UNITED NATIONS ENVIRONMENT PROGRAMME
INTERNATIONAL LABOUR ORGANISATION
WORLD HEALTH ORGANIZATION
INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY
ENVIRONMENTAL HEALTH CRITERIA 199
Cholordimeform
This report contains the collective views of an international group of
experts and does not necessarily represent the decisions or the stated
policy of the United Nations Environment Programme, the International
Labour Organisation, or the World Health Organization.
Environmental Health Criteria 199
First draft prepared by Dr P.J. Abbott, Australia and New Zealand Food
Authority, Canberra, Australia
Published under the joint sponsorship of the United Nations
Environment Programme, the International Labour Organisation, and the
World Health Organization
World Health Organization
Geneva, 1998
The International Programme on Chemical Safety (IPCS) is a joint
venture of the United Nations Environment Programme, the International
Labour Organisation, and the World Health Organization. The main
objective of the IPCS is to carry out and disseminate evaluations of
the effects of chemicals on human health and the quality of the
environment. Supporting activities include the development of
epidemiological, experimental laboratory, and risk-assessment methods
that could produce internationally comparable results, and the
development of manpower in the field of toxicology. Other activities
carried out by the IPCS include the development of know-how for coping
with chemical accidents, coordination of laboratory testing and
epidemiological studies, and promotion of research on the mechanisms
of the biological action of chemicals.
WHO Library Cataloguing in Publication Data
(Environmental health criteria ; 199)
1.Chlorphenamidine - toxicity 2.Chlorphenamidine - adverse effects
3.Environmental exposure 4.Occupational exposure
I.International Programme on Chemical Safety II.Series
ISBN 92 4 157199 3 (NLM Classification: QU 61)
ISSN 0250-863X
The World Health Organization welcomes requests for permission to
reproduce or translate its publications, in part or in full.
Applications and enquiries should be addressed to the Office of
Publications, World Health Organization, Geneva, Switzerland, which
will be glad to provide the latest information on any changes made to
the text, plans for new editions, and reprints and translations
already available.
(c) World Health Organization 1998
Publications of the World Health Organization enjoy copyright
protection in accordance with the provisions of Protocol 2 of the
Universal Copyright Convention. All rights reserved. The designations
employed and the presentation of the material in this publication do
not imply the expression of any opinion whatsoever on the part of the
Secretariat of the World Health Organization concerning the legal
status of any country, territory, city or area or of its authorities,
or concerning the delimitation of its frontiers or boundaries. The
mention of specific companies or of certain manufacturers' products
does not imply that they are endorsed or recommended by the World
Health Organization in preference to others of a similar nature that
are not mentioned. Errors and omissions excepted, the names of
proprietary products are distinguished by initial capital letters.
CONTENTS
ENVIRONMENTAL HEALTH CRITERIA FOR CHLORDIMEFORM
PREAMBLE
ABBREVIATIONS
1. SUMMARY
1.1. Identity, physical and chemical properties, and analytical
methods
1.2. Sources of human and environmental exposure
1.3. Environmental transport, distribution and transformation
1.4. Environmental levels and human exposure
1.5. Kinetics and metabolism in laboratory animals and humans
1.6. Effects on laboratory mammals and in vitro test systems
1.7. Effects on humans
1.8. Effects on other organisms in the laboratory and field
1.9. Evaluation of human health risks and effects on the
environment
1.10. Conclusions and recommendations
2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, AND ANALYTICAL
METHODS
2.1. Identity
2.2. Physical and chemical properties
2.3. Conversion factors
2.4. Analytical methods
2.4.1. Plants
2.4.2. Soil
2.4.3. Water
2.4.4. Formulations
2.4.5. Air
2.4.6. Urine
2.4.7. Tissues
3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE
3.1. Natural occurrence
3.2. Anthropogenic sources
3.2.1. Production levels and processes
3.2.2. Uses
4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION AND TRANSFORMATION
4.1. Transport and distribution between media
4.1.1. Air
4.1.2. Water
4.1.3. Soil
4.1.4. Vegetation and wildlife
4.1.5. Entry into food chain
4.2. Biotransformation
4.2.1. Degradation in plants
4.2.2. Degradation in soils
4.2.3. Bioaccumulation
4.3. Ultimate fate following use
5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE
5.1. Environmental levels
5.1.1. Air and water
5.1.2. Soil
5.2. General population exposure
5.2.1. Environmental sources
5.2.2. Residues in raw produce
5.2.3. Residues in processed food
5.3. Occupational exposure during manufacture, formulation
or use
5.3.1. Exposure during manufacture and formulation
5.3.2. Exposure during use
6. KINETICS AND METABOLISM IN LABORATORY ANIMALS AND HUMANS
6.1. Absorption, distribution and excretion
6.1.1. Mouse and rat
6.1.2. Other species
6.1.3. Human
6.2. Metabolic transformation
6.2.1. Mouse and rat
6.2.2. Other species
6.2.3. In vitro studies
7. EFFECTS ON EXPERIMENTAL ANIMALS AND IN VITRO TEST SYSTEMS
7.1. Single exposure
7.1.1. Oral
7.1.2. Other routes
7.2. Short-term exposure
7.2.1. Dietary
7.2.1.1 Mouse
7.2.1.2 Rat
7.2.1.3 Dog
7.2.2. Intubation
7.2.2.1 Rat
7.3. Long-term dietary exposure
7.3.1. Mouse
7.3.2. Rat
7.4. Skin and eye irritation; skin sensitization
7.5. Reproductive toxicity, embryotoxicity and
teratogenicity
7.5.1. Reproductive toxicity
7.5.1.1 Rat
7.5.1.2 Hamster
7.5.2. Embryotoxicity and teratology
7.5.2.1 Rat
7.5.2.2 Rabbit
7.6. Mutagenicity and related end-points
7.6.1. DNA damage and repair
7.6.2. Mutation
7.6.3. Chromosome damage
7.6.4. Cell transformation
7.7. Carcinogenicity
7.7.1. Mouse
7.7.2. Rat
7.8. Other special studies
7.8.1. Immunotoxicity
7.8.2. Behavioural effects
7.8.3. Pharmacological and biochemical effects
7.9. Factors modifying toxicity
7.10. Mechanisms of toxicity - mode of action
7.10.1. Mechanism of acute toxicity
7.10.2. Mechanism of carcinogenicity
8. EFFECTS ON HUMANS
8.1. General population exposure
8.1.1. Acute poisoning incidents
8.2. Occupational exposure
8.2.1. Acute poisoning incidents
8.2.2. Effects of long-term exposure
8.2.3. Epidemiological studies
8.2.3.1 4-Chloro- o-toluidine
8.2.3.2 Chlordimeform
9. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD
9.1. Laboratory experiments
9.1.1. Microorganisms
9.1.2. Aquatic organisms
9.1.2.1 Plants
9.1.2.2 Invertebrates
9.1.2.3 Vertebrates
9.1.3. Terrestrial organisms
9.1.3.1 Plants
9.1.3.2 Invertebrates
9.1.3.3 Vertebrates
9.2. Field observations
9.2.1. Microorganisms
9.2.2. Aquatic organisms
9.2.3. Terrestrial organisms
9.2.3.1 Plants
9.2.3.2 Invertebrates
9.2.3.3 Vertebrates
10. EVALUATION OF HUMAN HEALTH RISKS AND EFFECTS ON THE ENVIRONMENT
10.1. Evaluation of human health risks
10.1.1. Exposure
10.1.2. Toxicity
10.1.3. Risk evaluation
10.2. Evaluation of effects on the environment
11. CONCLUSIONS AND RECOMMENDATIONS FOR PROTECTION OF HUMAN HEALTH
AND THE ENVIRONMENT
11.1. Conclusions
11.2. Recommendations for protection of human health and the
environment
12. FURTHER RESEARCH
13. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES
REFERENCES
RÉSUMÉ
RESUMEN
NOTE TO READERS OF THE CRITERIA MONOGRAPHS
Every effort has been made to present information in the criteria
monographs as accurately as possible without unduly delaying their
publication. In the interest of all users of the Environmental Health
Criteria monographs, readers are requested to communicate any errors
that may have occurred to the Director of the International Programme
on Chemical Safety, World Health Organization, Geneva, Switzerland, in
order that they may be included in corrigenda.
* * *
A detailed data profile and a legal file can be obtained from the
International Register of Potentially Toxic Chemicals, Case postale
356, 1219 Châtelaine, Geneva, Switzerland (telephone no. + 41 22 -
9799111, fax no. + 41 22 - 7973460, E-mail irptc@unep.ch).
* * *
This publication was made possible by grant number
5 U01 ES02617-15 from the National Institute of Environmental Health
Sciences, National Institutes of Health, USA, and by financial support
from the European Commission.
Environmental Health Criteria
PREAMBLE
Objectives
In 1973 the WHO Environmental Health Criteria Programme was
initiated with the following objectives:
(i) to assess information on the relationship between exposure to
environmental pollutants and human health, and to provide
guidelines for setting exposure limits;
(ii) to identify new or potential pollutants;
(iii) to identify gaps in knowledge concerning the health effects of
pollutants;
(iv) to promote the harmonization of toxicological and
epidemiological methods in order to have internationally
comparable results.
The first Environmental Health Criteria (EHC) monograph, on
mercury, was published in 1976 and since that time an ever-increasing
number of assessments of chemicals and of physical effects have been
produced. In addition, many EHC monographs have been devoted to
evaluating toxicological methodology, e.g., for genetic, neurotoxic,
teratogenic and nephrotoxic effects. Other publications have been
concerned with epidemiological guidelines, evaluation of short-term
tests for carcinogens, biomarkers, effects on the elderly and so
forth.
Since its inauguration the EHC Programme has widened its scope,
and the importance of environmental effects, in addition to health
effects, has been increasingly emphasized in the total evaluation of
chemicals.
The original impetus for the Programme came from World Health
Assembly resolutions and the recommendations of the 1972 UN Conference
on the Human Environment. Subsequently the work became an integral
part of the International Programme on Chemical Safety (IPCS), a
cooperative programme of UNEP, ILO and WHO. In this manner, with the
strong support of the new partners, the importance of occupational
health and environmental effects was fully recognized. The EHC
monographs have become widely established, used and recognized
throughout the world.
The recommendations of the 1992 UN Conference on Environment and
Development and the subsequent establishment of the Intergovernmental
Forum on Chemical Safety with the priorities for action in the six
programme areas of Chapter 19, Agenda 21, all lend further weight to
the need for EHC assessments of the risks of chemicals.
Scope
The criteria monographs are intended to provide critical reviews
on the effect on human health and the environment of chemicals and of
combinations of chemicals and physical and biological agents. As
such, they include and review studies that are of direct relevance for
the evaluation. However, they do not describe every study carried
out. Worldwide data are used and are quoted from original studies,
not from abstracts or reviews. Both published and unpublished reports
are considered and it is incumbent on the authors to assess all the
articles cited in the references. Preference is always given to
published data. Unpublished data are only used when relevant
published data are absent or when they are pivotal to the risk
assessment. A detailed policy statement is available that describes
the procedures used for unpublished proprietary data so that this
information can be used in the evaluation without compromising its
confidential nature (WHO (1990) Revised Guidelines for the
Preparation of Environmental Health Criteria Monographs. PCS/90.69,
Geneva, World Health Organization).
In the evaluation of human health risks, sound human data,
whenever available, are preferred to animal data. Animal and
in vitro studies provide support and are used mainly to supply
evidence missing from human studies. It is mandatory that research on
human subjects is conducted in full accord with ethical principles,
including the provisions of the Helsinki Declaration.
The EHC monographs are intended to assist national and
international authorities in making risk assessments and subsequent
risk management decisions. They represent a thorough evaluation of
risks and are not, in any sense, recommendations for regulation or
standard setting. These latter are the exclusive purview of national
and regional governments.
Content
The layout of EHC monographs for chemicals is outlined
below.
