CHLORINATED NAPHTHALENES
First draft prepared by Mr P.D. Howe, Centre for Ecology & Hydrology, Monks Wood, United Kingdom, and Dr C. Melber, Dr J. Kielhorn, and Dr I. Mangelsdorf, Fraunhofer Institute for Toxicology and Aerosol Research, Hanover, Germany
Published under the joint sponsorship of the United Nations Environment Programme, the International Labour Organization, and the World Health Organization, and produced within the framework of the Inter-Organization Programme for the Sound Management of Chemicals.
World Health Organization
Geneva, 2001
The International Programme on Chemical Safety (IPCS), established in 1980, is a joint venture of the United Nations Environment Programme (UNEP), the International Labour Organization (ILO), and the World Health Organization (WHO). The overall objectives of the IPCS are to establish the scientific basis for assessment of the risk to human health and the environment from exposure to chemicals, through international peer review processes, as a prerequisite for the promotion of chemical safety, and to provide technical assistance in strengthening national capacities for the sound management of chemicals.
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WHO Library Cataloguing-in-Publication Data
Chlorinated naphthalenes.
(Concise international chemical assessment document ; 34)
1. Naphthalenes – toxicity
2. Risk assessment
3. Environmental exposure
4. Occupational exposure
I. International Programme on Chemical Safety
II. Series
ISBN 92 4 153034 0
(NLM Classification: QV 241)
ISSN 1020-6167
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©World Health Organization 2001
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TABLE OF CONTENTS
FOREWORD
1. EXECUTIVE SUMMARY
2. IDENTITY AND PHYSICAL/CHEMICAL PROPERTIES
3. ANALYTICAL METHODS
4. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE
5. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION
6. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE
6.1 Environmental levels
6.2 Human exposure
7. COMPARATIVE KINETICS AND METABOLISM IN LABORATORY ANIMALS AND HUMANS
8. EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS
8.1 Single exposure
8.2 Short-term exposure
8.3 Medium-term exposure
8.4 Long-term exposure and carcinogenicity
8.5 Genotoxicity and related end-points
8.6 Reproductive toxicity
8.6.1 Effects on fertility
8.6.2 Developmental toxicity
8.6.3 Endocrine disruption
8.7 Other toxicity/mode of action
8.7.1 Induction of microsomal enzymes and related effects
8.7.2 Effects on lipid peroxidation and antioxidant enzyme activities
8.7.3 Skin irritation, dermal lesions, and acne (including bovine hyperkeratosis)
8.7.4 Toxic equivalency factor (TEF) and relative potency (REP) concept
9. EFFECTS ON HUMANS
9.1 Occupational exposure
9.2 General population exposure
10. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD
10.1 Aquatic environment
10.2 Terrestrial environment
11. EFFECTS EVALUATION
11.1 Evaluation of health effects
11.1.1 Hazard identification and dose–response assessment
11.1.2 Criteria for setting tolerable intakes/concentrations or guidance values for chlorinated naphthalenes
11.1.3 Sample risk characterization
11.2 Evaluation of environmental effects
11.3 Uncertainties in the evaluation
12. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES
REFERENCES
APPENDIX 1 — SOURCE DOCUMENTS
APPENDIX 2 — CICAD PEER REVIEW
APPENDIX 3 — CICAD FINAL REVIEW BOARD
INTERNATIONAL CHEMICAL SAFETY CARDS
RÉSUMÉ D’ORIENTATION
RESUMEN DE ORIENTACIÓN
FOREWORD
Concise International Chemical Assessment Documents (CICADs) are the latest in a family of publications from the International Programme on Chemical Safety (IPCS) — a cooperative programme of the World Health Organization (WHO), the International Labour Organization (ILO), and the United Nations Environment Programme (UNEP). CICADs join the Environmental Health Criteria documents (EHCs) as authoritative documents on the risk assessment of chemicals.
