Document Zpbqa6DEjxjyvw81BgBN2aq0
AR226-2816
Trade Secret
Study Title
j^HHj^TVvo Year Oral Toxicity-Oncogenicity Study in Rats Peer Review of Ovaries A u th o rs Peter C. Mann, D.V.M. Experimental Pathology Laboratories, Inc. (EPL) PO Box 474 Herndon, VA 20172-0474
Steven R. Frame, D.V.M., Ph.D. E. I. du Pont de Nemours and Company Haskell Laboratory for Health and Environmental Science Elkton Road, P. 0 . Box 50 Newark, DE 19714-0050
Test Guideline: Not Applicable
Date Completed: June 25,2004
Laboratory Project ID : DuPont-15261
Work requestN um ber^jjB ^} Sendee Code Number.^tltJ
Subm itted By:
E. I. du Pont de Nemours and Company Haskell Laboratory for Health and Environmental Science Elkton Road, P. O. Box 50 Newark, DE 19714-0050
A u th o rs
DuPont-15261
(krv C .. Peter C. Mann, D.V.M., Diplomate A.V.C.P. Veterinary Pathologist
^ Date
ifpJTJl ^ 0 0 ^ / ________
-f/vL tA ji y Steven R. Frame, D.V.M., Ph.D., Diplomate A.V.C.P. Principal Research Pathologist and Research Manager, Pathology
Date
G ott*** San0' t
TSC&cB ' -o i COO'a'n . oo* 00
2
DuPont-15261
wo Year Oral Toxicity-Oncogenicity Study in Rats Peer Review of Ovaries
p ie slides from the ovaries f r o m ^ B ^ w o Year Oral Toxicity-Oncogenicity Study in
Rats were peer reviewed by two veterinary pathologists: Peter C. Mann, DVM,
EHplomate, American College o f Veterinary Pathologists and Steven R. Frame, D.V.M.
Ph.D, Diplomate, American College o f Veterinary Pathologists. The slides were
'
originally examined and reported by Dr. Robert Geil (study pathologist) for Riker
Laboratories Inc., 3M (Project Number 0281CR0012). The peer review focused on
proliferative lesions o f the ovary. The peer review pathologists discussed issues related
to diagnostic nomenclature and criteria and reached agreement on lesion diagnoses and
gradmg, as well as interpretation o f the peer review findings. This agreement is reflected
in the following report.
'
Materials and Methods
All shdeslisted as available by the study pathologist were made available for the peer review. The ovaries from a few animals were not present at the time o f the initial evaluation, and these same ovaries were not available for peer review. The original diagnoses and the peer review diagnoses for the ovaries for each animal are given in Appendix A. In those cases where the peer review pathologist agreed with the study pathologist, the peer review diagnosis is listed as "Agree". For the purposes o f analysis the data are separated mto those animals that died on or before 53 weeks on study, and ' those animals that died after 53 weeks on study. The animals that died on or before 53 weeks on study included those sacrificed at the interim sacrifice and early deaths. Since none of these animals had any proliferative lesions in the ovaries in either the initial or peer review evaluations, they were not included in the reporting or analysis o f data
Criteria for Diagnosis of Proliferative Changes in the Ovary
In the normal aging ovary o f rats, senescent corpora lutea develop into interstitial glands This gonadal stromal change presents as small glands, lined by cuboidal cells. In some cases, these cells may become more columnar and have a sertoliform appearance. In addition, luteal cells;may appear in the ovarian stroma. These (luteal) cells may also appear to form glands, but they have a characteristic fine granular, foamy appearance which is not present m interstitial glands, although the latter cells may have a
shSouSldSnZot bSeid-iVagaCnUose!d? as prolifera^tive changecsh. *nges TM normal for aging rats, and
let ionS hyperplasia or neoplasia) intrinsic to the ovary are generally
^
f " - " " Slr0mal
- B in origin
nh I al,rt. 999' Pe uf 311(1Gordon> 1992; Alison et al., 1990). Proliferative lesions
2 ^ Ved-in T ieS frm 016 CUrrent study were 311gonadal stromal in origin This category mcludes lesions composed o f granulosa, thecal, luteal or sertoli-like cells, or
1SC&CBI
. noe*n' con' a'n Co *f*i't s .n * e* - ~
DuPont-15261
mixed populations o f these cell types (Dixon et al, 1999; Peluso and Gordon, 1992). It has been recommended that for die purposes o f analysis and evaluation o f carcinogenic risk, tumors derived from gonadal stromal cells be combined (Peluso and Gordon, 1992). Thus, for this peer review, hypoplasia and neoplasia were diagnosed as gonadal stromal hyperplasia and gonadal stromal adenoma, respectively (Peluso and Gordon, 1992).