* Summary - a review of the salient facts and the risk evaluation
of the chemical
* Identity - physical and chemical properties, analytical methods
* Sources of exposure
* Environmental transport, distribution and transformation
* Environmental levels and human exposure
* Kinetics and metabolism in laboratory animals and humans
* Effects on laboratory mammals and in vitro test systems
* Effects on humans
* Effects on other organisms in the laboratory and field
* Evaluation of human health risks and effects on the environment
* Conclusions and recommendations for protection of human health
and the environment
* Further research
* Previous evaluations by international bodies, e.g., IARC, JECFA,
JMPR
Selection of chemicals
Since the inception of the EHC Programme, the IPCS has organized
meetings of scientists to establish lists of priority chemicals for
subsequent evaluation. Such meetings have been held in: Ispra, Italy,
1980; Oxford, United Kingdom, 1984; Berlin, Germany, 1987; and North
Carolina, USA, 1995. The selection of chemicals has been based on the
following criteria: the existence of scientific evidence that the
substance presents a hazard to human health and/or the environment;
the possible use, persistence, accumulation or degradation of the
substance shows that there may be significant human or environmental
exposure; the size and nature of populations at risk (both human and
other species) and risks for environment; international concern, i.e.
the substance is of major interest to several countries; adequate data
on the hazards are available.
If an EHC monograph is proposed for a chemical not on the
priority list, the IPCS Secretariat consults with the Cooperating
Organizations and all the Participating Institutions before embarking
on the preparation of the monograph.
Procedures
The order of procedures that result in the publication of an EHC
monograph is shown in the flow chart. A designated staff member of
IPCS, responsible for the scientific quality of the document, serves
as Responsible Officer (RO). The IPCS Editor is responsible for
layout and language. The first draft, prepared by consultants or,
more usually, staff from an IPCS Participating Institution, is based
initially on data provided from the International Register of
Potentially Toxic Chemicals, and reference data bases such as Medline
and Toxline.
The draft document, when received by the RO, may require an
initial review by a small panel of experts to determine its scientific
quality and objectivity. Once the RO finds the document acceptable as
a first draft, it is distributed, in its unedited form, to well over
150 EHC contact points throughout the world who are asked to comment
on its completeness and accuracy and, where necessary, provide
additional material. The contact points, usually designated by
governments, may be Participating Institutions, IPCS Focal Points, or
individual scientists known for their particular expertise. Generally
some four months are allowed before the comments are considered by the
RO and author(s). A second draft incorporating comments received and
approved by the Director, IPCS, is then distributed to Task Group
members, who carry out the peer review, at least six weeks before
their meeting.
The Task Group members serve as individual scientists, not as
representatives of any organization, government or industry. Their
function is to evaluate the accuracy, significance and relevance of
the information in the document and to assess the health and
environmental risks from exposure to the chemical. A summary and
recommendations for further research and improved safety aspects are
also required. The composition of the Task Group is dictated by the
range of expertise required for the subject of the meeting and by the
need for a balanced geographical distribution.
The three cooperating organizations of the IPCS recognize the
important role played by nongovernmental organizations.
Representatives from relevant national and international associations
may be invited to join the Task Group as observers. While observers
may provide a valuable contribution to the process, they can only
speak at the invitation of the Chairperson. Observers do not
participate in the final evaluation of the chemical; this is the sole
responsibility of the Task Group members. When the Task Group
considers it to be appropriate, it may meet in camera.
All individuals who as authors, consultants or advisers
participate in the preparation of the EHC monograph must, in addition
to serving in their personal capacity as scientists, inform the RO if
at any time a conflict of interest, whether actual or potential, could
be perceived in their work. They are required to sign a conflict of
interest statement. Such a procedure ensures the transparency and
probity of the process.
When the Task Group has completed its review and the RO is
satisfied as to the scientific correctness and completeness of the
document, it then goes for language editing, reference checking, and
preparation of camera-ready copy. After approval by the Director,
IPCS, the monograph is submitted to the WHO Office of Publications for
printing. At this time a copy of the final draft is sent to the
Chairperson and Rapporteur of the Task Group to check for any errors.
It is accepted that the following criteria should initiate the
updating of an EHC monograph: new data are available that would
substantially change the evaluation; there is public concern for
health or environmental effects of the agent because of greater
exposure; an appreciable time period has elapsed since the last
evaluation.
All Participating Institutions are informed, through the EHC
progress report, of the authors and institutions proposed for the
drafting of the documents. A comprehensive file of all comments
received on drafts of each EHC monograph is maintained and is
available on request. The Chairpersons of Task Groups are briefed
before each meeting on their role and responsibility in ensuring that
these rules are followed.
WHO TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA FOR CHLORDIMEFORM
Members
Dr P.J. Abbott, Australia and New Zealand Food Authority
(ANZFA), Canberra, Australia
Dr K. Barabás, Department of Public Health, Albert Szent-Gyorgyi,
University Medical School, Szeged, Hungary
Dr A.L. Black, Woden, ACT, Australia
Professor J.F. Borzelleca, Pharmacology and Toxicology,
Richmond, Virginia, USA
Dr P.J. Campbell, Pesticides Safety Directorate, Ministry of
Agriculture, Fisheries and Food, Kings Pool, York,
United Kingdom
Professor L.G. Costa, Department of Environmental Health,
University of Washington, Seattle, USA
Dr S. Dobson, Institute of Terrestrial Ecology, Monks Wood,
Abbots Ripton, Huntingdon, Cambridgeshire, United Kingdom
Dr I. Dewhurst, Mammalian Toxicology Branch, Pesticides Safety
Directorate, Ministry of Agriculture, Fisheries and Food,
Kings Pool, York, United Kingdom
Dr V. Drevenkar, Institute for Medical Research and Occupational
Health, Zagreb, Croatia
Dr W. Erickson, Environmental Fate and Effects Division,
US Environmental Protection Agency, Washington, D.C., USA
Dr A. Finizio, Group of Ecotoxicology, Institute of Agricultural
Entomology, University of Milan, Milan, Italy
Mr K. Garvey, Office of Pesticide Programs (7501C),
US Environmental Protection Agency, Washington, D.C., USA
Dr A.B. Kocialski, Health Effects Division, Office of Pesticide
Programs, US Environmental Protection Agency,
Washington, D.C., USA
Dr A. Moretto, Institute of Occupational Medicine, University of
Padua, Padua, Italy
Professor O. Pelkonen, Department of Pharmacology and
Toxicology, University of Oulu, Oulu, Finland
Dr D. Ray, Medical Research Council Toxicology Unit, University
of Leicester, Leicester, United Kingdom
Dr J.H.M. Temmink, Department of Toxicology, Wageningen
Agricultural University, Wageningen, The Netherlands
Observers
Dr J.W. Adcock, AgrEvo UK Limited, Chesterford Park, Saffron,
Waldon, Essex, United Kingdom
Mr D. Arnold, Environmental Sciences, AgrEvo UK Ltd.,
Chesterford Park, Saffron Waldon, Essex, United Kingdom
Dr E. Bellet, CCII, Overland Park, Kansas, USA
Mr Jan Chart, AMVAC Chemical Corporation, Newport Beach,
California, USA
Dr H. Egli, Novartis Crop Protection AG, Basel, Switzerland
Dr P. Harvey, AgrEvo UK Ltd., Chesterford Park, Saffron Walden,
Essex, United Kingdom
Dr G. Krinke, Novartis Crop Protection AG, Basel, Switzerland
Dr A. McReath, DowElanco Limited, Letcombe Regis, Wantage,
Oxford, United Kingdom
Dr H. Scheffler, Novartis Crop Protection AG, Basel, Switzerland
Dr A.E. Smith, Novartis Crop Protection AG, Basel, Switzerland
Secretariat
Dr L. Harrison, Health and Safety Executive, Bootle, Merseyside,
United Kingdom
Dr J.L. Herrman, International Programme on Chemical Safety,
World Health Organization, Geneva, Switzerland
Dr P.G. Jenkins, International Programme on Chemical Safety,
World Health Organization, Geneva, Switzerland
Dr D. McGregor, Unit of Carcinogen Identification and Evaluation,
International Agency for Research on Cancer, Lyon, France
Dr R. Plestina, International Programme on Chemical Safety,
World Health Organization, Geneva, Switzerland
Dr E. Smith, International Programme on Chemical Safety, World
Health Organization, Geneva, Switzerland
Dr P. Toft, International Programme on Chemical Safety, World
Health Organization, Geneva, Switzerland
IPCS TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA FOR CHLORDIMEFORM
The Core Assessment Group (CAG) of the Joint Meeting on
Pesticides (JMP) met at the Institute for Environment and Health,
Leicester, United Kingdom, from 3 to 8 March 1997. Dr L.L. Smith
welcomed the participants on behalf of the Institute, and
Dr R. Plestina on behalf of the three IPCS cooperating organizations
(UNEP/ILO/WHO). The CAG reviewed and revised the draft monograph and
made an evaluation of the risks for human health and the environment
from exposure to chlordimeform.
The first draft of the monograph was prepared by Dr P. Abbott,
Canberra, Australia. Extensive scientific comments were received
following circulation of the first draft to the IPCS contact points
for Environmental Health Criteria monographs and these comments were
incorporated into the second draft by the Secretariat.
Dr R. Plestina and Dr P.G. Jenkins, both members of the IPCS
Central Unit, were responsible for the overall scientific content and
technical editing, respectively. The efforts of all who helped in the
preparation and finalization of the monograph are gratefully
acknowledged.
ABBREVIATIONS
ACTH adrenocorticotropic hormone
ADI acceptable daily intake
a.i. active ingredient
BSP bromosulfophthalein
CIMS chemical ionization mass spectrometry
CNS central nervous system
CORT corticosteroid
DNA deoxyribonucleic acid
EC emulsifiable concentrate
ECG electrocardiography
GC gas chromatography
HPLC high performance liquid chromatography
IgM immunoglobulin M
JMPR Joint FAO/WHO Meeting on Pesticide Residues
MRL maximum residue limit
Mu Chinese measure of an area equivalent to 1/15 acre
or 1/60 ha or 166 m2
MS mass spectroscopy
NADPH reduced nicotinamide adenine dinucleotide
NC cell activity natural cytotoxic cell activity
NK cell activity natural killer cell activity
NOEL no-observable-effect level
PL prolactin
SAP serum alkaline phosphatase
SGOT serum glutamate-oxalate transaminase
SGPT serum glutamate-pyruvate transaminase
SIR standard incidence rate
SMR standardized mortality ratio
SPF specific pathogen free
TLC thin layer chromatography
TLm median tolerance limit
UV ultraviolet
1. SUMMARY
1.1 Identity, physical and chemical properties, and analytical
methods
Chlordimeform is a base of medium strength and forms stable salts
with strong acids. Both chlordimeform and its hydrochloride salt in
the pure state are colourless crystalline solids. Chlordimeform base
has a melting point of 32°C, while the hydrochloride salt has a
melting point of 225-227°C. Chlordimeform base is sparingly soluble in
water (250 mg/litre) and readily soluble in organic solvents, whereas
the hydrochloride salt is readily soluble in water but less soluble in
organic solvents. Chlordimeform base has a vapour pressure at 20°C of
48 mPa and a log Kow of 2.89. A wide range of analytical methods are
available for detection and quantification of chlordimeform in plants,
soil, water and urine.
1.2 Sources of human and environmental exposure
Chlordimeform does not occur naturally. It is manufactured
commercially by condensation of the Vilsmeier reagent (obtained by
reaction of dimethylformamide with POCl3, SOCl2 or COCl2) either
with 4-chloro- o-toluidine or with o-toluidine and subsequent
chlorination of the resulting intermediate . It has been used as a
broad spectrum acaricide and is active mainly against motile forms of
mites and ticks and against eggs and early instars of some
Lepidoptera insects. It is active in the vapour phase as well as by
contact. In the early period of its use, it was used on a wide variety
of crops such as pome fruits, stone fruits, cole crops, vegetables,
grapes, hops, citrus fruits, apples, pears, cherries and strawberries.
It was also used in cattle dips for the control of cattle ticks. In
the latter years, its use was generally restricted to cotton, although
in some countries, there was continued use on rice. Its registration
was voluntarily withdrawn in 1988/1989 in most countries. In China,
production stopped in 1992 and sales ceased in 1993.
