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    INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY



    ENVIRONMENTAL HEALTH CRITERIA 98



 
    TETRAMETHRIN












    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.

    Published under the joint sponsorship of
    the United Nations Environment Programme,
    the International Labour Organisation,
    and the World Health Organization

    World Health Orgnization
    Geneva, 1990


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    WHO Library Cataloguing in Publication Data

    Tetramethrin.

        (Environmental health criteria ; 98)

        1.Pyrethrins  I.Series

        ISBN 92 4 154298 5        (NLM Classification: WA 240)
        ISSN 0250-863X

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CONTENTS

ENVIRONMENTAL HEALTH CRITERIA FOR TETRAMETHRIN

INTRODUCTION

1. SUMMARY, EVALUATION, CONCLUSIONS, AND RECOMMENDATIONS

    1.1. Summary and evaluation
            1.1.1. Identity, physical and chemical properties, analytical 
                    methods
            1.1.2. Production and use
            1.1.3. Human exposure
            1.1.4. Environmental exposure and fate
            1.1.5. Uptake, metabolism, and excretion
            1.1.6. Effects on organisms in the environment
            1.1.7. Effects on experimental animals and  in vitro test 
                    systems
            1.1.8. Effects on human beings
    1.2. Conclusions
    1.3. Recommendations

2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS

    2.1. Identity
    2.2. Physical and chemical properties
    2.3. Analytical methods

3. SOURCES AND LEVELS OF HUMAN AND ENVIRONMENTAL EXPOSURE

    3.1. Industrial production
    3.2. Use patterns
    3.3. Residues in food
    3.4. Exposure levels from household use
    3.5. Environment levels

4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION

    4.1. Abiotic degradation in air and water

5. KINETICS AND METABOLISM

    5.1. Metabolism in mammals
    5.2. Enzymatic systems for biotransformation

6. EFFECTS ON ORGANISMS IN THE ENVIRONMENT

    6.1. Aquatic organisms
    6.2. Terrestrial organisms

7. EFFECTS ON EXPERIMENTAL ANIMALS AND  IN VITRO TEST SYSTEMS

    7.1. Single exposures
    7.2. Irritation and sensitization
            7.2.1. Eye irritation

            7.2.2. Skin irritation
            7.2.3. Sensitization
    7.3. Short-term exposure studies
            7.3.1. Oral
            7.3.2. Inhalation
    7.4. Long-term exposures and carcinogenicity
    7.5. Mutagenicity
    7.6. Reproduction, embryotoxicity, and teratogenicity
    7.7. Neurotoxicity - mode of action

8. EFFECTS ON HUMANS

9. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

REFERENCES

APPENDIX I

FRENCH TRANSLATION OF SUMMARY, EVALUATION, CONCLUSIONS, AND RECOMMENDATIONS

WHO TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA FOR TETRAMETHRIN

 Members 

Dr  V. Benes,    Toxicology   and   Reference   Laboratory,
    Institute   of   Hygiene   and  Epidemiology,   Prague,
    Czechoslovakia

Dr  A.J. Browning,  Toxicology Evaluation Section,  Depart-
    ment  of  Community  Services and  Health,  Woden, ACT,
    Australia

Dr  S. Dobson, Institute of Terrestrial Ecology, Monks Wood
    Experimental Station, Abbots Ripton, Huntingdon, United
    Kingdom  (Chairman)

Dr  P. Hurley,  Office of Pesticide Programme,  US Environ-
    mental Protection Agency, Washington DC, USA

Dr  K. Imaida,  Section  of  Tumor Pathology,  Division  of
    Pathology,  National  Institute  of Hygienic  Sciences,
    Setagaya-Ku, Tokyo, Japan

Dr  S.K. Kashyap,   National   Institute  of   Occupational
    Health, (I.C.M.R.) Ahmedabad, India  (Vice-Chairman)

Dr  Yu. I. Kundiev,  Research Institute of  Labour, Hygiene
    and  Occupational  Diseases,  Ul. Saksaganskogo,  Kiev,
    USSR

Dr  J.P. Leahey,  ICI Agrochemicals, Jealotts Hill Research
    Station, Bracknell, United Kingdom  (Rapporteur)

Dr  M. Matsuo,  Sumitomo Chemical Company, Biochemistry and
    Toxicology   Laboratory,   Kasugade-naka,  Konohana-Ku,
    Osaka, Japan

Dr  J. Sekizawa,   Division  of  Information   on  Chemical
    Safety,   National  Institute  of   Hygienic  Sciences,
    Setagaya-Ku, Tokyo, Japan  (Rapporteur)

 Representatives of Other Organization

Mr  M. L'Hotellier,  Groupement  International des  Associ-
    ations  Nationales  de  Fabricants  de  Produits  Agro-
    chimiques (GIFAP)

Dr  N. Punja,  Groupement  International  des  Associations
    Nationales  de  Fabricants  de  Produits  Agrochimiques
    (GIFAP)

 Secretariat

Dr  K.W. Jager, International Programme on Chemical Safety,
    World    Health   Organization,   Geneva,   Switzerland
     (Secretary)

Dr  R. Plestina,  Division  of Vector  Biology and Control,
    World Health Organization, Geneva, Switzerland

NOTE TO READERS OF THE CRITERIA DOCUMENTS

   Every  effort has been  made to present  information in
the  criteria documents as accurately  as possible without
unduly delaying their publication.  In the interest of all
users  of  the  environmental health  criteria  documents,
readers  are  kindly  requested to  communicate any errors
that may have occurred to the Manager of the International
Programme  on Chemical Safety, World  Health Organization,
Geneva, Switzerland, in order that they may be included in
corrigenda, which will appear in subsequent volumes.


                       *    *    *


   A  detailed  data  profile and  a  legal  file  can  be
obtained  from  the International  Register of Potentially
Toxic  Chemicals,  Palais  des Nations,  1211  Geneva  10,
Switzerland (Telephone No. 7988400 - 7985850).


                       *    *    *


   The  proprietary information contained in this document
cannot  replace  documentation for  registration purposes,
because the latter has to be closely linked to the source,
the  manufacturing route, and the purity/impurities of the
substance  to be registered.  The  data should be used  in
accordance  with  paragraphs  82-84  and   recommendations
paragraph  90  of  the Second  FAO Government Consultation
[5].

ENVIRONMENTAL HEALTH CRITERIA FOR TETRAMETHRIN

   A WHO Task Group on Environmental Health  Criteria  for
Tetramethrin  met in Geneva  from 24 to  28 October  1988.
Dr  M. Mercier, Manager, IPCS, opened the meeting and wel-
comed the participants on behalf of the three IPCS cooper-
rating  organizations (UNEP/ILO/WHO).  The  group reviewed
and  revised the draft monograph and made an evaluation of
the  risks  for  human  health  and  the  environment from
exposure to tetramethrin.

   The  first  draft  was prepared  by  DR J. MIYAMOTO and
DR M. MATSUO    of   Sumitomo   Chemical    Company,   and
DR J. SEKIZAWA  of  the  National  Institute  of  Hygienic
Sciences, Tokyo, Japan.

   The  second draft was prepared by the IPCS secretariat,
incorporating  comments received following  circulation of
the  first draft to the  IPCS contact points for  Environ-
mental  Health Criteria documents.  Dr K.W. Jager  and  Dr
P.G.  Jenkins, both members of the IPCS Central Unit, were
responsible  for  the  technical development  and editing,
respectively, of this monograph.

   The  assistance  of  the Sumitomo  Chemical  Company in
making  available to the IPCS and the Task Group its toxi-
cological  proprietary  information  on  tetramethrin   is
gratefully  acknowledged.  This allowed the  Task Group to
make its evaluation on the basis of more complete data.

                        *   *   *

   The  United  Kingdom  Department of  Health  and Social
Security generously supported the cost of printing.


ABBREVIATIONS


CA      chrysanthemic acid

FID-GC  gas chromatography with flame ionization detector

HPI     cyclohexane-1,2-dicarboximide

HPLC    high performance liquid chromatography

HPTLC   high performance thin-layer chromatography

ip      intraperitoneal

MTI      N -(hydroxymethyl)-3,4,5,6-tetrahydrophthalamide

NOEL    no-observed-effect-level

TLC     thin-layer chromatography

TPI     3,4,5,6-tetrahydrophthalimide

TPIA    3,4,5,6-tetrahydrophthalic acid

INTRODUCTION

SYNTHETIC PYRETHROIDS - A PROFILE

1.  During  investigations  to modify  the chemical struc-
    tures  of natural pyrethrins, a certain number of syn-
    thetic  pyrethroids were produced with improved physi-
    cal  and  chemical  properties and  greater biological
    activity. Several of the earlier synthetic pyrethroids
    were  successfully commercialized, mainly for the con-
    trol   of   household  insects.    Other  more  recent
    pyrethroids  have been introduced as  agricultural in-
    secticides because of their excellent activity against
    a wide range of insect pests and their non-persistence
    in the environment.

2.  The  pyrethroids constitute another group  of insecti-
    cides in addition to organochlorine, organophosphorus,
    carbamate,  and other compounds.   Pyrethroids commer-
    cially  available  to  date  include  allethrin,  res-
    methrin,  d-phenothrin, and tetramethrin  (for insects
    of public health importance), and cypermethrin, delta-
    methrin, fenvalerate, and permethrin (mainly for agri-
    cultural  insects).  Other pyrethroids are also avail-
    able  including furamethrin, kadethrin,  and tellalle-
    thrin  (usually for household insects), fenpropathrin,
    tralomethrin,  cyhalothrin, lambda-cyhalothrin, teflu-
    thrin, cyfluthrin, flucythrinate, fluvalinate, and bi-
    phenate (for agricultural insects).

3.  Toxicological evaluations of several synthetic pyreth-
    roids have been performed by the FAO/WHO Joint Meeting
    on Pesticide Residues (JMPR). The acceptable daily in-
    take (ADI) has been estimated by the JMPR for cyperme-
    thrin, deltamethrin, fenvalerate, permethrin, d-pheno-
    thrin, cyfluthrin, cyhalothrin, and flucythrinate.

4.  Chemically,   synthetic  pyrethroids  are   esters  of
    specific acids (e.g., chrysanthemic acid, halo-substi-
    tuted chrysanthemic acid, 2-(4-chlorophenyl)-3-methyl-
    butyric  acid)  and  alcohols (e.g.,  allethrolone, 3-
    phenoxybenzyl  alcohol).  For certain pyrethroids, the
    asymmetric  centre(s) exist in the acid and/or alcohol
    moiety,  and the commercial products sometimes consist
    of a mixture of both optical (1R/1S or d/1)  and  geo-
    metric  (cis/trans)  isomers.   However, most  of  the
    insecticidal  activity of such products  may reside in
    only  one or two isomers.  Some of the products (e.g.,
    d-phenothrin,  deltamethrin)  consist  only  of   such
    active isomer(s).

5.  Synthetic  pyrethroids are neuropoisons acting  on the
    axons in the peripheral and central nervous systems by
    interacting  with  sodium  channels in  mammals and/or

    insects.  A single dose produces toxic signs  in  mam-
    mals,  such as tremors, hyperexcitability, salivation,
    choreoathetosis,  and paralysis.  The  signs disappear
    fairly  rapidly,  and  the animals  recover, generally
    within  a week.  At near-lethal dose levels, synthetic
    pyrethroids  cause  transient  changes in  the nervous
    system,  such  as  axonal swelling  and/or  breaks and
    myelin  degeneration in sciatic nerves.   They are not
    considered  to cause delayed neurotoxicity of the kind
    induced by some organophosphorus compounds.  The mech-
    anism  of toxicity of synthetic  pyrethroids and their
    classification  into  two  types are  discussed in the
    Appendix.

6.  Some  pyrethroids  (e.g.,  deltamethrin,  fenvalerate,
    cyhalothrin,  lambda-cyhalothrin,  flucythrinate,  and
    cypermethrin)  may  cause  a transient  itching and/or
    burning sensation in exposed human skin.

7.  Synthetic  pyrethroids  are  generally metabolized  in
    mammals  through ester hydrolysis, oxidation, and con-
    jugation,  and there is  no tendency to  accumulate in
    tissues. In the environment, synthetic pyrethroids are
    fairly  rapidly degraded in soil and in plants.  Ester
    hydrolysis  and oxidation at various sites on the mol-
    ecule   are  the  major  degradation  processes.   The
    pyrethroids  are strongly adsorbed  on soil and  sedi-
    ments,  and hardly eluted with water.  There is little
    tendency for bioaccumulation in organisms.