Gonadal stromal hyperplasia is present when the interstitial and/or sertoliform cells (but not the normal luteal cells) form discrete or diffuse areas containing enlarged clusters or tubular profiles o f stromal cells with or without an increase in fibrous connective tissue. Hyperplasia was graded from 1-4, depending on the relative size o f the proliferation (increasing grade with increasing size).
Typically, there are no clear cytologjcal features that distinguish gonadal stromal hyperplasia from gonadal stromal adenoma. Therefore, to allow for some consistency in diagnosis, the criteria established for gonadal stromal adenoma is based primarily on the somewhat arbitrary feature o f two-dimensional size. Gonadal stromal adenomas are diagnosed if the diameter o f the lesions is greater than 3mm (Dixon et al, 1999). This corresponds to about a single field using the lOx microscope objective. If an anim al had both adenoma and hyperplasia present, only the adenoma was recorded. Since size is the primary criterion differentiating hyperplasia from tumor, the assessment o f incidence data for these lesions included an evaluation based on the total incidence o f proliferative gonadal stromal lesions (combined hyperplasia and adenoma).
Many o f the ovaries diagnosed with gonadal stromal hyperplasia during the peer review o f this study contained very small areas of proliferation which would probably not be diagnosed during a routine evaluation (Dixon et al, 1999; Peluso and Gordon, 1992). However, to ensure that no subtle dose-effect was overlooked, all possible proliferative changes were diagnosed during file review.
Incidences o f proliferative lesions (gonadal stromal hyperplasia, adenoma, or hyperplasia/adenoma combined) were evaluated by the Cochran-Armitage trend test and the Fisher's exact te st Statistical significance was judged at P < 0.05.
Results
The presence o f all proliferative lesions in the ovaries o f individual rats is presented in
Appendix A. The incidence of gonadal stromal hyperplasia and/or adenoma in the ovaries
o f all rats on study beyond the one-year (53-week) interim sacrifice is shown in Text
Table 1. Rats sacrificed at the one-year interim sacrifice, as well as rats that died prior to
the interim sacrifice, were not considered "at risk" for tumor development. This is
reflected in the fact that the number of animals/group, as given is Table 1, is less than 50
(as appears in the original report) and varies slightly among groups based on the number
o f deaths in each group that occurred before the interim sacrifice. The number o f anim als
examined per group also reflects animals for which no ovary was available for review.
Incidences o f ovarian lesions based on the original microscopic evaluation can be found
in the original study report (Sibinski, 1987)
tS C fr
Cit# * *
4
DuPont-15261
Table 1 Incidence of Gonadal Stromal Hyperplasia and Adenoma in Rats8
Dose
0 30
No. Examined
45 47
Hyperplasia (Total No.)
8
16
- Grade 1
6
7
- Grade 2
2
3
- Grade 3
0
5
Adenoma
- Grade 4
Adenoma and/or
0 4
1 0
Hyperplasia
12 16
Animals on study beyond the interim (53-week) sacrifice
300 46 15 5 1 6 3 2
17
There were no statistically significant increases in hyperplasia (total number), Hwinmac or hyperplasia/adenoma combined in treated groups compared to controls. Some evidence o f increased lesion grade for proliferative lesions was observed in the 300 ppm group. For example, incidences o f proliferative lesions diagnosed with a grade o f 3 or more (that is, grade 3,4, or adenoma) was 4/45,6/47 and 11/46 in the 0,30, and 300 ppm groups, respectively. The incidences of lesions of grade 3 and above were statistical significant at 300 ppm (P = 0.046 and 0.048 for the Cochran Armitage and Fisher's test, respectively). However, treatment-related progression o f proliferative lesions to the size criteria established for adenoma did not occur, as incidences o f arim n m a were highest in controls.
