NATIONAL TOXICOLOGY PROGRAM Technical Report Series No. 269 t-"'- SERVICts (~~+,~~\._ TOXICOLOGY AND CARCINOGENESIS STUDIES OF TELONEIIQD (Technical-Grade 1,3-Dichloropropene [CAS No. 542-75-6] Containing 1.0% Epichlorohydrin as a Stabilizer) IN F344/N RATS AND B6C3Ft MICE (GAVAGE STUDIES) U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service National Institutes of Health NATIONAL TOXICOLOGY PROGRAM The National Toxicology Program (NTP), established in 1978,develops and evaluates scientific information about potentially toxic and hazardous chemicals. This knowledge can be used for protecting the health of the American people and for the primary prevention of disease. By bringing together the relevant programs, staff, and resources from the U.S.Public Health Service, DHHS, the National Toxicology Program has centralized and strengthened activities relating to toxicology research, testing and test developmentivalidation efforts, and the dissemination of toxicological information to the public and scientific communities and to the research and regulatory agencies. The NTP is made up of four charter DHHS agencies: the National Cancer Institute (NCI), National Institutes of Health; the National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health; the National Center for Toxicological Research, Food and Drug Administration; and the National Institute for Occupational Safety and Health (NIOSH), Centers for Disease Control. In July 1981, the Carcinogenesis Bioassay Testing Program, NCI, was transferred to the NIEHS. Telone II@,NTP TR 269 NTP TECHNICAL REPORT ON THE TOXICOLOGY AND CARCINOGENESIS STUDIES OF TELONE II" (Technical-Grade 1,tDichloropropene [CAS No. 842-75-61 Containing 1.0%Epichlorohydrin as a Stabilizer) IN F344/N RATS AND B6C3F1 MICE (GAVAGE STUDIES) NATIONAL TOXICOLOGY PROGRAM P.O. Box 12233 ResearchTriangle Park, NC 27709 May 1986 NTP TR 269 NIH PubIication No. 86-2626 NTP-83-22 U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service National Institutes of Health NOTE TO THE READER Five categories of interpretative conc!usions were adopted for use in June 1983 in the Technical Reports series to specfically emphasize consistency and the concept of actual eridence of carcinoge$city. For each definitive study result (male rats, female rats, male rmce, female mice) one of the following quintet will be selected to describe the findings. These categories refer to *thestrength of the experimental evidence and not to either potency or mechanism. 0 Clear Evidence of Carcinogenicityis demonstratpl by studies that are interpreted as showing a chemically related increased incidence of malignant neo lasms, studies that qxhibit a substantially increasetj incidence of beni neoplasms, or s udies tha! exhibit a.n increased incidence of a combination of malignant angmgnneoplasms whereP each increases with dose. Some Evidence of Carcino enicit is demonstrated by studies that are inte reted as showing a chemicallx related increases inci&nce of.benign neoplqsms, rrtudie? $aT ephibif; marpal mcreases in nvplasms of ?everal orgadtissues, or studies that exhibit a slight increase in uncommon malignant or benign neoplasms. 0 Equiyocal Evidence of Carcinoge@city is demonstrated by studies that are interpreted as showrnga chemically related margmal increase of neoplasms. 0 No Eyidence of Cychogenicity is demonstrag by studies that are interpreted as showing no chemically related increases in malignant or benign neoplasms. 0 Inadequate Stud of Carcinogenicity demonstrates that because of. majpr qualitative or quantitative limitagons, the studies cannot be interpreted as valid for showing either the presence or absence of a carcinogenic effect. Additionally the followin concepts (as atternqd from the Intqrnational A ency for Research on Cancer Monographsj have been adopted by the #TP to pve further clarlfication ofti? ese issues: This stud was initiated b the National Cancer Institute's Carcinogenesis Bioassay Program now part of the Na6onal Institute or Environmental Health Sciences, National Toxicolo Program. The studies described in this Technical Report have been conducted in com liance with &P chemical health and det requirements and must meet or exceed all applicable FeCQeral, state, and local health and safety regugtions. All NTP toxicology and carcinogenesis studies are subjected to a data audit before being presented for peer review. Althou h every effort is made toprepare the Techniqal Re rts as accurately as possible, mistakes may occur. WeadFrs are r uested to ideptify any @stakes sq &it correc)ive actioqmay be +ken. Further, an one who IS aware 7o related ongomg or ublished studles not mentroned in this re rt is encouraged to &e this information known to the NT! Comments and uestions