Appendix_2__Sample_PDR_Report.pdf

PATHOLOGY DATA REVIEW

FOR

CHRONIC GAVAGE TOXICITY/CARCINOGENICITY

IN MALE AND FEMALE B6C3F1 MICE

CHEMICAL/TDMS NO.:

CONDUCTED BY:

Submitted to:

National Toxicology Program Research Triangle Park, NC 27709

Submitted by:

Research Triangle Park, NC 27709

Under Contract No.:

CHEMICAL NAME:

CHEMICAL NUMBER: TDMS NUMBER:

LAB:

STRAIN: B6C3F1 SEX/SPECIES: MALE AND FEMALE MICE

SACRIFICE: CHRONIC

STUDY PATHOLOGIST:

ROUTE OF ADMINISTRATION: GAVAGE

TABLE OF CONTENTS

I. Material(s) Reviewed

II. Pathology Narrative(s)

III. Animal Disposition Summary(ies)

IV. Discrepancies

Data Entry Errors – IANR Forms External Potential Masses Recorded In-Life But Not At Necropsy Date of Death Non-Correlations Unaccountable Gross Observations Observations to be Addressed During Pathology Quality Assessment

V. Potential Duplications In Topography and/or Morphology & Inappropriate Topography for a Specific Morphology and/or Other Potential Errors in Terminology

VI. Tumor Incidences in Control Groups Which Vary From Current NTP Historical Control Values

VII. Lesions with Unusual Incidences

VIII. Incidence of Potential Treatment-Related Lesions

IX. Significant Study Findings to be Reviewed and Addressed During the Quality Review

X. Recommended Organs and Lesions for Review

XI. Other Comments

XII. Conflict of Interest Statement

Table of Contents Continued

Attachments:

DISCREPANCY FORMS

Attachment A: Data Entry Errors – IANR Forms Attachment B: External Potential Masses Recorded In-Life But Not At Necropsy – N/A Attachment C: Date of Death Non-Correlations – N/A Attachment D: Unaccountable Gross Observations Attachment E: Observations to be Addressed During Pathology Quality Assessment

PATHOLOGY NARRATIVES

Attachment F: Prechronic PPR Report Attachment G: Pathology Narrative for the Subchronic Toxicity/Carcinogenicity Study Attachment H: Pathology Narrative for the Chronic Toxicity/Carcinogenicity Study

I. MATERIALS REVIEWED:

A. 13-WEEK SUBCHRONIC REPORT

Pathologists Peer Review (PPR) Chairperson’s Report of Three-Month Toxicity Study of Administered by Gavage to B6C3F1 Mice ( )

POST EXPERIMENT INFORMATION SYSTEM REPORTS

PEIS Report 03 - Incidence Rates of Non-Neoplastic Lesions by Anatomic Site ( ) PEIS Report 05 – Incidence Rates of Neoplasms by Anatomic Site ( ) PEIS Report 10 - Statistical Analysis of Non-Neoplastic Lesions ( ) PEIS Report 18 - Incidence Rates of Non-Neoplastic Lesions By Anatomic Site ( ) With Severity Grades

B. TWO-YEAR CORE GROUP

Chronic Gavage Toxicity/Carcinogenicity Study of in B6C3F1 Mice ( )

POST EXPERIMENT INFORMATION SYSTEM REPORTS

PEIS Report 02 - Incidence Rates of Neoplasms by Anatomic Site ( ) PEIS Report 03 - Incidence Rates of Non-Neoplastic Lesions by Anatomic Site ( ) PEIS Report 04 - Neoplasms by Individual Animal (CID SORT) ( ) PEIS Report 08 - Statistical Analysis of Primary Tumors ( ) PEIS Report 09 - Non-Neoplastic Lesions by Individual Animal (CID SORT) ( ) PEIS Report 10 - Statistical Analysis of Non-Neoplastic Lesions ( ) PEIS Report 11 - Statistical Analysis of Survival Data ( ) PEIS Report 14 - Individual Animal Pathology Data ( ) PEIS Report 17 - Neoplasms by Individual Animal/Abridged ( ) PEIS Report 18 - Incidence Rates of Non-Neoplastic Lesions By Anatomic Site ( ) With Severity Grades

EXPERIMENTAL INFORMATION SYSTEM REPORTS

EIS Report 01 - Animals Removal Summary/Treatment Group ( ) EIS Report 02 - Animals Removed From Experiment ( ) EIS Report 03 - Growth Curve (N/A) EIS Report 04 - Mean Body Weights and Survival Table ( ) EIS Report 05 - Clinical Observations Summary ( ) EIS Report 08 - Feed/Water and Compound Consumption (N/A) EIS Report 09 - Summary of Dermal Clinical Observation at Site of Application (N/A) EIS Report 11 - All Skin Papillomas By Animal and Week on Dose (N/A) EIS Report 12 - Animal History ( )

II. PATHOLOGY NARRATIVE:

A. 13-WEEK SUBCHRONIC REPORT

The following is abstracted from the final report, “Three-Month Toxicity

Study of Administered by Gavage to B6C3F1 Mice” dated

Administration of by gavage had no effect on survival of male or female mice…Administration of by gavage had no effect on body weights of male or female mice… Administration of by gavage produced no clinical signs of toxicity in male or female mice… Administration of was associated with statistically significant differences in the absolute and relative weights of the liver in male and female mice…The elevations in liver weights were considered to be treatment-related because they occurred in a generally dose-related fashion, and they occurred in mice of both sexes…No changes in hematology parameters…were considered to be due to administration…in male or female mice. No toxicologically significant changes in enzymes activity were observed in male or female mice. The mean activity of CYP1A1 and CYP1A2 in the liver showed mild dose-related trends toward higher activity for mice of both sexes in the highest dose group. While these changes were likely due to administration, they were of insufficient magnitude to be considered toxicologically significant. No definitive test article-related histopathologic lesions were observed in male or female mice treated with

B. CHRONIC TOXICITY/CARCINOGENICITY STUDY

Mice

The following is abstracted from the final report, “Chronic Gavage

Toxicity/Carcinogenicity Study of ( ( ; CAS No.

in B6C3F1 Mice ”:

After 105 weeks on study, overall survival for females in the 250 mg/kg dosage group was 90 percent, whereas survival for controls was 67 percent.

This higher than control survival was statistically significant (p=0.016). For all other dosage groups in both males and females, survival was at least 10 percent greater for mice receiving compared to controls, with the exception of females in the 125 mg/kg group, for whom survival was 17 percent lower than controls. With the exception of survival for females in the 250 mg/kg dosage group, none of these differences in survival were statistically significant…Group mean body weights for males dosed with remained within ±10 percent of control throughout 105 weeks of study. For females, group mean body weights for animals dosed with were within ±10 percent of control through the first 32 weeks of study. From 33 to 92 weeks on study, the 250 mg/kg female mean body weights ranged from 89.0 to 79.3 percent of control. At termination, body weights for female mice treated with were within ±10 percent of control body weights for all dosage levels. In addition, at termination, body weights for males treated with were within +10 percent of control body weights for all dosage levels…The gross data are not summarized; however, there were no apparent treatment-related trends in gross observations when compared to controls. No related clinical observations were reported during this study.

Male and female B6C3F1 mice were administered 0 (vehicle controls), 62.5, 125, and 250 mg/kg of in corn oil by gavage. There were increased incidences of hepatoblastomas and hepatocellular adenomas (multiple and total) in the 250 mg/kg males and increased hepatocellular carcinomas in the 62.5, 125, and 250 mg/kg males, though only the categories “Hepatocellular Carcinoma” and “Total Hepatocellular Carcinomas” were increased in the 62.5 mg/kg males, and only “Multiple Hepatocellular Carcinomas” and “Total Hepatocellular Carcinomas” were increased in the 250 mg/kg males. Hepatic foci (clear cell, eosinophilic and mixed cell) were increased in incidence in the 62.5, 125, and 250 mg/kg males.

Lesions of the glandular stomach characterized as chronic inflammation, epithelial hyperplasia and epithelial necrosis were noted at an incidence and severity greater than control in the 125 and 250 mg/kg males and females, and in the 62.5 mg/kg females.

Nasal lesions characterized as olfactory epithelial degeneration and hyperplasia of glands and respiratory epithelium were noted with increased incidence and severity in all treated groups of males and in 125 and 250 mg/kg females. Nerve atrophy in the mucosa of the region of olfactory nerve endings in the nasal mucosa was noted with increased frequency in the 250 mg/kg males and females, and with slightly increased frequency in the 125 mg/kg females. Nasal inflammation was found with increased incidence in the 125 and 250 mg/kg females.

Rats

The following is abstracted from the final report, “Chronic Gavage

Toxicity/Carcinogenicity Study of ( ( ; CAS No.

in Harlan Sprague-Dawley Rats ( )”:

None of the survival data for males or females in any dosage groups was statistically different from the vehicle control; however, the survival was decreased in all the male groups compared to control… treated animals were similar to vehicle controls in overt behavior and in general health and appearance….For core males, group mean body weights remained within 10 percent of vehicle control. Likewise, group mean body weights for core females in the 75 and 300 mg/kg dosage groups were within 10 percent of vehicle control for the entire study. Only core females in the 150 mg/kg dosage group had body weights that were more than ± 10 percent of control mean body weights; for females in this dosage group, group mean body weights were 11.3 and 10.9 percent lower than control body weights at 701 days on study and at termination, respectively…Among core rats, there were apparent increases in liver masses and cysts in -treated rats of both sexes and in uterine masses in treated female rats when compared to vehicle controls.