Discussion and Conclusions
The slides o f ovaries o f rats from a two-year feeding study withjjBMBB^vere peer reviewed with emphasis on proliferative lesions o f the ovary. Lesions cfiagnosed by the peer review pathologists as gonadal stromal hyperplasia or gonadal stromal adenoma corresponded to the diagnoses o f tubular hyperplasia or tubular adenoma by the study pathologist (one granulosa cell tumor-a type o f gonadal stromal tumor-was also diagnosed by the study pathologist). The diagnostic terms used by the peer review pathologists were based on more recently published nomenclature, and the more generic designation o f gonadal stromal lesions better reflected the spectrum o f morphologic changes observed in the proliferative lesions. Furthermore, based on current diagnostic nomenclature, tubular hyperplasia or adenoma would suggest an origin from ovarian surface epithelium rather than from ovarian stromal cells.
Except for differences in diagnostic nomenclature, results o f the peer review were similar to those of the original study for the 300 ppm group. More disparate results occurred for die control and 30 ppm groups where more hyperplastic lesions (irrespective o f the
. o^ - . ^ ` wTSC` CB'
DuPont-15261
nomenclature used) were observed by the peer review pathologists. Based on the results o f the peer review, there were no statistically significant increases in gonadal stromal hyperplasia, adenoma, or adenoma and hyperplasia combined in treated groups relative to controls. Some evidence o f increased lesion grade, which would correspond to an increase in size o f stromal lesions, was observed in the 300 ppm group. However, adenomas occurred in greater incidences in the control group than in either o f the treated groups. References Alison RH, Morgan KT, and Montgomery Jr. CA (1990). Ovary. In Boorman GA, Eustis SL, Elwell MR, Montgomery Jr. CA, and Mackenzie WF, (eds) Pathology o fthe Fisher Rat. Academic Press, San Diego, pp429-442 Dixon D, Leininger JR, Valerio MG, Johnson AN, Stabinski LG and Frith CH (1999). Proliferative lesions o f the Ovary, Uterus, Vagina, Cervix and Oviduct in Rats. URG-5. In: Guides for Toxicologic Pathology. STTVARP/AFIP, Washington, DC. Peluso JJ and Gordon LR (1992). Nonneoplastic and Neoplastic Changes in the Ovary. In: Mohr U, Dungworth DL, and Capen CC (eds) Pathobiology o f the Aging Rat, Vol 1. ILSI Press, Washington, DC, pp 351-364. Sibinski, U (1987). Two Year Oral (Diet) Toxicity /Oncogenicity study of Fluorochemical FC-143 in Rats. Riker Experiment No. 0281CR0012, Riker Laboratories, Inc./3M Company.