8.  Because of low application rates and rapid degradation
    in  the  environment,  residues in  food are generally
    low.

9.  Synthetic  pyrethroids have been shown to be toxic for
    fish, aquatic arthropods, and honey-bees in laboratory
    tests.   But, in practical  usage, no serious  adverse
    effects  have been noticed because of the low rates of
    application  and lack of  persistence in the  environ-
    ment.   The toxicity of synthetic pyrethroids in birds
    and domestic animals is low.

10. In  addition to the  evaluation documents of  FAO/WHO,
    there  are several good reviews and books on the chem-
    istry,  metabolism, mammalian toxicity,  environmental
    effects,  etc.  of  synthetic  pyrethroids,  including
    those by  Elliott [3], Miyamoto [34], Miyamoto & Kear-
    ney [35], and Leahey [26].

1.  SUMMARY, EVALUATION, CONCLUSIONS, AND RECOMMENDATIONS

1.1  Summary and Evaluation

1.1.1  Identity, physical  and  chemical  properties, analytical methods

    Tetramethrin  was first synthesized in  1964 and first
marketed in 1965. Chemically, it is an ester  of  chrysan-
themic  acid (2,2-dimethyl-3-(2,2-dimethylvinyl)-cyclopro-
panecarboxylic  acid)  with 3,4,5,6-tetrahydrophthalimido-
methyl  alcohol.  It is  a mixture of  four stereoisomers:
[1R,trans], [1R,cis], [1S,trans], and [1S,cis]. In techni-
cal  products,  the composition  ratio  of the  isomers is
roughly  4:1:4:1. Among the isomers, the [1R,trans] isomer
is the most active biologically followed by  the  [1R,cis]
isomer.   A mixture of the [1R,cis] and [1R,trans] isomers
(1:4)  is  commercialized under  the  trade name  of `Neo-
Pynamin Forte' (designated as 1R, cis/trans-tetramethrin in
this monograph).

    Technical  grade  tetramethrin  is a  colourless solid
with  a melting point of 65-80°C.  The specific gravity is
1.11  at  20 °C,  and  the  vapour  pressure  is 0.946 mPa
(7.1 x 10-6 mmHg)    at 30 °C.  It is sparingly soluble in
water  (4.6 mg/litre at 30 °C) but soluble in organic sol-
vents  such as hexane, methanol, and xylene.  It is stable
to  heat but unstable to light and air. The [1R,cis/trans]
isomer  of  tetramethrin is  a  yellow viscous  liquid but
otherwise  has physical and chemical properties similar to
tetramethrin.

    Residue  analysis  is  carried out  by  quantification
using   dual-wavelength  densitometry  (370-230 nm).   Gas
chromatography  with flame ionization detector is used for
technical  product analysis.  Formulation analysis  can be
carried out by high-performance liquid chromatography with
an infra-red detector.

1.1.2   Production and use

    The  annual  world-wide production  of tetramethrin is
estimated to be a few hundred tonnes.  It is  mostly  used
for  indoor  pest control,  formulated  as an  aerosol, an
emulsifiable concentrate, or a mosquito coil. Formulations
in  combination with other insecticides and synergists are
also prepared.

1.1.3   Human exposure

    The  general population may be exposed to tetramethrin
primarily  through its use  in indoor pest  control.  When
tetramethrin is used as recommended, the aerial levels and
those of its 1R isomer are unlikely to  exceed  0.5 mg/mg3,
and  the  compound  will degrade  rapidly.  Therefore, the
exposure  of the general population is expected to be very
low.  Tetramethrin is not used on food crops.



1.1.4   Environmental exposure and fate

    Rapid  degradation occurs when  a thin film  of tetra-
methrin  is exposed to sunlight.  The major photoreactions
during  a 2-h exposure (30% conversion)  were: epoxidation
at  the isobutenyl double  bond; oxidation at  the   trans-
methyl   of the isobutenyl  group to hydroxymethyl,  alde-
hyde,   and  carboxylic  acid;  and  hydroperoxidation  to
allylic hydroperoxide.

    No  data are available on  the exact levels of  tetra-
methrin  in the environment, but with the current domestic
pattern  of use  and when  tetramethrin is  used  as  rec-
ommended,  environmental exposure is  expected to be  very
low. Degradation to less toxic products is rapid.

1.1.5   Uptake, metabolism, and excretion

    In  rats,  tetramethrin  radiolabelled in  the acid or
alcohol  moiety  is  readily taken  up,  metabolized,  and
excreted  after oral or subcutaneous  administration.  Ap-
proximately 95% is excreted in 5-7 days in the  urine  and
faeces in more or less equal amounts.  The tissue residues
from both administration routes are very low.   The  meta-
bolic  reactions are: ester cleavage; loss of the hydroxy-
methyl group from the alcohol moiety; reduction of the 1-2
bond  of the alcohol  moiety; oxidation at  the isobutenyl
methyl  moiety of the acid  and at the 2-, 3-, and  4-pos-
itions of the alcohol moiety; conjugation of the resultant
acids and alcohols with glucuronic acid; and cis/transiso-
merization.

1.1.6   Effects on organisms in the environment

    Only  very  limited information  is available.  Tetra-
methrin is highly toxic for fish, the 96-h  LC50    values
for two species being 19 and 21 µg/litre.  A third species
showed  a 48-h LC50   of 200 µg/litre   and a no-observed-
effect level of 50 µg/litre.  The no-observed-effect level
for  Daphnia is 50 µg/litre.    Tetramethrin  has very low
toxicity  to birds but is  toxic for honey bees.   Because
tetramethrin  is rapidly degraded, and provided its use is
limited  to buildings, as recommended,  the potential that
it  has for producing  effects on the  environment is  un-
likely to be realised.

1.1.7   Effects on  experimental animals and  in vitro test systems

    The acute oral toxicity of tetramethrin is  low.   The
LD50 for  rats is >5000 mg/kg with both the  racemic mix-
ture  and the 1R, cis/trans isomer, whereas for mice it is
about  2000 mg/kg  (racemate)  and  1060 mg/kg  (1R,  cis/
trans). The acute dermal toxicities in both rat and mouse,
as  well as in the rabbit, are also low; the LD50 in  rats
and  mice is  >5000 mg/kg, while  in rabbits it is >2000

mg/kg  (all studies were  done with racemic  mixture).  In
acute inhalation studies, the LC50 in  rats and  mice  was
2500 mg/m3 for   the racemic mixture and >1180 mg/m3  for
the 1R, cis/trans isomer. The toxic signs include hyperex-
citability,  tremor, ataxia, and depression (general signs
combined  from all the acute studies).  Mice were somewhat
more  susceptible than rats,  but no differences  were ob-
served   in  susceptibility  between  males  and  females.
Tetramethrin,  either as the  racemic mixture or  the  1R,
cis/trans  isomer, is virtually non-irritating to the rab-
bit eye and is non-irritating to rabbit skin. In addition,
neither the racemic mixture nor the 1R,  cis/trans  isomer
is a sensitizer in guinea-pigs.

    Tetramethrin  is  a  type I pyrethroid.   In  mammals,
tremor  (T-syndrome) is the characteristic poisoning symp-
tom.

    When rats were fed tetramethrin at dietary  levels  of
up  to 5000 mg/kg diet  for 91 days, reduced  body  weight
gain was observed at 5000 mg/kg diet.  The results from 3-
or  6-month feeding studies using the 1R, cis/trans isomer
in  rats at dietary levels  ranging from 25 mg/kg diet  to
3000 mg/kg  diet  indicated  that  the  no-observed-effect
level  was 200 mg/kg diet for males and 300 mg/kg diet for
females  (observations  included  decreases  in  the  body
weight gain and in final body weight, and effects  on  the
kidney  and liver).  The effects on the liver were thought
to  be an adaptive response to the feeding of the corn oil
vehicle.

    The  no-observed-effect  level  in a  26-week study in
dogs was 1250 mg/kg diet.

    When  mice and rats were exposed to aerosolized tetra-
methrin  by  inhalation  at a concentration  of 200 mg/m3
for  3-4 h/day for up to 4 weeks, no significant compound-
related  changes were observed.  An  additional inhalation
study, in which rats were exposed to a  mist  (1.2-1.5 µm
diameter  droplets)  of 1R,cis/trans  isomer in deodorized
kerosene  at  concentrations  up to  87 mg/m3,    3 h/day,
7 days/week  for  28 days, indicated  a no-observed-effect
level of 49 mg/m3.    Toxic signs were noted  only  during
the exposure period.

    Neither tetramethrin nor its 1R,cis/trans isomers were
mutagenic  in a variety of  in  vivo and  in vitro test sys-
tems,  which investigated gene mutations,  DNA damage, DNA
repair, and chromosomal effects.

    Three  104-week  chronic/oncogenicity feeding  studies
have been conducted on tetramethrin, two in rats  and  one
in  mice.  In mice, tetramethrin was fed at dose levels up
to  1500 mg/kg diet.  No oncogenic  effects were observed.

Decreased  pituitary and thyroid/parathyroid  weights were
observed at 60 mg/kg diet or more.  The no-observed-effect
level  for systemic effects was 12 mg/kg diet in mice.  In
the rat studies, the test animals were exposed  to  tetra-
methrin at dose levels up to 5000 mg/kg diet  in utero  and
through  long-term feeding.  In both studies in rats, body
weight  gains were significantly lower  in animals exposed
to  3000 mg/kg diet or  more.  In addition,  increases  in
liver  weight were observed at these dose levels.  The no-
observed-effect level for systemic effects in both studies
in  rats was 1000 mg/kg diet.  The incidence of testicular
interstitial cell tumours at 3000 mg/kg diet or  more  was
higher than the level in the concurrent control  group  in
both  studies.  Testicular interstitial cell tumours occur
spontaneously  in aged rats,  and the incidence  can  very
greatly in control groups.  This tumour is thought  to  be
hormonally  mediated.  There was no evidence of malignancy
and no evidence of this type of tumour in mice.  It can be
concluded  that the tumorigenic  effect, if real,  is most
unlikely to be relevant to human exposure.

    Tetramethrin  was  not  teratogenic or  embryotoxic at
dose levels up to 1000 mg/kg body weight in rats and up to
500 mg/kg body weight in rabbits (these were  the  highest
dose levels tested).  In a fertility study in  which  rats
were  given tetramethrin at  dose levels up  to 1000 mg/kg
body  weight per day, the no-observed-effect level for the
parents'  reproductive ability and  growth of the  fetuses
was  300 mg/kg body weight  per day.  In  a perinatal  and
post-natal  reproduction  study in  rats, the no-observed-
effect  level  was  100 mg/kg  body  weight  per  day (the
highest level tested).

    When  dose levels of 1000-6000 mg/kg  diet were tested
in  a one-generation reproduction study on tetramethrin in
rats,  the  no-observed-effect level  was 1000 mg/kg diet.
Levels  of the 1R,cis/trans isomer  of 100-3000 mg/kg were
tested  in a two-generation reproduction study, which gave
a no-observed-effect level of 500 mg/kg diet.

1.1.8   Effects on human beings

    Although tetramethrin and its 1R isomer have been used
for many years, there have been no reports of poisoning or
adverse effects in human beings.

    There  are no indications that tetramethrin or its 1R-
isomer will have an adverse effect on human beings  if  it
continues  to be used  in low concentrations  and only  to
control household pests.

1.2  Conclusions

(a)    General  Population:   The exposure  of  the general
population  to tetramethrin, as  it is currently  used, is

expected  to be low.  It is not likely to present a hazard
if used as recommended.

(b)  Occupational  Exposure:  When good work practices, hy-
giene measures and safety precautions are followed, tetra-
methrin  is unlikely to  present a hazard  to those  occu-
pationally exposed.

(c)   Environment:  It is highly unlikely that tetramethrin
or its degradation products will reach levels  that  could
cause adverse environmental effects.

1.3  Recommendations

    Although tetramethrin and its 1R isomer have been used
for  many years  with no  reports of  adverse  effects  in
humans, observations of human exposure should continue.

