EVIDENCE ON THE CARCINOGENICITY OF

CHLORAL HYDRATE (2003 UPDATE)

DRAFT July 2003

Reproductive and Cancer Hazard Assessment Section Office of Environmental Health Hazard Assessment California Environmental Protection Agency

AUTHORS AND REVIEWERS

The Office of Environmental Health Hazard Assessments Reproductive and Cancer Hazard Assessment Section was responsible for the preparation of this document. Members of other technical sections within the Office of Environmental Health Hazard Assessment were drawn from to conduct internal peer review.

Primary Authors

2003 update

John B. Faust, Ph.D.

Staff Toxicologist

Reproductive and Cancer Hazard Assessment Section

1995 document

Andrew Salmon, M.A., D. Phil.

Chief, Air Toxicology and Risk Assessment Unit

Air Toxicology and Epidemiology Section

(formerly with the Reproductive and Cancer Hazard Assessment Section)

Internal OEHHA Reviewers George V. Alexeeff, Ph.D., D.A.B.T. Deputy Director for Scientific Affairs

Lauren Zeise, Ph.D.

Chief, Reproductive and Cancer Hazard Assessment Section

Martha S. Sandy, Ph.D. Chief, Cancer Toxicology and Epidemiology Unit Reproductive and Cancer Hazard Assessment Section

Amy J. Dunn, M.P.H. Research Scientist II Reproductive and Cancer Hazard Assessment Section

John Budroe, Ph.D.

Staff Toxicologist

Air Toxicology and Epidemiology Section

Robert Howd, Ph.D.

Senior Toxicologist

Pesticide and Environmental Toxicology Section

Chloral hydrate -i- July 2003 DRAFT

PREFACE The Safe Drinking Water and Toxic Enforcement Act of 1986 (Proposition 65, California Health and Safety Code 25249.5 et seq.) requires that the Governor cause to be published a list of those chemicals known to the state to cause cancer or reproductive toxicity. The Act specifies that a chemical is known to the state to cause cancer or reproductive toxicity...if in the opinion of the states qualified experts the chemical has been clearly shown through scientifically valid testing according to generally accepted principles to cause cancer or reproductive toxicity. The lead agency for implementing Proposition 65 is the Office of Environmental Health Hazard Assessment of the California Environmental Protection Agency. The states qualified experts regarding findings of carcinogenicity are identified as the members of the Carcinogen Identification Committee of the OEHHA Science Advisory Board (22 CCR 12301).

During a public meeting held in Sacramento, California, on March 1, 1994 the Committee selected chloral hydrate as a candidate for evaluation and requested that OEHHA staff prepare a review of the scientific evidence relevant to the carcinogenic potential of this chemical. A review of pertinent information was contained in the draft document Evidence on the Carcinogenicity of Chloral Hydrate. This document was released to the public and a notice of its availability was published in the California Regulatory Notice Register on March 10, 1995.

At the May 11, 1995 meeting of the Committee, OEHHA staff summarized scientific studies pertinent to the question of carcinogenicity available at that time. Following discussion and deliberation, the Committee did not determine that chloral hydrate has been clearly shown through scientifically valid testing according to generally accepted principles to cause cancer. A motion to find the evidence inadequate failed (four votes for, three against, with one abstention), while a motion to find the evidence sufficient failed (three votes for, five against). The Committee unanimously decided to express to the National Toxicology Program their concern at the lack of adequate animal testing data to evaluate the carcinogenic potential of chloral hydrate. OEHHA expressed the concern of the Committee in a letter to the National Toxicology Program (NTP). Subsequently, NTP initiated and completed a series of bioassays.

At the November 16, 2000 meeting of the Committee, OEHHA staff reported on the status of these NTP studies, and the Committee requested that OEHHA update the chloral hydrate hazard identification document to include the new information. This document has been updated from that presented in 1995 to reflect the new data published since 1995 relevant to carcinogenicity.

Chloral hydrate -ii- July 2003 DRAFT

TABLE OF CONTENTS

PREFACE....................................................................................................................................... ii

TABLE OF CONTENTS............................................................................................................... iii

LIST OF TABLES...........................................................................................................................v

LIST OF FIGURES ....................................................................................................................... vi

1 EXECUTIVE SUMMARY .................................................................................................1

2 INTRODUCTION ...............................................................................................................2

3 DATA ON THE CARCINOGENICITY OF CHLORAL HYDRATE...............................2

3.1 Epidemiological Studies of Carcinogenicity in Humans ........................................ 3

3.2 Carcinogenicity Studies in Animals........................................................................ 3

3.2.1 Oral Exposure Studies..............................................................................................3

Male mice: Single oral exposure. Rijhsinghani et al., 1986 ..........................................3

Male mice: 104-Week drinking water study. Daniel et al., 1992 ..................................4

Male mice: Two-year drinking water study. George et al., 2000 ..................................5

Female mice: 104-Week gavage study (Regimen A). NTP, 2002a...............................6

Female mice: Gavage stop-exposure studies with observation for two years (Regimen

B). NTP, 2002a ..................................................................................................7

Female mice: Single gavage exposure of 28-day-old mice, with observation for two years (Regimen C). NTP, 2002a ........................................................................8

Female mice: Single gavage exposure of 15-day-old mice, with observation for two years (Regimen D). NTP, 2002a........................................................................9

Male mice: Two-year gavage study. NTP, 2002b .........................................................9

Male mice: Single gavage exposure of 15-day-old mice, with observation for two

years (Regimen E). NTP, 2002a ......................................................................11

Male and female rats: Two-year drinking water studies. Leuschner and Beuscher,

1998..................................................................................................................11

Male rats: Two-year drinking water study. George et al., 2000 ..................................11

3.2.2 Intraperitoneal Exposure Studies ...........................................................................12

Male and female mice: Neonatal exposure studies. Von Tungeln et al., 2002............12

3.2.3 Dermal Exposure Study .........................................................................................13

Male mice: Repeated dermal exposure study. Roe and Salaman, 1955 ......................13

3.3 Other Relevant Data.............................................................................................. 14

3.3.1 Genetic Toxicology................................................................................................14

3.3.2 Structure-Activity Comparisons ............................................................................18

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3.3.3 Pharmacokinetics and Metabolism ........................................................................19

3.3.4 Pathology ...............................................................................................................19

3.4 Mechanism............................................................................................................ 19

4 OTHER REVIEWS ...........................................................................................................20

5 SUMMARY AND CONCLUSIONS ................................................................................21

5.1 Summary of Evidence........................................................................................... 21

5.2 Conclusion ............................................................................................................ 22

6 REFERENCES ..................................................................................................................22

Chloral hydrate -iv- July 2003 DRAFT

LIST OF TABLES

Table 1. Tumors in B6C3F1 Male Mice Receiving a Single Oral Dose of Chloral Hydrate

(Rijhsinghani et al., 1986). ..................................................................................................... 4

Table 2. Tumors in B6C3F1 Male Mice Receiving Chloral Hydrate (1 g/l in Drinking Water) for

104 Weeks (Daniel et al., 1992). ............................................................................................ 5

Table 3. Liver Tumors Among Male B6C3F1 Mice Treated