6
DuPont-15261
Appendix A: Individual Animal Peer Review Results
Company SanWtad. Do contato TSCACSf
7
DuPont-15261
0 ppm (Group 1)
WKS ANIMAL# ON TEST
ORIGINAL DX
IR-4576 IR-4607
25 40
WITHIN NORMAL UMITS
MAUGNANT LYMPHOMA, LYMPHOCYTIC
IR-4580 52
WITHIN NORMAL UMITS
IR-4576 53
WITHIN NORMAL UMITS
IR-4582 53
WITHIN NORMAL UMITS
IR-4S85 53
WITHIN NORMAL UMITS
IR-4588 53
WITHIN NORMAL UMITS
IR-4589 53
WITHIN NORMAL UMITS
IR-4590 53
WITHIN NORMAL UMITS
IR-4601 53
WITHIN NORMAL UMITS
IR-4608 53
WITHIN NORMAL UMITS
IR-4610 53
WITHIN NORMAL UMITS
IR-4620 53
WITHIN NORMAL UMITS
IR-4629 53
WITHIN NORMAL UMITS
IR-4630 53
WITHIN NORMAL UMITS
IR-4631 53
WITHIN NORMAL UMITS
IR-4632 53
CYST. UNILATERAL
IR-4840 53 ^ ^ W IT O IN N O R M A U JM jT ^ ^ ^
PEER REVIEW DX AGREE
AGREE AGREE AGREE AGREE AGREE AGREE AGREE AGREE AGREE AGREE AGREE AGREE AGREE AGREE AGREE AGREE
IR-4577 IR-4579 IR-4581
IR-4583 IR-4584 IR-4586 IR-4587 IR-4591 IR-4592 IR-4593 IR-4594
IR-4595 IR-4596
IR-4597
IR-4598 IR-4599 IR-4600
99 WITHIN NORMAL UMITS 84 WITHIN NORMAL UMITS 85 WITHIN NORMAL UMITS
AGREE AGREE AGREE
GONADAL STROMAL ADENOMA,
105 TUBULAR ADENOMA. UNILATERAL
UNILATERAL
105 WITHIN NORMAL UMITS
AGREE
105 NOT EXAMINED. MISSING
AGREE
105 WITHIN NORMAL UMITS
AGREE
105 WITHIN NORMAL UMITS
AGREE
88 WITHIN NORMAL UMITS
AGREE
105 WITHIN NORMAL UMITS WITHIN NORMAL UMITS. ONE OF PAIR
79 MISSING
AGREE AGREE
GONADAL STROMAL
HYPERPLASIA,
MINIMAL,
105 WITHIN NORMAL UMITS
UNILATERAL
78 WITHIN NORMAL UMITS
AGREE
GONADAL STROMAL
ADENOMA,
105 TUBULAR ADENOMA. UNILATERAL
UNILATERAL
GONADAL STROMAL
ADENOMA,
105 TUBULAR ADENOMA
UNILATERAL
102 MAUGNANT LYMPHOMA. HISTIOCYTIC
AGREE
99 CYST. UNILATERAL
AGREE
Compan*
noteoot*'0 T S C A C B l
8
DuPont-15261
0 ppm (Group 1) - continued
WKS ANIMAL# ON TEST
ORIGINAL OX
PEER REVIEW DX
IR-4602 IR-4603 IR-4604
105 105 105
WITHIN NORMAL UMITS WITHIN NORMAL UMITS
CYST. UNILATERAL
GONADAL STROMAL HYPERPLASIA, MINIMAL, UNILATERAL
AGREE
AGREE
IR-4805 IR-4606
77 105
CYST. UNILATERAL NOT EXAMINED. MISSING
GONADAL STROMAL HYPERPLASIA, MINIMAL, UNILATERAL
AGREE
IR4809 IR-4811 IR-4612 IR-4813 IR-4614 IR-4815 IR-4616
105 105 105 89 105 105 105
IR-4617 IR-4618 IR-4619
73 93 64
IR-4621 IR-4622 IR-4623
99 82 96
IR-4624 IR-4825 IR-4826
100 100 105
WITHIN NORMAL UMITS WITHIN NORMAL UMITS WTTHIN NORMAL UMITS WITHIN NORMAL UMITS WITHIN NORMAL UMITS WITHIN NORMAL UMITS
CYST. UNILATERAL
LEIOMYOMA WITHIN NORMAL UMITS WITHIN NORMAL UMITS
WITHIN NORMAL UMITS WITHIN NORMAL UMITS WITHIN NORMAL UMITS
CYST. UNILATERAL WITHIN NORMAL UMITS WITHIN NORMAL UMITS