International Chemical Safety Cards on the relevant chemical(s) are attached at the end of the CICAD, to provide the reader with concise information on the protection of human health and on emergency action. They are produced in a separate peer-reviewed procedure at IPCS. They may be complemented by information from IPCS Poison Information Monographs (PIM), similarly produced separately from the CICAD process.
CICADs are concise documents that provide sum maries of the relevant scientific information concerning the potential effects of chemicals upon human health and/or the environment. They are based on selected national or regional evaluation documents or on existing EHCs. Before acceptance for publication as CICADs by IPCS, these documents undergo extensive peer review by internationally selected experts to ensure their completeness, accuracy in the way in which the original data are represented, and the validity of the conclusions drawn.
The primary objective of CICADs is characteri zation of hazard and dose–response from exposure to a chemical. CICADs are not a summary of all available data on a particular chemical; rather, they include only that information considered critical for characterization of the risk posed by the chemical. The critical studies are, however, presented in sufficient detail to support the conclusions drawn. For additional information, the reader should consult the identified source documents upon which the CICAD has been based.
Risks to human health and the environment will vary considerably depending upon the type and extent of exposure. Responsible authorities are strongly encouraged to characterize risk on the basis of locally measured or predicted exposure scenarios. To assist the reader, examples of exposure estimation and risk characterization are provided in CICADs, whenever possible. These examples cannot be considered as representing all possible exposure situations, but are provided as guidance only. The reader is referred to EHC 170.1
While every effort is made to ensure that CICADs represent the current status of knowledge, new information is being developed constantly. Unless otherwise stated, CICADs are based on a search of the scientific literature to the date shown in the executive summary. In the event that a reader becomes aware of new informa tion that would change the conclusions drawn in a CICAD, the reader is requested to contact IPCS to inform it of the new information.
Procedures
The flow chart on page 2 shows the procedures followed to produce a CICAD. These procedures are designed to take advantage of the expertise that exists around the world — expertise that is required to produce the high-quality evaluations of toxicological, exposure, and other data that are necessary for assessing risks to human health and/or the environment. The IPCS Risk Assessment Steering Group advises the Co-ordinator, IPCS, on the selection of chemicals for an IPCS risk assessment, the appropriate form of the document (i.e., EHC or CICAD), and which institution bears the responsibility of the document production, as well as on the type and extent of the international peer review.
The first draft is based on an existing national, regional, or international review. Authors of the first draft are usually, but not necessarily, from the institution that developed the original review. A standard outline has been developed to encourage consistency in form. The first draft undergoes primary review by IPCS to ensure that it meets the specified criteria for CICADs.
The second stage involves international peer review by scientists known for their particular expertise and by scientists selected from an international roster compiled by IPCS through recommendations from IPCS national Contact Points and from IPCS Participating Institutions. Adequate time is allowed for the selected experts to undertake a thorough review. Authors are required to take reviewers’ comments into account and revise their draft, if necessary. The resulting second draft is submitted to a Final Review Board together with the reviewers’ comments. At any stage in the international review process, a consultative group may be necessary to address specific areas of the science.
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to ensure that each CICAD has been subjected to an appropriate and thorough peer review;
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to verify that the peer reviewers’ comments have been addressed appropriately;
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to provide guidance to those responsible for the preparation of CICADs on how to resolve any remaining issues if, in the opinion of the Board, the author has not adequately addressed all comments of the reviewers; and
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to approve CICADs as international assessments.
Board members serve in their personal capacity, not as representatives of any organization, government, or industry. They are selected because of their expertise in human and environmental toxicology or because of their experience in the regulation of chemicals. Boards are chosen according to the range of expertise required for a meeting and the need for balanced geographic representation.