The uterus, liver, and small intestines (duodenum and jejunum) were targets of exposure. Uterine endometrial carcinomas were present only in treated female rat groups (75, 150, and 300 mg/kg). Cholangiocarcinomas were found in the livers of treated groups in both sexes. There was an increased incidence of hepatocellular adenomas in the 150 mg/kg female dosage group when compared to vehicle controls. The incidence of bile duct cysts was greater in 150 and 300 mg/kg male and female rats when compared to vehicle controls. There were increased incidences of clear cell and eosinophilic foci in the 300 mg/kg females. Lymphatic ectasia was present in the small intestine (jejunum and duodenum) in treated 150 and 300 mg/kg male and female rats and appeared morphologically unchanged from the lesions observed in the 4-week special study. This lesion was also present in a previous 3-month study of in Fischer-344 rats (Hébert, et al, 2006b). The significance of duodenal and jejunal lymphatic ectasia is unknown, but there was no apparent association with morbidity and mortality in these animals.

III. ANIMAL DISPOSITION SUMMARY:

A. Chronic Toxicity/Carcinogenicity Study

MALE MICE

0 mg/kg 62.5 mg/kg 125 mg/kg 250 mg/kg Animals Initially in Study 50 50 50 50 Early Deaths Natural Death 6 7 6 8 Moribund Sacrifice 17 12 11 9 Accidentally Killed - - - 1 Dosing Accident - - 1 - Survivors – Natural Death 1 - - - Survivors – Terminal Sacrifice 26 31 32 32 Animals Examined Microscopically 50 50 50 50

FEMALE MICE

0 mg/kg 62.5 mg/kg 125 mg/kg 250 mg/kg Animals Initially in Study 50 50 50 50 Early Deaths Natural Death 6 4 9 2 Moribund Sacrifice 10 6 15 3 Dosing Accident 1 - - - Survivors – Moribund Sacrifice - - 1 - Survivors – Terminal Sacrifice 33 40 25 45 Animals Examined Microscopically 50 50 50 50

IV. DISCREPANCIES

DATA ENTRY ERRORS – IANR FORMS

Discrepancies in the completeness, accuracy, and internal consistency of information entered on Individual Animal Necropsy Records (IANR) forms and data in Experimental Information System (EIS) Reports for all animals are listed on

DATA ENTRY ERROR forms (Attachment A).

EXTERNAL POTENTIAL MASSES RECORDED IN-LIFE BUT NOT AT

NECROPSY:

There were no discrepancies in the correlation of observations of external potential masses between the Experimental Information System (EIS) Reports 02, 12, and IANR forms for all.

DATE OF DEATH NON-CORRELATIONS:

There were no discrepancies in the correlation for animal survival (date and reason for removal) between the Experimental Information System (EIS) Reports

02, 12, PEIRPT14, and IANR forms.

UNACCOUNTABLE GROSS OBSERVATIONS:

Discrepancies in the extent to which each gross observation recorded on the IANR form for all animals is accounted for either by a microscopic diagnosis on

PEIRPT14 or by an appropriate note on the IANR form or PEIRPT14 are listed on

UNACCOUNTABLE GROSS OBSERVATIONS forms (Attachment D).

OBSERVATIONS TO BE ADDRESSED DURING PATHOLOGY QUALITY

ASSESSMENT

Potential duplicate diagnoses and organ notes on the PEIRP14 in which a diagnosis is listed that needs to be addressed during the QA slide review are listed in Attachment E.

V. POTENTIAL DUPLICATIONS IN TOPOGRAPHY AND/OR MORPHOLOGY &

INAPPROPRIATE TOPOGRAPHY FOR A SPECIFIC MORPHOLOGY AND/OR

OTHER POTENTIAL ERRORS IN TERMINOLOGY:

Eye – Degeneration Heart – Cardiomyopathy Heart – Inflammation, Chronic Heart, Myocardium – Mineralization Heart, Myocardium – Necrosis Intestine, Small, Duodenum – Polyp Adenomatous Intestine, Small, Jejunum – Polyp, Adenomatous Kidney – Glomerulosclerosis Kidney – Infiltration Cellular, Mononuclear Cell Kidney – Inflammation, Chronic Kidney – Nephropathy Kidney, Renal Tubule – Hyperplasia Oral Mucosa – Regeneration Prostate – Infiltration Cellular, Mononuclear Cell Prostate – Inflammation, Chronic Seminal Vesicle – Infiltration Cellular, Mononuclear Cell Seminal Vesicle – Inflammation, Chronic Skin, Epidermis – Keratoacanthoma Spleen – Atrophy Thyroid, Follicle – Cytoplasmic Alteration

Adrenal Cortex – Cytoplasmic Alteration Eye – Inflammation, Chronic Eye, Cornea – Inflammation, Chronic Heart – Cardiomyopathy Heart – Inflammation, Chronic Heart, Myocardium – Mineralization Lung – Hyperplasia, Lymphoid Lung – Inflammation, Chronic Ovary – Cytoplasmic Alteration Salivary Glands – Infiltration Cellular Salivary Glands – Infiltration Cellular, Mononuclear Cell Skin – Hemangioma Stomach, Glandular – Hyperplasia, Lymphoid Stomach, Glandular – Inflammation, Chronic

VI. TUMOR INCIDENCES IN CONTROL GROUPS WHICH VARY FROM CURRENT

NTP HISTORICAL CONTROL VALUES:

Concurrent

Control Historical Control

Route: Gavage Vehicle: Corn oil

Historical Control Route: All Routes Vehicle: All Vehicle

No./(%)

Ave.

± SD

Range

Ave.

± SD

Range

SMALL INTESTINE,

DUODENUM

Polyp Adenomatous 2/(4%) 0 0 0 0.08% 0.4% 0-2%

SMALL INTESTINE,

JEJUNUM

Polyp Adenomatous 1/(2%) 0 0 0 0 0 0

LIVER

Histiocytic Sarcoma 2/(4%) 0 0 0 0.4% 0.82% 0-2%

SALIVARY GLAND

Adenoma 1/(2%) 0 0 0 0 0 0

THYMUS

Thymoma, Benign 1/(2%) 0 0 0 0 0 0 The Historical Control values used for comparison were taken from “Tumor Incidence for Selected Control Animal Groups” prepared by NIEHS by , B6C3F1 Mice, All Routes/All Vehicles and B6C3F1 Mice, Inhalation/Air.

Concurrent Control

Historical Control Route: Gavage Vehicle: Corn oil

Historical Control Route: All Routes Vehicle: All Vehicle

No./(%)

Ave.

± SD

Range

Ave.

± SD

Range

INTESTINE, LARGE,

CECUM

Leiomyosarcoma 1/(2%) 0 0 0 0 0 0 The Historical Control values used for comparison were taken from “Tumor Incidence for Selected Control Animal Groups” prepared by NIEHS by , B6C3F1 Mice, All Routes/All Vehicles and B6C3F1 Mice, Inhalation/Air.

VII. LESIONS WITH UNUSUAL INCIDENCES:

Control 62.5 mg/kg 125 mg/kg 250 mg/kg (Survivors to Terminal Sacrifice) 26 31 32 32

ADRENAL CORTEX (NO. EX.) (50) (50) (50) (50)

HYPERTROPHY 0 4 (8%)

[1.5] 2 (4%) [2.0]

HEART, ARTERY (NO. EX.) (50) (50) (50) (50)

INFLAMMATION, CHRONIC 2 (4%)

[1.5] 0 0 0

LYMPH NODE, MESENTERIC (NO. EX.) (48) (48) (49) (50)

HYPERPLASIA, LYMPHOID 0 0 0 2 (4%)

[2.0]

PANCREAS (NO. EX.) (50) (50) (50) (50)

INFLAMMATION, CHRONIC 0 0 0 2 (4%)

[3.5]

PREPUTIAL GLAND (NO. EX.) (50) (50) (50) (50)

CYST 14 (28%)

[2.0] 10 (20%)

[1.9] 6 (12%)

[2.0] 6 (12%)

[2.0]

INFLAMMATION, SUPPURATIVE 2 (4%)

[2.0] 0 0 0

SEMINAL VESICLE (NO. EX.) (50) (50) (50) (50)

INFILTRATION CELLULAR, MONONUCLEAR

CELL

0 5 (10%) [1.0]

0 0

STOMACH, FORESTOMACH (NO. EX.) (50) (50) (50) (50)

ULCER 6 (12%)

[2.7] 5 (10%)

[2.4] 7 (14%)

[2.4] 1 (2%) [2.0]

TOOTH (NO. EX.) (25) (36) (32) (18)

MALFORMATION 25 (100%)

[2.4] 36 (100%)

[2.6] 32 (100%)

[2.5] 18 (100%)

[2.1] [ ] = Average Severity Grade (Non-Neoplastic Lesions) ( ) = Percentage of Affected Animals (Neoplastic and Non-Neoplastic Lesions)

(Survivors to Terminal Sacrifice) 33 40 25 45

BRAIN, HYPOTHALAMUS (NO. EX.) (50) (50) (50) (50)

COMPRESSION 2 (4%)

[3.0] 0 0 0

HARDERIAN GLAND (NO. EX.) (50) (50) (50) (50)

INFILTRATION CELLULAR, MONONUCLEAR

CELL

24 (48%) [1.0]

18 (36%) [1.1]

8 (16%) [1.0]

22 (44%) [1.0]

ISLETS, PANCREATIC (NO. EX) (50) (50) (50) (50)

HYPERPLASIA 5 (10%)

[1.0] 1 (2%) [1.0]

4 (8%) [2.3]

1 (2%) [1.0]

KIDNEY (NO. EX.) (50) (50) (50) (50)

MINERALIZATION 4 (8%)

[1.3] 1 (2%) [1.0]