2.  IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS

2.1  Identity

Molecular formula:      C19H25NO4

Chemical structure:

FIGURE 1

    Tetramethrin  was  first  synthesized in  1964 by Kato
et  al.  [19]  and is  prepared  by  the esterificaton  of
(1RS ,cis,trans)-2,2-dimethyl-3- (2,2-dimethylvinyl)-cyclo-
propanecarboxylic acid (chrysanthemic acid)  with 3,4,5,6-
tetrahydrophthalimidomethyl  alcohol.  It  is a mixture of
four stereoisomers  (Fig. 1).   The cis:trans ratio is re-
ported to be 1:4 and the optical  ratio of  1R:1S  is  1:1
(racemic).  Thus  its  composition is  roughly 4:1:4:1 for
the [IR,trans], [IR,cis],[IS,trans], and [IS,cis] isomers.
The [1R,trans] isomer is the most  active  biologically of
the  isomers, followed by the [1R,cis] isomer. Neo-Pynamin
Forte is a mixture of the [1R,cis,] and [IR,trans] isomers
in the ratio of 1:4 (Table 1).

2.2     Physical and Chemical Properties

    Some  physical and chemical properties of tetramethrin
are given in Table 2.

    No  data  are  available  for   boiling  point  and n-
octanol/water   partition  coefficient.   Technical  grade
tetramethrin  is stable to  heat (50 °C for  6 months) but
unstable to light and air and to alkaline  condition  [30,
31, 76].

2.3     Analytical Methods

    Dislodgeable  residues of tetramethrin can be analysed
by dual-wavelength densitometry after clean-up of the hex-
ane  washings  by  high-performance silica  gel thin-layer
chromatography  (Table 3).   To  analyse  technical  grade
tetramethrin, the product and tributoxyethyl phosphate (an
internal standard) were dissolved in acetone, and the sol-
ution  was injected into a gas chromatograph equipped with
flame  ionization detector (FID) [37]). Analysis of tetra-
methrin  formulations can also  be carried out  using high
performance liquid chromatography (HPLC) with an infra-red
selective detector [42].
Table 1.  Chemical identity of tetramethrins of various stereoisomeric 
compositions
                                                                                                
Common name/            CAS Index name (9CI)                    Stereoisomeric    Synonyms and
CAS Registry no./       Stereospecific nameb,c                  compositiond      trade names
NIOSH Accession no.a    
                                                                                                
Tetramethrine           Cyclopropanecarboxylic acid,            (1):(2):(3):(4)   Tetramethrine,
(racemic mixture)       2,2-dimethyl-3-(2-methyl-1-propenyl)-,  = 4:1:4:1         Phthalthrin,
7696-12-0               (1,3,4,5,6,7-hexahydro-1,3-dioxo-2H -                     Neo-Pynamin,
GZ173000a               isoindol-2-yl)methyl ester                                FMC-9260

                        3,4,5,6-Tetrahydrophthalimidomethyl
                        (1RS, cis,trans)-2,2-dimethyl-3-
                        (2,2-dimethylvinyl)cyclopropane-
                        carboxylate
                                     or
                        3,4,5,6-Tetrahydrophthalimidomethyl-
                        (1RS, cis,trans)-chrysanthemate

(+)- trans-Tetramethrin  Same as tetramethrin                                      (+)- trans- 
                                                                                  Phthalthrin
GZ1710000a              3,4,5,6-Tetrahydrophthalimidomethyl
                        (1R, trans)-chrysanthemate

(+)-Tetramethrin        Same as tetramethrin                    (1):(2) = 4:1     Neo-Pynamin
                        3,4,5,6-Tetrahydrophthalimidomethyl                       Forte
GZ1720000a              (1R, cis,trans)-chrysanthemate

                                                                                                
a Registry of Toxic Effects of Chemical Substances (RTECS) (1981-82 edition).
b (1R), d, (+) or (1S), l, (-) in the acid part of tetramethrin signify the same stereospecific 
  conformation, respectively.
c Chrysanthemic acid is a name of the acid that forms the acid part.
d Numbers in parentheses identify the structures shown in Fig. 1.
e ISO common name: common names for pesticides and other agrochemicals approved by the Technical 
  Committee of the International Organization for standardization.
Table 2.  Some physical and chemical properties of tetramethrin
                                                                  
                           Racemic mixture     (1R) isomer
                                                                  

Physical state             crystalline solid   viscous liquid

Colour                     colourless          yellow or brown

Odour                      pyrethrum-like      pyrethrum-like

Relative molecular mass    331.45              331.45

Melting point (°C)         60 - 80

Water solubility           4.6 mg/litre        2 - 4 mg/litre
                           (30 °C)             (23 °C)

Solubility in organic      solublea            solubleb
solvents
                            20                    25
Density                    d20 1.108 (20 °C)     d25 1.11

Vapour pressure (20 °C)    4.67 x 10-3 mPa     3.2 x 10-4 mPa
                           (3.5 x 10-8 mmHg)   (2.4 x 10-9 mmHg)
                (30 °C)    9.46 x 10-1 mPa
                           (7.1 x 10-6 mmHg)

                                                                  
a  Methanol (53 g/kg), hexane (20 g/kg), xylene (1 kg/kg), 
   acetone, toluene.
b  Hexane (>1 kg/kg), methanol, xylene.


Table 3.  Analytical methods for tetramethrin
                                                                                                         
Sample                       Sample preparation                   Determination     % Recovery     Refer-
                Extraction  Partition      Clean up               Detection method  (fortification ence
                Solvent                 Column  Elution           and conditions    level)a                 
                      
                                                                                                         

Environmental
 analysis

Dishb           n-hexane    n-hexane/   HPTLC   benzene/CCl4      dual-wavelength   76-95 (0.3 mg) 61
Apple                       CH3CN               (1/1)             densitometry      88 (0.3 mg)
Spinach                                         n-hexane/ether/   R = 370 nm;       94 (0.3 mg)
 (dislodgeable                                  formic acid       S = 230 nm
 residue)                                       (70/30/1)      
                                                Rf = 0.35

Product analysis

Technical       acetone                                           FID-GC, N2 40 ml/min,            37
 grade                                                            1-m column, 2% DEGS,
                                                                  200°C, 12.4 min
                                                                  (retention time)

Formulations                                                      HPLC, 0.01-mm Partisil           42
                                                                  column, CC14: CH2Cl2:
                                                                  CHCl3: CH3CN = 42.5:
                                                                  42.5: 14.85: 0.15, with
                                                                  IR detection
                                                                                                          

a  fortification level = concentration of tetramethrin added to control samples for the measurements of 
   recovery.
b  Wood, glass, china, or polypropylene.

3.  SOURCES AND LEVELS OF HUMAN AND ENVIRONMENTAL EXPOSURE

3.1     Industrial Production

    Tetramethrin was first marketed in 1964 [15]. Although
no information on production volume is publicly available,
it is estimated that a few hundred tonnes are manufactured
annually in the world, mainly in Japan.

3.2     Use Patterns

    Tetramethrin  is used in aerosol formulations, emulsi-
fiable  concentrates, and mosquito  coils for indoor  pest
control.   It is also formulated in combination with other
insecticides  (e.g.,  resmethrin)  and  synergists  (e.g.,
piperonyl butoxide).

3.3     Residues in Food

    Tetramethrin is not used on food crops.

3.4     Exposure Levels from Household Use

    With  conventional household aerosol spraying  or mos-
quito  coil fumigation, the aerial  levels of tetramethrin
and its 1R isomer are unlikely to exceed 0.5 mg/m3 [38].

3.5     Environmental Levels

    No data are available.

4.  ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION

4.1     Abiotic Degradation in Air and Water

    The  photodegradation  pathways  for tetramethrin  are
summarized  in Fig. 2.  Exposure  of   trans-[carboxyl-14C]
tetramethrin (5)a,  as a thin  film  (0.1-0.3 mg/cm2),  to
sunlight  resulted  in  rapid  degradation.  During  a 2-h
exposure  (30%  conversion), the  major photoproducts were
the  (1RS)-epoxides (7) (14% of the reaction mixture), the
aldehyde  derivative (10) (19%) oxidized at the (E)-methyl
group  in  the  acid moiety,  the caronaldehyde derivative
(16) (6%) from cleavage upon ozonolysis, and  the  allylic
hydroperoxide  (15) (6%) from the hydroperoxidation at the
1 -position  of the isobutenyl moiety.  In addition, small
amounts  of  cis-tetramethrin   (14) (2%),  the alcohol (9)
(5%)  and carboxy (11)  (3%) derivatives oxidized  at  the
(E)-methyl group, and the hydroxy derivative (6)  (3%)  at
the  allylic methylene group in the alcohol moiety and its
epoxide  (8) (2%) were  detected.  These identified  ester
photoproducts accounted for approximately 80% in a 5% con-
version but only approximately 20% in a 50-70% conversion.
Chrysanthemic  acid (12) and  N-(hydroxymethyl)-tetrahydro-
phthalimide  (13),  formed  by ester  bond  cleavage, were
minor  products, and much  of the radiocarbon  remained at
the origin on the TLC plate. The  cis/trans   isomerization
was an inefficient reaction in an oxygen-containing atmos-
phere [50].

FIGURE 2
                                                                       
a  Numbers in parentheses refer to numbered chemical structures in 
   Figures 2 and 3.

5.  KINETICS AND METABOLISM
    
5.1     Metabolism in Mammals

    The  metabolic pathways of tetramethrin in mammals are
summarized in Fig. 3.

    Tetramethrin is readily absorbed and excreted by rats.
Following  a  single  oral administration  of [1RS, trans]-
tetramethrin  (17],  labelled  with 14C  at  the  carbonyl
group of the alcohol moiety, to male Wistar rats at a con-
centration  of 500 mg/kg, 47%  and 42% of  the  radiolabel
were  excreted  into  the urine  and faeces, respectively,
during  the subsequent 2 days and 95% was recovered during
the  5-day period that followed dosing.  The tissue levels
during the first 2 days after administration were very low
and  the  tetramethrin content  in  tissues was  less than
0.01%  of  the dosed  radioactivity.  Unmetabolized  trans-
tetramethrin (17) was not excreted into the urine, and the
major urinary metabolite was 3-hydroxy-cyclohexane-1,2-di-
carboximide (19) (3-OH-HPI) in free and glucuronide forms.
 N-(Hydroxymethyl)-3,4,5,6-tetrahydrophthalimide (20) (MTI),
3,4,5,6-tetrahydrophthalimide (21) (TPI), and cyclohexane-
1,2-dicarboximide (22) (HPI) were identified as minor uri-
nary and faecal metabolites [36].

    Following a single oral or subcutaneous administration
to Sprague-Dawley rats of [1R, trans]-   or [1R, cis]-tetra-
methrin (17,18), labelled with 14C  in the acid or alcohol
moieties at concentrations of 3.2-5.3 mg/kg, the radiocar-
bon  was rapidly and almost completely eliminated from the
rat body. The total recoveries 7 days after administration
were 93-97% for the trans isomer and 90-101% for  the  cis
isomer  (approximately  equal amounts  being eliminated in
urine  and faeces).  In the case of the oral dose of acid-
labelled  tetramethrin,  1-3%  of the  radiolabel  was ex-
creted as 14CO2,    whereas in other cases the  amount  of
14CO2 accounted  for less than 1% of the dose.  The tissue
residue 7 days after  administration was  very low.    The
transisomer  yielded somewhat more complete radiolabel re-
covery and  lower tissue residues  than the cis isomer. In
addition,  labelling  resulted in  slightly  lower  tissue
residues  than did alcohol labelling.  However, there were
no  significant differences, according to  sex or adminis-
tration  route,  in  the total  radiocarbon recoveries and
tissue residue levels [18].  The major metabolic reactions
of  both  [1R, trans]-  and [1R, cis]-tetramethrin  were
ester cleavage, loss of the hydroxymethyl group  from  the
alcohol moiety, reduction of the 1-2 bond of  the  alcohol
moiety,  and oxidation at the isobutenyl group of the acid
moiety and at the 2-, 3-, and 4-positions of  the  alcohol
moiety.  The metabolites produced via these reactions were
in part conjugated with glucuronic acid. None of the trans
isomer remained unmetabolized, whereas 0.3-1.2% of the cis

isomer was found unchanged in the faeces. The major metab-
olites  from the acid moiety of both isomers were chrysan-
themic  acid (23, 24) (CA) and its derivatives oxidized at
the trans-methyl of the isobutenyl group. 3-(2'-E-Carboxy-
1'-propenyl)-2,2-dimethyl-1-cyclopropanecarboxylic acid (25,
26) ( w t-acid- t,c-CA)      accounted for 17-27% and 7-9% of
the dose of the trans and cis isomers, respectively. Other
significant   metabolites  were  3-(2'-E-hydroxymethyl-1'-
propenyl)-2,2-dimethyl-1-cyclopropanecarboxylic acid(27,28)
( w t-alc-t,c-CA), 3-(2'-Z-carboxy-1'-propenyl)-2,2-dimethyl-
1-cyclopropanecarboxylic acid (29, 30) ( w c-acid- t,c-CA),and
3-(2'-Z-hydroxymethyl-1'-propenyl)-2,2-dimethyl-1-cyclopro-
panecarboxylic acid (31, 32) ( w c-alc- t,c-CA).