GONADAL STROMAL HYPERPLASIA, MINIMAL, UNILATERAL
AGREE
AGREE
AGREE
AGREE AGREE
AGREE NOT PRE8ENT ON SUDE, ONE OV IS WITHIN NORMAL
UMITS
AGREE
AGREE
GONADAL STROMAL HYPERPLASIA, MILD,
BILATERAL
AGREE
AGREE
GONADAL STROMAL HYPERPLASIA, MILD,
UNILATERAL
AGREE
AGREE
GONADAL STROMAL
ADENOMA,
TUBULAR ADENOMA. UNILATERAL
UNILATERAL;
IR-4627 105
CYST BILATERAL
CYST BILATERAL
IR-4628 IR-4633 IR-4834
105 63 105
WITHIN NORMAL UMITS WITHIN NORMAL UMITS WTTHIN NORMAL UMITS
GONADAL STROMAL HYPERPLASIA, MINIMAL, UNILATERAL
AGREE
AGREE
Sa,,auoa.yoe.|o, co.iW`n t s c a c b i
Company
9
DuPont-15261
t 0 ppm (Group 1) - continued
WKS ANIMAL* ON TEST
IR-4635 IR-4838 IR-4837 IR-4638 IR-4639
94 105 82 105 56
ORIGINAL DX
WITHIN NORMAL LIMITS WITHIN NORMAL LIMITS WITHIN NORMAL LIMITS WITHIN NORMAL LIMITS WITHIN NORMAL LIMITS
PEER REVIEW DX
GONADAL STROMAL HYPERPLASIA, MINIMAL, UNILATERAL AGREE AGREE AGREE AGREE
Company tawRIiud. DoaoM l oonHittTSCA CBI
10
DuPont-15261
30 ppm (Group 6)
WKS ANIMAL ON TEST
ORIGINAL OX
IR-4751 42
WITHIN NORMAL UMITS
IR-4744 48
WITHIN NORMAL UMITS
IR-473S 50 _ __________ WITHIN NORMAL LIMITS__________
PEER REVIEW DX AGREE AGREE AGREE
IR-4706
IR-4707 IR-4708 IR-4709 IR-4710 IR-4711 IR-4712 IR-4713 IR-4714 IR-4715 IR-4716
IR-4717 IR-4718 IR-4710
IR-4720 IR-4721 IR-4722
IR4723
IR4724 IR4725
IR4726
IR4727 IR-4728
72 WITHIN NORMAL LIMITS
AGREE GONADAL
STROMAL
HYPERPLASIA,
90 WITHIN NORMAL LIMITS-ONE OF PAIR PRESENT MILD. UNILATERAL
105 WITHIN NORMAL LIMITS
AGREE
99 WITHIN NORMAL LIMITS
AGREE
105 CYST
AGREE
105 WITHIN NORMAL LIMITS
AGREE
94 CYST
AGREE
97 WITHIN NORMAL LIMITS
AGREE
105 WITHIN NORMAL LIMITS
AGREE
105 CYST. UNILATERAL
AGREE
105 CYST. UNILATERAL
AGREE GONADAL
STROMAL
HYPERPLASIA,
MINIMAL,
105 WITHIN NORMAL LIMITS
UNILATERAL
94 WITHIN NORMAL LIMITS
AGREE
96 CYST. UNILATERAL
AGREE GONADAL
STROMAL
HYPERPLASIA,
MINIMAL,
105 WITHIN NORMAL LIMITS
UNILATERAL
95 WITHIN NORMAL LIMITS-ONE OF PAIR PRESENT
AGREE
83 WITHIN NORMAL LIMITS
AGREE GONADAL
STROMAL
HYPERPLASIA,
MODERATE,
105 TUBULAR HYPERPLASIA. MODERATE
UNILATERAL GONADAL
STROMAL
HYPERPLASIA,
105 TUBULAR HYPERPLASIA. BILATERAL MILD
MODERATE, BILATERAL
94 WITHIN NORMAL LIMITS
AGREE GONADAL
STROMAL HYPERPLASIA,
105 WITHIN NORMAL LIMITS
MINIMAL, UNILATERAL
GONADAL
STROMAL
HYPERPLASIA,
MINIMAL,
105 CYST
UNILATERAL
84 WITHIN NORMAL LIMITS
AGREE
Company Sanftizsd. D ots n o tc ^ a ln TSCA CBI
DuPont-15261
30 ppm (Group 6) - continued
WKS ANIMAL i t DN TEST
ORIGINAL DX
PEER REVIEW DX
IR-4729 105 _________ WITHIN NORMAL LIMITS___________
AGREE
IR-4730 74 _________ WITHIN NORMAL LIMITS___________