4 (8%) [1.3]

LIVER (NO. EX.) (50) (50) (50) (50)

TENSION LIPIDOSIS 6 (12%)

[1.0] 1 (2%) [1.0]

10 (20%) [1.0]

3 (6%) [1.0]

LUNG (NO. EX.) (50) (50) (50) (50)

INFLAMMATION, CHRONIC 2 (4%)

[1.0] 1 (2%)

2.0] 0 0

SPLEEN (NO. EX.) (50) (50) (50) (50)

LYMPHOID FOLLICLE, HYPERPLASIA 2 (4%)

[2.5] 0 0 0

STOMACH, FORESTOMACH (NO. EX.) (50) (50) (50) (50)

ULCER 9 (18%)

[2.6] 4 (8%) [2.5]

8 (16%) [2.1]

3(6%) [2.3]

URINARY BLADDER (NO. EX.) (50) (50) (50) (50)

INFILTRATION CELLULAR, MONONUCLEAR

CELL

3 (6%) [1.0]

0 0 0

VIII. INCIDENCE OF POTENTIAL TREATMENT-RELATED LESIONS:

Survivors to Terminal Sacrifice 26 31 32 32

ALL ORGANS

MALIGNANT TUMORS 28 (56%) 30 (60%) 42 (84%) 41 (82%)

EPIDIDYMIS (NO. EX.) (50) (50) (50) (50)

GRANULOMA SPERM 0 2 (4%)

[1.5] 0 1 (2%)

[3.0]

INFILTRATION CELLULAR, MONONUCLEAR

CELL

1 (2%) [1.0]

6 (12%) [1.2]

3 (6%) [1.0]

5 (10%) [1.0]

HARDERIAN GLAND (NO. EX.) (50) (50) (50) (50)

HYPERPLASIA 1 (2%)

[1.0] 4 (8%) [2.3]

5 (10%) [2.0]

3 (6%) [2.7]

INFILTRATION, CELLULAR, MONONUCLEAR

CELL

8 (16%) [1.0]

16 (32%) [1.0]

13 (26%) [1.0]

19 (38%) [1.1]

INTESTINE SMALL, DUODENUM (NO. EX.) (50) (50) (50) (50)

CARCINOMA 0 0 0 2 (4%)

ISLETS, PANCREATIC (NO. EX.) (50) (50) (50) (50)

HYPERPLASIA 36 (72%)

[1.7] 31 (62%)

[1.7] 32 (64%)

[1.6] 22 (44%)

[1.5]

KIDNEY (NO. EX.) (50) (50) (50) (50)

MINERALIZATION 6 (12%)

[1.7] 37 (74%)

[1.1] 17 (34%)

[1.0] 23 (46%)

[1.0]

NEPHROPATHY 33 (66%)

[1.6] 47 (94%)

[1.3] 45 (90%)

[1.5] 41 (82%)

[1.3]

LIVER (NO. EX.) (50) (50) (50) (50)

CLEAR CELL FOCUS 7 (14%) 17 (34%) 17 (34%) 22 (44%)

EOSINOPHILIC FOCUS 24 (48%) 35 (70%) 31 (62%) 31(62%)

FATTY CHANGE 29 (58%) 26 (52%) 28 (56%) 37 (74%)

MIXED CELL FOCUS 1 (2%) 10 (20%) 12 (24%) 11 (22%)

HEPATOBLASTOMA 3 (6%) 3 (6%) 1 (2%) 6 (12%)

HEPATOBLASTOMA, MULTIPLE 1 (2%) 3 (6%) 7 (14%)

HEPATOCELLULAR ADENOMA 13 (26%) 12 (24%) 12 (24%) 8 (16%)

HEPATOCELLULAR ADENOMA, MULTIPLE 15 (30%) 16 (32%) 12 (24%) 30 (60%)

HEPATOCELLULAR CARCINOMA 10 (20%) 15 (30%) 13 (26%) 10 (20%)

HEPATOCELLULAR CARCINOMA, MULTIPLE 5 (10%) 5 (10%) 23 (46%) 18 (36 %)

NOSE (NO. EX.) (50) (50) (50) (50)

POLYP, INFLAMMATORY

0 1 (2%) [1.0]

3 (6%) [1.0]

1 (2%) [2.0]

GLANDS, RESPIRATORY EPITHELIUM,

HYPERPLASIA

13 (26%) [1.0]

18 (36%) [1.0]

25 (50%) [1.2]

28 (56%) [1.8]

OLFACTORY EPITHELIUM, DEGENERATION 13 (26%)

[1.0]

19 (38%) [1.2]

25 (50%) [1.4]

29 (58%) [1.8]

Survivors to Terminal Sacrifice 26 31 32 32

SPLEEN (NO. EX.) (50) (50) (50) (50)

HEMATOPOIETIC CELL PROLIFERATION 16 (32%)

[1.9] 17 (34%)

[2.2] 24 (48%)

[1.8] 21 (42%)

[2.1]

STOMACH, FORESTOMACH (NO. EX.) (50) (50) (50) (50)

INFLAMMATION, CHRONIC 0 1 (2%)

[1.0] 4 (8%) [1.8]

1 (2%) [2.0]

STOMACH, GLANDULAR (NO. EX.) (50) (50) (50) (50)

INFLAMMATION, CHRONIC 1 (2%)

[1.0] 0 11 (22%)

[1.0] 37 (74%)

[1.1]

EPITHELIUM, HYPERPLASIA 0 1 (2%)

[1.0] 27 (54%)

[1.1] 47 (94%)

[1.5]

EPITHELIUM, NECROSIS 0 1 (2%)

[1.0] 24 (48%)

[1.0] 44 (88%)

[1.0]

TESTES, GERMINAL EPITHELIUM (NO. EX.) (50) (50) (50) (50)

ATROPHY 0 1 (2%)

[1.0] 0 3 (6%)

[1.7]

Survivors to Terminal Sacrifice 33 40 25 45

BONE (NO. EX.) (50) (50) (50) (50)

FIBROSIS 5 (10%)

[1.6] 5 (10%)

[1.6] 3 (6%) [1.7]

11 (22%) [1.5]

HARDERIAN GLAND (NO. EX.) (50) (50) (50) (50)

ATROPHY 0 0 0 5 (10%)

[1.2]

HYPERPLASIA 3 (6%)

[1.7] 3 (6%) [1.7]

6 (12%) [2.3]

10 (20%) [1.6]

KIDNEY (NO. EX.) (50) (50) (50) (50)

NEPHROPATHY 25 (50%)

[1.3] 17 (34%)

[1.3] 14 (28%)

[1.2] 15 (30%)

[1.1]

LIVER (NO. EX.) (50) (50) (50) (50)

EOSINOPHILIC FOCUS 15 (30%) 22 (44%) 21 (42%) 20 (40%)

MIXED CELL FOCUS 4 (8%) 10 (20%) 10 (20%) 5 (10%)

HEPATOBLASTOMA 0 0 1 (2%) 1 (2%)

HEPATOCELLULAR ADENOMA 5 (10%) 11 (22%) 7 (14%) 9 (18%)

Survivors to Terminal Sacrifice 33 40 25 45

NOSE (NO. EX.) (50) (50) (50) (50)

INFLAMMATION 4 (8%)

[1.5] 1 (2%) [1.0]

8 (16%) [1.1]

39 (78%) [1.2]

GLANDS, RESPIRATORY EPITHELIUM,

HYPERPLASIA

13 (26%) [1.0]

11 (22%) [1.0]

23 (46%) [1.1]

50 (100%) [3.0]

NERVE, ATROPHY 0 0 1 (2%)

[2.0]

50 (100%) [3.0]

OLFACTORY EPITHELIUM, DEGENERATION 13 (26%)

[1.0]

11 (22%) [1.0]

23 (46%) [1.2]

50 (100%) [3.0]

OVARY (NO. EX.) (50) (50) (50) (50)

CYST 17 (34%)

[1.4] 15 (30%)

[1.4] 10 (20%)

[1.6] 8 (16%)

[1.3]

PITUITARY GLAND (NO. EX.) (50) (50) (50) (50)

PARS DISTALIS, HYPERPLASIA 4 (8%)

[1.5] 15 (30%)

[1.7] 10 (20%)

[1.4] 8 (16%)

[1.3]

PARS DISTALIS, ADENOMA 5 (10%) 5 (10%) 0 1 (2%)

SALIVARY GLANDS (NO. EX.) (50) (49) (50) (50)

INFILTRATION CELLULAR, MONONUCLEAR

CELL

21 (42%) [1.0]

31 (63%) [1.0]

26 (52%) [1.0]

27 (54%) [1.1]

SPLEEN (NO. EX.) (50) (50) (50) (50)

HEMATOPOIETIC CELL PROLIFERATION 32 (64%)

[1.9] 32 (64%)

[1.4] 28 (56%)

[1.4] 21 (42%)

[1.4]

STOMACH, GLANDULAR (NO. EX.) (50) (50) (50) (50)

INFLAMMATION, CHRONIC 0 6 (12%)

[1.0] 14 (28%)

[1.1] 44 (88%)

[1.3]

EPITHELIUM, HYPERPLASIA 1 (2%)

[2.0] 5 (10%)

[1.4] 8 (16%)

[1.0] 35 (70%)

[1.4]

EPITHELIUM, NECROSIS 0 7 (14%)

[1.0] 16 (32%)

[1.0] 46 (92%)

[1.1]

IX. SIGNIFICANT STUDY FINDINGS TO BE REVIEWED AND ADDRESSED

DURING THE QUALITY REVIEW:

ORGAN MORPHOLOGY FINDING

MALIGNANT TUMORS ALL ORGANS INCREASED INCIDENCE

ADRENAL CORTEX HYPERTROPHY INCREASED INCIDENCE

EPIDIDYMIS INFILTRATION CELLULAR,

MONONUCLEAR CELL

INCREASED INCIDENCE

HARDERIAN GLAND INFILTRATION, CELLULAR,

MONONUCLEAR CELL

INCREASED INCIDENCE

HEART, ARTERY INFLAMMATION, CHRONIC DECREASED INCIDENCE

ISLETS, PANCREATIC HYPERPLASIA DECREASED INCIDENCE

KIDNEY MINERALIZATION INCREASED INCIDENCE

KIDNEY NEPHROPATHY INCREASED INCIDENCE

LIVER CLEAR CELL FOCUS INCREASED INCIDENCE

LIVER EOSINOPHILIC FOCUS INCREASED INCIDENCE

LIVER FATTY CHANGE INCREASED INCIDENCE

LIVER MIXED CELL FOCUS INCREASED INCIDENCE

LIVER HEPATOBLASTOMA INCREASED INCIDENCE

LIVER HEPATOBLASTOMA, MULTIPLE INCREASED INCIDENCE

LIVER HEPATOCELLULAR ADENOMA INCREASED INCIDENCE

LIVER HEPATOCELLULAR ADENOMA,

MULTIPLE

INCREASED INCIDENCE

LIVER HEPATOCELLULAR CARCINOMA INCREASED INCIDENCE

LIVER HEPATOCELLULAR CARCINOMA,

MULTIPLE

INCREASED INCIDENCE

LUNG, ALVEOLAR EPITHELIUM HYPERPLASIA DECREASED INCIDENCE

LYMPH NODE, MESENTERIC HYPERPLASIA, LYMPHOID INCREASED INCIDENCE

NOSE, GLANDS, RESPIRATORY

EPITHELIUM

HYPERPLASIA INCREASED INCIDENCE

NOSE, NERVE ATROPHY INCREASED INCIDENCE

NOSE, OLFACTORY

EPITHELIUM

DEGENERATION INCREASED INCIDENCE

PANCREAS INFLAMMATION, CHRONIC INCREASED INCIDENCE

PREPUTIAL GLAND CYST DECREASED INCIDENCE

PREPUTIAL GLAND INFLAMMATION, SUPPURATIVE DECREASED INCIDENCE

SEMINAL VESICLE INFILTRATION CELLULAR,

MONONUCLEAR CELL

INCREASED INCIDENCE

STOMACH, FORESTOMACH INFLAMMATION, CHRONIC INCREASED INCIDENCE

STOMACH, FORESTOMACH ULCER DECREASED INCIDENCE

STOMACH, GLANDULAR INFLAMMATION, CHRONIC INCREASED INCIDENCE

STOMACH, GLANDULAR HYPERPLASIA INCREASED INCIDENCE

STOMACH, GLANDULAR NECROSIS INCREASED INCIDENCE

TESTES, GERMINAL

EPITHELIUM

ATROPHY INCREASED INCIDENCE

BONE FIBROSIS INCREASED INCIDENCE

BRAIN, HYPOTHALAMUS COMPRESSION DECREASED INCIDENCE

HARDERIAN GLAND ATROPHY INCREASED INCIDENCE

HARDERIAN GLAND HYPERPLASIA INCREASED INCIDENCE

HARDERIAN GLAND INFILTRATION CELLULAR,

MONONUCLEAR CELL

DECREASED INCIDENCE

ISLETS, PANCREATIC HYPERPLASIA DECREASED INCIDENCE

KIDNEY MINERALIZATION DECREASED INCIDENCE

KIDNEY NEPHROPATHY DECREASED INCIDENCE

LIVER HEPATOBLASTOMA INCREASED INCIDENCE

LIVER HEPATOCELLULAR ADENOMA INCREASED INCIDENCE

LUNG INFLAMMATION, CHRONIC DECREASED INCIDENCE

NOSE INFLAMMATION INCREASED INCIDENCE

NOSE, GLANDS, RESPIRATORY HYPERPLASIA INCREASED INCIDENCE

EPITHELIUM

NOSE, NERVE ATROPHY INCREASED INCIDENCE

NOSE, OLFACTORY EPITHELIUM DEGENERATION INCREASED INCIDENCE

OVARY CYST DECREASED INCIDENCE

PITUITARY GLAND, PARS

DISTALIS

HYPERPLASIA INCREASED INCIDENCE

SALIVARY GLANDS INFILTRATION CELLULAR,

MONONUCLEAR CELL

INCREASED INCIDENCE

SPLEEN HEMATOPOIETIC CELL PROLIFERATION DECREASED INCIDENCE

SPLEEN, LYMPHOID FOLLICLE HYPERPLASIA DECREASED INCIDENCE

STOMACH, GLANDULAR INFLAMMATION, CHRONIC INCREASED INCIDENCE

STOMACH, GLANDULAR EPITHELIUM, HYPERPLASIA INCREASED INCIDENCE

STOMACH, GLANDULAR EPITHELIUM, NECROSIS INCREASED INCIDENCE

URINARY BLADDER INFILTRATION CELLULAR,

MONONUCLEAR CELL

DECREASED INCIDENCE

X. RECOMMENDED ORGANS AND LESIONS FOR REVIEW:

A. ORGANS TO BE REVIEWED FOR ALL LESIONS

The following organs are to be considered potential target organs:

MALE MICE

Liver Stomach, Glandular Nose Thyroid Gland

Liver Stomach, Glandular Nose Thyroid Gland Ovary

B. ORGANS TO BE REVIEWED FOR SPECIFIC LESIONS

The following organs (incidence organs) will be reviewed from all animals in all groups for the designated diagnoses only:

Harderian Gland – Hyperplasia Harderian Gland – Infiltration Cellular, Mononuclear Cell Islets, Pancreatic – Hyperplasia Kidney – Mineralization Kidney – Nephropathy Spleen – Hematopoietic Cell Proliferation Testes, Germinal Epithelium – Atrophy Intestine, Small, All Sections – Lymphangiectasis Lymph Node, Mesenteric – Ectasia Liver – Fatty Change

Bone – Fibrosis Harderian Gland – Atrophy Harderian Gland – Hyperplasia Kidney – Nephropathy Pituitary Gland, Pars Distalis – Hyperplasia Pituitary Gland, Pars Distalis – Adenoma Spleen – Hematopoietic Cell Proliferation Intestine, Small, All Sections – Lymphangiectasis Lymph Node, Mesenteric – Ectasia Bone – Fibrosis Liver – Fatty Change

C. SPECIFIC LESIONS FOR REVIEW

These organs will be reviewed only when the specific diagnosis is present.

Eye – Degeneration Heart – Cardiomyopathy Heart – Inflammation, Chronic Heart, Myocardium – Mineralization Heart, Myocardium – Necrosis Intestine, Small, Duodenum – Polyp Adenomatous Intestine, Small, Jejunum – Polyp Adenomatous

MALE MICE – CONT’D

Kidney – Glomerulosclerosis Kidney – Infiltration Cellular, Mononuclear Cell Kidney – Inflammation, Chronic Kidney, Renal Tubule – Hyperplasia Oral Mucosa - Regeneration Prostate – Infiltration Cellular, Mononuclear Cell Prostate – Inflammation, Chronic

Seminal Vesicle – Infiltration Cellular, Mononuclear Cell Seminal Vesicle – Inflammation, Chronic Skin, Epidermis – Keratoacanthoma Spleen – Atrophy Thyroid, Follicle – Cytoplasmic Alteration Tooth – Malformation

All Tumors in All Organs from All Animals

All diagnoses with organ notes in which either the note or the diagnosis indicate a possible discrepancy in the diagnosis of a neoplastic lesion.

Comment as to the appropriateness of the organ note.

All organs with possible duplicated entries as listed in the Observations to be Addressed During Pathology Quality Assessment. Recommend appropriate action; for example, deletion of one entry, add qualifier such as multiple, combine grades, combine TGL Numbers. Determine if lesions are multiple or different areas of the same lesion.

Adrenal Cortex – Cytoplasmic Alteration Eye – Inflammation, Chronic Eye, Cornea – Inflammation, Chronic Heart – Cardiomyopathy Heart – Inflammation, Chronic Heart, Myocardium – Mineralization Lung – Hyperplasia, Lymphoid Lung – Inflammation, Chronic Ovary – Cytoplasmic Alteration Salivary Glands – Infiltration Cellular Salivary Glands – Infiltration Cellular, Mononuclear Cell Skin – Hemangioma Stomach, Glandular – Hyperplasia, Lymphoid Stomach, Glandular – Inflammation, Chronic

All Tumors in All Organs from All Animals

FEMALE MICE – CONT’D

All diagnoses with organ notes in which either the note or the diagnosis indicate a possible discrepancy in the diagnosis of a neoplastic lesion.

Comment as to the appropriateness of the organ note.

All organs with possible duplicated entries as listed in the Observations to be Addressed During Pathology Quality Assessment. Recommend appropriate action; for example, deletion of one entry, add qualifier such as multiple, combine grades, combine TGL Numbers. Determine if lesions are multiple or different areas of the same lesion.

XI. OTHER COMMENTS:

Lesions recommended for review include those with increased or decreased incidences associated with exposure to those with unusual incidences associated with exposure to that the author considered to be potentially biologically significant and those that are potential errors and/or duplications in terminology.

The glandular stomach was considered a target organ based in the increased incidence of chronic inflammation, epithelial hyperplasia and necrosis, while the nose exhibited an increase in glandular hyperplasia in the respiratory epithelium, olfactory epithelial degeneration and nerve atrophy in male and female mice. In addition, there was an increase in tumors observed in the liver (hepatocellular carcinoma (males only), hepatoblastomas, and hepatocellular adenomas).