1.3 Environmental transport, distribution and transformation
Chlordimeform has a moderate vapour pressure but its evaporation
from plant surfaces is less than would be expected. The hydrolytic
stability of chlordimeform is strongly pH-dependent; it is stable in
acid conditions but rapidly hydrolysed in alkaline conditions.
Chlordimeform has the potential to adsorb to dissolved organic matter.
In soils, chlordimeform is primarily dissipated by microbial
action with some contribution by chemical hydrolysis. There is little
evidence of leaching despite its water solubility, which may be
due to its adsorption to clay minerals, soil organic matter and
biodegradation. The principal metabolites are N-formyl-4-chloro-
o-toluidine and 4-chloro- o-toluidine.
There is a low but measurable uptake of chlordimeform into plants
from soil, sufficient to affect plant-feeding pests. When applied to
the leaves, chlordimeform has only limited capacity to penetrate the
cuticular layers. Chlordimeform is degraded rapidly in plants. The
principal metabolites are demethylchlordimeform, N-formyl-4-
chloro- o-toluidine and 4-chloro- o-toluidine, though not all plants
studied produced the 4-chloro- o-toluidine.
In soils, chlordimeform and its metabolites are dissipated
according to first-order kinetics with a half-life of 20-40 days.
Bioaccumulation studies have demonstrated low uptake of
chlordimeform by aquatic organisms and rapid depuration on transfer to
clean water.
1.4 Environmental levels and human exposure
Levels have not been measured in air and water. Following
applications to paddy fields residues of up to 2900 µg/kg in the top
5 cm of soil and 150 µg/kg in the next 5 cm have been found.
Maximum residue levels were set for a wide range of raw produce
and, in some cases, the residues carried over into processed food. The
Codex maximum residue limits for chlordimeform have been withdrawn.
Occupational exposure to chlordimeform has taken place during
manufacture, formulation and application. In recent years, total
urinary levels of chlordimeform and its metabolites have been used as
a monitor for exposure, and the urine level correlates well with the
degree of skin contamination. Where agricultural workers in the cotton
industry have undergone extensively surveillance for urinary excretion
of chlordimeform, the highest exposure levels were in loaders, washers
and mechanics, with lower levels in flagmen and pilots.
1.5 Kinetics and metabolism in laboratory animals and humans
Chlordimeform is readily absorbed from the gastrointestinal tract
and through the skin of mammals. Rapid excretion follows, with
approximately 80% in the urine and 10-15% in faeces. Low residue
levels are evident in all tissues after approximately 10 days, and
there is no evidence of bioaccumulation. Following dermal
administration in humans, similar rapid excretion through the urine is
observed.
Several oxidized and conjugated metabolites of chlordimeform are
excreted in the urine, demethylchlordimeform, N-formyl-4-chloro-
o-toluidine and 4-chloro- o-toluidine being the major metabolites.
In in vitro studies, the same metabolites are formed,
4-chloro- o-toluidine being the major metabolite.
1.6 Effects on laboratory mammals and in vitro test systems
Chlordimeform has moderate acute toxicity when tested in several
species by oral and dermal routes of administration. The major
metabolites have low oral toxicity when tested in rats. Chlordimeform
causes only slight skin and eye irritation in rabbits. Following
either short- or long-term exposure in both mice and rats with either
chlordimeform or its metabolites, treatment-related changes can be
observed in haematological parameters, and there is some evidence of
hyperplasia of the epithelium of the bile duct and urinary bladder at
the high dose levels. Chlordimeform does not cause an increase in
tumour incidence in rats. In mice, following dietary administration
of either chlordimeform, N-formyl-4-chloro- o-toluidine or
4-chloro- o-toluidine, there is a dose-related increase in
haemorrhagic malignant tumours of vascular origin classified as
malignant haemangioendotheliomas, which cause a dose-related increase
in mortality.
Chlordimeform does not affect reproductive parameters, nor does
it have any teratogenic potential.
Chlordimeform has been tested in a broad range of in vitro and
in vivo genotoxicity assays. No positive responses have been
reported with any of these tests in which unformulated chlordimeform
was tested. In addition, there have been several sporadic and
unconfirmed reports of mutagenic activity induced by N-formyl-
4-chloro- o-toluidine and 4-chloro- o-toluidine. A single report
describes cell transformation induction by both chlordimeform and
4-chloro- o-toluidine. Binding to DNA occurs in the liver of dosed
mice and rats. One major hydrophobic adduct is found at a much higher
level in mice than in rats.
Chlordimeform induces a variety of pharmacological and
biochemical effects in animals, including cardiovascular changes,
hypothermia, hyperexcitability, effects on central visual and auditory
functions, and modulation of biogenic amines and drug-metabolizing
enzymes.
1.7 Effects on humans
Acute poisoning causes fatigue, nausea and loss of appetite, and,
in more severe cases, somnolence, cyanosis, urgency in urination,
cystitis, cardiovascular effects (tachycardia, bradycardia, ECG
changes), coma and shock. Generally, there is complete recovery from
acute intoxication.
Following chronic exposure to chlordimeform, additional symptoms
include abdominal pain, skin itching and rashes (dermal exposure), and
gross and microscopic haematuria. A large number of cases with
clinical symptoms of chronic exposure have been reported in both
chlordimeform-manufacturing plants as well as in agricultural workers.
Following occupational exposure, epidemiological evidence has
provided a strong association between exposure to the metabolite
4-chloro- o-toluidine and the incidence of human urinary bladder
cancer. There is currently only weak evidence for an association
between exposure to chlordimeform and human bladder cancer.
1.8 Effects on other organisms in the laboratory and field
There were no significant effects on populations of soil fungi,
bacteria or actinomycetes following application of chlordimeform to
soil.
There are no laboratory toxicity data on freshwater
invertebrates. Growth of larval oysters was inhibited by chlordimeform
with an EC50 of 5.7 mg/litre. The 96-h LC50 for pink shrimp, the only
crustacean studied, was 7.1 mg/litre and the 96-h LC50 values for
fish ranged from 1 to 54 mg/litre. There are no chronic aquatic
toxicity data available. A mixture of laboratory and field data shows
that chlordimeform is toxic to a wide range of terrestrial non-target
arthropods.
The contact toxicity LD50 for bees has been reported to be
120 µg/g and that for oral toxicity 187 µg/g. There was no mortality
in the field following exposure of species of bees to residues on
alfalfa 3 h after spraying.
The dietary LC50 for various birds species ranged from >1000 to
>5000 mg/kg diet.
1.9 Evaluation of human health risks and effects on the environment
Heavy exposure during manufacture or use, possibly resulting from
inadequate safety precautions, has led to signs of acute poisoning in
workers. Since both production and use are reported to have ceased
worldwide, acute poisoning should no longer occur. The risk associated
with chronic exposure, however, particularly the risk of bladder
cancer, will continue to be of concern for many years. Health
screening of significantly exposed individuals from manufacturing
plants from those rural communities where chlordimeform was
extensively used should be continued.
Since chlordimeform is no longer used, no quantitative risk
assessment for the environment has been performed. There are not
expected to be any long-term detrimental effects on the environment as
a result of past use of chlordimeform.
1.10 Conclusions and recommendations
Chlordimeform has significant potential to cause both immediate
and long-term toxicity in exposed individuals. Current information
supports an association between an increased incidence of human
bladder cancer and exposure to 4-chloro- o-toluidine and, to a lesser
extent, chlordimeform.
Chlordimeform does not persist in the environment, and therefore
there are not expected to be any long-term detrimental effects on the
environment as a result of past use.
Future commercial production or use of chlordimeform is not
recommended. Existing stocks should be disposed of safely.
Those with occupational exposure to chlordimeform should
participate in a health screening programme that includes urinary
cytology and the detection of haematuria.
2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, AND ANALYTICAL METHODS
2.1 Identity
Common name: Chlordimeform
Chemical structure:
Chemical formula: C10H13ClN2
Relative molecular mass: 196.7
CAS name: N'(4-chloro-2-methylphenyl)-
N, N-dimethyl-methanimidamide
IUPAC name: N2-(4-Chloro- o-tolyl)-
N1, N1-dimethylformamidine
CAS registry number: 6164-98-3 (chlordimeform)
19750-95-9 (chlordimeform hydrochloride)
RTECS number: LQ4375000
Common synonyms: Chlorphenamidine; chlorfenamidine;
chlorophedine; chlorophenamide;
chlorophenamidin; chlorophenamidine;
N'-(4-chloro- o-tolyl)- N,
N-dimethylformamidine;
N, N-dimethyl- N'-(2-methyl-4-
chlorophenyl)-formamidine;
N, N-dimethyl- N'-(2-methyl-4-
chlorophenyl)formadin;
ENT 27335; ENT 27567; EP-333;
N'-(2-methyl-4-chlorophenyl)- N,
N-dimethylformamidine
Trade names: Acaron; Bellotion Especial; Bermat;
Bermatchlorfenamidine; C8514; Carzol;
CDM; CDMS; CGS500; CGS800SP;
Chlorfenamidine; Ciba 8514; Ciba C8514;
COTIP 500EC; Fundal; Fundal 500; Fundex;
Galecron; OMS-1209; Ovatoxion; OVINA;
OVITIX; RS 141; Schering 36268;
Sn 36268; Spanon; Spanone;
SPIKE ULVAIR.
Technical grade chlordimeform is greater than 95% pure and
contains the following impurities: N-formyl-4-chloro-2-toluidine
( N-formyl-4-chloro- o-toluidine), 4-chloro-2-toluidine
(4-chloro- o-toluidine hydrochloride) and sodium chloride.
Chlordimeform free base has been formulated as a 500 g/litre
emulsifiable concentrate. Chlordimeform hydrochloride has been
formulated as a 300 or 800 g/kg water-soluble powder, a 20 g/kg dust
or as 50 g/kg granules.
2.2 Physical and chemical properties
Some of the physical and chemical properties of chlordimeform
base and chlordimeform HCl are shown in Table 1. The molecular
structure of chlordimeform has been investigated by Gifkins & Jacobson
(1980) using single crystal X-ray diffraction.
Table 1. Some physical and chemical properties of chlordimeform
basea
Physical state colourless crystalline solid
Boiling point at 14 mmHg 163 - 165°C
Melting point 32°C
Log Kow 2.89
Vapour pressure at 20°C 48 mPa (3.5 × 10-4 mmHg)
Density (d30) 1.10
Solubility in water at 20°C 250 mg/litre
Solubility in acetone, benzene,
chloroform, ethyl acetate, hexane,
methanol at 20°C >200 g/litre
Half-life at pH 7
(30°C in water, 5% methanol) 42 h
Half-life at pH 9
(30°C in water, 5% methanol) 5 h
Reactivity Forms salt with acids
a From: Worthing (1979); IARC (1978)
Chlordimeform has a solubility in water of 250 mg/litre but is
readily soluble in organic solvents. It forms salts with acids and the
hydrochloride salt is readily soluble in water. When pure,
chlordimeform forms colourless crystals.
Chlordimeform is a base of medium strength with pKa of 6.8 in
50% aqueous methanol (Voss et al., 1973) and forms stable salts with
strong acids.
Chlordimeform is sensitive to light, especially in alkali, and
slowly decomposes in neutral and alkaline aqueous solution. The pH
dependence of photodecomposition of chlordimeform was noted by Su &
Zabik (1972), who observed that an aqueous solution of chlordimeform
hydrochloride (pH 3.1) was unaffected by mercury lamp irradiation for
up to 12 days at 25°C, while a solution of the free base at pH 7-8
decomposed in the same period to a mixture consisting of N-formyl-4-
chloro- o-toluidine and a bis-formamidine. Photo-decomposition of
chlordimeform has also been studied on silica gel chromatographic
plates with irradiation by long- and short-wave ultraviolet light,
fluorescent light and sunlight (under glass) for periods of 10 to 20 h
(Knowles & Sen Gupta, 1969). The major degradation product was again
N-formyl-4-chloro- o-toluidine with either sunlight or UV light.