FIGURE 3

    Judging  from  the  metabolites derived  from the acid
moiety, cis to trans isomerization of the oxidized deriva-
tives  of CA occurs,  as happens in  resmethrin metabolism
[60].

    Although both cis to trans and trans to cis isomeriza-
tions of tetramethrin were observed by Kaneko et al. [18],
cis  to trans conversion seemed to be predominant.  On the
other  hand,  the  detected metabolites  from  the alcohol
moiety  were TPI, HPI, 3-OH-TPI  (33), 3,4,5,6-tetrahydro-
phthalic  acid amide (34) (TPIA),  2-OH-HPI (35), 3-OH-HPI
(19),  and 4-OH-HPI (36).  Of  these metabolites, 2-OH-HPI
was found in relatively large amounts.

    Smith  et  al. [55]  found  that tetramethrin  and TPI
readily  underwent the Michael addition  with thiols.  The
tetramethrin-gluthathione (GSH) conjugate was formed under
physiological  conditions in the  presence of mouse  liver
homogenate   fractions,   probably   by  a   non-enzymatic
reaction.   The soluble thiol level of mouse liver was de-
creased by intraperitoneal administration of TPI. However,
mercapturic  acid and GSH conjugates  of tetramethrin were
not  detected in the bile or urine of rats or mice treated
intraperitoneally with tetramethrin.

5.2     Enzymatic Systems for Biotransformation

    When   alcohol-  or  acid-labelled  [1RS, trans]-tetra-
methrin (1 mmol/litre) was incubated for 1 h at 37 °C with
30 mg  protein of a  rat liver subcellular  fraction (i.e.
nuclei  plus  mitochondria, microsomes,  and soluble frac-
tion),  the microsomes and nuclei  plus mitochondria frac-
tions  were active in  degrading tetramethrin. Rat  micro-
somal  fraction degraded [1RS, trans]-tetramethrin   to CA,
MTI,  and TPI in the absence of NADPH.  In the presence of
NADPH,  tetramethrin  was  more rapidly  degraded to yield
oxidized tetramethrin ( wt-alc-,  wt-ald-, and  wt-acid-tetra-
methrin), oxidized CA ( wt-alc-,  wt-ald-,  and  wt-acid-CA),
TPI,  and unidentified metabolites in  larger amounts. The
major  metabolite TPI was  shown to be  produced non-enzy-
matically  from MTI. The degradation  rate of tetramethrin
was  greatly reduced by the inhibition of ester hydrolysis
with paraoxon [57].

6. EFFECTS ON ORGANISMS IN THE ENVIRONMENT

    As the use of tetramethrin is limited to  indoor  pest
control,  there is a paucity of data concerning its effect
on the environment.

6.1     Aquatic Organisms

    Data  on  the  toxicity of  tetramethrin to non-target
aquatic organisms are given in Table 4.

    Tetramethrin is highly acutely toxic to fish  in  lab-
oratory  tests, the 96-h LC50s   for two species being ap-
proximately 20 µg/litrea.     The 48-h LC50 for  killifish
is  about 200 µg/litre,   with a  no-observed-effect level
(NOEL)  of 50 µg/litre  [33].  The  NOEL for  Daphnia pulex
was   reported by Miyamoto  [33] to be  50 µg/litre    for
racemic tetramethrin and 10 µg/litre  for [1R, trans]-   or
[1R, cis]-tetramethrin.

6.2     Terrestrial Organisms

    Tetramethrin has low toxicity to birds. The acute oral
LD50   for Bobwhite quail is >2510 mg/kg body weight, and
the 8-day dietary LC50 to  Mallard duck and Bobwhite quail
is >5620 mg/kga.

    Tetramethrin is toxic to bees [14].



                                                                        
a  written comment from US EPA to IPCS, 1987.


Table 4.  Acute toxicity of tetramethrin to non-target aquatic organisms
                                                                                            
Species                Size   Parameter  Toxicity   Formulation  System  Temperature  Refer-
                                         (mg/litre)                       (°C)         ence 
                              
Fish
  Killifish            adult  48-h LC50    0.2      Technical    Static      25       33
  ( Oryzias latipes)    adult  48-h LC50    0.2      (+)-trans    Static      25       33
                       adult  48-h LC50    0.15     (+)-cis      Static      25       33
  Bluegill sunfish            96-h LC50    0.019                                       a 
  ( Lepomis macrochirur)
  Rainbow trout               96-h LC50    0.021                                       a
  ( Salmo gairdneri)

Arthropods
   Daphnia pulex               3-h LC50      >50    Technical    Static      25       33
                              3-h LC50      >50    (+)-trans    Static      25       33
                              3-h LC50      >50    (+)-cis      Static      25       33
                                                                                            

a Written comment from US EPA to IPCS, 1987.

7.  EFFECTS ON EXPERIMENTAL ANIMALS AND  IN VITRO TEST SYSTEMS

7.1     Single Exposures

    The acute toxicity of tetramethrin to rats and mice is
low (Table 5).

Table 5.  Acute toxicity of tetramethrin to rats and mice
                                                                               
Compound         Species  Sex   Route              LD50        Reference
                                                   (mg/kg body
                                                   weight)
                                                                               
Racemic          rat      M,F   oral               4600        41
                 rata     M,F   oralb              >5000      17
                 rat      M,F   dermalb            >10 000    41
                 mousea   M     oralb              1920        17
                 mousea   F     oralb              2000        17
(1R, cis/trans)-  rata     M,F   oralb              >5000      16
                 rat      M,F   subcutaneous       >5000      16
                 rat      M     intraperitoneal    770         16
                 rat      F     intraperitoneal    548         16
                 rat      M,F   dermal(>24 h)b    >5000      16
                 mousea   M     oral               1060        16
                 mousea   F     oral               1040        16
                 mouse    M     subcutaneous       2020        16
                 mouse    F     subcutaneous       1950        16
                 mouse    M     intraperitoneal    631         16
                 mouse    F     intraperitoneal    527         16
                 mouse    M,F   dermal (>24 h)b   >5000      16
                 rabbit         dermal (>24 h)b   >2000      20
                                                                               

a  Animals were not fasted.
b  Corn oil was used as vehicle.

    Sprague-Dawley  rats (10 of each  sex per group)  were
exposed  to a respirable  mist (droplet diameter  of  1.2-
1.5 µm) of [1R, cis/trans]-tetramethrin  (technical  grade,
95.6%  purity) in deodorized  kerosene (0, 26,  131,  243,
595,  and  1180 mg active  ingredient  per m3 air)   for a
duration of 3 h. At 131 mg/m3 or  more, salivation, hyper-
excitability, irregular respiration, urinary incontinence,
muscular  fibrillation, limb paralysis, decrease  in spon-
taneous activity, and other toxic signs were  observed  in
males and females.  At 1180 mg/m3,   10% of female animals
died,  but the body weight gain was similar to that of the
control  rats.   The  no-observed-effect level  (NOEL) for
inhalation of the compound in rats was 26 mg/m3,   and the
LC50 value was >1180 mg/m3 in both sexes [58].

    The  toxic symptoms observed following [1R, cis/trans]-
tetramethrin administration were hyperexcitability, muscle

twitching,  tremor,  ataxia,  irregular  respiration,  and
depression.   Mice  were invariably  more susceptible than
rats.   No  differences  in susceptibility  were  observed
between male and female animals [16, 17, 33].

7.2     Irritation and Sensitization

7.2.1   Eye irritation

    In  a study by Okuno et al. [39], 50 mg of the techni-
cal  product (91.3% purity)  was instilled in  one eye  of
Japanese  albino male rabbits.  The treated eye was washed
with  distilled water 5 min  (group I) or 24 h  (group II)
thereafter.  The conjunctiva, cornea, and pupil were exam-
ined,  1,  24, 72 h  and 7, 14,  and 21 days after  appli-
cation.   No particular changes  were noted except  that a
very  slight erythema and  oedema of the  conjunctiva  was
transiently observed in the rabbits in group II.

    In  a  separate study,  0.1  ml  [1R, cis/trans]-tetra-
methrin (technical grade, 95.6% purity) was applied to one
eye  of Japanese albino rabbits.  The treated eye was sub-
sequently  washed in five rabbits  but not in three  other
rabbits.   The material did not produce any lesions in the
cornea or iris of the treated eyes that were  not  washed,
but  slight hyperemia and/or chemosis  of the  conjunctiva
was observed 1 h after application.  In the  washed  eyes,
slight  hyperemia of the  conjunctiva was observed  in all
animals  1 h after treatment.  These changes, however, had
disappeared by 48 h after application in the unwashed eyes
and 24 h in the washed eyes. The irritating potency of the
material was judged to be minimal in the unwashed eyes and
negative in the washed eyes [11].

7.2.2   Skin irritation

    In  a study by Okuno et al. [39], 0.5 g of the techni-
cal  product (91.3% purity)  was applied on  a lint  patch
(3.8 x 3.8 cm) to the abraded or intact skin of  six  rab-
bits.   The skin was assessed for severity of erythema and
oedema 4, 24, 48, 72 h and 7, 14, and 21 days after appli-
cation, but no particular changes were noted.

    When 0.5 ml [1R, cis/trans]-tetramethrin     (technical
grade,  95.6%  purity)  was  applied  on  a   lint   patch
(2.5 x 2.5 cm)  to abraded or intact  skin on the back  of
rabbits,  again no irritating  reactions such as  erythema
and oedema were observed [11].

7.2.3   Sensitization

    In  a  skin-sensitization  study  of  tetramethrin  in
guinea-pigs,  Hartley  male guinea-pigs  (seven per group)
were  sensitized ten times at intervals of one or two days
by  intracutaneous  injections (first  injection: 0.05 ml,

subsequent ones: 0.1 ml) of a 1% solution of the technical
product (91.3% purity) in corn oil. The sensitized animals
were then challenged against the same concentration in the
same manner (0.5 ml injection) 14 days later, but no skin-
sensitization reaction was noted [40].

    In  another  skin-sensitization  test on  Hartley male
guinea-pigs, 0.5 ml [1R, cis/trans]-tetramethrin   (techni-
cal product, 95.6% purity) in 0.5 ml acetone  was  applied
topically by lint patch to the back of animals  ten  times
(three times per week). The animals were challenged in the
same  manner 2 weeks after the last sensitizing treatment,
but no allergic reactions were observed 24 h later [12].

7.3     Short-Term Exposure Studies

7.3.1   Oral

    When groups of 10 male Wistar rats were maintained for
91 days on a diet containing 0, 500, 1000, 3000,  or  5000
mg  tetramethrin/kg diet, there was a reduced rate of body
weight gain at 5000 mg/kg but not at 3000 mg/kg  or  less.
The  liver glycogen level  was reduced at  3000 mg/kg  and
5000 mg/kg.   The kidney, spleen, heart,  small intestine,
and brain showed no abnormal signs, either macroscopically
or  microscopically, and there were no significant changes
in blood parameters.  There was no increase in the protein
or glucose levels in the urine of test animals [59].

    When technical (1R, cis/trans)-tetramethrin     in corn
oil  was administered to  Sprague-Dawley rats for  3 or  6
months at 0, 100, 300, 1000, or 3000 mg/kg diet, no treat-
ment-related  changes were observed in  clinical signs, or
food  and  water  consumption, or  in  an ophthalmological
examination.  However, the body weight gain and final body
weight of males and females in the 3000-mg/kg  group  were
significantly lower than those of the controls. There were
slight  increases in urine protein  level in the rats  fed
more  than 1000 mg/kg and  in serum calcium  level in  the
male rats fed more than 300 mg/kg.  During  a  histopatho-
logical  examination, eosinophilic bodies in  tubular epi-
thelial  cells and hyaline droplets in kidney tubular epi-
thelium  cytoplasm were observed  in males fed  3000 mg/kg
diet,  along with an  increase in relative  organ  weight.
There  were dose-dependent increases in absolute and rela-
tive liver weight in all treated male rats and  in  female
rats  fed  more than  1000 mg/kg  diet.  There  were  also
slightly  higher serum cholesterol concentrations  in rats
of both sexes fed more than 1000 mg/kg and  a  significant
reduction  in  liver lipid  content  among males  fed 1000
mg/kg  or  more.  However,  these  liver effects  were not
accompanied  by damage to  hepatocytes and were  therefore
considered  to be an  adaptation to the  corn oil  without
toxicological  significance.   Furthermore, there  were no

marked effects, even at 200 mg/kg, when an additional sub-
chronic  study was conducted at tetramethrin levels of 25,
50, 100, and 200 mg/kg diet without corn oil in  order  to
confirm  the NOEL in male rats.  The NOEL for tetramethrin
in rats in the 6-month study was concluded to be 200 mg/kg
diet for males and 300 mg/kg diet for females [16].