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1. EXECUTIVE SUMMARY
This CICAD on chlorinated naphthalenes was prepared by the Centre for Ecology & Hydrology, Monks Wood, United Kingdom, and the Fraunhofer Institute for Toxicology and Aerosol Research, Hanover, Germany. It is based on the United Kingdom’s Environ mental hazard assessment: Halogenated naphthalenes (Crookes & Howe, 1993) and the work of the German Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area (Greim, 1997), supplemented by a literature search (June 2000). Information on the nature of the peer review and availability of the source documents is presented in Appendix 1. Information on the peer review of this CICAD is presented in Appendix 2. This CICAD was approved as an international assessment at a meeting of the Final Review Board, held in Geneva, Switzerland, on 8–12 January 2001. Participants at the Final Review Board meeting are listed in Appendix 3. The International Chemical Safety Cards for trichloronaphthalene (ICSC 0962), tetrachloronaphthalene (ICSC 1387), pentachloronaphthalene (ICSC 0935), hexachloronaphthalene (ICSC 0997), and octachloronaphthalene (ICSC 1059), produced by the International Programme on Chemical Safety (IPCS, 1993a,b,c, 1999a,b), have also been reproduced in this document.
There are 75 possible congeners of chlorinated naphthalenes. Commercial products are generally mixtures of several congeners and range from thin liquids to hard waxes to high melting point solids. Their main uses have been in cable insulation, wood preservation, engine oil additives, electroplating masking compounds, capacitors, and refractive index testing oils and as a feedstock for dye production.
The major sources of release of chlorinated naphthalenes into the environment are likely to be from waste incineration and disposal of items containing chlorinated naphthalenes to landfill.
Chlorinated naphthalenes are expected to adsorb onto soil and sediments to a large extent. Predicted soil organic carbon/water partition coefficients show an increase as the degree of chlorination in the chlorinated naphthalene increases. Thus, the lower chlorinated congeners are likely to show a moderate sorption tendency, and the higher chlorinated congeners are likely to show a strong sorption tendency.
Chlorinated naphthalenes have been shown to be highly bioaccumulative in fish, but less so in shrimp and algae. The amount of bioaccumulation observed increases with the degree of chlorination of the chlorinated naphthalenes, but the most highly chlorinated naphthalenes (e.g., octachloronaphthalene) do not appear to bioaccumulate due to their very limited absorption.
Monochloronaphthalenes appear to be readily degradable by soil and water microorganisms under aerobic conditions. No information was found on the biodegradation of higher chlorinated congeners by microorganisms.
One report gave an atmospheric half-life of 2.7 days for 1,4-dichloronaphthalene. No other information was found regarding the atmospheric fate of other chlorinated naphthalenes. As all chlorinated naphthalenes absorb light at environmentally relevant wavelengths, direct photolysis reactions may occur in water, in air, or on soil.
In the past, chlorinated naphthalene concentrations of up to 14.5 mg/m3 have been measured in the work place, while levels of 25–2900 ng/m3 have been recorded in outdoor air in the vicinity of manufacturing sites. More recently, monitoring studies have revealed chlorinated naphthalene concentrations of up to 150 pg/m3 at "semirural" sites and 1–40 pg/m3 at remote sites. Predominant congeners in outdoor air were tri- and tetrachloronaphthalenes. In the 1970s, surface water concentrations of up to 5.5 µg/litre were measured near chlorinated naphthalene manufacturing plants, with higher levels recorded in groundwater. Recent studies have found surface water levels in the low ng/litre range. A single study on chlorinated tap water revealed chlorinated naphthalene concentrations of up to 0.15 ng dichloronaphthalene/litre and up to 0.44 ng monochloronaphthalene/litre. Sediment levels of up to 100 mg/kg have been recorded in the past; however, recent results show levels of 0.2 µg/kg at unpolluted sites and 250 µg/kg at polluted sites. Similarly, soil levels of up to 1300 mg/kg were measured at contaminated sites in the early 1980s compared with a more recent value for a former chlor-alkali plant of 18 mg/kg dry weight. Chlorinated naphthalene concentrations in fish range up to a maximum of around 300 µg/kg lipid weight. Tetra- and pentachloronaphthalene congeners tend to predominate in biota. Monitoring studies with seabird eggs have revealed a decrease in chlorinated naphthalene levels between 1974 and 1987.