Given the changes seen with related compounds, the thyroid gland should be reviewed with special attention for follicular-related changes like hypertrophy, hyperplasia and adenoma.

The diagnosis of Ovary – Cytoplasmic Alteration should be described or terminology changed.

Section B:

Lesions should be reviewed to confirm the incidence in the groups.

Liver – Fatty Change, distribution to be described.

Bone – Fibrosis, the diagnosis to consider for this lesion is “fibro-osseous lesion”.

Section C:

Eye – Degeneration and Spleen – Atrophy need a morphologic qualifier for clarification.

Other diagnoses for the heart should be reviewed to determine if they should be combined under the diagnosis of cardiomyopathy.

Other diagnoses for the kidney should be reviewed to determine if they should be combined under the diagnosis of nephropathy.

For the intestinal tumors, the diagnosis of adenoma should be considered as an alternative for “polyp adenomatous.”

In cases where “infiltration cellular” and “chronic inflammation” were both diagnosed within an organ, these lesions should be reviewed to determine if these are the same lesion with duplicate diagnoses.

Diagnoses of “cytoplasmic alteration” should be reviewed to either describe the changes or determine other appropriate diagnoses/terminology.

For Skin, Epidermis – Keratoacanthoma, the preferred diagnosis for this tumor does not include the “epidermis” qualifier.

For Skin – Hemangioma, the preferred diagnosis for this tumor includes the “subcutaneous” qualifier.

The incidence of “Tooth – Malformation” is high in males in the current study; a review of these lesions and a description is recommended. The preferred NTP diagnosis is “Tooth – Dysplasia”.

XII. CONFLICT OF INTEREST STATEMENT

This statement is to certify that the personnel listed below, employed by participated in the Pathology Data

Review (PDR) of the Chronic Gavage Toxicity/Carcinogenicity Study of

( ( ; CAS No. in Male and Female B6C3F1 Mice

( ). They have not been involved in any aspect of the study for any organization other than NTP which conducted the study nor the generation and/or evaluation of materials or data which were reviewed prior to the PDR. Hence, their participation in the PDR poses no apparent or actual conflict of interest.

Diplomate, ACVP Veterinary Pathologist

Date

HMKR:cap

CHEMICAL:

ATIACHMENTA

ATIACHMENTB

ATIACHMENTC

ATIACHMENTD

ATIACHMENTE

ATIACHMENTA

ATIACHMENTB

ATIACHMENTC

ATIACHMENTD

ATIACHMENTE

PATHOLOGY DATA REVIEW DISCREPANCY SUMMARY FORM

C#ITDMS#: SPECIES: Mice

VM

D

NC

NC

NC

NC

VF

D

NC

NC

NC

NC

UM=N/A

VM = 0 mg/kg

LM = 62.5 mg/kg

MM = 125 mg/kg

HM = 250 mg/kg

MALE DOSE GROUPS

LM MM

D D

NC NC

NC NC

NC D

NC NC

FEMALE DOSE GROUPS

LF

D

NC

NC

NC

D

DOSE GROUPS

UF= N/A

VF= 0 mg/kg

LF = 62.5 mg/kg

MF = 125 mg/kg

HF = 250 mg/kg

MF

D

NC

NC

D

NC

NC = No Commeflt; N/A = Not Applicable; D = Discrepancy Present - See Corresponding Attachment

Form No. 5-1

LAB:

HM

D

NC

NC

NC

NC

HF

D

NC

NC

NC

D

ATTACHMENT A

DATA ENTRY ERRORS

IANR FORMS

ANIMAL HISTOLOGY

GROUPISEX NUMBER NUMBER

ALL 1,3

ALL 5,24

LM, VF, 86, 201

LF, MF, HF

VM 38

LM 84

MM 102

HM 158

LF 253

DATA ENTRY ERRORS

IANRFORMS

C#ITDMS#: SPECIES: Mice

DESCRIPTION OF DATA ENTRY DISCREPANCY

LAB:

GENERAL COMMENT: ITEM 29 "CLINICAUREMOVAL OBSERVATIONS" ON PAGE 2 LISTS DATES AND , HOWEVER

DOES NOT CORRELATE TO E12 REPORT FOR IN-LIFE OBSERVATIONS (262 TOTAL ANIMALS).

GENERAL COMMENT: THE LENGTH OF TIME OCCURRING BETWEEN ITEM 25 "PROSECTOR/NECROPSY DATE" AND ITEM 27

"TRIMMER DATE" WAS GREATER THAN 6 MONTHS (22 TOTAL ANIMALS).

GENERAL COMMENT: THE LENGTH OF TIME OCCURING BETWEEN ITEM 25 "PROSECTOR/NECROPSY DATE" AND ITEM 27

"TRIMMER DATE" WAS GREATER THAN 3 MONTHS AFTER TSAC DATE (194 TOTAL ANIMALS).

ITEM 20 "MORPHOLOGY" LISTED AS THICK. NO DIMENSIONS GIVEN.

ITEM 20 "MORPHOLOGY" LISTED AS THICK. NO DIMENSIONS GIVEN.

ITEM 27 ''TRIMMER DATE" DOES NOT MATCH. PAGE 1 LISTS DATE AS AND ON PAGE 2 AS .

ITEM 29 "CLINICAUREMOVAL OBSERVATIONS", LAST FORMAL IN-LIFE OBSERVATION DATE LISTED AS ; HOWEVER, E12

REPORT LISTS DATE AS .

NO CALLOUT NUMBER OR CORRECTION COMMENT PRESENT FOR CROSSOVER ON PAGE NUMBER.

ITEM 24 "NOTES" STATES "THERE ARE MORE NODULES/MASSES PRESENT; 5 LARGEST RECORDED" BUT DOES NOT SPECIFY

ORGAN.

ITEM 25 "PROSECTOR/NECROPSY DATE" ( ) INCONSISTENT WITH ITEM 26 "PATHOLOGIST DATE" ( ).

ITEM 30 "CORRECTION COMMENTS" DOES NOT CORRESPOND WITH CROSSOVER FOR CALLOUT NO.1.

ITEM 20 "MORPHOLOGY" LISTED AS "THICK". NO DIMENSIONS GIVEN.

REVIEWER'S SIGNATURE:

DATE:

Form No. 5-2 ( )

A-1

ANIMAL HISTOLOGY

GROUPISEX NUMBER NUMBER

LF 266

MF 339

HF 377

DATA ENTRY ERRORS

IANRFORMS

C#ITDMS#: SPECIES: Mice

DESCRIPTION OF DATA ENTRY DISCREPANCY

LAB:

ITEM 29 "CLINICAUREMOVAL OBSERVATIONS" LISTS THIN AS LAST FORMAL IN-LIFE OBSERVATION; HOWEVER E12 REPORT

LISTS OBSERVATION AS UNREMARKABLE.

ITEM 21 "SIZE" LISTED AS UP TO 2X2 WITH NO UNIT OF MEASUREMENT RECORDED.

ITEM 29 "CLINICAUREMOVAL OBSERVATIONS" LISTS THIN AND RUFFLED FUR AS REMOVAL OBSERVATION FOR . E12

LISTS REMOVAL OBSERVATIONS AS UNREMARKABLE FOR .

ITEM 27 'TRIMMER DATE" DOES NOT MATCH. PAGE 1 LISTS DATE AS AND ON PAGE 2 AS .

REVIEWER'S SIGNATURE:

DATE:

Form No. 5-2

A-2

,0

BiD Bli BiZ-

8i3

INDIVIDUAL ANIMAL 1. FACILITY

NECROPSY RECORD

7. STUDY - TEST NUMBER

111. HISTOLOGY NUMBER

14. DISPOSITION

eOTHER*

MSAC TSAC

SSAC NATD

* DEFINE OTHER:

D

DACC

ACCK

MISS

Attachment.1L.Pagelof~ 2a. STUDY NUMBER 3. PHASE

2b. CHEMICAL X CHRONIC

4. DAYS ON TEST 1- 15. DOSE Is.ROUTE SUBCHRONIC

. SI o mg/kg GV

I-- REPEATED DOSE

8. SPECIES/STRAIN I 9. SEX I 10. ANIMAL NUMBER

Mice I B6C3F1 MALE 1 - 1 - - 1 - 1

15. CONDITION 1Ga. IDENTIFICATION INFORMATI N

D

CANN/NTT

PTCANN

OTHER *

VERIFIED [J ID NUMBER:

IDENTIFICATION COMMENT:

1Gb. WET TISSUE REVIEW

18. ORGAN 19. SITE 20. MORPHOLOGY 21. SIZE 22. DISTRIBUTION / COLOR 23. TGL 24. NOTES A B

I(V~.'L Ie ff- {V\,Prss " 0)(.1 5 X. re,-I'- hUJ

1 ID

IC\eteA....' I." .ff-' .('-;)C ,', \..77 tv 3 i'-. 3,~",- +<t.N" /h..., It.'!l Ie.. 2 ,/,/-11 r've'L- t1'\e..cL, v,\·t-1 ~:::,S g')\ 5' J( If""",- -h ... tJ 3 f2, {,VfZ.A....., ('('.<2 J ,'f,tj N (.)cL"Ae '3X.3X~ +CL...,f 4 i.3

25. PROSECTOR/NECROPSY DATE 28. PROBABLE CAUSE OF MORIBUNDITY/DEATH: 30. CORRECTION COMMENTS:

{j)JJtJ-

1- _. C_L-jINa-IC-jAHUI/;-R-jEMHO",VOiirAL OBSERVATIONS:

YIN

27. TRIMMER/DATE

REVISED 8/00

(j) '7

PAGE 1 OF=-U

p

Attachment A. tl 1)\ 3' . ------rage.m....of ---2..