    When  technical grade tetramethrin (94.6%  purity) was
administered  for 26 weeks to beagle dogs (six of each sex
per  group) at  levels of  0, 1250,  2500, and  5000 mg/kg
diet,  nervousness and tremors were observed in both males
and females at 2500 and 5000 mg/kg diet. A lack of oestrus
activity in females was also noted clinically and  a  lack
of  corpora  lutea  was confirmed  histologically  at 5000
mg/kg  diet.  Absolute liver weight was increased in males
at  2500 and 5000 mg/kg and relative liver weight was sig-
nificantly  increased in males and  females at 5000 mg/kg.
Decreased  absolute/relative ovary weights were  noted for
females at 5000 mg/kg.  No other treatment-related changes
were  observed with respect to survival, body weight gain,
food  consumption, haematology, urinalysis, ophthalmology,
gross pathology or histopathology. The NOEL was 1250 mg/kg
diet [43].

    In a study by Weir & Crus (1966), groups of three male
and  three female beagle  dogs were fed  tetramethrin dis-
solved  in  corn oil  for 13 weeks at  levels of 0,  1250,
2500, and 5000 mg/kg diet. There were no effects on haema-
tological,  clinical  chemistry,  or  urinary  parameters.
Organ  weights  were not  affected  by the  treatment, and
there  were  no  significant  histopathological  findings.
Clinical signs were not recorded. The NOEL was >5000 mg/kg
diet.

7.3.2   Inhalation

    Sprague-Dawley  rats (10 of  each sex per  group) were
exposed  to a respirable mist (droplet diameter of 1-2 µm)
of  tetramethrin at concentrations of 0, 26, 49, and 87 mg
active ingredient per m3 air,  3 h a day, 7 days  a  week,
for  a period of 28 days. At 87 mg/m3,   irregular respir-
ation,  slight  salivation,  and  hyperexcitability   were
observed  as  toxic signs  every  day during  the exposure
period,  but no cumulative toxicity was noted.  There were
no  compound-related effects on body weight gain, food and
water  consumption, urinalysis, haematology, biochemistry,
organ  weight, and histopathology.   The NOEL in  subacute
inhalation  was considered to be 49 mg/m3 [58].  This NOEL
is  approximately 100 times higher than the aerial concen-
tration attained during normal use of tetramethrin [33].


7.4     Long-Term Exposures and Carcinogenicity

 Appraisal

     Testicular interstitial cell tumours occur spontaneously in
 aged  rats,  and  the incidence  can  vary  greatly in  control
 groups.   This tumour is  believed to be  hormonally  mediated.
 There was no evidence of malignancy in three rat studies and no
 evidence  of this type of tumour in mice. It can  be  concluded
 that  the tumorigenic effect, if  real, is most unlikely  to be
 relevant to human exposure.

    When  tetramethrin (technical grade)  was administered
to  Sprague-Dawley CRCDR rats  (50 of each sex  per group,
F1A weanlings   from parental animals pre-treated with the
compound  at  dose levels  of  1000, 3000,  and 6000 mg/kg
diet)  at dose levels of 0, 1000, 3000, or 5000 mg/kg diet
for  104 weeks, no compound-related effects  were detected
in  investigations  of  appearance,  behaviour,  survival,
haematology, blood chemistry, urinalysis, eye examination,
and organ weight at up to 5000 mg/kg diet.   However,  the
body weight gain of male and female rats fed 3000 mg/kg or
more was significantly lower than that of  controls.   The
incidence  for  testicular  interstitial cell  tumours was
increased at dose levels of 3000 mg/kg or more [49].

    Tetramethrin  (technical grade, 90.0/93.6% purity) was
tested  for long-term toxic effects and tumorigenic poten-
tial  in Sprague-Dawley CRCDR  and Long-Evans hooded  rats
by  in utero exposure and 104-week chronic exposure at dose
levels  of 0, 200, 1000, and 5000 mg/kg diet.  No distinct
compound-related  effects  were observed  in either strain
with  regard to fertility rate, mortality, clinical signs,
and  clinical laboratory data.  However, body weight gains
were  significantly  lower  in both  strains at 5000 mg/kg
diet,  and absolute and  relative liver weights  were  in-
creased in both strains at 5000 mg/kg diet.  The incidence
of interstitial cell tumours in both strains at 5000 mg/kg
diet  was above the level in the concurrent control groups
[44].

    When  tetramethrin  (technical product,  93.3% purity)
was fed daily to B6C3F1 mice  (dose levels of 0,  12,  60,
300, or 1500 mg/kg diet) for 104 weeks, there were no sig-
nificant dose-related changes in survival, clinical signs,
mean body weight, or food consumption. However,  the  mor-
tality of male mice at 300 mg/kg was  significantly  lower
than  that of control  males.  The absolute  and  relative
weight  of  pituitary  and thyroid/parathyroid  glands was
decreased for males fed 60 mg/kg diet or  more.   Absolute
spleen weights were also decreased for males fed 300 mg/kg
diet  or more.  However, gross and microscopic examination
of  these  tissues  did not  reveal  any treatment-related

histomorphological  changes.   There were  no other histo-
pathological  findings attributable to tetramethrin admin-
istration.   The NOEL was  considered to be  12 mg/kg diet
[45].

7.5     Mutagenicity

    The  results of mutagenicity tests on tetramethrin are
summarized in Table 6.

    Ding  et al. [2] reported the induction of unscheduled
DNA  synthesis in human  amnion FL cells  by  tetramethrin
(72% industrial grade of unknown origin). The same product
gave  weakly positive results in an Ames test with Salmon-
ella typhimurium TA 97.  It is not clear if the effect was
caused by tetramethrin itself or by the unidentified (28%)
portion of the industrial grade material.

7.6     Reproduction, Embryotoxicity, and Teratogenicity

    In  a study by Miyamoto [33], groups of 10-15 pregnant
New  Zealand white rabbits received tetramethrin orally on
days  6-18 of gestation at doses of 0, 30, or 90 mg/kg per
day.   Fetuses were obtained by caesarean section prior to
parturition  and were examined  for external and  skeletal
abnormalities.   Seven extra pregnant animals were allowed
to  give birth naturally  and the pups  were examined  for
several weeks to check their growth and  development.   No
significant adverse effects were observed.

    Tetramethrin  (technical product) was  orally adminis-
tered  (dose levels of  0, 100, 300,  and 1000 mg/kg  body
weight per day) to 6-week-old male Slc: SD rats  (SPF,  20
per  group) for not  less than 9 weeks  and to  9-week-old
females  (20 per  group)  for 2 weeks  of the non-pregnant
period and up to day 7 of pregnancy.  The effects  of  the
material  on the mating ability of male and female animals
and on the fetuses were investigated.  In males, the liver
weight  increased at all dose  levels and a kidney  weight
increase was noted at 1000 mg/kg.  Salivation and a slower
body  weight increase were observed during the latter half
of  the administration period at 300 and 1000 mg/kg.  How-
ever, no effects on the reproductive ability of males were
noted. In females, no changes were observed in the rate of
pregnancy,  but there were effects on the sexual cycle and
an ovulation-inhibiting effect at 1000 mg/kg.  In fetuses,
growth  inhibition was suspected at  1000 mg/kg.  However,
all these changes were slight.  The NOEL was considered to
be  300 mg/kg body weight per day for reproductive ability
of parents and growth of fetuses [51].


Table 6.  Mutagenicity studies on tetramethrin
                                                                                    
Test System   Test object      Concentration        Purity/    Results    Reference
                                                    Compound
                                                                                    

Ames test     S. typhimurium   up to 10 mg/plate    93 - 100%  Negative   33
              TA 1535          without activation
              TA 1538

Ames test      Escherichia coli up to 10 mg/plate    93 - 100%  Negative   33
              W 3623           without activation
              W 3012

Ames test     S. typhimurium   1 - 10 000 ug/plate  technical  Negative   56
              TA 100           with and without     racemic
              TA 98            activation
              TA 1535
              TA 1538

Ames test     S. typhimurium   100 - 5000 ug/plate  94.0%      Negative   81
              TA 100           with and without     racemic
              TA 98            activation
              TA 1535
              TA 1537
              TA 97

Ames test      E. coli          100 - 5000 ug/plate  94.0%      Negative   81
              WP2  uvr A        with and without     racemic
                               activation

Ames test     S. typhimurium   10 - 5000 ug/plate   95.6%,     Negative   22
              TA 100           with and without     1R, cis/trans
              TA 98            activation
              TA 1535
              TA 1537
              TA 1538

Ames test      E. coli          10 - 5000 ug/plate   95.6%,     Negative   22
              WP2  uvr A                             1R, cis/trans

Ames test     S. typhimurium   5 - 500 ug/plate     72%        Positivea  2
              TA 97            without activation   industrial
                                                    grade

Rec-assay      Bacillus         1 - 10 000 ug/disk   technical  Negative   56
               subtilis         racemic
              M45 rec- and H17
              (wild type)
     
Rec-assay      Bacillus         50 - 5000 ug/disk    95.6%,     Negative   22
               subtilis                              1R, cis/trans
              M45 rec- and H17
              (wild type)
     
                                                                                    

Table 6 (contd).
                                                                                    
Test System   Test object      Concentration        Purity/    Results    Reference
                                                    Compound
                                                                                    

Host-mediated ICR male mice    200 - 1000 mg/kg     technical  Negative   56
assay         S. typhimurium   body weight (oral)   racemic
              G46

 In vivo                                                                   
chromosomal   ICR male mice    1200, 2400, 5000     93.4%      Negative   80
aberration    bone marrow      mg/kg body           racemic
                               weight (ip)
 In vivo 
chromosomal   ICR male mice    150, 300, 600 mg/kg  95.6%,     Negative   13
aberration    bone marrow      body weight (ip)     1R, cis/trans

Unscheduled 
DNA           Human amnion     Not recorded         72%,       Positivea  2
synthesis     FL cells                              industrial
                                                    grade

Unscheduled 
DNA           Rat hepatocyte    0, 0.2, 1,          94.0%      Negative   21
synthesis     primary cultures  5, 25, 50,          racemic
                                and 100 ug/ml

                                                                                    
a  The test material was of unknown origin and it was unclear whether or not 
   positive results were due to the 28% impurities.

    Tetramethrin  (technical product) was  orally adminis-
tered  (dose levels of  0, 100, 300,  and 1000 mg/kg  body
weight  per day) to  Slc: SD rats  (SPF, 30 per group)  on
days  7-17 of  pregnancy, and  its  effects on  the  dams,
fetuses, and growth of pups were investigated. In dams, an
inhibition  of body weight increase and a decrease of food
consumption were observed at 1000 mg/kg, in addition to an
increase  in  liver  and kidney  weights  at  the time  of
caesarean  section.  In fetuses, no  abnormalities such as
embryo   lethality,  growth  inhibition,   or  teratogenic
effects  were detected.  In addition, the tetramethrin had
no effect on the growth of the young after birth or on the
reproductive  ability of the offspring.  The NOEL was con-
sidered to be 300 mg/kg body weight per day for  the  dams
and  >1000 mg/kg  body  weight per  day for teratogenicity
[52].

    When  tetramethrin  (technical  product)  was   orally
administered  at dose levels of  0, 50, 150, or  500 mg/kg
body  weight per day  to pregnant Japanese  white rabbits,
(10 per group) on days 8-18 of pregnancy, a slight transi-
ent  decline in the body  weight of the dams  was noted in

the  middle  of the  treatment  period at  500 mg/kg.   No
adverse  effects such as  embryo lethality, inhibition  of
fetal growth, or teratogenic action were observed  at  any
dose  level.  The NOEL  for teratogenicity in  rabbits was
considered to be >500 mg/kg body weight per day [53].