Chlorinated naphthalenes, especially dioxin-like congeners, have been detected in adipose tissue, liver, blood, and breast milk samples of the general population at concentrations in the ng/kg lipid range. The chlorinated naphthalene congener/isomer pattern found in human specimens was significantly different from that in commercial chlorinated naphthalene mixtures. The dominating congeners in almost all human specimens examined were two penta- and two hexa-isomers, namely 1,2,3,5,7/1,2,4,6,7-pentachloronaphthalene and 1,2,3,4,6,7/1,2,3,5,6,7-hexachloronaphthalene, and to a lesser extent some tetra-isomers.
Chlorinated naphthalenes can be absorbed via oral, inhalative, and dermal routes, with absorption and dis tribution over the whole body after oral administration. The main target organs are liver and fat tissue (besides kidney and lung), both showing a high retention, especially for higher chlorinated congeners such as 1,2,3,4,6,7/1,2,3,5,6,7-hexachloronaphthalene. Half-lives of 1,2,3,4,6,7/1,2,3,5,6,7-hexachloronaphthalene were calculated to be 41 days in adipose tissue and 26 days in the liver of rats. Calculations with monitoring data from human blood samples suggested half-lives of 1.5– 2.4 years for these hexa-isomers in humans. Hydroxy metabolites have been identified mostly for the lower chlorinated naphthalenes (mono- to tetra-) in experimental animals. There are also preliminary indications for the occurrence of methylthio- or methylsulfoxide chloronaphthalene metabolites in faeces of rats. Elimination of parent compounds and/or metabolites occurs via faeces and urine. There was also a transfer of 1,2,3,4,6,7-hexachloronaphthalene to offspring of rats via placental and lactational routes.
LD50 values of some chlorinated naphthalenes ranged from >3 (2,3,6,7-tetrachloronaphthalene) to 1540(1-monochloronaphthalene) mg/kg body weight. Short-term exposure to higher chlorinated naphthalenes resulted in mortality, liver damage, degeneration of kidneys, etc., in rats, rabbits, and cattle. Cattle developed severe systemic disease (bovine hyperkeratosis) during a 5- to 10-day oral exposure to 1.7–2.4 mg/kg body weight per day of penta-, hexa-, hepta-, or octachlorinated naphthalenes. Similar symptoms (death, severe weight loss, and liver damage) have also been observed during medium-term oral or inhalative exposures of laboratory and domestic animals. The higher chlorinated congeners appeared to be more toxic than the lower chlorinated ones. Inhalation of 1.4 mg/m3 (8 h/day) of a penta/hexachlorinated naphthalene mixture for 143 days resulted in slight to moderate histological liver damage in rats.
Long-term and carcinogenicity studies with chlorinated naphthalenes have not been performed.
The few chlorinated naphthalenes tested for mutagenicity — 1-monochloronaphthalene and 1,2,3,4-tetrachloronaphthalene — have proved to be not mutagenic in the Salmonella Ames test.
1,2,3,4,6,7-Hexachloronaphthalene has been found to accelerate the onset of spermatogenesis in male offspring of rats when given to dams at 1 µg/kg body weight per day on days 14–16 of gestation.
Like related compounds, chlorinated naphthalenes have been demonstrated to be inducers of the cytochrome P-450 (CYP)–dependent microsomal enzymes. Two very persistent (and frequently identified in human and environmental samples) hexachlorinated naphthalene isomers (i.e., 1,2,3,4,6,7/1,2,3,5,6,7-hexachloronaphthalene) caused induction of CYP1A1 — typical for dioxin-like compounds — in several in vitro and in vivo test systems. Chlorinated naphthalenes were also found to change lipid peroxidation and antioxidant enzyme activities in rats in a manner indicative of increased oxidative stress. At least some of the biological and toxic responses of chlorinated naphthalenes are believed to be mediated via the cytosolic Ah receptor, resembling those of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds.