Fluorescent light caused little decomposition. Sunlight resulted in
12% decomposition in 10 h, while UV resulted in 25% decomposition in
20 h. When 4-chloro- o-toluidine was irradiated with UV light,
numerous decomposition products were found but these were not
characterized further.
Chlordimeform has relatively high volatility and is thus capable
of efficient fumigation action. The hydrochloride salt has negligible
volatility.
2.3 Conversion factors
1 ppm = 8.04 mg/m3 1 mg/m3 = 0.12 ppm
2.4 Analytical methods
2.4.1 Plants
Geissbühler et al. (1971) described in detail a method for the
determination of total residues of chlordimeform and its metabolites,
which can be used for routine analysis of plant and soil samples. In
this method, chlordimeform and its metabolites are hydrolysed to
4-chloro- o-toluidine by successive treatments with acetic acid and
sodium hydroxide, respectively. The hydrolysis product is then steam
distilled, extracted with isooctane, diazotized and coupled with
N-ethyl-1-naphthylamine yielding a purple dye, which, after column
chromatography on cellulose, is determined by colorimetry. Interfering
azo-dyes from aromatic plants or soil are removed by chromatography on
a cellulose column. This colorimetric method has a limit of detection
of 0.05 mg/kg. If required, the identity of the residues can be
verified by thin-layer chromatography on a cellulose column. This
procedure is sensitive to about 0.1 mg/kg. Alternatively, the
hydrolysis product, 4-chloro- o-toluidine, is diazotized and
iodinated, and the iodinated derivative is measured by electron-
capture gas chromatography. This alternative method has a limit of
detection of 0.05 mg/kg.
Kossmann et al. (1971) refined the method of Geissbühler et al.
(1971) to permit separate determination of residue quantities of the
parent compound and its potential degradation products in plant
materials. In this procedure, plant material is subject to a two-fold
extraction, the first with methanol/hydrochloric acid and the second
with the lipophilic mixture, methanol/methylene chloride. Separation
of chlordimeform and its degradation products is accomplished by
thin-layer chromatography. The separated eluants are converted to
4-chloro- o-toluidine and analysed as described by Geissbühler et al.
(1971). The limits of detection for the separated compounds,
chlordimeform, demethylchlordimeform and 4-chloro- o-toluidine are
0.02 to 0.03 mg/kg.
Grübner (1977) described a thin-layer chromatographic method for
the determination of chlordimeform residues alone or together with its
metabolite, 4-chloro- o-toluidine, in cucumbers and apples. The
limits of detection for chlordimeform and 4-chloro -o-toluidine were
0.1 and 0.05 mg/kg, respectively. The rates of recovery were 76-85 and
90-105%, respectively.
Fan & Ge (1982) described an alkali flame ionization
gas-chromatographic method for the determination of chlordimeform and
three potential metabolites in cargo rice and husk. Residues of
chlordimeform and its metabolites were extracted with absolute alcohol
or hexane and cleaned up on neutral alumina columns, before being
chromatographed in a column of 1% DEGS coated on 60-80 mesh
405 support (PEG 20M bonded phase). The detection limits for
chlordimeform, 4-chloro- o-toluidine, 2,2'-dimethyl-4,
4'-dichloroazobenzene, and N-formyl-4-chloro- o-toluidine were
0.03, 0.028, 0.11 and 0.43 mg/kg, respectively, for cargo rice and
0.03, 0.028, 0.22 and 0.43 mg/kg, respectively, for husk. Recovery for
chlordimeform was 81-93% for cargo rice and 103-104% for husk.
Recovery for 4-chloro- o-toluidine was 71-73% for both cargo rice
and husk. Recovery for 2,2'-dimethyl-4,4'-dichloroazobenzene was
81.8-112% for cargo rice and 109-118% for husk. Recovery for
N-formyl-4-chloro- o-toluidine was 66% for husk. Mattern et al.
(1991) described a rapid analytical procedure for 17 pesticides,
including chlordimeform, using gas chromatography/chemical ionization
mass spectrometry (GC/CIMS) for detection in various commodities
including peppers, spinach, lettuce and snap beans. Percentage
recoveries for chlordimeform were 87.8% (peppers), 72.6% (spinach),
99.7% (lettuce) and 94.7% (beans). The limits of detection for
chlordimeform were 0.05 mg/kg (beans), 0.05 mg/kg (lettuce),
0.05 mg/kg (peppers) and 0.10 mg/kg (spinach).
2.4.2 Soil
The method of Geissbühler et al. (1971) described in section
2.4.1 for plants can equally be applied to the determination of total
residues of chlordimeform in soil.
2.4.3 Water
Machin & Dingle (1977) described a UV spectrographic method for
the determination of chlordimeform in cattle dipping baths and
sprays. Preliminary clean-up removes UV-absorbing impurities and
converts chlordimeform to its hydrochloride. Following silica gel
chromatography, the absorbance of the non-eluted material is measured
at 240 nm to determine chlordimeform content. Optimum results are
obtained in the concentration range of 0.02-0.06% (w/v) chlordimeform.
2.4.4 Formulations
Voss et al. (1973) described two methods for the determination of
chlordimeform in formulations. The first relies on acid titration of
the free base with hydrochloric acid. The hydrochloride salt is
converted into the free chlordimeform base, which is extracted into an
organic solvent. After evaporation of the solvent, the active
ingredient is determined potentiometrically. The second method makes
use of gas chromatography, and in this case the chlordimeform
hydrochloride preparations have to be converted into the base form
prior to injection into the gas chromatograph.
Gale & Hofberg (1985) described a gas chromatographic procedure
for the determination of chlordimeform in emulsifiable concentrate
formulations. Chlordimeform was extracted with methylene chloride,
chromatographed on CBWX-20M and detected by flame ionization.
2.4.5 Air
There are no published methods described for the determination of
chlordimeform in air.
2.4.6 Urine
Liu & Mao (1980) described a method for the gas chromatographic
separation of chlordimeform, demethylchlordimeform, N-formyl-4-
chloro- o-toluidine and 4-chloro- o-toluidine in urine. Optimum
separation was achieved on a column with 1% polyvinylpyrolidone and 8%
PEG 20M on 80-100 mesh white diatomeous support no. 101 (acid and base
washed). The column was suitable for both qualitative and quantitative
analysis.
A method to analyse urinary residues of workers occupationally
exposed to chlordimeform was developed by Ciba-Geigy in 1980
(Anonymous, 1980a). The method relies on the hydrolysis of
chlordimeform and other residues to 4-chloro- o-toluidine with sodium
hydroxide, followed by extraction with hexane and separation on
reverse-phase liquid chromatography fitted with a UV detector. A
published version of this method was prepared by Geyer & Fattal (1987)
in which the alkaline hydrolysate of urine is extracted with hexane,
the solvent is evaporated, and the hydrolysate is reconstituted with
aqueous acetonitrile. Separation was performed on a reverse-phase Novo
Pak 5 mm C18 column with a UV absorbance detector equipped with a 254
nm filter. A similar method was described by Cheung et al. (1989) for
the analysis of chlordimeform from urine of field workers. Ross &
Leisten (1989) have refined this method with the use of synchronous
spectral data which provides a improved signal-to-noise ratio, which
gives lower minimum detectable levels while still allowing a
well-resolved spectrum. This system may allow detection of levels
equivalent to 1 mg/litre in urine.
2.4.7 Tissues
A gas chromatographic method for the determination of residues of
chlordimeform in animal tissues was first described in the early 1970s
(Anonymous, 1971a). The method involves hydrolysis of chlordimeform to
4-chloro- o-toluidine by successive treatments with acetic acid and
sodium hydroxide. The hydrolysis product is steam distilled and
extracted into isooctane. Following diazotization of the 4-chloro-
o-toluidine, the diazo-moiety is exchanged for iodine by potassium
iodide treatment. The iodinated derivative is gas chromatographed
using electron-capture detection. The limit of detection using this
method is 0.02 mg/kg.
Rieger et al. (1985) have described a gas chromatography/flame
ionization detection method for the determination of chlordimeform and
its major metabolite, demethylchlordimeform, from human tissue
samples, namely, human whole blood and human liver (1:1 aqueous
homogenate). Tissues were first extracted with an organic solvent,
transferred to an acid aqueous medium (0.1M hydrochloric acid),
re-extracted into a small volume of organic solvent and separated on
GC or GC/MS. Using extraction with either chloroform or n-butanol,
recoveries of 81 and 75%, respectively, were obtained.
3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE
3.1 Natural occurrence
Chlordimeform does not occur naturally.
3.2 Anthropogenic sources
3.2.1 Production levels and processes
Chlordimeform was first commercialized in 1966. It can be
manufactured commercially by two methods (Voss et al., 1973), both
starting with the conversion of dimethylformamide to the Vilsmeier
reagent by reaction with POCl3, SOCl2 or COCl2.
By the first method, condensation of the Vilsmeier reagent with
4-chloro-amino-toluene (or 5-chloro-2-aminotoluene, 5-CAT) leads
directly to chlordimeform hydrochloride. Treatment with a strong base
gives the free chlordimeform base.
By the second method, the Vilsmeier reagent is reacted with
o-toluidine to give phenamidine, which is chlorinated in a second
step. The chlorination gives rise to a certain amount of isomers as
unwanted side-products. The crude chlordimeform so obtained has to be
purified either by recrystallization of its chlorohydrate or by
rectification of the free base.
Chlordimeform has been produced at various times in Switzerland,
Germany, United Kingdom, USA, Italy, Argentina and China.
Little information is available on the production levels of
chlordimeform. Information from the US International Trade Commission
(IARC, 1983) indicated that imports of chlordimeform to the USA
through the principal US customs districts amounted to 745 tonnes in
1979 and 198 tonnes in 1980.
In 1974, total usage of chlordimeform in the USA is estimated to
have been 590 tonnes, 77% of which was used on cotton, 15% on
deciduous fruits and nuts, and 8% on vegetables. In 1976, the US
Department of Agriculture reported that 2000 tonnes of chlordimeform
was used in the USA on major crops (IARC, 1983). In 1980, total usage
in the USA was 227 tonnes, all of which was used on cotton to control
budworm/bollworm.
Chlordimeform has been used in China throughout the 1970s and the
1980s at the rate of approximately 10 000 to 15 000 tonnes per year
(Xue, personal communication). In the Chinese province of Hu-bei, the
average annual usage during the period 1984-1988 was 3276 tonnes
(Huang et al., 1989).
3.2.2 Uses
Chlordimeform is a broad spectrum acaricide and is active mainly
against eggs and motile forms of mites and ticks and against eggs and
early instars of some Lepidoptera insects. It kills eggs, larvae and
adults not only by contact but also in the vapour phase. The major use
initially was in the control of mites on deciduous fruit.
In 1971, chlordimeform products were registered in many countries
for use on a wide variety of crops such as pome fruits, stone fruits,
cole crops, vegetables, grapes, hops, citrus, apples, pears, cherries
and strawberries. Chlordimeform also had important veterinary uses as
an acaricide. In Australia, chlordimeform was registered for use in
cattle dips for the control of cattle ticks (Boophilis mictopus), in
combination with organophosphorus acaricides (FAO/WHO, 1972).
In 1975, it was reported that the use pattern of chlordimeform
had been extended to include control of stemborers in irrigated rice,
control of Lepidoptera larvae on cotton, and control of a wide range
of Lepidoptera larvae on cabbage and tomatoes (FAO/WHO, 1976). At
this time, the control of stemborers in irrigated rice proved to be
one of the most important uses of chlordimeform. In the case of
cotton, chlordimeform became one of the most important substitutes for
DDT and other organochlorine pesticides.
Chlordimeform has had no significant usage in non-crop situations
other than on ornamentals.
In 1976, the manufacturers temporarily suspended the sale of
chlordimeform from all markets worldwide, on the basis of adverse
carcinogenicity findings in chronic mouse studies.
In 1978, having completed a number of toxicology, metabolism and
residue studies, the manufacturers re-applied in a number of countries
for registration to allow limited commercial use in cotton crops only.
The proposal was to use chlordimeform by aerial application under
supervised conditions that limited the uptake by operators and
by-standers. Chlordimeform was re-introduced for insect control in
cotton in USA, Central America, Columbia, Israel, Australia and China.