    Tetramethrin  (technical product) was  orally adminis-
tered  (dose levels of  0, 100, 300,  and 1000 mg/kg  body
weight per day) to Slc: SD rats (SPF, 20 per  group)  from
day 17  of gestation to day 21 of lactation (perinatal and
postnatal period).  In dams, a liver weight  increase  was
noted at 300 and 1000 mg/kg but there were  no  abnormali-
ties at delivery or during lactation.  Tetramethrin had no
detectable  effects on the  survival rate of  pups, growth
and  development, sensory function, motor function, learn-
ing  ability,  or  reproductive  ability.   The  NOEL  was
considered  to be 100 mg/kg body  weight per day for  dams
and >1000 mg/kg body weight per day for pups [54].

    In  studies  by  Rutter [48],  tetramethrin (technical
grade)  was  administered  to Sprague-Dawley  rats at dose
levels of 0, 1000, 3000, and 6000 mg/kg diet  for  9 weeks
through  weaning  of  the  F1A generation.    Body  weight
reduction  occurred at 6000 mg/kg diet in the parent rats.
The  lactation index was depressed  for the F1A generation
at  6000 mg/kg diet, and the weaning body weights for both
sexes of the F1A generation  were reduced at doses of 3000
mg/kg  diet or more.  There were no other compound-related
adverse effects.  The NOEL was considered to be 1000 mg/kg
diet.

    (1R, cis/trans)-tetramethrin (technical product,  93.4%
purity)  was administered at dose  levels of 0, 100,  500,
and  3000 mg/kg  diet  to two  successive  generations  of
Sprague-Dawley CDR albino rats to determine the effects on
the growth and reproductive performance.  The body weights
of  parental females were  significantly lower during  the
pre-mating  growth, gestation, lactation, and post-weaning
periods,  and the body weight of offsprings of both gener-
ations  decreased  during  lactation at  3000 mg/kg  diet.
Slight  bile duct hyperplasia  was noted in  F1    females
sacrificed after a 30-day feeding period following weaning
of  the F2 offspring  at  3000 mg/kg diet. This  was, how-
ever, a commonly observed change in old rats. Thus, tetra-
methrin  did  not  affect the  reproductive performance of
male and female rats in two successive generations  at  up
to 500 mg/kg diet [46].

7.7  Neurotoxicity - Mode of Action

    Tetramethrin is classified as a Type I pyrethroid. The
mode of action of pyrethroids in general is  described  in
Appendix I.

    In electrophysiological studies, tetramethrin produced
repetitive   discharges in housefly muscle  and uncoupling
in  motor units [1, 32]  and caused repetitive  firing  in
cockroach  cercal  sensory  nerves at  a  concentration of
3 x 10-13 mol/litre [8].

    The  effects  of  tetramethrin on  the  sodium channel
gating  mechanism were studied using the squid giant axons
under voltage clamp conditions [27, 28]. Tetramethrin pro-
longed the falling phase of sodium current during depolar-
ization  and  increased  and prolonged  the  tail  current
associated  with repolarization.  The prolongation  of the
sodium current was due to the channel remaining open.  The
channel returned slowly to the resting state upon repolar-
ization.

    Analysis  of the dose  dependence of the  two  kinetic
phases of tail current development suggests that  the  ap-
parent  dissociation  constant  for  1R, trans-tetramethrin
depends on the conformational state of the channel.  Thus,
it  can  be concluded  that  tetramethrin binds  to sodium
channels  and modifies  the state  of the  channel in  the
resting, open, or inactivated state [28].

    1R, trans-Tetramethrin    markedly  prolongs  the  open
time  of single sodium  channels recorded by  the gigaohm-
seal voltage clamp technique in a membrane  patch  excised
from  the N1E-115 neuroblastoma cell.  Single channel con-
ductance is not altered by tetramethrin.  The modification
by  tetramethrin occurs in  an all-or-nothing manner  in a
population of sodium channels.  The observed tetramethrin-
induced  modification of single sodium channels is compat-
ible with previous sodium current data from axons [78].

    Tetramethrin  greatly  prolongs  the  sodium   current
during  step  depolarization  and the  sodium tail current
associated with step repolarization of the squid axon mem-
brane.   Non-linear current-voltage relationships  for the
sodium  tail  current were  analyzed  to assess  the  open
sodium  channel properties, which included  the permeation
of various cations, calcium block, and cation selectivity.
Tetramethrin had no effect on any of these properties.  It
was  concluded that tetramethrin modifies the sodium chan-
nel gating mechanism without affecting the pore properties
[79].

8. EFFECTS ON HUMANS

    Although tetramethrin has been used for many years, no
adverse  effects and no cases of human poisoning have been
reported in the published literature.

    In  a semi-closed patch test, an aqueous emulsion con-
taining 1.0% tetramethrin was applied to the skin  of  200
human volunteers (aged 15-80, both male and female), using
cotton gauze, for 4 days. After 2 weeks, an additional ap-
plication was made in a same manner.  Dermatological exam-
ination  showed  that  tetramethrin is  neither  a primary
irritant nor a human skin sensitizer [73].

9.  PREVIOUS EVALUATION BY INTERNATIONAL BODIES

    In the WHO Recommended Classification of Pesticides by
Hazard,  technical tetramethrin is classified  as unlikely
to present an acute hazard in normal use [75].


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43. PENCE,  D.H., HAGEN, W.H., ALSAKER, R.D., DAWKINS, B.G., MARSHALL,
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44. PENCE,  D.H.,  SEROTA,  D.G.,  ALSAKER,  R.D.,  BANAS,  D.A.,  &
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45. PENCE, D.H., COX, R.H., DUDECK, L.E., ALSAKER, R.D., JONES, S.R.,
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48. RUTTER, H.A., Jr (1974)  One-generation reproduction study in  rats.
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49. RUTTER,  H.A., Jr, NELSON, L.W.,  KUNDZINS, W., & MCHUGH  (1974)
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50. RUZO,  L.O.,  SMITH,  I.H.,  &  CASIDA,  J.E.  (1982)  Pyrethroid
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52. SATO, T. & NARAMA, K.  (1980b)  Reproduction test of Neopynamin. Part 2:
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54. SATO,  T., TAGAWA, G., &  NARAMA, K. (1980)  Reproduction test  of
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55. SMITH, I.H., WOOD, E.J., & CASIDA, J.E.  (1982) Glutathione conjugate
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56. SUZUKI,  H.  & MIYAMOTO,  J.  (1977)   Studies  on mutagenicity of
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57. SUZUKI, T. & MIYAMOTO, J.  (1974)  Metabolism of tetramethrin  in
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58. SUZUKI,  T.,  KOHDA,  H.,  MISAKI,  Y.,  OKUNO,  Y., KOYAMA,  Y.,
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59. TANAKA,  H.,  TAKADA,  S.,  ISEKI,  M.,  SANO,  R.,  AIHARA,  H.,
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61. UNO,  M.,  OKADA,  T., OHMAE,  T.,  TERADA,  I., &  TANIGAWA, K.
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62. VAN DEN BERCKEN, J.  (1977) The action of allethrin on the peripheral
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63. VAN  DEN  BERCKEN, J. & VIJVERBERG, H.P.M.  (1980)  Voltage clamp
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64. VAN  DEN  BERCKEN,  J.,  AKKERMANS,  L.M.A.,  &  VAN  DER  ZALM,
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65. VAN  DEN  BERCKEN,  J.,  KROESE,  A.B.A.,  &  AKKERMANS,  L.M.A.
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66. VERSCHOYLE,  R.D.  &  ALDRIDGE,  W.N.  (1980)  Structure-activity
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67. VIJVERBERG,  H.P.M.  &  VAN  DEN  BERCKEN,  J.  (1979)  Frequency
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68. VIJVERBERG,  H.P.M.  &  VAN DEN  BERCKEN, J.  (1982)  Action  of
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69. VIJVERBERG,  H.P.M.,  RUIGT,  G.S.F.,  &  VAN  DEN  BERCKEN,  J.
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    (Submitted to WHO by Sumitomo Chemical Co.).


APPENDIX I

    On the basis of electrophysiological studies with per-
ipheral nerve preparations of frogs ( Xenopus laevis, Rana
temporaria,  and Rana esculenta), it is possible to dis-
tinguish between 2 classes of pyrethroid insecticides:
(Type I and Type II). A similar distinction between these
2 classes of pyrethroids has been made on the basis of the
symptoms of toxicity in mammals and insects [10, 23, 65,
66, 74]. The same distinction was found in studies  on
cockroaches [8].

    Based  on the binding assay  on the alpha-aminobutyric
acid  (GABA)   receptor-ionophore   complex,   synthetic
pyrethroids  can also be  classified into two  types:  the
alpha-cyano-3-phenoxybenzyl   pyrethroids  and  the  non-cyano
pyrethroids [7, 9, 24, 25].

     Pyrethroids  that  do  not  contain  an alpha-cyano  group
 (allethrin, d-phenothrin,  permethrin, tetramethrin, cisme-
 thrin,  and bioresmethrin) (Type I: T-syndrome)

    The  pyrethroids that do not contain an alpha-cyano  group
give  rise  to  pronounced repetitive  activity  in  sense
organs  and in sensory nerve fibres [64]. At room tempera-
ture,  this repetitive activity usually consists of trains
of 3-10 impulses and occasionally up to 25 impulses. Train
duration is between 10 and 5 milliseconds.

    These  compounds  also  induce  pronounced  repetitive
firing  of  the presynaptic  motor  nerve terminal  in the
neuromuscular  junction  [62].   There was  no significant
effect  of the insecticide on  neurotransmitter release or
on the sensitivity of the subsynaptic membrane, nor on the
muscle  fibre membrane.  Presynaptic repetitive firing was
also  observed  in  the sympathetic  ganglion treated with
these pyrethroids.

    In the lateral-line sense organ and in the motor nerve
terminal,  but not in the  cutaneous touch receptor or  in
sensory  nerve  fibres, the  pyrethroid-induced repetitive
activity  increases  dramatically  as the  temperature  is
lowered, and a decrease of 5 °C in temperature may cause a
more  than 3-fold increase in the number of repetitive im-
pulses  per train. This effect is easily reversed by rais-
ing  the temperature. The  origin of this  "negative tem-
perature coefficient" is not clear [71].

    Synthetic pyrethroids act directly on the axon through
interference with the sodium channel gating mechanism that
underlies  the generation and conduction of each nerve im-
pulse.   The transitional state  of the sodium  channel is
controlled  by  2  separately  acting  gating  mechanisms,
referred  to as the  activation gate and  the inactivation
gate.   Since pyrethroids only appear to affect the sodium

current  during depolarization, the  rapid opening of  the
activation gate and the slow closing of  the  inactivation
gate proceed normally. However, once the sodium channel is
open, the activation gate is restrained in the  open  pos-
ition  by the pyrethroid molecule.   While all pyrethroids
have  essentially the same basic mechanism of action, how-
ever, the rate of relaxation differs substantially for the
various pyrethroids [6].

    In the isolated node of Ranvier, allethrin causes pro-
longation of the transient increase in sodium permeability
of the nerve membrane during excitation [63].  Evidence so
far  available indicates that allethrin  selectively slows
down the closing of the activation gate of a  fraction  of
the sodium channels that open during depolarization of the
membrane.   The time constant of closing of the activation
gate  in  the  allethrin-affected channels  is  about  100
milliseconds  compared with less than  100 microseconds in
the  normal sodium channel, i.e.,  it is slowed down  by a
factor  of more than  100. This results  in a marked  pro-
longation  of the sodium current across the nerve membrane
during  excitation, and this  prolonged sodium current  is
directly  responsible for the repetitive  activity induced
by allethrin [71].

    The  effects of cismethrin on synaptic transmission in
the frog neuromuscular junction, as reported by Evans [4],
are  almost identical to those of allethrin, i.e., presyn-
aptic  repetitive  firing,  and no  significant effects on
transmitter release or on the subsynaptic membrane.

    Interestingly, the action of these pyrethroids closely
resembles  that of the  insecticide DDT in  the peripheral
nervous  system of the  frog.  DDT also  causes pronounced
repetitive  activity  in  sense organs,  in  sensory nerve
fibres,  and  in  motor nerve  terminals,  due  to a  pro-
longation of the transient increase in sodium permeability
of the nerve membrane during excitation.  Recently, it was
demonstrated  that allethrin and DDT  have essentially the
same  effect on sodium  channels in frog  myelinated nerve
membrane.  Both compounds slow down the rate of closing of
a  fraction of the sodium channels that open on depolariz-
ation of the membrane [64, 65, 70].