All chlorinated naphthalenes tested caused skin irritations, and the penta- and hexachlorinated naphthalenes showed hyperkeratotic activity in the rabbit ear test and in hairless mice, consistent with findings in cattle (bovine hyperkeratosis or X-disease) and humans (chloracne).
Severe skin reactions (chloracne) and liver disease have both been reported after occupational exposure to chlorinated naphthalenes. Chloracne was common among workers handling chlorinated naphthalenes in the 1930s and 1940s.
Other symptoms described in workers exposed to chlorinated naphthalenes included irritation of the eyes, fatigue, headache, anaemia, haematuria, impotentia, anorexia, nausea, vomiting, and occasionally severe abdominal pain. At least 10 deaths were reported from acute atrophy of the liver. Systemic effects resulting in liver disease have been reported only from the inhalation of chloronaphthalenes.
After dermal application of various Halowax samples to adult subjects, only Halowax 1014, containing penta- and hexachloronaphthalenes, produced chloracne; Halowaxes containing mono-, di-, tri-, tetra-, hepta-, and/or octachloronaphthalenes did not.
A cohort mortality study on workers exposed to chlorinated naphthalenes at a cable manufacturing plant found an excess of deaths from cirrhosis of the liver. However, individuals who had shown symptoms of chloracne did not show a higher mortality due to liver cirrhosis compared with other workers. The mortality from all cancers was slightly but significantly elevated among all exposed men (standardized mortality ratio = 1.18) but was not more elevated in the subcohort with chloracne. This subcohort showed statistically significant excess mortality from cancer of the oesophagus and from "benign and unspecified neoplasms."
There are only a few miscellaneous reports on the effects of incidental exposure to chlorinated naphthalenes on the general population. With one exception, they involve ingestion of oil contaminated with other chemicals as well as chlorinated naphthalenes, resulting in general systemic symptoms followed by chloracne.
Chlorinated naphthalenes appear to be of moderate to high acute toxicity to aquatic organisms.
2. IDENTITY AND PHYSICAL/CHEMICAL PROPERTIES
Chlorinated naphthalenes are a group of compounds based on the naphthalene ring system, but where one or more hydrogen atoms have been replaced by chlorine. The generic molecular formula is C10H8ånCln, where n = 1–8. There are 75 possible chlorinated naphthalenes, and they are usually identified using the numbering system shown below:
Chlorinated naphthalenes are often called polychlorinated naphthalenes, or PCNs.
Most of the industrially produced PCNs are not pure materials, but are usually a mixture of several congeners. The commercial products range from thin liquids to hard waxes to high melting point solids, with melting points ranging from -40 to 180 °C. Liquid PCNs are soluble in most organic solvents, whereas the waxy or solid PCNs are soluble in chlorinated solvents, aromatic solvents, and petroleum naphthas and can be mixed with petroleum waxes, chlorinated paraffins, polyisobutylates, and plasticizers. PCNs have low flammability and are of medium to low volatility, volatility decreasing with increasing chlorination.
Some relevant physical and chemical properties of PCNs and commercial PCNs are listed in Tables 1 and 2, respectively. Additional physical/chemical properties are presented in the International Chemical Safety Cards reproduced in this document.
3. ANALYTICAL METHODS
Highly sensitive and specific analytical techniques are necessary for the measurement of PCNs because of their complexity. Another analytical complication is the co-occurrence of bulk quantities of polychlorinated biphenyls (PCBs) or organochlorine pesticides in environmental matrices when typical gas chromatography– electron capture detector methods are used (Falandysz, 1998).
Various methods have been used to overcome this difficulty, typically to perchlorinate the PCNs and PCBs to give octachloronaphthalene and