Guidelines for the handling and use of chlordimeform were set in
Australia, Columbia, Israel and USA (California). Application rates
were set to minimize the occurrence of residues in cotton fibres and
cotton seed oil. In China, extensive use of chlordimeform continued
through the 1980s on rice and cotton.
Use of chlordimeform ceased in most countries in the mid to late
1980. The Joint FAO/WHO Meeting on Pesticide Residues (JMPR) withdrew
its temporary Acceptable Daily Intake (ADI) in 1987 and recommended
that chlordimeform should not be used where its residues, or those of
its metabolite, 4-chloro- o-toluidine, could arise in food. (FAO/WHO,
1988).
In 1988-1989, Ciba-Geigy and Schering voluntarily and finally
halted marketing of chlordimeform and decided to withdraw registration
worldwide. In China, production stopped at the end of 1992, and sales
ceased in June 1993.
4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION AND TRANSFORMATION
4.1 Transport and distribution between media
4.1.1 Air
Chlordimeform has relatively high volatility, and thus when
sprayed on crops considerable evaporation would be expected from plant
surfaces as well as from the soil. Studies in plants, however,
indicate a lower rate of evaporation than expected. In bean plants,
disappearance from the surface in the first few hours was found to be
of the order of only 30-40% of the original dose applied (FAO/WHO,
1972). This result was obtained when either chlordimeform or its
hydrochloride salt was used and is considered to be due to the
buffering capacity of plant exudates with a resulting equilibrium
between the free base and salts. The low volatility from plant
surfaces was confirmed by Sen Gupta & Knowles (1969) on apple
seedlings and by Ehrhardt & Knowles (1970) on grapefruit seedlings. In
cotton plants, approximately 55% of the dose applied to leaves was
volatilized from the surface of the leaves within 2 h (Bull, 1973).
No studies are available on the volatilization of chlordimeform
from soil surfaces, but it is likely to be at least as high as from
leaf surfaces.
4.1.2 Water
While chlordimeform base has only low solubility in water, the
solubility of the hydrochloride salt is relatively high. Its stability
in water, however, is highly pH-dependent, and in the normally neutral
to slightly alkaline conditions of rivers and lakes its half-life
would be relatively short.
It also has the potential to adsorb readily to dissolved organic
matter resulting in precipitation (Maqueda et al., 1989).
The hydrolytic stability of chlordimeform is highly pH-dependent.
It slowly hydrolyses in neutral pH and is stable in strongly acid
conditions. The half-life at 10°C is about 38 days at pH 7, compared
to 8 days at pH 8. At 30°C, these values are reduced to about 3 and
0.5 days, respectively. A solution of the hydrochloride salt (pH 3-4)
showed no appreciable hydrolysis over several days (Su & Zabik, 1972).
The principal product of hydrolysis is N-formyl-4-chloro- o-
toluidine, which at room temperature is very slowly converted to
4-chloro- o-toluidine by further hydrolysis. The second step may be
accelerated by heating with strong acid or alkali.
4.1.3 Soil
Hydrolysis of chlordimeform to N-formyl-4-chloro- o-toluidine
would be expected to be significant under the slightly acid or
slightly alkaline conditions that normally prevail in soils.
Despite the reasonably high solubility of the hydrochloride salt
of chlordimeform, there appears to be little leaching from the site of
application in the soil (FAO/WHO, 1972).
In the studies by Fischer & Cassidy on the uptake of
chlordimeform from soil into cotton plants, the levels of
chlordimeform in the soil were also analysed (FAO/WHO, 1979). Soil was
treated when the cotton reached 10 weeks of maturity. Radioactivity in
the top 75-mm layer of silt loam soil accounted for 1.23 mg/kg
chlordimeform equivalents after treatment. At 7 weeks, this level had
decreased to 0.33 mg/kg and at 13 weeks to 0.20 mg/kg. Extraction of
this layer revealed partition of 32% into the organic layer and 20%
into the polar fraction, and 44% was non-extractable, indicating rapid
degradation. For all but one sample, the level of radioactivity as
chlordimeform equivalents in the lower soil levels, 75-150 mm and
150-200 mm, was less than 0.01 mg/kg, indicating that leaching did not
occur in silt loam. In later experiments with regular over-the-top
spray treatment throughout the maturation of the cotton plants, the
same rapid decrease in radioactivity (as chlordimeform equivalents)
was seen in the top 75 mm of soil. Radioactivity in deeper layers was
again equivalent to less than 0.01 mg/kg. At harvest of the cotton
plants, up to 91% of the radioactivity in the soil could be converted
to 4-chloro- o-toluidine.
The nature of the non-extractable portion of chlordimeform in
soil was investigated by Perez-Rodriguez & Hermosin (1979) and by
Hermosin & Perez-Rodriguez (1981) in experiments examining the
interaction of chlordimeform with clay minerals, montmorillonite,
kaolinite, illite and vermiculite. The earlier work indicated that the
adsorption of chlordimeform on clay is essentially a cation-exchange
reaction and that chlordimeform ions lie between the silicate layers,
thus being difficult to disperse with water or aqueous solutions of
inorganic cations. In the later study, chlordimeform adsorption to the
clay minerals montmorillonite, illite and vermiculite was found to be
an irreversible process, whereas chlordimeform adsorbed on kaolinite
is only weakly bonded and easily removed by washing with water.
The role of soil organic matter in the adsorption and degradation
of chlordimeform in soil was examined in experiments by Maqueda et al.
(1983, 1989). In the first study, the interaction of chlordimeform
with humic acid extracted from the top 20 cm of a clay soil classified
as Typic Chromozerert soil was examined. Adsorption is essentially a
cation-exchange process, although other mechanisms, such as charge
transfer, H-bonding, and van der Waals forces may contribute to the
high adsorption capacity. The variety of mechanism may make it
difficult to ascertain the long-term fate in the environment. In the
second study, the interaction of chlordimeform and other pesticides
with fulvic acids extracted from a spodosol soil was examined. Fulvic
acids are the fraction of humic substances that dissolves in both acid
and alkaline media, and thus are readily found solubilized in lakes
and rivers. The adsorption of chlordimeform was again shown to be a
cation-exchange process, together with H-bonding and charge transfer
mechanisms. Precipitation occurred upon interaction of chlordimeform
with fulvic acids. The amount of precipitate increased in a
dose-related manner up to levels of 100 mmol chlordimeform/litre.
4.1.4 Vegetation and wildlife
Benezet & Knowles (1981) examined the degradation of
chlordimeform by two algal types, Chlorella, the green alga,
and Oscillatoria, a cyanobacterium. In the presence of either
Chlorella or Oscillatoria, chlordimeform was hydrolysed to
N-formyl-4-chloro- o-toluidine, probably by a largely non-enzymatic
reaction. Further reaction formed 4-chloro- o-toluidine and some
CO2. Oxidative N-demethylation was not a major path for chlordimeform
degradation by algae.
The solubility of chlordimeform was sufficient to allow uptake
by the roots of bean and rice plants and to be transported to
plant-feeding pests, as demonstrated by the efficacy experiments of
Dittrich (1967) and Dittrich & Loncarevic (1971).
The ability of plants to take up chlordimeform from soil was
further demonstrated by the experiments of Fischer & Cassidy
(FAO/WHO, 1979), where the soil of a cotton field was treated with
[14C]-chlordimeform when the cotton was 10 weeks old. Uptake of the
radioactivity by the cotton plant was noted to occur in small
quantities, and the highest levels were found in the seeds and fibres.
Biphasic extraction showed 42% in the organic fraction and 34% in the
polar fraction, and 24% was not extractable. Thirteen weeks after
treatment, the mature cotton contained 0.09 mg/kg in the leaves.
The low level of translocation of chlordimeform in plants was
demonstrated by Sen Gupta & Knowles (1969) in experiments where
[14C]-chlordimeform was injected into the stem of apple seedlings
followed by analysis of stem and leaf radioactivity for a period of 20
days. For the first 4 days after injection, 95% of the radioactivity
was localized in the stems, predominantly as the parent compound.
After 20 days, 71.6% of the radioactivity still remained in the stem,
with 25.4% in the leaves, and only 17.9% remained as the parent
compound. The major portion of the radioactivity in the stems after 20
days was unextractable with chloroform and acetone.
In the experiments of Ehrhardt & Knowles (1970) with grapefruit
seedlings, there was no detectable movement of radioactivity into
adjacent stems and leaves 8 days after application of [14C]-
chlordimeform to two upper leaves or two lower leaves. Considerable
movement into stems and leaves was noted when [14C]-chlordimeform was
injected into the main stem, and also to the periphery of grapefruit
leaves when it is applied centrally. Thus, movement of chlordimeform
occurred mainly in the direction of the xylematic transpiration
stream.
Application of chlordimeform directly to the leaves of apple
seedlings (Sen Gupta & Knowles, 1969) or the leaves of grapefruit
seedlings (Ehrhardt & Knowles, 1970) demonstrated the limited capacity
of chlordimeform to penetrate the cuticular layers. Ercegovich et al.
(1972) reported that chlordimeform appeared to adhere to the outer
surface of fruit and did not appear to translocate readily to the
fleshy parts. The chief factors which seem to account for the decrease
of chlordimeform residues in fruit appear to be volatilization,
weathering and growth dilution.
Similarly, the application of [14C]-chlordimeform to cotton
leaves resulted in little movement of radioactivity (and none of
chlordimeform itself) into the untreated plant parts. The small amount
of translocated radioactivity consisted exclusively of polar, mainly
non-extractable substances (Gross, 1977).
In a field experiment, Fischer & Cassidy treated a cotton field
plot over-the-top with [14C]-chlordimeform at a rate of 1 kg/ha when
plants were 12-14 weeks old (FAO/WHO, 1979). Radioactivity in the
cotton plants immediately after treatment was the equivalent of
2.44 mg/kg chlordimeform. At harvest, the radioactivity calculated as
[14C]-chlordimeform was 12.91 mg/kg in the leaves, 0.99 mg/kg in
the stalks, 0.03 mg/kg in the fibre, and 0.26 mg/kg in the seed, with
0.07 mg/kg in the oil and 0.19 mg/kg in the meal. Parent chlordimeform
accounted for 31% and 45.2% in the leaves and stalks, respectively.
The data indicated that although leaf radioactivity is high, there is
still little translocation of [14C]-chlordimeform metabolites to the
seed or fibre.
Supervised residue trials to determine the residue levels in
cottonseed and cottonseed products have been conducted (FAO/WHO,
1979). In general, there is a correlation between the application rate
and the residue level but the interval between the last application
and the harvest also has a strong influence on the residue level. The
decrease of residues with time was most pronounced during the first 10
days after treatment of the cotton plants. At the maximum application
rate of 1 kg/ha, the residue level rarely exceeded 2 mg/kg in
cottonseed, seed meal or crude oil.
When used for the control of rice stem borer in Japan,
chlordimeform resulted in low levels of residues in rice grains and
straws. In rice grain after three treatments, the residue levels of
chlordimeform, demethylchlordimeform, N-formyl-4-chloro- o-
toluidine and 4-chloro- o-toluidine were 48, 0.4, 15 and 53 µg/kg,
respectively. The results indicate a low level of penetration of
chlordimeform into rice plants. The chlordimeform that entered the
plant was gradually degraded to 4-chloro- o-toluidine (Iizuka &
Masuda, 1979).
There have been no studies conducted on the uptake of
chlordimeform by wildlife. Studies with experimental animals suggest
rapid metabolism and excretion, with negligible retention.
4.1.5 Entry into food chain
Potential routes of entry of chlordimeform into the human diet
include the direct consumption of crops containing chlordimeform
residues, the consumption of processed food prepared from treated
crops, or the consumption of animal products derived from animals
treated topically with chlordimeform or raised on chlordimeform-
containing feed such as cottonseed.
Since the temporary withdrawal of the use of chlordimeform from
the market in 1976 in most countries and the later restriction to use
on cotton, dietary consumption of chlordimeform residues on crops in
these countries has virtually ceased. However, dietary consumption of
chlordimeform residues is likely to have continued at least until the
late 1980s in some areas (see section 5.2.2). The maximum residue
levels (MRLs) which were used for chlordimeform are discussed in
section 5.2.2.