    In  the  electrophysiological experiments  using giant
axons  of crayfish, the  type I pyrethroids and  DDT  ana-
logues  retain sodium channels  in a modified  open  state
only intermittently, cause large depolarizing after-poten-
tials,  and evoke repetitive firing with minimal effect on
the resting potential [29].

    These  results  strongly  suggest that  permethrin and
cismethrin,  like  allethrin, primarily  affect the sodium
channels in the nerve membrane and cause a prolongation of
the  transient increase in sodium permeability of the mem-
brane during excitation.

    The  effects  of  pyrethroids on  end-plate and muscle
action  potentials were studied  in the pectoralis  nerve-
muscle  preparation of the clawed  frog ( Xenopus  laevis).
Type I  pyrethroids (allethrin, cismethrin, bioresmethrin,
and  1R,  cis-phenothrin)  caused moderate  presynaptic re-
petitive activity, resulting in the occurrence of multiple
end-plate potentials [47].

     Pyrethroids  with an alpha-cyano  group  on the 3-phenoxy-
 benzyl alcohol (deltamethrin,  cyhalothrin, lambda-cyhalo-
 thrin,   cypermethrin,  fenvalerate,  and    fenpropanate)
 (Type II: CS-syndrome)

    The  pyrethroids with an alpha-cyano   group cause an  in-
tense repetitive activity in the lateral line organ in the
form  of  long-lasting trains  of  impulses [69].   Such a
train may last for up to 1 min and contains  thousands  of
impulses. The duration of the trains and the number of im-
pulses  per train increase  markedly on lowering  the tem-
perature.  Cypermethrin does not cause repetitive activity
in  myelinated  nerve  fibres.  Instead,  this  pyrethroid
causes  a  frequency-dependent  depression of  the nervous
impulse,  brought about by a progressive depolarization of
the  nerve membrane as  a result of  the summation of  de-
polarizing  after-potentials during train stimulation [67,
71].

    In  the isolated node  of Ranvier, cypermethrin,  like
allethrin, specifically affects the sodium channels of the
nerve  membrane and causes a  long-lasting prolongation of
the transient increase in sodium permeability during exci-
tation,  presumably  by slowing  down  the closing  of the
activation  gate of the sodium channel [67, 71].  The time
constant of closing of the activation gate in  the  cyper-
methrin-affected  channels is prolonged  to more than  100
milliseconds.   Apparently, the amplitude of the prolonged
sodium current after cypermethrin is too small  to  induce
repetitive  activity in nerve fibres, but is sufficient to
cause  the long-lasting repetitive firing  in the lateral-
line sense organ.

    These  results suggest that alpha-cyano   pyrethroids pri-
marily  affect the sodium  channels in the  nerve membrane
and  cause  a  long-lasting prolongation  of the transient
increase  in  sodium  permeability of  the membrane during
excitation.

    In  the  electrophysiological experiments  using giant
axons  of crayfish, the Type II  pyrethroids retain sodium
channels in a modified continuous open state persistently,
depolarize  the membrane, and  block the action  potential
without causing repetitive firing [29].

    Diazepam, which facilitates GABA reaction, delayed the
onset of action of deltamethrin and fenvalerate,  but  not
permethrin and allethrin, in both the mouse and cockroach.
Possible  mechanisms  of  the Type II  pyrethroid syndrome
include action at the GABA receptor complex or  a  closely
linked class of neuroreceptor [9].

    The  Type II syndrome of  intracerebrally administered
pyrethroids  closely  approximates that  of the convulsant
picrotoxin  (PTX).   Deltamethrin inhibits  the binding of
[3H]-dihydropicrotoxin    to rat brain synaptic membranes,
whereas  the non-toxic R  epimer of deltamethrin  is inac-
tive.   These findings suggest a possible relation between
the Type II pyrethroid action and the GABA  receptor  com-
plex.  The stereospecific correlation between the toxicity
of  Type II pyrethroids and  their potency to  inhibit the
[35S]-TBPS    binding was established using a radioligand,
[35S]- t-butylbicyclophosphorothionate [35S]-TBPS.  Studies
with  37 pyrethroids  revealed  an  absolute  correlation,
without  any  false  positive or  negative,  between mouse
intracerebral  toxicity and  in vitro inhibition: all toxic
cyano   compounds  including  deltamethrin,  1R, cis-cyper-
methrin,  1R, trans-cypermethrin,   and [2S, alphaS]-fenvalerate
were  inhibitors,  but their  non-toxic stereoisomers were
not; non-cyano pyrethroids were much less potent  or  were
inactive [24].

    In the [35S]-TBPS   and [3H]-Ro   5-4864 (a convulsant
benzodiazepine  radioligand) binding assay, the inhibitory
potencies  of  pyrethroids  were closely  related to their
mammalian  toxicities.  The most toxic pyrethroids of Type
II  were the most  potent inhibitors of  [3H]-Ro    5-4864
specific  binding  to  rat  brain  membranes.   The  [3H]-
dihydropicrotoxin  and  [35S]-TBPS   binding  studies with
pyrethroids  strongly  indicated  that Type II  effects of
pyrethroids are mediated, at least in part, through an in-
teraction with a GABA-regulated chloride ionophore-associ-
ated binding site. Moreover, studies with [3H]-Ro   5-4864
support  this hypothesis and,  in addition, indicate  that
the pyrethroid-binding site may be very closely related to
the convulsant benzodiazepine site of action [25].

    The  Type II pyrethroids (deltamethrin, 1R,  cis-cyper-
methrin  and  [2S,alphaS]-fenvalerate)    increased the  input
resistance of crayfish claw opener muscle fibres bathed in
GABA.  In contrast, two non-insecticidal stereoisomers and
Type I  pyrethroids  (permethrin,  resmethrin,  allethrin)
were  inactive.  Therefore, cyanophenoxybenzyl pyrethroids
appear to act on the GABA receptor-ionophore complex [7].

    The  effects  of  pyrethroids on  end-plate and muscle
action  potentials were studied  in the pectoralis  nerve-
muscle  preparation of the clawed  frog ( Xenopus  laevis).

Type II   pyrethroids (cypermethrin and  deltamethrin) in-
duced  trains of repetitive muscle action potentials with-
out  presynaptic repetitive activity.  However,  an inter-
mediate group of pyrethroids (1R-permethrin, cyphenothrin,
and  fenvalerate) caused both  types of effect.   Thus, in
muscle or nerve membrane the pyrethroid induced repetitive
activities  due to a  prolongation of the  sodium current.

    But  no clear distinction  was observed between  non-cyano
and alpha-cyano  pyrethroids [47].

Appraisal

    In  summary,  the  results strongly  suggest  that the
primary  target  site  of pyrethroid  insecticides  in the
vertebrate  nervous system is  the sodium channel  in  the
nerve  membrane.   Pyrethroids without  an alpha-cyano   group
(allethrin,   d-phenothrin,  permethrin,  and  cismethrin)
cause a moderate prolongation of the transient increase in
sodium  permeability  of  the nerve  membrane during exci-
tation. This results in relatively short trains of repeti-
tive  nerve impulses in  sense organs, sensory  (afferent)
nerve  fibres, and, in  effect, nerve terminals.   On  the
other hand, the alpha-cyano   pyrethroids cause a long-lasting
prolongation  of  the  transient increase  in  sodium per-
meability  of the nerve membrane  during excitation.  This
results  in long-lasting trains of  repetitive impulses in
sense  organs and a frequency-dependent  depression of the
nerve  impulse in nerve fibres.  The difference in effects
between  permethrin and cypermethrin, which have identical
molecular  structures  except  for the  presence of an alpha-
cyano  group on the phenoxybenzyl  alcohol, indicates that
it  is this alpha-cyano    group that is  responsible for  the
long-lasting prolongation of the sodium permeability.

    Since  the  mechanisms  responsible for  nerve impulse
generation  and conduction are basically the same through-
out   the  entire  nervous system,  pyrethroids  may  also
induce  repetitive activity in various parts of the brain.
The   difference  in  symptoms  of  poisoning  by alpha-cyano
pyrethroids,  compared with the classical  pyrethroids, is
not  necessarily  due  to  an  exclusive  central  site of
action.   It may be related to the long-lasting repetitive
activity  in sense organs and  possibly in other parts  of
the  nervous system,  which, in  a more  advance state  of
poisoning,  may  be  accompanied by  a frequency-dependent
depression of the nervous impulse.

    Pyrethroids  also cause pronounced repetitive activity
and  a prolongation of  the transient increase  in  sodium
permeability  of the nerve  membrane in insects  and other
invertebrates.   Available information indicates  that the
sodium  channel in  the nerve  membrane is  also the  most
important  target site of pyrethroids  in the invertebrate
nervous system [74, 77].

    Because  of the universal  character of the  processes
underlying  nerve excitability, the action  of pyrethroids
should  not be considered restricted  to particular animal
species,  or to a  certain region of  the nervous  system.
Although  it has been  established that sense  organs  and
nerve  endings are the  most vulnerable to  the action  of
pyrethroids,  the ultimate lesion  that causes death  will
depend  on  the animal  species, environmental conditions,
and on the chemical structure and physical characteristics
of the pyrethroid molecule [68].

1.  RESUME, EVALUATION, CONCLUSIONS ET RECOMMANDATIONS

1.1  Résumé et évaluation 

1.1.1   Identité, propriétés physiques et chimiques, méthodes d'analyse

    La  tétraméthrine a été  synthétisée pour la  première
fois  en 1964 et commercialisée  et en 1965.  Sur  la plan
chimique, c'est un ester de l'acide chrysanthémique (acide
diméthyl-2,2(diméthyl-2,2 vinyl)-3 cyclopropanecarboxylique
et  de  l'alcool tétrahydro-3,4,5,6  phatlimidométhylique.
Elle  est constituée d'un mélange de quatre stéréoisomères
[1R,trans],  [1R,cis], [1S,trans] et [1S,cis]. Les stéréo-
isomères  qui  entrent  dans la  composition  des produits
techniques  sont à peu près dans la proportion de 4:1:4:1.
De tous les isomères, c'est l'isomère [1R,trans]  qui  est
le  plus  actif  biologiquement; vient  ensuite  l'isomère
1R,cis].   On commercialise sous le  nom de "Neo-pynamine
Forte" (désignée dans la présente monographie sous le nom
de  1R, cis/trans-tetraméthrine),   un mélange des isomères
[1R,cis] et [1R,trans] dans le proportion de 1:4.

    La  tétraméthrine de qualité  technique est un  solide
incolore  dont le  point de  fusion est  de 60-80 °C.   Sa
densité  est de 1,11  à 20 °C et  sa tension de  vapeur de
0,946 mPa  (7,1 x 10-6 mm   Hg) à 30 °C.  Peu soluble dans
l'eau (4,6 mg/litre à 30 °C), elle est en revanche soluble
dans  certains solvants organiques  tels que l'hexane,  le
méthanol  et le xylène.  Elle est stable à la chaleur mais
instable à la lumière et à l'air. L'isomère [1R,cis/trans]
est un liquide visqueux de couleur jaune dont  les  autres
propriétés  physiques et les propriétés chimiques sont les
mêmes que celles de la tétraméthrine.

    Le  dosage des résidus s'effectue  par densitométrie à
deux  longueurs  d'onde  (370-230 nm). Pour  l'analyse des
produits  techniques,  on  utilise la  chromatographie  en
phase  gazeuse  avec  détection par  ionisation de flamme.
Une  analyse des différentes formulations peut s'effectuer
au  moyen  d'un chromatographe  en  phase liquide  à haute
performance muni d'un détecteur infrarouge.

1.1.2   Production et usage

    La  production mondiale annuelle de  tétraméthrine est
évaluée à quelques centaines de tonnes. Elle  est  princi-
palement  utilisée pour la  lutte contre les  nuisibles  à
l'intérieur  des  habitations,  sous forme  d'aérosols, de
concentrés  émulsionnables  ou  de serpentins  anti-moust-
iques.  La tétraméthrine entre  également dans la  compos-
ition  d'autres formulations insecticides  additionnées ou
non de synergisants.

1.1.3   Exposition humaine

    L'exposition  de la population dans  son ensemble peut
résulter de l'utilisation de ce produit pour  la  destruc-
tion des nuisibles dans les habitations. Lorsqu'on utilise
la tétraméthrine conformément aux recommandations, sa con-
centration  atmosphérique ainsi que celle  de l'isomère 1R
ne  devraient  pas  dépasser 0,5 mg/m3;    par ailleurs le
composé  se dégrade rapidement.  L'exposition de la  popu-
lation générale est donc vraisemblablement très faible. On
n'utilise  pas de tétraméthrine pour  traiter les cultures
vivrières.

