Implantations  14.5  14.0  15.3  13.8 
Mean % Preimplantation Loss  8.8  11.4  8.9  9.8 
Mean No. Live Conceptuses  13.3  13.3  14.3  12.8 
Mean No. Resorptions  1.2  0.7  1.0  1.0 
No. Dead Conceptuses  0  0  0  0 
Mean % Postimplantation Loss  8.3  5.0  6.5  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  Females: 1 mg/kg 
0
F  Litters: 5 mg/kg 
1
Daily Dose (mg/kg)  0 (Control)  1  5  25 
Dams/Does:  Toxicokinetics: AUCb (mcg-hr/ml)  - 2.6  31  345 
No. Pregnant  20  19  20  20
No. Died or Sacrificed Moribund  0  1  1  0
No. Aborted or with Total Resorption of Litter  0  0  0  3 
Clinical Observations  - - - ++ 
Necropsy Observations  - - - -
Body Weight (%a)  3.2 kg  0  -15*  -20**
Food Consumption (%a)  60 g/day  0  -9*  -16**
Mean No. Corpora Lutea  9.4  9.3  9.4  10.4
Mean No. Implantations  7.9  8.1  9.1  9.4
Mean % Preimplantation Loss  15.8  13.1  4.0  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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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
  18  16  17  18 
No. Live Fetuses
  140  126  148  86* 
Mean No. Resorptions
  0.2  0.3  0.4  4.7** 
No. Dead Fetuses
  1  0  0  0 
Mean % Postimplantation Loss
  4.3  2.8  5.4  49.0** 
Mean Fetal Body Weight (g)
  44.82  42.44  42.14  42.39 
Fetal Sex Ratios (% males)
  46.3  57.7  57.4  52.8 
Fetal Anomalies:
 
Gross External 
Lower jaw: Short 
No. Fetuses (%)  0  0  0  7 (8.0)* 
No. Litters (%)  0  0  0  5 (27.8)** 
Visceral Anomalies 
Tongue: Absent 
No. Fetuses (%)  0  0  0  6 (6.9)* 
No. Litters (%)  0  0  0  6 (33.3)** 
Skeletal Anomalies 
Mandible: Cleft 
No. Fetuses (%)  0  0  0  10 (11.5)** 
No. Litters (%)  0  0  0  8 (44.4)** 
Ribs: Cervical 
No. Fetuses (%)  2 (1.4)  0  1 (0.7)  0 
No. Litters (%)  1 (5.6)  0  1 (5.9)  0 
Sternebrae: Misshapen 
No. Fetuses (%)  2 (1.4)  1 (0.8)  0  1 (1.2) 
No. Litters (%)  2 (11.1)  1 (6.3)  0  1 (5.6) 
Total Affected Fetuses (Litters)  2 (2)  1 (1)  0  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  Females: 7.5 mg/kg
 