4.2 Biotransformation
4.2.1 Degradation in plants
Data reviewed by JMPR (FAO/WHO, 1972) demonstrated that
chlordimeform was quite rapidly degraded in plants with a high
inherent metabolic activity (e.g., bean plants) but was only slowly
degraded in ripe fruits. Green fruits (e.g., grapes) and stems have
an intermediate rate of degradation of chlordimeform. Tentative
identification of the observed metabolites indicated that in
leaves both N'-(4-chloro- o-tolyl)- N-methylformamidine
(demethylchlordimeform) and N-formyl-4-chloro- o-toluidine were
major metabolites. In ripe apple and pear fruit, however, only
N'-formyl-4-chloro- o-toluidine was detected. In all tissues,
4-chloro- o-toluidine was either not detected or present in small
quantities, even when six-fold overdose treatment was used.
In the experiments of Sen Gupta & Knowles (1969), [3H]- or
[14C]-chlordimeform was applied to apple seedlings by either leaf
treatment or stem injection. The half-life of degradation was about
12-16 days, and after 20 days 40% of the radioactivity was still
unchanged chlordimeform. Organosoluble degradation products were
identified as demethylchlordimeform, N-formyl-4-chloro- o-toluidine
and 4-chloro- o-toluidine, with the last two representing less than
1% of the total radioactivity. Non-extractable radioactivity, possibly
chlordimeform degradation products complexed with polymeric cell
constituents, was observed only after stem application.
In the experiments of Ehrhardt & Knowles (1970), both
[14C]-chlordimeform and [14C]-chlordimeform hydrochloride were
applied to the leaf surface of growing grapefruit seedlings. After 20
days, only 10-20% of total radioactivity was recovered, possibly due
to evaporation from leaves, and only 1% of radioactivity was unchanged
chlordimeform. The pattern of metabolites was essentially the same as
in apple seedlings, but the levels were smaller.
Witkonton & Ercegovich (1972) examined the metabolites found in
six different fruits (apples, pears, cherries, plums, strawberries and
peaches) following treatment at varying rates with chlordimeform.
Samples of the fruit were collected at various intervals after the
last application from orchards and plants that had been treated with
aqueous sprays of chlordimeform. Of the three potential degradation
products analysed for, only one, namely, N-formyl-4-chloro- o-
toluidine, was detected, together with the parent compound. The other
potential degradation products, namely, demethylchlordimeform and
4-chloro- o-toluidine, were not detected. There was no correlation
between the amount of chlordimeform and 4-chloro- o-toluidine and the
application rate or the sampling interval. The nature of the fruit and
environmental factors were accredited as the major contributing
factors governing the formation and retention of 4-chloro- o-
toluidine. At harvest, the total residue in all crops was
approximately 1 mg/kg, except in peaches, which had approximately
2 mg/kg of total residue. The chief factors which appeared to account
for the decrease in chlordimeform residues were weathering and growth
dilution, rather than chemical or enzymatic degradation.
The potential formation of azo-derivatives of chlordimeform or
its metabolite, 4-chloro- o-toluidine, in treated fruit and
vegetables under field conditions was investigated by Geissbuhler et
al. (1971) using a sensitive gas-chromatographic residue method that
allowed the detection of 0.01 mg/kg of 2,2'-dimethyl-4,4'-
dichloroazobenzene. At 20, 30 or 40 days after a 4-fold overdose
treatment by chlordimeform to apple fruits and leaves, residues of the
azobenzene compound were either not detectable or detected at very low
levels (0.04 mg/kg) in leaves. At normal levels of treatment, residues
of azobenzene compounds would be unlikely to be detected. This result
is supported by the experiments of Witkonton (1973), who analysed
the residues on apple surfaces 60 days after treatment with
[14C]-chlordimeform. The results of these experiments do not support
the in vitro studies of Rose (1969a,b), which indicate the potential
formation of azobenzene derivatives in plants by plant peroxidases.
The metabolism of chlordimeform in cotton plants was first
examined by Bull (1973) following treatment of individual leaves with
[14C]-chlordimeform by petiole injection or by foliar application.
About 45% of the applied dose was absorbed by the leaves, and the
balance volatilized from the leaf surface within 2 h. Tentative
identification of metabolites included demethylchlordimeform,
N-formyl-4-chloro- o-toluidine and 4-chloro- o-toluidine. After
1 h, only 2% of the applied dose could be recovered from leaf
surfaces. The unextractable radioactivity was considered to represent
decomposition products bound to insoluble plant material.
Gross (1977) studied the metabolism of [14C]-chlordimeform in
greenhouse-grown cotton plants following treatment of leaves at a rate
equivalent to 0.6 kg a.i./ha. Metabolites were extracted into hexane,
methylene chloride and water-soluble fractions at various times up to
11 weeks after treatment. The radioactivity in the organic fractions
consisted of at least seven substances. Four were characterized by TLC
as chlordimeform, N-demethylchlordimeform, 4-chloro- o-toluidine
and N-formyl-4-chloro- o-toluidine. Fifty-six percent of the dose
was found in the plant after one week, the balance being lost by
volatilization. The main degradation pathway was hydrolysis,
demethylation only being significant at later sampling times. The loss
of chlordimeform from the surface of leaves was confirmed by
Wolfenbarger et al. (1979) who noted that 24 h after cotton leaves
were treated topically with chlordimeform, only 5% of the EC form was
recovered, whereas 25% of the HCl salt was recovered.
Fischer & Cassidy (FAO/WHO, 1979) identified the metabolites in
leaves after [14C]-chlordimeform was sprayed over-the-top on cotton
plants. At mature harvest, the radioactivity in the leaves consisted
of chlordimeform (60.3%), demethylchlordimeform (4.1%), 4-chloro-
o-toluidine ((7.6%) and N-formyl-4-chloro- o-toluidine (7%). The
results indicate that the parent chlordimeform will be the major
chemical residue in the mature cotton foliage.
Honeycutt & Cassidy (1977) investigated the metabolism of
chlordimeform in cottonseed following injection of [14C]-
chlordimeform into the stem of a growing cotton plant. Forty percent
of the radioactivity in the cottonseed was not extractable. Total
hydrolysis of the radioactivity in the cottonseed showed that a total
of 19.8% of the radioactivity could be converted to 4-chloro- o-
toluidine. The data indicated that the metabolism of chlordimeform in
cottonseed is extensive and results in conjugation to natural
products.
4.2.2 Degradation in soils
The potential for microbial degradation of chlordimeform in
the soil was first identified by Johnson & Knowles (1970), who
demonstrated the capability of several bacteria (Aerobacter
aerogenes and Serratia marcesens), actinomycetes (Streptomyces
griseus) and fungi (Fusarium moniliforme and Rhizopus nigricans)
in culture media to degrade chlordimeform extensively. The
principal metabolite of the bacterial and fungal species was
N-formyl-4-chloro- o-toluidine, while for the actinomycete,
Streptomyces griseus, the principal metabolite was 4-chloro- o-
toluidine. 4-Chloro- o-toluidine was also formed by the bacteria and
fungi. None of the microbes formed symmetrical azo-compounds.
The metabolic fate of chlordimeform in sandy loam over a one-year
period was examined by Iwan & Goller (1975). Soil samples containing
2 µCi of either [14C- ring]- or [14C- tolyl]-chlordimeform were
prepared in an environmental chamber and methanol/benzene extracts
examined at various intervals. Extractability decreased to 50% within
7 days and was less than 2% after 360 days. In sterilized soil
samples, on the other hand, extractability decreased only slowly, and
70% was still extractable after 180 days. This result indicates that
microbial activity plays a major role in soil degradation of
chlordimeform to non-extractable components. Even though bound to
soil, degradation of chlordimeform continued, as shown by the release
of CO2 as a consequence of oxidative attack upon the tolyl group.
Little CO2 was released under anaerobic conditions and no CO2 was
released from sterile samples. The major pathway of metabolism was
through hydrolysis to 4-chloro- o-toluidine but oxidative
N-demethylation was also a significant pathway leading to
4-chloro- o-toluidine. Further hydrolysis steps followed. The azo
compound, 2,2'-dimethyl-4,4'-dichloroazobenzene, was formed in small
amounts only when the initial chlordimeform concentration was
200 mg/kg in the soil samples. Anaerobic conditions produced the same
metabolic products with the exception of oxidative products such as
demethylchlordimeform. The data suggests that even under sterile
conditions, the degradation of chlordimeform is rapid and its
half-life in non-sterile soils should not exceed one month.
In a further study, Iwan et al. (1976) isolated from
chlordimeform-treated soil four coupling products formed by one-
electron oxidation of 4-chloro- o-toluidine by soil microorganisms.
The four products, one of which is 2,2'-dimethyl-4,4'-
dichloroazobenzene, are formed only from high concentrations of
chlordimeform (70-100 mg/kg), which are at least 10 times higher than
the levels occurring after field application.
4.2.3 Bioaccumulation
There is no data to indicate that chlordimeform bioaccumulates in
plant or animal tissues. However, with a low Kow of 2.89, this
indicates a moderate potential to bioaccumulate.
4.3 Ultimate fate following use
Chlordimeform in the air and in water would be expected to
undergo photodecomposition. In water as well as in soil, chemical
hydrolysis occurs together with adsorption to organic and clay
materials. In plants, residues form complexes with polymeric cell
constituents.
Chlordimeform can be hydrolysed readily to 4-chloro- o-toluidine
by heating with alkali. For the disposal of small quantities of unused
pesticide, the following method is recommended: mix with excess lime
(CaO) or sodium hydroxide (NaOH) and sand and bury at least 0.5 m
below the surface in clay soils. Commercial formulations require
0.5-1.0 kg alkali per kg of pesticide. Alkali can be reduced by 50%
for dilute formulations, e.g., 1% solution or dust. For very
concentrated pesticides (> 50% a.i.), double the amount of alkali and
mix the pesticide with soapy water, before reaction with alkali. Test
reaction on small scale to discover whether or not it will be too
vigorous. Larger quantities should be treated in small batches or
burned in a high-temperature incinerator equipped with effluent gas
scrubbing (IRPTC, 1992).
5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE
5.1 Environmental levels
5.1.1 Air and water
There are no specific data available on the monitoring of
chlordimeform levels in air and water. In neutral and alkaline
solutions, relatively rapid degradation would be expected owing to
hydrolytic instability. Under acidic conditions, slower degradation
would be expected (Su & Zabik, 1972). Adsorption to organic matter in
water would also be expected under field conditions. In both media,
there would be degradation due to photodecomposition (Knowles & Sen
Gupta, 1969).
5.1.2 Soil
Chlordimeform deposited inadvertently on soil surfaces after
spray application may be expected to dissipate by the following
processes: volatilization, chemical hydrolysis, photodecomposition and
microbial degradation. Under field conditions, chlordimeform and its
4-chloro- o-toluidine-containing metabolites are dissipated according
to first-order reactions with half-lives ranging from 20 to 40 days
(Guth & Senn, 1969; FAO/WHO, 1972). The conclusion from these
experiments is that accumulation of chlordimeform in the soil would
not be expected.
Following three applications to rice paddy fields for the control
of rice stem borer, residues of chlordimeform, demethylchlordimeform,
N-formyl-4-chloro- o-toluidine and 4-chloro- o-toluidine were
2900, 9, 190 and 68 µg/kg, respectively, in the top 5 cm of soil, and
were 150, 1, 8 and 20 µg/kg, respectively, in the 5-10 cm level of
soil. These results indicate the presence of chlordimeform and its
degradation products mainly in the upper layer with minimal movement
downward (Iizuka & Masuda, 1979).
5.2 General population exposure
5.2.1 Environmental sources
There are no longer any environmental sources for exposure of the
general population to chlordimeform. While chlordimeform was being
used on cotton, there was potential for general population exposure to
spray drift from aerial application. The persistence of residues of
chlordimeform on the leaves of cotton also raised the possibility of
exposure through contact with the leaves during the growing period or
during harvesting.