1.1.4   Exposition et destinée dans l'environnement

    Une  fine  pellicule  de tétraméthrine  exposée  à  la
lumière solaire se dégrade rapidement.  On a  observé  que
les  principales réactions photochimiques qui  se produis-
aient au cours d'une exposition de 2 heures (conversion de
30%)  étaient:  une époxydation  au  niveau de  la  double
liaison  du radical isobutényle, une oxydation en hydroxy-
méthyle,  en aldéhyde et  en acide carboxylique  du groupe
méthyle  en  position  trans  du  groupement  isobutényle;
enfin, une  hydroperoxydation en  hydroperoxyde allylique.

    On  ne connaît pas avec  exactitude les concentrations
exactes de tétraméthrine dans l'environnement, mais compte
tenu de l'utilisation qui en est faite  actuellement  pour
traiter  les  habitations et  pourvu  que le  produit soit
utilisé  conformément aux recommandations, il est vraisem-
blable  que l'exposition dans l'environnement devrait être
très  faible.  La tétraméthrine se décompose rapidement en
produits moins toxiques.

1.1.5   Absorption, métabolisme, et excrétion

    Des rats à qui l'on avait administré par voie orale ou
sous-cutanée  de la tétraméthrine radio-marquée  au niveau
du  reste acide ou du reste alcool ont rapidement absorbé,
métabolisé  et excrété le produit.  L'excrétion s'effectue
en  5 à 7 jours  dans la proportion  d'environ 95%, à  peu
près autant par la voie urinaire que par la  voie  fécale.
Par ces deux voies, les résidus présents dans  les  tissus
sont  très faibles.  La métabolisation  s'effectue par les
réactions  suivantes:  coupure de  l'ester; élimination du
groupe  hydroxyméthyl  du  reste alcool;  réduction  de la
double liaison 1-2 du reste alcool; oxydation  du  groupe-
ment  méthyle de l'isobutényle au niveau du reste acide et
en  2, 3 et 4  au niveau du reste  alcool; conjugaison des
acides  et des alcools résultant avec l'acide glucuronique
et enfin isomérisation cis/trans.

1.1.6   Effets sur les êtres vivant dans leur milieu naturel

    On  ne dispose  que de  très peu  d'informations à  ce
sujet.   La tétramethrine est extrêmement toxique pour les
poissons, la valeur de la CL50 à  96-h pour  deux  espèces
se situant respectivement à 19 et 21 µg/litre.    Pour une
troisième  espèce, on a obtenu  une CL50   à 48 heures  de
200 µg/litre   et la dose sans effet observable  était  de
50 µg/litre.     Pour  la  daphnie,  la  dose  sans  effet
observable est également de 50 µg/litre.  La tétraméthrine
est  en revanche très  peu toxique pour  les oiseaux  mais
elle est toxique pour les abeilles.  Cependant du fait que
le  produit est rapidement dégradé et dans la mesure où on
ne  l'utilise, conformément aux recommandations,  que dans
les habitations, il est peu probable qu'il puisse excercer
des effets nocifs sur l'environnement.

1.1.7   Effets  sur les animaux d'expérience et sur les systèmes d'épreuve 
in-vitro

    La  tétraméthrine a une faible toxicité aiguë par voie
orale.   La  DL50   pour  le  rat est  >5000 mg/kg,  qu'il
s'agisse  du  racémique  ou de  l'isomère  (1R,cis/trans),
tandis  que pour la  souris elle est  d'environ 2000 mg/kg
(racémique) et de 1060 mg/kg (1R,cis/trans).  Chez le rat,
la  souris et le lapin  la toxicité aiguë par  voie percu-
tanée e st également faible; la  DL50   chez le rat  et la
souris  étant   <5000 mg/kg  et  <2000 mg/kg  chez  le lapin
(toutes les études portaient sur le racémique). Les études
de toxicité aiguë par inhalation ont donné une CL50   chez
le rat et la souris de 2500 mg/m3   pour le  racémique  et
>1180 mg/m3    pour  l'isomère (1R,cis/trans).   Parmi les
signes d'intoxication on a noté une hyperexcitabilité, des
tremblements,   de  l'ataxie  et  une  dépression  (signes
généraux  observés dans l'ensemble des  études de toxicité
aiguë).  Les souris se sont révélées un peu plus sensibles
que  les rats  mais il  n'y avait  pas de  différences  de
sensibilité  entre mâles et femelles.   Qu'ils s'agisse du
racémique ou de l'isomère (1R,cis/trans), la tétraméthrine
ne  provoque  pratiquement  aucune irritation  oculaire ou
cutanée  chez le lapin.  En  outre, ni l'un ni  l'autre de
ces  produits  n'exercent d'effet  sensibilisateur chez le
cobaye.

    La tétraméthrine est un pyréthroïde du type  I.   Chez
les  mammifères ce sont les  tremblements (syndrome-T) qui
constituent le symptôme d'intoxication caractéristique.

    Chez des rats ayant reçu de la tétraméthrine  mêlée  à
leur  nourriture à des concentrations  allant jusqu'à 5000
mg/kg de nourriture pendant 91 jours, on a noté une réduc-
tion du gain de poids à la dose la plus forte. D'après les
résultats d'études de 3 et 6 mois, au cours desquelles des
rats ont reçu l'isomère 1R(cis/trans) dans leur nourriture
à  des doses allant de 25 mg/kg à 3000 mg/kg d'aliment, la

dose sans effet observable était de 200 mg/kg  de  nourri-
ture  pour les  mâles et  de 300 mg/kg  pour les  femelles
(parmi les anomalies observées, on notait une réduction du
gain  de  poids  et du  poids  final  du corps  ainsi  que
certains effets sur les reins et le foie).  Les effets sur
le  foie  résultent, semble-t-il,  d'une réaction d'adapt-
ation  à  la  présence  dans  l'alimentation  du  véhicule
utilisé, à savoir l'huile de maïs.

    Une  étude  de  26 semaines  sur  des  chiens  a  fait
ressortir  une dose sans effet observable de 1250 mg/kg de
nourriture.

    Des souris et des rats à qui l'on avait  fait  inhaler
de  la tétraméthrine en aérosol à une concentration de 200
mg/m3,   3 à 4 heures par jour pendant des périodes allant
jusqu'à  quatre  semaines, n'ont  présenté aucune anomalie
imputable  à ce  produit.  Lors  d'une autre  étude de  ce
type,  au cours de laquelle des rats ont été exposés à une
brumisation  (gouttelettes  de  1,2-1,5 µm   de  diamètre)
d'isomère (1R,cis/trans) dans du kérosène désodorisé à des
concentrations allant jusqu'à 87 mg/m3,   trois heures par
jour  et sept  jours par  semaine pendant  28 jours, on  a
obtenu,  pour la dose sans effet observable, une valeur de
49 mg/m3.     Les signes d'intoxication n'ont été observés
qu'au cours de l'exposition.

    Ni  la tétraméthrine ni ses isomères (1R,cis/trans) ne
se  sont révélés mutagènes dans  divers systèmes d'épreuve
 in   vivo et  in vitro utilisés pour étudier  les mutations
génétiques,  les lésions et les réparations de l'ADN ainsi
que les effets sur les chromosomes.

    Trois  études, dont deux  chez le rat  et une chez  la
souris  ont été menées pendant 104 semaines afin d'étudier
la  cancérogénicité à long terme de la tétraméthrine.  Les
souris ont reçu de la tétraméthrine dans leur nourriture à
des  doses allant jusqu'à 1500 mg/kg de nourriture.  Aucun
effet oncogène n'a été observé.  A partir de  60 mg/kg  de
nourriture   on  observait  une  réduction   du  poids  de
l'hypophyse, de la thyroïde et de la  parathyroïde.   Chez
la  souris,  la  dose  sans  effet  général  observable se
situait à 12 mg/kg de nourriture.  Quant aux rats, ils ont
été  exposés à  de la  tétraméthrine à  des  doses  allant
jusqu'à 5000 mg/kg de nourriture soit  in  utero   soit  au
cours d'une période prolongée.  Les deux études  ont  fait
ressortir un gain de poids sensiblement moindre  chez  les
animaux  recevant  3000 mg  de  tétraméthrine  par  kg  de
nourriture  ou davantage.  En outre, à ces concentrations,
on a observé une augmentation du poids du foie.   Pour  ce
qui  est des effets généraux,  la dose sans effet  observ-
able  se situait  dans les  deux études,  à 1000 mg/kg  de
nourriture.   A  la  dose  de  3000 mg/kg  de  nourriture,
l'incidence des tumeurs testiculaires à cellules de Leydig
était supérieure à la valeur notée dans le  groupe  témoin

et  ce, pour les deux  études.  Les tumeurs à  cellules de
Leydig  se produisent spontanément  chez les rats  âgés et
leur  incidence  peut  varier énormément  dans les groupes
témoins. On pense que cette tumeur est  d'origine  hormon-
ale.  Aucun signe de malignité et aucune tumeur de ce type
n'ont  été relevés chez les  souris.  On peut en  conclure
que  cet effet oncogène,  s'il existe réellement,  ne peut
être  pris  en considération pour ce qui concerne l'homme.

    La  tétraméthrine  ne  s'est révélée  ni tératogène ni
embryotoxique à des doses allant jusqu'à 1000 mg par kg de
poids corporel chez les rats et jusqu'à 500 mg/kg chez des
lapins  (il  s'agit  des concentrations  les  plus  fortes
étudiées).   Lors  d'une étude  de  fécondité au  cours de
laquelle des rats ont reçu de la tétraméthrine à des doses
allant jusqu'à 1000 mg/kg de poids corporel par  jour,  la
dose sans effet observable sur la reproduction des parents
et  la croissance des  foetus, se situait  à 300 mg/kg  de
poids corporel par jour.  Une étude de  reproduction  chez
le  rat,  portant  sur la  période  périnatale  et sur  la
période  post-natale,  a permis  de  fixer à  100 mg/kg de
poids  corporel la dose quotidienne  sans effet observable
(la  dose la  plus forte  administrée au  cours  de  cette
étude).

    Lors  d'une  étude  de reproduction  portant  sur  une
génération  de rats, on a administré aux animaux 1000-6000
mg de tétraméthrine par kg de nourriture et  constaté  que
la  dose sans effet observable était de 1000 mg/kg.  Selon
une autre étude portant cette fois sur  deux  générations,
au  cours  de  laquelle les  rats  ont  reçu de  l'isomère
(1R,cis/trans)  à des doses allant de 100 à 3000 mg/kg, la
dose   sans  effet  observable   était  de  500 mg/kg   de
nourriture.

1.1.8   Effets sur l'homme

    Bien  que la tétraméthrine  et son isomère  1R  soient
utilisées  depuis  des années,  on  ne signale  aucun  cas
d'intoxication  ou  d'effets  indésirables  chez  l'homme.

    Rien  n'indique que la tétraméthrine ou son isomère 1R
puissent  avoir  des  effets  nocifs  sur  l'homme  si  on
continue  de  les  utiliser à  faibles  concentrations  et
seulement  pour la destruction des nuisibles à l'intérieur
des habitations.

1.2  Conclusions 

a)  Population  générale:  l'exposition  de la  population
générale  à la tétraméthrine,  dans son utilisation  actu-
elle,  est  vraisemblablement  faible.  Si  ce produit est
utilisé  conformément aux recommandations, il  ne présente
probablement aucun risque.

b)  L'exposition  professionnelle:   moyennant  de  bonnes
méthodes de travail, l'application de mesures d'hygiène et
avec quelques précautions, la tétraméthrine ne devrait pas
présenter de danger pour les personnes qui y sont exposées
de par leur profession.

c)  Environnement:  il est tout  à fait improbable  que la
tétraméthrine  ou  ses produits  de décomposition s'accum-
ulent  au point d'avoir des effets nocifs sur l'environne-
ment.

1.3  Recommandations 

    Bien  que la tétraméthrine  et son isomère  1R  soient
utilisés  depuis  des années  sans  qu'on ait  à  déplorer
d'effets  nocifs  chez  l'homme, il  est  souhaitable  que
l'exposition humaine continue d'être surveillée.






See Also:
        Tetramethrin (ICSC)
        Tetramethrin (UK PID)