AGREE
IR-4731 99
MALIGNANT LYMPHOMA. HISTIOCYTIC
LYMPHOMA GONADAL
STROMAL
HYPERPLASIA,
MINIMAL,
IR-4732 99
WITHIN NORMAL LIMITS
UNILATERAL
IR-4733 105 IR-4734 95
WITHIN NORMAL LIMITS WITHIN NORMAL LIMITS
AGREE
AGREE GONADAL
STROMAL
HYPERPLASIA,
IR-4736 105
WITHIN NORMAL LIMITS
MILD. UNILATERAL GONADAL
STROMAL
HYPERPLASIA,
MODERATE,
IR-4737 IR-4738 IR-4739 IR-4740 IR-4741
IR-4742 IR-4743
105 TUBULAR HYPERPLASIA. BILATERAL MODERATE 101 WITHIN NORMAL LIMITS 105 WITHIN NORMAL LIMITS 105 WITHIN NORMAL LIMITS 97 WITHIN NORMAL LIMITS 83 WITHIN NORMAL LIMITS 97 WITHIN NORMAL LIMITS
BILATERAL AGREE AGREE AGREE AGREE AGREE AGREE
GONADAL
IR-4746 105 IR-4748 87
TUBULAR HYPERPLASIA. UNILATERAL, MODERATE
GRANULOSA CELL TUMOR, BENIGN, UNILATERAL
WITHIN NORMAL LIMITS
STROMAL HYPERPLASIA,
MODERATE, UNILATERAL
AGREE GONADAL
STROMAL
HYPERPLASIA,
MINIMAL,
UNILATERAL;
IR-4747 IR-4748
105 81
CYST. UNILATERAL WITHIN NORMAL LIMITS
CYST
AGREE GONADAL
STROMAL
HYPERPLASIA,
MINIMAL,
IR-4749 IR-4750
82 97
WITHIN NORMAL LIMITS WITHIN NORMAL LIMITS
UNILATERAL
AGREE GONADAL
STROMAL
HYPERPLASIA,
IR-4752 105
CYST, BILATERALTUBULAR HYPERPLASIA, BILATERAL. MODERATE
SEVERE, BILATERAL GONADAL
STROMAL
HYPERPLASIA,
MODERATE,
IR-4753 IR-4754
105 TUBULAR HYPERPLASIA. BILATERAL, MODERAIT 105 CYST. UNILATERAL
UNILATERAL
AGREE GONADAL
STROMAL
HYPERPLASIA,
IR-4755 105 TUBULAR HYPERPLASIA. BILATERAL, MODERAT!E MILD. BILATERAL
jDoiiipeny SsrrffirML Does oot contain TSC CB!
DuPont-15261
300 ppm (Group 5)
WKS ANIMAL ON TEST IR-4678 49 IR-4842 53 IR-4652 53 IR-4855 53 IR-48S8 53 IR-4684 63 IR-4866 53 IR-4669 53 IR-4871 53 IR-4674 53
IR-4676 53 IR-4687 53 IR-4689 53 IR-4692 63 IR-4689 53 IR-4704 53
ORIGINAL OX
PEER REVIEW DX
WITHIN NORMAL LIMITS
AGREE
WITHIN NORMAL LIMITS
AGREE
WITHIN NORMAL LIMITS
AGREE
WITHIN NORMAL LIMITS
AGREE
WITHIN NORMAL LIMITS
AGREE
WITHIN NORMAL LIMITS
AGREE
WITHIN NORMAL LIMITS
AGREE
WITHIN NORMAL LIMITS
AGREE
WITHIN NORMAL LIMITS
AGREE
WITHIN NORMAL LIMITS
AGREE
WITHIN NORMAL LIMITS
AGREE
WITHIN NORMAL LIMITS
AGREE
WITHIN NORMAL LIMITS
AGREE
WITHIN NORMAL LIMITS
AGREE
WITHIN NORMAL LIMITS
AGREE
____ WITHIN NORMAL LIMITS___________
AGREE
IR-4641 73
NOT EXAMNED. MISSING
AGREE
IR-4643 78
WITHIN NORMAL LIMITS
AGREE
IR-4644 105
WITHIN NORMAL LIMITS
AGREE
IR-4845 105
WITHIN NORMAL LIMITS
AGREE GONADAL
STROMAL
HYPERPLASIA,
IR-4846 105
TUBULAR HYPERPLASIA. MODERATE
MODERATE, UNILATERAL
IR-4647 105
CYST. UNILATERAL
AGREE
IR-4648 88
WITHIN NORMAL LIMITS
AGREE GONADAL
STROMAL
HYPERPLASIA,
IR-4649 105 TUBULAR HYPERPLASIA. BILATERAL MODERATE
SEVERE, BILATERAL
GONADAL STROMAL