5.2.2 Residues in raw produce
Prior to the temporary suspension of its use in 1976,
chlordimeform was used on a wide variety of crops and on livestock.
The temporary maximum residue levels (MRLs) shown in Table 2 were
established at the 1971 meeting of the Joint Meeting on Pesticide
Residues (JMPR) (FAO/WHO, 1972) as a result of numerous residue trials
in various countries. Residue trials indicated that whilst there was a
sharp drop in the residue level between the day of application and the
second or third day post-treatment, thereafter the rate of decline was
remarkably slow with a half-life on apples, grapes, pears and tomatoes
exceeding 21 days.
Table 2. Temporary tolerances for chlordimeform established in 1971
(FAO/WHO, 1972)
Temporary tolerance mg/kg
Pears, peaches, prunes 5
Apples, grapes, plums, strawberries 3
Brassicas, cherries, citrus fruit, cotton seed oil
(crude and refined), cotton seed 2
Beans 0.5
Fat, meat and meat products of cattle 0.5
Milk (whole) 0.05
Butter 0.5
In 1975, the temporary MRL for pears was raised to 10 mg/kg, and
new temporary MRLs were established for tomatoes (1 mg/kg) and hulled
rice (0.1 mg/kg) (FAO/WHO, 1976). In 1978, the JMPR meeting retained
only the MRLs for cottonseed and recommended that for cottonseed oil
(edible), meat of cattle, pigs, poultry and sheep, and milk and milk
products no residues should occur at the current limit of detection
(0.05 mg/kg) (FAO/WHO, 1979).
The proportion of metabolites and parent compound in the residues
remaining on fruits at various times after application have been
determined in numerous trials. In general, the parent compound
represents the major residue (>80%), followed by N-formyl-4-chloro-
o-toluidine, N'-(4-chloro- o-tolyl)- N-methylformamidine
(demethylchlordimeform) and 4-chloro- o-toluidine.
In Chinese residue trials, chlordimeform residues on green
cabbage after application by direct spraying of a 800-fold dilution of
25% chlor-dimeform formulation were 20.9 mg/kg after 4 h, 11.5 mg/kg
after 2 days, 4.2 mg/kg after 7 days and 0.02 mg/kg after 14 days
(Anonymous, 1980b).
In a paper by the Chinese Special Task Group on the residues of
chlordimeform (Anonymous, 1981), the residues of chlordimeform in rice
plants during the period 1974-1980 were examined. In the period
1974-1975, after a single application of 25% aqueous chlordimeform
(9-11 litre/ha) the residue levels on rice harvested after 33-40 days
were 0.25-0.28 mg/kg. When applied at half this rate, residue levels
on rice harvested after 20-74 days were 0.17-0.71 mg/kg. In
field studies in Beijing in 1977, with the same single rate of
application, residue levels on rice harvested after 19-42 days were
0.37-0.51 mg/kg. If 2-3 applications were used, the residue levels on
rice harvested after 19-31 days were 1.3-1.8 mg/kg. The authors noted
the difficulty in meeting the requirement for a residue level of
0.1 mg/kg regardless of the pattern of application. In field studies
in Hu-bei Province in 1978 with the same application rate, the residue
levels in rice harvested after 25-42 days were 0.19-1.20 mg/kg. In
field studies in Zhe-jiang Province in 1978, residue levels in rice
when harvested after 30 days were 0.080-0.112 mg/kg, while residues in
rice harvested after 80 days were 0.039-0.100 mg/kg. In field studies
in Guang-dong Province in 1978, residues in rice harvested after 30
days were 0.042-0.149 mg/kg. In other field studies in the Guang-dong
Province in 1980, residue levels on rice harvested after 56 days were
0.185 mg/kg, but when the harvest was performed at 72 days, the
residue level was less than 0.10 mg/kg (Anonymous, 1981).
Huang et al. (1989) reported the residues of chlordimeform on
both rice and cotton plants in the Hu-bei Province of China between
1984 and 1988. With 1-3 applications to rice plants, followed by
harvest after 25-55 days, the chlordimeform residues were generally in
the range of 0.066-0.820 mg/kg for the rice, 7.70-22.30 mg/kg for the
husk, and 16.5-21.2 mg/kg for the stem. The authors noted that the
residue levels seldom met the 1975 JMPR recommended MRL of 0.10 mg/kg
for hulled rice (FAO/WHO, 1976). In further work on rice plants, it
was noted that the residue levels for late rice were generally higher
(approximately 2-fold) in late rice compared to early rice, and that
the residue levels in both the rice and the husk reduced by more than
90% when the time to harvest was increased from 26 to 72 days. With a
72-day harvest, the residue level in the rice was 0.065 mg/kg. The
residue levels in the stem (18-41 mg/kg), on the other hand, remained
relatively unchanged over the 72-day period. With 1-3 applications to
cotton plants, followed by harvest after 40 days, the chlordimeform
residues were 0.053-0.151 mg/kg in the kernel and 0.118 mg/kg in the
bracket.
Chlordimeform residues were also found in 8/15 honey samples
(Huang et al., 1989). The highest residue found was 32.2 mg/kg, and
the majority of the samples contained less than half this level. In
1994 the US FDA collected and analysed samples of honey imported from
the People's Republic of China. Of 60 samples analysed, 39 had
detectable residues, the highest being 0.058 mg/kg (Krick, 1994).
Moore (1971) summarized the results of residue trials on the use
of chlordimeform as an acaricide in cattle dips in Australia. The
residues were examined in cattle muscle, fat and liver as well as in
milk and butter from the first milking. Chlordimeform was used at
concentrations of 0.0125-0.1% in buffered cattle dips. Residues in
muscle, fat and liver did not increase greatly with increasing dose
of chlordimeform, and showed significant reductions between day 1
and day 3 post-treatment. The maximum residue levels found at day
3 post-treatment in muscle, fat and liver were 0.33, 0.51 and
0.69 mg/kg, respectively. At the first milking, the residues levels
showed a closer relationship with the concentration of chlordimeform
in the dip. The residue levels in milk and butter at a concentration
of 0.0125% were 0.01 and 0.30 mg/kg, respectively. The maximum
residue levels in milk and butter, which were found at the highest
concentration used (0.2 %), were 0.31 and 1.6 mg/kg, respectively.
In the study by Burkhard (1971), cows washed with a 0.5%
solution of chlordimeform to the hindquarters (3 treatments at 7-day
intervals), had total residue levels in milk, meat and fat below the
level of detection (0.03 mg/litre), except in milk on the day after
treatment when the levels rose to 1 mg/kg. In a further study by Voss
& Burkhard (1971), when cows were fed a concentrate containing
40-240 mg/kg chlordimeform for periods up to 42 days, the total
residues of chlordimeform and its metabolites in all milk, meat
and fat samples were below the limit of detection (0.03 mg/litre or
mg/kg). In liver and kidney samples, residues rose to a peak between
14 and 21 days (0.58 mg/kg in liver and 0.13 mg/kg in kidney), which
was followed by a slow decline.
In a study by Palmer et al. (1977), residues of chlordimeform
were determined in tissues and milk of cattle after spray application
to control cattle tick. In subcutaneous fat from animals sprayed with
0.45, 0.15 or 0.05% chlordimeform, the residue levels were 2.88, 0.46
and 0.15 mg/kg, respectively. The half-life of disappearance in all
cases was 2.46 days. Lower residue levels were found in six other
tissues, including kidney, muscle and liver. Residue levels in whole
milk of lactating cows at the three treatment levels were 1.42, 0.28
and 0.03 mg/litre, respectively. The half-life of disappearance from
milk was 0.45 days.
White Leghorn hens fed a laying mash containing chlordimeform at
levels of 0.25, 0.75 or 1.0 mg/kg were examined for residues in eggs
and tissues (breast, fat and liver) for periods of up to 28 days. No
residues were detected in breast meat. Residues were detected in fat
(0.22 mg/kg) at the 21 days only. Residues in the liver were highest
between 7 and 14 days (0.20 mg/kg) and reduced rapidly upon withdrawal
from the chlordimeform-containing feed. There were no detectable
residues of chlordimeform in eggs (FAO/WHO, 1972).
Residue trails on cotton were conducted between the years 1969
and 1978 (FAO/WHO, 1979). The application rates ranged from 0.125 to
3.6 kg/ha and resulted in mean residue levels of 0.1 to 13.1 mg/kg in
cottonseed when it was harvested immediately after application. The
final residue level was dependent on a number of factors including
application rate, number of applications, and length of waiting period
before harvest. The application rate had the largest influence.
5.2.3 Residues in processed food
Total residues of chlordimeform and its metabolites do not reduce
substantially during cooking processes, since while the proportion of
parent compound is reduced, there is an increase in the hydrolysis
product, N-formyl-4-chloro- o-toluidine. Residues of chlordimeform
itself in crops decrease through hydrolysis, but volatilization in
steam during cooking is not an important factor. The rate of
hydrolysis of chlordimeform is a function of pH and occurs much more
rapidly in weakly acid or neutral crops such as cauliflower (pH 6) or
green beans (pH 5) than in strongly acid crops such as apples (pH 2.5)
or tomatoes (pH 3). These results have been derived from studies in
different crops such as apples, grapes, tomatoes, cauliflower, beans
and sugar beet. These studies have also shown that residues of
chlordimeform and its metabolites are located in the outer parts of
crops, such as fruit peel. Excessive residues might therefore be
removed by peeling fruit (apples, citrus) or trimming the outer leaves
of leaf crops. In general, washing will remove only a small part of
the total residue (FAO/WHO, 1972).
Chlordimeform residues in whole apples reduced to approximately
40% of this level in pressed apple juice, while the level in the wet
pomace doubled (FAO/WHO, 1972) This is consistent with studies that
have shown that the residue level in the skin and outer layer is
approximately 50-fold higher than that found in the flesh (FAO/WHO,
1972).
Chlordimeform residues in tea leaves were found to be extractable
into tea prepared from these leaves to the extent of approximately 50%
of the total residues (Blass, 1972a).
Chlordimeform residues in grapes reduced to approximately 60% of
this level in grape juice (Blass, 1972b). This is consistent with
studies that have shown that the residue level in the grape skin was
between 60 and 76% of total residues (FAO/WHO, 1972). Fermentation
of the grape juice over a period of 72 days yielded a wine that
contained residue levels similar to those in grape juice (Blass,
1972c), indicating that the fermentation process does not
significantly lower the total chlordimeform residue level.
Chlordimeform residues in green hop cones, when used to prepare
beer, were found to be reduced to levels below the level of detection
(0.03 mg/kg) (Voss, 1971).
Residues associated with the processing of cottonseed have been
reported (FAO/WHO, 1979). Separation of the cottonseed oil leaves the
majority of the residues in the hulk and meal, although a significant
residue still remains in the crude oil. Additional refining processes
including bleaching, hydrogenating and deodorizing reduce the residue
level to below the level of detection. Cottonseed oil for human
consumption is subject to the bleaching and deodorizing processes and
thus residues of chlordimeform will be virtually zero.
5.3 Occupational exposure during manufacture, formulation or use
5.3.1 Exposure during manufacture and formulation
In the cases described by Folland et al. (1978) of
hospitalization of three factory workers in the USA who were exposed
to chlordimeform, the urinary levels of chlordimeform plus 4-chloro-
o-toluidine were 1.29, 6.32 and 4.85 mg/litre, respectively, three
days after exposure. This report is described in more detail in
section 8.2.2.
In a study on workers in the USA engaged in chlordimeform
production and packaging in 1976, urine was monitored in more than
100 workers. In more than 800 individual urine samples, total urinary
levels ranged from 0.05 to 50 mg/litre (personal communication by J.W.
Barnett, Ciba-Geigy Agricultural Division, Greenborough, North
Carolina, USA, to California Department of Food and Agriculture).
In China, there have been several studies in which the level of
exposure of workers to chlordimeform in chemical factories has been
examined together with a medical examination to detect any evidence of
toxicity in these workers. These are described in section 8.2.