INDIVIDUAL ANIMAL 1, FACILITY 2a. STUDY NUMBER 3. PHASE

NECROPSY RECORD 2b. CHEMICAL rx CHRONIC

4. DAYS ON TEST 15. DOSE I 6. ROUTE SUBCHRONIC

13i o mg/kg GV

- REPEATED DOSE

7. STUDY - TEST NUMBER B. SPECIES/STRAIN I 9. SEX 110. ANIMAL NUMBER

Mice I B6C3F1 MALE I I I -I II ,-

111. HISTOLOGY NUMBER

CONTINUATION PAGE

1B. ORGAN 19. SITE 20. MORPHOLOGY 21. SIZE 22. DISTRIBUTION / COLOR 23. TGL 24. NOTES A B

25. PROSECTOR/NECROPSY DATE 2B. PROBABLE CAUSE OF MORIBUNDITY/DEATH: 30. CORRECTION COMMENTS:

29. CLINICAUREMOVAL OBSERVATIONS: YIN

REVISED B/OO PAGE 2 OF-L

TDMS No. E12: ANIMAL HISTORY Date Report Requested:

Test Type: CHRONIC Time Report Requested: 12:08;34

Route: GAVAGE CAS Number: First Dose MlF:

Species/Strain: MICElB6C3F1 Lab:

CAGE: 1 SEX: MALE TRT#: 1 TRT: 0 mglkg

ANIMALID: 1

~.g:¥

OP DOSE WEIGHT WEIGHT OBS

DAY DATE ID TIME TIME WT(G) STATUS TIME OBSERVATIONS

1 114 07:30:49 23.2 8 114 10:11:00 25.9 15 114 11:23:36 26.6 22 114 12:02:05 28.7 29 114 13:07:58 30.2 13:07:58 Unremarkable 36 114 10:22:03 32.3 43 114 09:27:03 33.5 50 114 09:31:32 33.8 57 114 10:13:49 36.6 10:13:49 Unremarkable 64 114 09:52:24 36.6 71 114 13:23:20 37.2 78 114 09:34:17 40.7 85 102 12:51:40 40.9 12:51:40 Unremarkable 113 114 10:06:09 44.9 10:06:09 Unremarkable 141 167 12:25:39 48.4 12:25:39 Unremarkable 169 167 11:02:09 50.1 11:02:09 Unremarkable 197 167 13:10:00 46.6 11:59:54 Unremarkable 225 167 11:59:18 52.3 11:59:18 Unremarkable 253 167 11:47:55 53.4 11:47:55 Unremarkable 281 127 11:31:11 52.8 11:31:11 Unremarkable 309 167 12:33:31 54.5 12:33:31 Unremarkable 337 167 12:41:21 53.8 12:41:21 Unremarkable 365 167 10:09:18 55.2 10:09:18 Unremarkable 393 164 13:12:56 49.2 13:12:56 Unremarkable 421 167 12:28:35 57.7 12:28:35 Unremarkable 449 157 12:40:17 57.4 12:40:17 Unremarkable ~ 477 167 11 :51 :51 59.8 11:51:51 Unremarkable III

505 167 12:46:36 59.2 12:46:36 Unremarkable :::r- :3

533 167 11:52:30 59.3 11:52:30 Unremarkable CD ::l

561 167 12:39:59 60.5 12:39:59 Unremarkable

~. 589 167 11:40:09 60.6 11:40:09 Unremarkable 617 167 11:46:10 62.1 11:46:10 Unremarkable 645 167 11:39:15 62.2 11:39:15 Unremarkable 673 167 11:29:45 64.0 11:29:45 Unremarkable cl' 701 167 10:23:34 64.9 10:23:34 Unremarkable Il't:! ,.,. CD , /(p REMOVED**REASON-TSAC 731 167 06:22:12 65.4 06:22:12 Unremarkable 0

Attachment A Page-Lof~ INDIVIDUAL ANIMAL 1. FACILITY 2a. STUDY NUMBER 3. PHASE

NECROPSY RECORD 2b. CHEMICAL X CHRONIC

4. DAYS ON TEST 15. DOSE 16. ROUTE SUBCHRONIC

1-7:;'2 o mg/kg GV r--- REPEATED DOSE

7. STUDY - TEST NUMBER 8. SPECIES/STRAIN I 9. SEX I 10. ANIMAL NUMBER

Mice I 86C3F1 MALE 1 - 1 - - 1 - 1 3

111. HISTOLOGY NUMBER

12. DEATH DATE I 113. BODY WEIGHT (G)

I 1 1 1 1 1 1 1 1 1 1 51~ 1 10

14. DISPOSITION 15. CONDITION 16a. IDENTIFICATION INFORMATION

BarnER' 8DA~ D~N~ VERIFIED [Z] IDNUMBER:

- MSAC. . TSAC ACCK >1 FRESH PTCANN

IDENTIFICATION COMMENT:

- SSAC NATD MISS· ~ AUTom OTHER'

'""*15EFINE OTHER: '""*15EFINE OTHER: 16b. WET TISSUE REVIEW h<l PERFORMED

NOT REQUIRED.

18. ORGAN 19. SITE 20. MORPHOLOGY 21. SIZE 22. DISTRIBUTION / COLOR 23. TGL 24. NOTES A B

1.rn+C6-\-r,'\r' SI'r\. 1"..1 J1 ()h<>.llIun NO'hL 0 c>. .?')( 'I Y. ~mn~ -I-A-rJ 1 10 N /1 --.?l-~ ,...,." ,~?I cJt- ,\.l< 47Jj ~C'.h ~'~I .1 .16 c.i./ u.o6 i'l...\MO m~-\.1:J\e. I0h;-\-e 2 1/

I 3

28. PROBABLE CAUSE OF MORIBUNDITY/DEATH: 30. CORRECTION COMMENTS:

~WtJ-

PATHOLOGIST/DATE 29. CLiNICAUREMOVAL OBSERVATIONS: YIN

111\~UI\DII'ADI C

VI' IYlntl \nULL.

A=NORMAL J I

B=OBSERVED

C=MISSING

o = PRESENT, NOT EXAMINED

~ REVISED 8/00 PAGE 1 OF

INDIVIDUAL ANIMAL 1. FACILITY 2a. STUDY NUMBER NECROPSY RECORD 2b. CHEMICAL

4. DAYS ON TEST DOSE

"7-37-.. o mg/kg

7. STUDY - TEST NUMBER 8. SPECIES/STRAIN I 9. SEX

Mice I 86C3F1 MALE

111. HISTOLOGY NUMBER

CONTINUATION PAGE

18. ORGAN 19. SITE 20. MORPHOLOGY 21. SIZE 22. DISTRIBUTION I COLOR

A=N R A

B=OBSERVED

C=MISSING

D = PRESENT, NOT EXAMINED

REVISED 8/00

28. PROBABLE CAUSE OF MORIBUNDITY/DEATH:

29. CLINICAUREMOVAL OBSERVATIONS:

Attachment Pt- Page ~Of~

3. PHASE

X CHRONIC

16. ROUTE SUBCHRONIC

GV

- REPEATED DOSE

110. ANIMAL NUMBER

1 ~I-I -I - 13 ~

23. TGL 24. NOTES

A B

30. CORRECTION COMMENTS:

YIN

PAGE 2 OF~

Test Type: CHRONIC Time Report Requested: 12:08:34

Route: GAVAGE CAS Number: First Dose MlF: /

Species/Strain: MICElB6C3F1 Lab:

CAGE: 3 SEX: MALE TRT#: 1 TRT: 0 mglkg

ANIMALID: 3

OP DOSE WEIGHT WEIGHT OBS

DAY DATE ID TIME TIME WT(G) STATUS TIME OBSERVATIONS

1 114 07:31:18 22.9 8 114 10:11:35 25.1

15 114 11:22:14 26.2 22 114 12:01:03 27.7 29 114 13:06:52 28.6 13:06:52 Unremarkable 36 114 10:21:00 31.1 43 114 09:27:28 31.7 50 114 09:32:00 32.8 57 114 10:14:15 34.3 10:14:15 Unremarkable 64 114 09:52:46 34.5 71 114 13:23:47 34.1 78 114 09:34:49 37.0 85 102 12:52:44 37.1 12:52:44 Unremarkable 113 114 10:05:02 41.7 10:05:02 Unremarkable 141 167 12:27:00 43.4 12:27:00 Unremarkable 169 167 11:02:44 42.7 11:02:44 Unremarkable 197 167 12:00:46 47.1 12:00:46 Unremarkable 225 167 11:57:32 52.9 11:57:32 Unremarkable 253 167 11:48:35 52.7 11:48:35 Unremarkable 281 127 11:31:53 55.1 11:31 :53 Unremarkable 309 167 12:31:00 54.6 12:31 :00 Unremarkable 337 167 12:42:08 54.9 12:42:08 Unremarkable

365 167 10:33:57 58.3 10:33:57 Unremarkable 393 164 12:19:20 57.1 12:19:20 Unremarkable 421 167 12:26:59 59.1 12:26:59 Unremarkable

(Q) 449 157 12:40:49 59.6 12:40:49 Unremarkable D>

477 167 11:52:21 59.1 11:52:21 Unremarkable (') ::r

505 167 12:45:24 60.0 12:45:24 Unremarkable 3

CD

533 167 11:56:37 60.3 11:56:37 Unremarkable :::I -1 !~! 561 167 12:40:51 60.9 12:40:51 Unremarkable