0
F  Males: 75 mg/kg
 
1
F  Females: 75 mg/kg
 
1
Daily Dose (mg/kg)	  0 (Control)  7.5  75  750 
F  Females:  Toxicokinetics: AUCb (mcg-hr/ml)  - 2.4  21  150 
0
No. Pregnant  23  21  22  23 
No. Died or Sacrificed Moribund  0  0  0  8 
Clinical Observations  - - ++  +++ 
Necropsy Observations  - - - -
Gestation Body Weight (%a)  225 g  0  0  -25** 
Lactation Body Weight (%a)  210 g  0  0  0 
Gestation Food Consumption (%a)  15 g  0  0  -12* 
Lactation Food Consumption (%a)  16 g  0  0  0 
Mean Duration of Gestation (days)  22.1  22.2  22.1  23.5+ 
Abnormal Parturition  - - - -
- 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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2.6.7.14  Reproductive and Developmental Toxicity  Study No. 95201 
(Continued) 
Daily Dose (mg/kg)  0 (Control) 7.5
 75	  750 
F  Litters:	  No. Litters Evaluated  23  21  22  15 
1
(Preweaning)	  Mean No. Pups/Litter  13.6  13.8  14.9  11.2++ 
Mean No. Liveborn Pups/Litter  13.5  13.8  14.6  9.4++ 
Mean No. Stillborn Pups/Litter  0.1  0.0  0.3  1.8+ 
Postnatal Survival to Day 4  - - - -
Postnatal Survival to Weaning  - - - -
Change in Pup Body Weightsa (g)  60  58  62  53* 
Pup Sex Ratios (% males)  51  53  49  51 
Pup Clinical Signs  - - - -
Pup Necropsy Observations  - - - -
F  Males:	  No. Evaluated Postweaning  23  21  22  15 
1
(Postweaning)	  No. Died or Sacrificed Moribund  - - - -
Clinical Observations  - - - -
Necropsy Observations  - - - -
Body Weight Changeb (g)  200  195  195  186* 
Food Consumption (%b)  15 g  0  0  -11* 
Preputial Separation  - - - -
Sensory Function  - - - -
Motor Activity  - - - -
Learning and Memory  - - - -
Mean No. Days Prior to Mating  2.4  3.3  2.9  3.5 
No. of Males that Mated  23  21  21  23 
No. of Fertile Males  23  21  19  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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2.6.7.14 Reproductive and Developmental Toxicity  Study No. 95201 
(Continued) 
Daily Dose (mg/kg)  0 (Control)  7.5  75         750 
F  Females:  No. Evaluated Postweaning  23  21  22  23 
1
(Postweaning)  No. Died or Sacrificed Moribund  0  1  0  0 
Clinical Observations  - - - -
Necropsy Observations  - - - -
Premating Body-Weight Changea (g)  226  230  235  196* 
Gestation Body-Weight Change (g)  153  160  144  158 
Premating Food Consumption (%b)  15 g  0  0  -13* 
Gestation Food Consumption (%b)  16 g  0  0  0 
Mean Age of Vaginal Patency (days)  - - - -
Sensory Function  - - - -
Motor Activity  - - - -
Learning and Memory  - - - -
Mean No. Days Prior to Mating  2.4  3.3  3.1  3.5 
No. of Females Sperm Positive  23  21  21  23 
No. of Pregnant Females  23  21  20  21 
Mean No. Corpora Lutea  16.4  16.2  15.8  15.5 
Mean No. Implantations  15.8  15.2  14.4  14.9 
Mean % Preimplantation Loss  3.8  6.3  12.3  3.7 
F  Litters:  Mean No. Live Conceptuses/Litter  15.0  14.9  13.6  14.4 
2
Mean No. Resorptions  0.8  0.3  0.8  0.5 
No. Dead Conceptuses  0  0  0  0 
Mean % Postimplantation Loss  5.1  2.2  5.2  3.4 
Fetal Body Weights (g)  3.69  3.65  3.75  3.81 
Fetal Sex Ratios (% males)  53  49  54  54 
Fetal Anomalies  - - - -
-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). 
114
  The Common Technical Document  Safety 
EXAMPLE 
2.6.7.17 Other Toxicity Studies  Test Article: Curitol Sodium 
Species/  Method of  Duration  Doses  Gender and  Study 
Strain  Administration  of Dosing  (mg/kg)  No. per Group  Noteworthy Findings  Number 
Antigenicity 
Guinea  Subcutaneous
  Weekly  0, 5 mg  5M, 5F  Mildly positive delayed hypersensitivity  97012 
Pigs 
 for  reaction.  No evidence of passive 
3 weeks;  cutaneous anaphylaxis or systemic 
challenge  anaphylaxis. 
1 week 
later. 
Impurities 
WISTAR  Gavage 
 2 Weeks  0, 1000,  10M, 10F  MM-180801 fortified with 2% of the Z- 97025 
Rats
  2000  isomer impurity; toxicologic effects 
comparable to MM-180801 without 
impurity. 
115