In the study by Lu et al. (1981), the air concentrations
in 1974 in a chlordimeform-producing factory were generally below
0.036 mg/m3, with shorter periods at higher levels (0.108-
0.33 mg/m3), during specific tasks. Skin contamination on hands and
forearms was 9.1 mg/h for chemical operators and 964.2 mg/h for
packers. The urinary excretion levels for chlordimeform and
4-chloro- o-toluidine in controls were 0.015 and 0.042 mg/litre,
respectively, in chemical operators were 0.065 and 0.108 mg/litre,
respectively, and in packers were 0.263 and 0.398 mg/litre,
respectively.
In the study by Li et al. (1985b), 24 packers (9 male, 15 female)
in a chlordimeform manufacturing plant in Jiang-su Province of China,
were exposed to chlordimeform air concentrations (9 samples over 3
consecutive days) of 0.066 mg/m3 (range 0.017-0.121 mg/m3). Skin
contamination of the hands and forearms was 110 µg/100 cm2
(S.D. 39 µg/100 cm2). Urinary chlordimeform levels were
0.20 ħ 0.13 mg/litre, and urinary 4-chloro- o-toluidine levels
were 0.48 ħ 0.29 mg/litre.
In a further study (Anonymous, 1985a) in a chlordimeform
manufacturing factory in China, packers had the highest urinary
chlordimeform and 4-chloro- o-toluidine levels at 0.39 mg/litre which
significantly correlated with skin contamination but not with air
concentration.
In the study by Tao et al. (1985), 61 employees (25 chemical
operators, 36 packers) of a pesticide factory in China were exposed to
air levels in the range 0.074 to 0.160 mg/m3. Skin contamination of
packers (2.99 mg/day) was higher than for chemical operators
(0.784 mg/day). The urinary excretion rate of chlordimeform and
4-chloro- o-toluidine in packers was also higher (0.513 mg/litre)
than for chemical operators (0.206 mg/litre) or controls
(0.055 mg/litre).
5.3.2 Exposure during use
In a company report by Kossmann (1980), summary data was provided
on the results of occupational exposure surveillance programmes on
agricultural workers associated with chlordimeform in nine countries.
Surveys of aerial pesticide applications to cotton entailed the
monitoring of about 600 airstrips in 1979 in the nine countries. Over
28 000 urine samples were analysed from workers in all phases of the
application situation. The urine was monitored and residue data
expressed as chlordimeform equivalents. In 1% of the assays,
substantial chlordimeform urinary residues indicated a significant
occupational exposure. Over 75% of the samples were at or below the
lowest level of analytical detection. This report states that, in
general, the conditions in two countries, the USA and Australia, were
indicative of favourable working conditions where only about 1% of the
samples contained a residue level indicating a higher-than-desired
level of exposure. In a subsequent report by Kenyon et al. (1993),
however, it is stated that at least 20% of the urine samples in
agricultural workers associated with chlordimeform in New South Wales,
Australia, exceeded the maximum permissible exposure level for
chlordimeform equivalents in urine, which was set at 0.2 mg/litre.
Operators who exceeded this level were required to be withdrawn from
the site until the urinary level fell below 0.1 mg/litre. The mean
sample assays for both ground rig operators and workers involved in
aerial application exceeded the set level in 1984-1985. Furthermore, a
number of workers experienced exposures that exceeded the limit on
multiple occasions. The urine monitoring programme in operation in New
South Wales, Australia, also grossly underestimated the worker
exposure levels since its protocol did not allow urine sample
collection in the first 24 h following potential exposure (Kenyon et
al., 1993). In the report by Kossman (1980), it is stated that working
conditions in some other countries (i.e., Colombia, El Salvador,
Guatemala and Honduras) were less favourable and thus exposure was
higher. However, in some areas where flagmen were unavoidably exposed,
the urinary residue levels were low, indicating that with precautions
exposure can be controlled. In New South Wales and Israel, urine
monitoring for agricultural workers was mandatory, while in the USA,
urine monitoring was conducted on a voluntary basis.
In a report by Henderson (1985), monitoring studies on operator
exposure during the 1984-1985 cotton season in NSW, Australia, were
summarized. Urine samples were examined in operators involved in
application of chlordimeform by both ground-rig (Strong & Bull, 1985a)
and aerial (Strong & Bull, 1985b) methods. Chlordimeform application
by ground-rig to 26 444 hectares involved 48 people. A total of 85
urine samples were examined; in 78.8% of samples the chlordimeform
level was below 0.20 mg/litre, and in 90.5% of samples it was below
0.50 mg/litre. The mean sample assay was 0.21 mg/litre. Chlordimeform
application by aerial spraying to 315 694 hectares involved
222 people. A total of 919 urine samples were examined and in 80.3% of
samples, the chlordimeform level was below 0.20 mg/litre, and in 89.8%
of samples was below 0.50 mg/litre. The mean sample assay was
0.24 mg/litre.
The exposure data for chlordimeform used on cotton in seven
countries (Australia, Columbia, El Salvador, Guatemala, Mexico,
Nicaragua, USA) for the period 1980-1984 has been compiled in a
company report by Limmer (1985). Urine samples indicated that in all
countries, the chlordimeform level was less than 0.3 mg/litre for
between 70 and 92% of the exposed workers, and was >5 mg/litre in
less than 2% of workers. The highest levels were recorded in the
loaders, washers and mechanics, while the lower levels were found in
the pilots and flagmen.
In a study by Jiang et al. (1985), exposure of workers engaged
in spraying chlordimeform with fine mist sprayers in both rice fields
and cotton fields was examined. The air concentration of chlordimeform
surrounding the workers during spraying was 0.80 mg/m3. Skin
contamination from spraying in a rice field was 0.777 mg/100 cm2/h
(16 samples), and from spraying in a cotton field was 0.445 mg/100
cm2/h for one group (40 samples) and 1.216 mg/100cm2/h for a
second group (40 samples). Urinary excretion of chlordimeform and
4-chloro- o-toluidine together was 0.756 mg/litre for rice workers,
and 0.490, 0.465 and 1.125 mg/litre in three separate groups (40 each)
for cotton workers. Good correlation was noted between skin
contamination and urinary excretion. It was noted that contamination
of the lower extremities of the body was significantly different
between workers with protection (0.490 mg/100 cm2 per h) and those
without (1.179 mg/100 cm2 per h).
In a study by Ling et al. (1986) and Zhang et al. (1986a),
excretion of chlordimeform and 4-chloro- o-toluidine was examined as
a measure of occupational exposure. Chlordimeform applicators (7 male,
6 female; 20-41 years) were examined during spraying of cotton for
three consecutive days for 4.7, 3.0 and 4.4 h respectively in July
1985. Protective measures included gauze mask, plastic gloves and
plastic apron, although it was noted that extensive contamination
occurred. Air levels in the breathing zone on each of the three days
were 0.011, 0.014, 0.011 mg/m3, respectively. Skin contamination on
each of the three days was estimated by the method of Zhang et al.
(1986b) to be 10.99, 4.32, and 4.45 mg/day, respectively. Urinary
chlordimeform and 4-chloro- o-toluidine together were measured over
the 3 days of exposure and for 7 days after cessation of exposure.
Urinary levels ranged from a peak of 2.408 mg/litre during exposure to
0.036 mg /litre after 7 days. Excretion of chlordimeform occurred very
rapidly and the highest level was detected in the sample collected at
the end of each shift. There was a close correlation between skin
contamination and urinary excretion. Metabolism occurred very rapidly
since 4-chloro- o-toluidine usually accounted for 70-93 % of the
total amount in the urine. The authors concluded that the level of
urinary chlordimeform plus 4-chloro- o-toluidine is an accurate index
of chlordimeform exposure.
Maddy et al. (1986) reported the results between 1982 and 1985 of
a programme of monitoring the urine of more than 200 workers who had
received training in the use of chlordimeform on cotton in California.
Protective clothing was required for all employees who handled
containers, prepared mixtures, loaded application vehicles, applied
chemical, flagged or did repair work on equipment exposed to
chlordimeform. This included cloth overalls, washable hat, waterproof
boots, waterproof gloves, and a full-face shield. Chlordimeform was
detectable in urine as early as 4 h after dermal exposure, but did not
increase during the work season. The chlordimeform concentrations
averaged about 90 µg/litre, with the highest levels found in
mixer-loaders and somewhat less in equipment washers, and the lowest
levels in pilots and flaggers. Urinary levels in the 8-10 h following
a work shift gave a good indication of exposure for the shift just
completed.
Kurtz et al. (1987) reported the results of a monitoring
programme of agricultural workers exposed to chlordimeform when used
on cotton in Imperial Valley, California, during the 1982 season. More
than 1000 urine samples were taken from 132 workers, including pilots,
mixers/loaders, flaggers and equipment maintenance workers.
Chlordimeform metabolites were detected in all workers at some time
during the study despite the use of protective clothing. The level of
urinary metabolites was positively correlated with the length of
exposure and the nature of job activity as shown in Table 3.
Mixer/loaders and maintenance workers had the highest levels.
Metabolites appeared in urine within 4 h and approximately 75% of
urinary excretion occurred within the first 24 h.
Table 3. Chlordimeform metabolite concentrations in urine (mg/litre)
of agricultural workers during an 11-week application period
(Kurtz et al., 1987)
Work group Immediately post-work Following morning
No. Mean SD No. Mean SD
All groups 535 0.12 0.41 572 0.10 0.23
Pilots 145 0.08 0.10 163 0.08 0.10
Mixers/Loaders 156 0.19a 0.71 162 0.15b 0.36
Flaggers 202 0.07 0.08 213 0.07 0.09
Others 32 0.25 0.45 34 0.21c 0.36
a Significantly greater versus flagger group (P<0.01)
b Significantly greater versus pilots (P<0.01) and flaggers
(P<0.001)
c Significantly greater versus pilots (P<0.001) and flaggers
(P<0.001)
Lemesch et al. (1987) provided the results of monitoring for
chlordimeform exposure in agricultural workers in Israel during
1980-1985. Chlordimeform was used only on cotton by aerial application
and all workers were monitored for urinary chlordimeform and its
metabolites on a weekly basis. The results indicated 86.8% of the
urine samples contained less 0.05 mg/litre, and 1.4% contained more
than 0.30 mg/litre. Overall, the loaders had the highest exposure
followed by the mechanic and then the pilots (see Table 4).
Table 4. Chlordimeform metabolite concentrations in urine (mg/litre)
of agricultural workers in Israel during 1980-1985
according to occupation (Lemesch et al., 1987)
Occupation < 0.05 0.05 - 0.30 > 0.30 Total
No. % No. % No. %
Loaders 666 79.0 157 18.6 20 2.4 843
Mechanics 383 94.8 19 4.7 2 0.5 404
Pilots 287 98.2 5 1.7 - - 292
Total 1336 86.8 181 11.8 22 1.4 1539
Balu (1989) has provided the results of monitoring field worker
exposure to chlordimeform from aerial application on cotton. During
the years 1978-1984, urine samples using a grab sample technique from
approximately 4600 field workers were examined. For mixer/loaders,
between 0.5 and 1.9% had levels >5 mg/litre, and between 2.1 and 18%
had levels of 1.0-5.0 mg/litre. The majority (46-78%) had levels in
the range <0.05-0.10 mg/litre. There was no apparent change in the
proportion of workers in the various exposure levels over the course
of the study. For the pilots, between 0.3 and 0.7% had levels
>5.0 mg/litre, while 63-90% had levels between <0.05 and
0.10 mg/litre.
The clinical signs associated with chlordimeform exposure in
these studies are described in section 8.2.2.
6. KINETICS AND METABOLISM IN LABORATORY ANIMALS AND HUMANS
6.1 Absorption, distribution and excretion
6.1.1 Mouse and rat
The earliest investigations on the kinetics and distribution of
chlordimeform were performed in a series of studies on rats (FAO/WHO,
1972). Four male and four female rats were treated orally with 270 µg
[3H-phenyl]-chlordimeform. Over a 24 h period, 52.8% (range
41.8-59.6%) of the radioactivity was eliminated in urine and 2.5%
(range 0.13-5.30%) in faeces, while 19-23% of the dose was excreted
into the bile. Follo