589 167 11:40:34 62.4 11:40:34 Unremarkable l> 617 167 11:44:37 63.2 11:44:37 Unremarkable 645 167 11:39:51 63.9 11:39:51 Unremarkable cl' 673 167 11:32:10 64.6 11:32:10 Unremarkable ()"q

CD

701 167 10:35:38 48.5 10:35:38 Unremarkable

I~ ~ REMOVED**REASON-TSAC 0

732 167 06:05:10 59.6 06:05:10 Unremarkable -+0

I~

Attachment . A Page-LocL

INDIV!DUAL ANIMAL 1. FACILITY 2a. STUDY NUMBER 3. PHASE

NECROPSY RECORD 2b. CHEMICAL X CHRONIC

4. DAYS ON TEST

15. DOSE I 6. ROUTE SUBCHRONIC

(03 o mg/kg GV I-

REPEATED DOSE

7. STUDY - TEST NUMBER 8. SPECIES/STRAIN I 9. SEX I 10. ANIMAL NUMBER

Mice / B6C3F1 MALE I - I - - I - I 5 r--=-===-:=------. -+

12. DEATH DATE 1 1 13• BODY WEIGHT (G) I

i5. I ~I b I 13~

111. HISTOLOGY NUMBER

14. DISPOSITION 15. CONDITION 16a. IDENTIFICATION INFORMATION D OTH'R' DD~C D~Nm VERIFIED Gr IDNUMBER:

i3Z MSAC TSAC ACCK ~-1RESH PTCANN

IDENTIFICATION COMMENT:

SSAC NATD MISS c-- AUTOm OTHER' r.-oEFINE OTHER: ro-oEFINE OTHER: 16b. WET TISSUE REVIEW b1 PERFORMED

NOT REQUIRED

18. ORGAN 19. SITE 20. MORPHOLOGY 21. SIZE 22. DISTRIBUTION / COLOR 23. TGL 24. NOTES A B

Eue- R,qkr d, 5(!.O/ll r"ui,d .- - / OiJ/11/ lIe.

1 q A l't anil'hl.i Lhab u.ru;

/,{{J."JiJ"Ili i1 G .. L j(i~kf en / dilll e.A ... .~x - /IfJ1i/~ 2 q ,~rfOv'W1!'ot at hl11l1.

J..II/e'r ilr ;:~A'kl'"lt>, /J 0& / e. d xdA';';?n?m .~ L .77-f/J 3 10

I

30. CORRECTION COMMENTS:

-;:u;;===;-;:;;:v===:----'-- ..---I 0 Jt)1'tJ1!f ttJIJ Nfl

REVISED 8/00 PAGE10F_1_

C

INDIVIDUAL ANIMAL 1. FACILITY 2a. STUDY NUMBER 3. PHASE

NECROPSY RECORD 2b. CHEMICAL X CHRONIC

4. DAYS ON TEST 15. DOSE 16. ROUTE. SUBCHRONIC

l{(oq o mg/kg GV I--

REPEATED DOSE

7. STUDY - TEST NUMBER 8. SPECIES/STRAIN I 9. SEX I 10. ANIMAL NUMBER

Mice I B6C3F1 MALE I - I - - I 2 1 4 ~

111. HISTOLOGY NUMBER 1 1 13. BODY WEIGHT (G)

. 1 s It-I I

14. DISPOSITION 15. CONDITION 16a. IDENTIFICATION INFORMATION D arnE~ OMCC DcmN~ VERIFIED D- ID NUMBER:

'[ MSAC TSAC ACCK r--::: .-FRESH PTCANN

IDENTIFICATION COMMENT:

-+"- SSAC NATD MISS

- AUTOn! OTHER'

""'*'iSEFINE OTHER: ""'*'iSEFINE OTHER: 16b. WET TISSUE REVIEW P9 PERFORMED

NOT REQUIRED

18. ORGAN 19. SITE 20. MORPHOLOGY 21. SIZE 22. DISTRIBUTION / COLOR 23. TGL 24. NOTES .d;YI(i;

rtl6i1'h rnA I.!., 6k I,;, /H.-1" 1

A=NORMAL

B=OBSERVED

C=MISSING

,) A I, .41',' /Nlt.-· r

D = PRESENT, NOT EXAMINED

REVISED 8/00

A B

~. 'I();>'~jX2o .- 1 /1..\ 7Gt ..#;r ~. 4~ ~. ',-,,5'S '??n... n.-.-..

~ 7, x: ').. i\, ,,,,- da--rl<- 2 /1/(01- ·17.::fk...r Fi,..,.,....~ ...... 114-(j 3

No ~A"J f }-cO'), j.,..} "';--r .In It. t·

5 ·L. 'T I~ JI :L 6 !

28. PROBABLE CAUSE OF MORIBUNDITY/DEATH: 30. CORRECTION COMMENTS:

C)lllml.rrvu."k

@O ~r~ GL p tri7J7) ,,?u

I---'-"-'-':"'=::':'-'-'--~~"'-= '--:--!r-- /}ULtlJ

PAGE10F_1_

INDIVIDUAL ANIMAL

NECROPSY RECORD

1. FACILITY 2a. STUDY NUMBER

2b. CHEMICAL

4. DAYS ON TEST """L

,'3';2..

,---.,._-1 8. SPECIES/STRAIN

Mice I B6C3F1 MALE

Attachment A Page..LoLJ..

3. PHASE

X CHRONIC

SUBCHRONIC

~1. HISTOLOGY NUMBER I 1 EAJ! 13• BODY WEIGHT (G)

.....L1-L--l..--.I.--'----'--L-.-l.---'-----'. . 1 Lfi D 1 .

14. DISPOSITION 15. CONDITION 1Ga. IDENTIFICATION INFORMATION -E-OTHER' §MCC Dc~~n VERIFIED rg] 10 NUMBER:

I-- MSAC TSAC ACCK X FRESH PTCANN

I-- SSAC NATO

IDENTIFICATION COMMENT:

MISS f-- AUTOm OTHER * f-;-oEFINE OTHER: ~EFINE OTHER: 1Gb. WET TISSUE REVIEW

IQ Irp

~ PERFORMED

NOT REQUIRED

18. ORGAN

L; J..v.r

1... :,""~r hi .... ...,.

I . \I;::-Q.

A=NORMAL

B=OBSERVED

C=MISSING

19. SITE

1'1'1.......? "l, ""-rn:;,,/: "'-t4.r ~ f';r-sf F>-tJ

D = PRESENT, NOT EXAMINED

REVISED 8/00

20. MORPHOLOGY 21. SIZE 22. DISTRIBUTION / COLOR

r'"I'"lA.AA 3DX- LfJXt ) i11 11~ .-?N.fJ.&J.

"""'A.'~ 2?r/blCJI'>"I'" A'fA" 4.- ~,,{J

.r'1'YIIVJ.? qX 1x' S '1') YJ-.-.. -fl tl"h II Jl 0 (0 'j.. '5 y. Otr.0\ -I-f>.N

PROBABLE CAUSE OF MORIBUNDITYIDEATH:

23. TGL 24. NOTES

A B 1 10

2 iI.

3 12- 4 1/

30. CORRECTION COMMENTS:

(j)W/J-:

YIN

COpy

(j) /"2

PAGE10F~

7. STUDY - TEST NUMBER

1. FACILITY

Attachment A p~ge....!of ~ 2a. STUDY NUMBER 3. PHASE

2b. CHEMICAL X CHRONIC r-4·.;::;DA;;:;y;;CS;-;O"'N:;-:T -=:':":"':'-'-----,-;;:-;:;"",,==----+'-=--l SUBCHRONIC

REPEATED DOSE

8. SPECIES/STRAIN

Mice I B6C3F1 MALE

CONTINUATION PAGE

18. ORGAN 19. SITE 20. MORPHOLOGY 21. SIZE 22. DISTRIBUTION / COLOR 23. TGL 24. NOTES

A=NORMAL

B=OBSERVED

C=MISSING

D = PRESENT, NOT EXAMINED

REVISED 8/00

28. PROBABLE CAUSE OF MORIBUNDITY/DEATH:

29. CLINICAUREMOVAL OBSERVATIONS:

A B

30. CORRECTION COMMENTS:

/3/0 l? II

INDIVIDUAL ANIMAL

NECROPSY RECORD

14. DISPOSITION

OTHER'

- MSAC 'TSAC

I-- SSAC NATD

I-7oEFINE OTHER:

B

DACC

ACCK

MISS

Attachment A Pageiof ~

2a. STUDY NUMBER 3. PHASE

2b. CHEMICAL X CHRONIC

~~~~~~----~~~5·.PD~O~S~E--~2-~~----.. ~~~--------~~

15. CONDITION

Z FRESH

, AUTom

""""*DEFINE OTHER:

CANN/NTT

PTCANN

OTHER'

FEMALE

\1 I 113. BODY WEIGHT (G)

. .. ICdSI· 16a. IDENTIFICATION INFORMATION

VERIFIED IDNUMBER:

IDENTIFICATION COMMENT:

16b. WET TISSUE REVIEW kl PERFORMED

NOT REQUIRED

17a.ORGAN 17b.

NEC

17c.

WGT

(MG)

17a. ORGAN 17b. 17c. 17a. ORGAN 17b. 17c.

NEC WGT NEC WGT

(MG) ,---;==o-;;:-;:;---~":" (MG) ADRENAL GL. A INTEST SMALL t~r\;0(~!';' , LYMPH NODE BLOOD ./l DUODENUM,I} BRONCHIAL

BLOOD VESSEL A JEJUNUM /9 MEDIASTINAL A

BONE ,<7 ILEUM /J MANDIBULAR /9

BONE MARROW AI INTEST LARGE :'i~,\:g~~;~; MESENTERIC h' BRAIN /l CECUM A OTHER ~/

CARCASS /l COLON.t9 MAMMARY GL A

CAVITIES.4 RECTUM./7 MESENTERY /1

CLITORAL GL.t:, KIDNEY /f NOSE ,,4

ESOPHAGUS A LACRIMAL GL./9 OVARIES L1

EYE /9 LARYNX./9 OVIDUCT A

GALLBLADDER /! LIVER ... K PANCREAS!9

17a.ORGAN

SALIVARY GLS

SKELETAL MUSCLE

SKIN

SPINAL CORD

SPLEEN

STOMACH

THYMUS

THYROIDGL

TISSUE NOS

TONGUE

TOOTH

TRACHEA

17b. 17c.

NEC WGT

(MG)

/J A /9 /9 /l A A

,4 /J /1

~ __ ~~=Li=UiK=N{G========1==t==t===;0jl __ JE~~0~~~~~?~~~:;~~8~~~Y~~:'IT::lli~~G2~L~,,'~~~j;~~~2L~~~~~====jt~=1==~

URETER ,.-9

URINARY BLADDER A'

UTERUS ./9

VAGINA /9.

ZVMBALSGL -?I

18. ORGAN 19. SITE 20. MORPHOLOGY 21. SIZE 22. DISTRIBUTION I COLOR 23. TGL 24. NOTES A B k f2JIl /"Y114vr? fX:f'J<."7 fill?-- _~f) 1 tD ., L' tJ \ h-v 'Y t .,/.;1:;:;-,., ,'~ '1u-k.J.A- ~?<?i-.i-i?1~ _'fi;'Y'-

2 II "'-"'-

\J 3

':;':P~ABLE CAUSE OF MORIBUNDITY/DEATH: 30. CORRECTION COMMENTS:

0wN-

PATHOLOGIST/DA-'fE 29. CLiNICAUREMOVAL OBSERVATIONS: YIN

" ~ BlIil!lI

1 I ~ :JC ~nll lJ ~ ,I~

27. TRIMMER/DATE ~ It-Hun l IIsImm

A=NORMAL 0 \ COpy B=OBSERVED

C=MISSING

D = PRESENT, NOT EXAMINED

F~ REVISED 8/00 ""'''

I

Attachment It Page~of ~

3. PHASE

X CHRONIC

1--T'F;ii~~:.:E;;'T'"----':':'::':;T~~'=:':":==----""""";,,,",,;-----j-..!.::...j SUBCHRONIC

REPEATED DOSE

Mice I B6C3F1 FEMALE

CONTINUATION PAGE

18. ORGAN 19. SITE 20. MORPHOLOGY 21. SIZE 22. DISTRIBUTION / COLOR 23. TGL 24. NOTES A B

30. CORRECTION COMMENTS:

YIN

REVISED 8/00

COpy.

2 OF~

Attachment 1\ Page_{ of~

NECROPSY RECORD 2b. CHEMICAL X CHRONIC

4. DAYS ON TEST 15. DOSE 16. ROUTE SUBCHRONIC

730 o mg/kg GV t-- REPEATED DOSE

7. STUDY - TEST NUMBER B. SPECIESISTRAIN I 9. SEX I 10. ANIMAL NUMBER

Mice I B6C3F1 MALE 1 1 131 8 -' - - -

"" 111. HISTOLOGY NUMBER

1 113. BODY WEIGHT (G)

_ I-51 Q I IS~P

14. DISPOSITION 15. CONDITION 16a. IDENTIFICATION INFORMATION B o'"~· DM~ B ~'MIT VERIFIED IT IDNUMBER:

- MSAC TSAC ACCK -:::; FRESH PTCANN

IDENTIFICATION COMMENT:

- SSAC NATD MISS - AUTOm OTHER·

"""*i5EFINE OTHER: """*i5EFINE OTHER: 16b. WET TISSUE REVIEW bzI PERFORMED NOT REQUIRED f

1B. ORGAN 19. SITE 20. MORPHOLOGY 21. SIZE 22. DISTRIBUTION I COLOR 23. TGL 24. NOTES

BiO

8-//

BIZ,

BIZ.

602-t:.Bi3 j,.;'1-W /YI~;'L>1..

t.;.-J.-,,,..,,.- r-+ -Ivv!f;,:' Iv /Jr./~ -~ i-1'1.. ,/ j)>>I,f"-

S:fi-~'-n~ ~, 1 }'r\-}!·.""M",/';, hr

~\-of'llA e:h fi\lACDS j<:T

25. PROSECTOR/NECROPSY DATE

REVISED B/OO

.-.nWv~ 17X IJ"X/tJ j 11 IYL - -?/"L:<vI<? .3 t/ X '2.0 Xl.i , t)1J1. 1,;, )~

/h-I~ J-XS-X''f h1 J11 - -'114-ttt...iL m~qfo'l ~4' JI1 In. -d,-Jo/m;{;~ ~"")('3Ih""- ~ -th: c..lc::. - ~h(·+e...

2B, PROBABLE CAUSE OF MORIBUNDITY/DEATH:

29. CLINICAUREMOVAL OBSERVATIONS:

A :--HB

1 to

II

I:L •

4 1"J...

5 ;;..

~ 6 13 ..

-- 7

30. CORRECTION COMMENTS:

~ Iv ~ 11../.\ )1J,...t.,.,. /

YIN @W('J-

PAGE 1 OF@i;Z

Attachment A. Page'Aof.&.

INDIVIDUAL ANIMAL 1, FACILITY 2a. STUDY NUMBER 3. PHASE

NECROPSY RECORD 2b. CHEMICAL rx CHRONIC

4. DAYS ON TEST 730 DOSE

,6. ROUTE SUBCHRONIC

o mg/kg GV r-- REPEATED DOSE

7. STUDY - TEST NUMBER B. SPECIES/STRAIN I 9. SEX 110. ANIMAL NUMBER

Mice I B6C3F1 MALE 1 -I -1-1 sl~

111. HISTOLOGY NUMBER

CONTINUATION PAGE

lB. ORGAN 19. SITE 20. MORPHOLOGY 21. SIZE 22. DISTRIBUTION / COLOR .23. TGL 24. NOTES A B

25. PROSECTOR/NECROPSY DATE 2B. PROBABLE CAUSE OF MORIBUNDITY/DEATH: 30. CORRECTION COMMENTS:

26. PATHOLOGISTIDATE 29. CLINICAUREMOVAL OBSERVATIONS: YIN

REVISED B/OO

Attachment~Page-Lof -l

NECROPSY RECORD 2b. CHEMICAL X CHRONIC

4. DAYS ON TEST 01 15. DOSE 0 mg/kg IG. ROUTE SUBCHRONIC

GV

I-

REPEATED DOSE

7. STUDY - TEST NUMBER 8. SPECIES/STRAIN I 9. SEX I 10. ANIMAL NUMBER

Mice I B6C3F1 MALE I - I - - 1 4 I 1

112. DEATH DATE I

113. BODY WEIGHT (G)

141~1

B03 £3;0 Sil

DD7

BI2

14. DISPOSITION 15. CONDITION lGa. IDENTIFICATION INFORMATION D O,"E" [r~ [r~NMTI

VERIFIED 0

- MSAC TSAC ACCK - FRESH PTCANN

- SSAC NATO 4 AUTom

IDENTIFICATION COMMENT:

MISS OTHER·

----DEFINE OTHER: • DEFINE OTHER: 1Gb. WET TISSUE REVIEW

18. ORGAN 19. SITE 20. MORPHOLOGY 21. SIZE 22. DISTRIBUTION / COLOR 23. TGL

A B

~l.Il.b/"JtJ" J riC';Jt- -r>t-),i"rl',.JJ "2Y a No/><....--

<is j; f!...- ,..f",~.- ' ~ 'lox ':J il x"2.0 .J dink 2 1O .,.. m m(St'-n~...u ~'T ""71ntJ..JJ,., ."oA..,t, S· )<'s'y. _n.::;~l>.~~ 3 1/ 'I.e..l~ / );.I~:JV!\I.. .e.. lJu:J~ ~ ~~ 4

L" .r..t .,-},. l~ ), A ..,." i'h/:k - ''l'l.,L,~ .f X r'X '3 j ... YI. 0/ f WJ,:, i-.". 5 I:'" I if J 6

28. PROBABLE CAUSE OF MORIBUNDITY/DEATH:

IkrJit. ~..--&-'~

29. CLINICAUREMOVAL OBSERVATIONS: YIN

REVISED 8/00

ID NUMBER:

f>d PERFORMED

NOT REQUIRED

24. NOTES

It .. l.. ; :M.YI--/ - IJ ) J <?..;f

-r/),C 'I -f'l".... ..Gut""'LI rJ.. -.t. ~. rf P/.'n 'ktJ t:/L

"'0 -.1,.;) /" / l~ A ~:c:;; J,- I ~lt.h.. :,., h '1'"rLl.I~~ r G L 1/ . cvel .. l --71'/4 (/!'t.J"Ct';'?i ",.lL v h'; j1.... <!j, l)/!. jw' .<;

30. CORRECTION COMMENTS:

PAGE10F_1_

!.t;

'r

I

Attachment A Pageiof a

INDIVIDUAL ANIMAL

NECROPSY RECORD

1. FACILITY 2a. STUDY NUMBER 3. PHASE

2b. CHEMICAL X CHRONIC

1-4 •• -;:;D""AY~S:;-:O;:;:;N;;-CT;;:;E:;;;S;;;;T--Z------'1-;5;-.