about the Rational Toxicolo Program Tecwcal Reports on Toxicolo and Carcino neqis &dies should be directed to Dr. J.E. H$ Nahonal To~lcologyProgram, P.O. BoxR233, ResearXTnangle Park, NC 27709 (919-541-3780). These NTP Technical Reports are available. for sale from the National Technical Information Service, U.S.De rtpent of Commerce, 5285 Port Royal. Road, Springfield VA 22161 (703-487-4660), Sin le CO ies oEhls Technical Re rt are available without char e and while supplies last) from the NI P P&ic Information Office, I$ational Toxicology Program, P.6&ox 12233, Research Triangle Park,NC 27709. Telone II@,NTP TR 269 2 CONTENTS PAGE ABSTRACT .......................... ................................................... 8 CONTRIBUTORS ...................... .................................................. 11 PEER REVIEW PANEL ................................................................... 18 SUMMARY OF PEER REVIEW COMMENTS ................................................. 13 I. INTRODUCTION ................................................................... 15 IJ. MATERIALS AND METHODS ........................................................ 89 PROCUREMENT AND CHARACTERIZATION OF TELONE II* ......................... 94 PREPARATION AND CHARACTERIZATION OF DOSE MIXTURES ...................... 44 TWO-YEAR AND ANCILLARY STUDIES ............................................. 85 STUDY DEBIGN ............................................................... 85 SOURCE AND SPECIFICATIONS OF TEST ANIMALS ............................... 85 ANIMAL MAINTENANCE ....................................................... 88 CLINICAL EXAMINATIONS AND PATHOLOGY .................................... 96 STATISTICAL METHODS ....................................................... 86 m. RESULTS ......................................................................... 31 RATS ......................................................................... *3a TWO-YEAR STUDIES AND ANCILLARY STUDIES ................................. -5% BODY WEIGHTS AND CLINICAL SIGNS ........................................ 38 SURVIVAL ................................................................. 34 ANCILLARY STUDIES ....................................................... 34 PATHOLOGY AND STATISTICAL ANALYSES OF RESULTS ....................... 36 WCE u 0 ....................... 41 TWO-YEAR STUDIES I . ....................... 41 BODY WEIGHTS AND CLINICAL SIGN8 ....................................... 41 SURVIVAL ................................................................. 45 PATHOLOGY AND STATISTICAL ANALYSES OF RESULTS ....................... 49 IV . DISCUSSION AND CONCLUSIONS .................................................... 49 V. REFERENCES ..................................................................... 57 3 Telone [email protected] TR 269 TABLES PAGE TABLE 1 ANALYSIS OF CHEMICALNEHICLE MIXTURES IN THE TWO-YEAR GAVAGE STUDIES OF TELONE II* ..................................................... .24 TABLE a EXPERIMENTAL DESIGN AND MATERIALS AND METHODS IN THE TWO-YEAR GAVAGE STUDIES OF TELONE II* ................................ ;............a7 TABLE 3 MEAN BODY WEIGHTS AND SURVIVAL OF RATS IN THE TWO-YEAR GAVAGE STUDIES OF TELONE II* ............................................ .32 TABLE 4 SURVIVAL OF RATS IN THE TWO-YEAR GAVAGE STUDIES OF TELONE II* ........34 TABLE II ANALYSIS OF FORESTOMACH LESIONS IN RATS IN THE TWO-YEAR AND ANCILLARY GAVAGE STUDIES OF TELONE II* ................................ .37 TABLE 6 ANALYSIS OF LIVER TUMORS IN MALE RATS IN THE TWO-YEAR AND ANCILLARY GAVAGE STUDIES OF TELONE II* ............................... ..a TABLE 7 INCIDENCE OF FORESTOMACH AND LIVER LESIONS IN RATS IN THE ANCILLARY STUDIES OF TELONE II* ........................................ .39 TABLE 8 ANALYSIS OF ADRENAL GLAND TUMORS IN MALE RATS IN THE TWO-YEAR GAVAGE STUDY OF TELONE II* .............................................. .39 TABLE 9 ANALYSIS OF THYROID GLAND LESIONS IN RATS IN THE TWO-YEAR GAVAGE STUDIES OF TELONE II* ............................................ .40 TABLE 10 MEAN BODY WEIGHTS AND SURVIVAL OF MICE IN THE TWO-YEAR GAVAGE STUDIES OF TELONE II* .................................................... .41 TABLE 11 SURVIVAL OF MICE IN THE TWO-YEAR GAVAGE STUDIEB OF TELONE II' .......43 TABLE 12 ANALYSIS OF URINARY BLADDER LESIONS IN MICE IN THE TWO-YEAR GAVAGE STUDIES OF TELONE II* ............................................ .45 TABLE 13 ANALYSIS OF LUNG TUMORS IN MICE IN THE TWO-YEAR GAVAGE STUDIES OF TELONE II* .................................................... .46 TABLE 14 ANALYSIS OF FORESTOMACH LESIONS IN MICE IN THE TWO-YEAR GAVAGE STUDIES OF TELONE II* .................................................... .47 TABLE 15