HYPERPLASIA,
IR-4850 104 TUBULAR HYPERPLASIA. BILATERAL MODERATE
SEVERE, BILATERAL
IR-4851 96
NO DIAGNOSIS. INADEQUATE SECTION
AGREE
IR-4653 87
WITHIN NORMAL LIMITS
AGREE
IR-4654 57
WITHIN NORMAL LIMITS
AGREE
IR-4857 105
WITHIN NORMAL LIMITS
AGREE
IR-4658 105
CYST. UNILATERAL
AGREE
IR-4659 105
WITHIN NORMAL LIMITS
AGREE
IR-4660 105
WITHIN NORMAL LIMITS
AGREE
IR-4681 105
WITHIN NORMAL UMTS
AGREE
IR-4662 105
WITHIN NORMAL LIMITS
AGREE
IR-4663 105
WITHIN NORMAL LIMITS
AGREE
Company Sans**Owa not contain T S Q t O f
DuPont-15261
300 ppm (Group 5) - continued
WKS ANIMAL 4 DN TEST
ORIGINAL DX
PEER REVIEW DX GONADAL
8TROMAL
HYPERPLASIA,
MODERATE,
IR-4665 94
TUBULAR HYPERPLASIA. MODERATE
BILATERAL GONADAL
STROMAL HYPERPLASIA,
IR-4687 IR-4668 IR-4870
105 81 92
TUBULAR HYPERPLASIA. MILD WITHIN NORMAL LIMITS WITHIN NORMAL LIMITS
MINIMAL BILATERAL
AGREE
AGREE GONADAL
STROMAL
HYPERPLASIA,
MODERATE,
IR-4672 IR-4573 IR-4675
105 TUBULAR HYPERPLASIA. UNILATERAL MODERATE 79 WITHIN NORMAL LIMITS 105 WITHIN NORMAL LIMITS
BILATERAL AGREE AGREE
GONADAL
STROMAL
IR-4677 105
TUBULAR ADENOMA. UNILATERAL
ADENOMA, UNILATERAL
GONADAL
STROMAL HYPERPLASIA,
MODERATE,
IR-4679 105
TUBULAR HYPERPLASIA. BILATERAL MILD
BILATERAL
GONADAL STROMAL
HYPERPLASIA,
IR-4680 104
TUBULAR HYPERPLASIA. MODERATE
MINIMAL BILATERAL
GONADAL STROMAL
IR-4681 IR-4682
97 94
TUBULAR HYPERPLASIA. MODERATE NOT EXAMINED. MISSING
HYPERPLASIA, MODERATE, UNILATERAL
AGREE GONADAL STROMAL HYPERPLASIA,
IR-4683
105 TUBULAR HYPERPLASIA. BILATERAL MODERATE
MODERATE, BILATERAL
GONADAL
STROMAL
HYPERPLASIA,
IR-4684 103
TUBULAR HYPERPLASIA. MODERATE
MINIMAL UNILATERAL
IR-4685 75
WITHIN NORMAL LIMITS
AGREE GONADAL
STROMAL HYPERPLASIA,
IR-4886 105
WITHIN NORMAL LIMITS
MINIMAL UNILATERAL
T S C fcC B l
14
DuPont-15261
300 ppm (Group 5) - continued
ANIMAL#
IR-4688 IR-4690 IR-4691 IR-4603 IR-4694
IR-4695 IR-4696 IR-4697
IR-4688
IR-4700 IR-4701 IR-4702 IR-4703 IR-4705
WKS ON TEST
105 105 100 105 105
105 105 105
105
96 105 87 105 62
ORIGINAL DX
PEER REVIEW DX GONADAL
STROMAL
HYPERPLASIA,
TUBULAR HYPERPLASIA. MODERATE
SEVERE, UNILATERAL
WITHIN NORMAL UMITS
AGREE
WITHIN NORMAL LIMITS
AGREE
WITHIN NORMAL UMITS
AGREE
CYST. UNILATERAL
AGREE GONADAL
STROMAL HYPERPLASIA
WITHIN NORMAL UMITS
MINIMAL, UNILATERAL
CYST. UNILATERAL
AGREE
WITHIN NORMAL UMITS
AGREE GONADAL
STROMAL
HYPERPLASIA,
CYST. UNILATERAL
MILD. BILATERAL GONADAL
STROMAL
ADENOMA
TUBULAR HYPERPLASIA. MARKED
UNILATERAL
_________ WITHIN NORMAL UMITS_________
AGREE
TUBULAR HYPERPLASIA. MODERATE
AGREE
WITHIN NORMAL UMITS
AGREE
WITHIN NORMAL UMITS
AGREE
tsc a c b i
15
