<b>Bijsluiter</b>. De hyperlink naar het originele document werkt niet meer. Daarom laat Woogle de tekst zien die in dat document stond. Deze tekst kan vreemde foutieve woorden of zinnen bevatten en de opmaak kan verdwenen of veranderd zijn. Dit komt door het zwartlakken van vertrouwelijke informatie of doordat de tekst niet digitaal beschikbaar was en dus ingescand en vervolgens via OCR weer ingelezen is. Voor het originele document, neem contact op met de Woo-contactpersoon van het bestuursorgaan.<br><br>====================================================================== Pagina 1 ======================================================================

<pre>Pyrethrum (pyrethrins)
(CAS No: 8003-34-7)
Health-based Reassessment of Administrative Occupational Exposure Limits
Committee on Updating of Occupational Exposure Limits,
a committee of the Health Council of the Netherlands
No. 2000/15OSH/138 The Hague, November 9, 2004
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<pre>Preferred citation:
Health Council of the Netherlands: Committee on Updating of Occupational
Exposure Limits. Pyrethrum (pyrethrins); Health-based Reassessment of
Administrative Occupational Exposure Limits. The Hague: Health Council of the
Netherlands, 2004; 2000/15OSH/138.
all rights reserved
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<pre>1      Introduction
      The present document contains the assessment of the health hazard of pyrethrum
      (pyrethrins) by the Committee on Updating of Occupational Exposure Limits, a
      committee of the Health Council of the Netherlands. The first draft of this
      document was written by J Krüse, Ph.D., JAGM van Raaij, Ph.D., WK de Raat,
      Ph.D. (OpdenKamp Registration & Notification, Zeist, the Netherlands).
           The evaluation of the toxicity of pyrethrum has been based on reviews
      published in the monographs ‘Handbook of Pesticide Toxicology’ (Ray91) and
      ‘Pyrethrum Flowers’ (Cas95a) and by the American Conference of Industrial
      Hygienists (ACG99). Where relevant, the original publications were reviewed
      and evaluated as will be indicated in the text. In addition, in December 1998,
      literature was searched in the on-line databases Toxline, Medline, and Chemical
      Abstracts, starting from 1965-1966, and Extoxnet, and using the following key
      words: pyrethrum, pyrethrins, and 8003-34-7. Data from unpublished studies
      were generally not taken into account. Exceptions were made for studies that
      were summarised and evaluated by the Food and Agricultural Organization/
      World Health Organization (FAO/WHO: Joint Meeting of the FAO Panel of
      Experts on Pesticide Residues in Food and the Environment and the WHO Core
      Assessment Group - JMPR) (FAO65, FAO71, FAO00). The final literature
      search was carried out in Toxline and Medline in October 2003.
           In October 2003, the President of the Health Council released a draft of the
      document for public review. Comments were received from the following
      individuals and organisations: A Aalto (Ministery of Social Affairs and Health,
      Tampere, Finland). These comments were taken into account in deciding on the
      final version of the document.
2     Identity
      Pyrethrum is extracted from the dried flowers of Chrysanthemum
      cinerariaefolium. The extract contains a mixture of 3 naturally occurring, closely
      related insecticidal esters of chrysanthemic acid (the pyrethrins I) and 3 closely
      related esters of pyrethric acid (the pyrethrins II). The pyrethrins I comprise
      pyrethrin I, cinerin I, and jasmolin I, and the pyrethrins II comprise pyrethrin II,
      cinerin II, and jasmolin II. Pyrethrins is the collective term for these 6
      insecticidal ingredients. The first stage of extraction of pyrethrum flowers with
      low-boiling petroleum solvents results in crude extract or oleoresin (‘OR
      concentrate’) containing 30-35% pyrethrins. The most refined commercial grade
138-3 Pyrethrum (pyrethrins)
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<pre>              pyrethrum (‘pale extract’) contains about 55-60% total pyrethrins (FAO00,
              Gri73). A typical pyrethrins I/pyrethrins II ratio is 1.85; the ratio of pyrethrin (I
              and II), cinerin (I and II) and jasmolin (I and II) in the mixture is 71:21:7
              (FAO00, Rob99).
              Data on the identity of the 6 constituents of pyrethrum (CAS No: 8003-34-7 are
              presented below.
name                   pyrethrin I                       cinerin I                         jasmolin I
synonyms               cyclopropanecarboxylic acid, 2,2- cyclopropanecarboxylic acid, 2,2- cyclopropanecarboxylic acid, 2,2-
                       dimethyl-3-(2-methyl-1-           dimethyl-3-(2-methyl-1-           dimethyl-3-(2-methyl-1-
                       propenyl)-2-methyl-4-oxo-3-(2,4-  propenyl)-3(2-butenyl)-2-methyl-  propenyl)-2-methyl-4-oxo-3-(2-
                       pentadienyl)-2-cyclopenten-1-yl   4-oxo-2-cyclopenten-1-yl ester    pentenyl)-2-cyclopenten-1-yl
                       ester [1R-[1α[S*(Z)],3β]];        [1R-[1α[S*(Z)],3β]]               ester [1R-[1α[S*(Z)],3β]];
                       chrysanthemummonocarboxylic                                         4’,5’-dihydropyrethrin I
                       acid pyrethrolone ester
molecular formula      C21H28O3                          C20H28O3                          C21H30O3
structural formula
CAS number             121-21-1                          25402-06-6                        4466-14-2
name                   pyrethrin II                      cinerin II                        jasmolin II
synonyms               cyclopropanecarboxylic acid,      cyclopropanecarboxylic acid,      cyclopropanecarboxylic acid,
                       3-(3-methoxy-2-methyl-3-oxo-1-    3-(3-methoxy-2-methyl-3-oxo-1-    3-(3-methoxy-2-methyl-3-oxo-1-
                       propenyl)-2,2-dimethyl-2-         propenyl)-2,2-dimethyl-3-(2-      propenyl)-2,2-dimethyl-2-
                       methyl-4-oxo-3-(2,4-              butenyl)-2-methyl-4-oxo-2-        methyl-4-oxo-3-(2-pentenyl)-2-
                       pentadienyl)-2-cyclopenten-1-yl   cyclopenten-1-yl ester [1R-       cyclopenten-1-yl ester [1R-
                       ester [1R-[1α[S*(Z)],3β] (E)];    [1α[S*(Z)],3β] (E)]               [1α[S*(Z)],3β] (E)];
                       chrysanthemumdicarboxylic acid                                      4’,5’-dihydropyrethrin II
                       monomethyl ester pyrethrolone
                       ester
molecular formula      C22H28O5                          C21H28O5                          C22H30O5
structural formula
CAS number             121-29-9                          121-20-0                          1172-63-0
138-4         Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>3                 Physical and chemical properties
                            pyrethrum      pyrethrin I cinerin I      jasmolin I     pyrethrin II   cinerin II      jasmolin II
molecular weight            316-374        328.5       316.4          330.5          372.5          360.4           357.7
boiling pointa              -              170oC0.013  136-138oC0.001 -              200oC0.013     182-184oC0.00013-
melting point               -              -           -              -              -              -               -
flash point                 82-88oC (open  -           -              -              -              -               -
                            cup)
vapour pressure             at 20oC: 0     3x10-3 Pab                                5x10-3 Pab
solubility in water         insoluble      insoluble   insoluble      insoluble      poorly soluble insoluble       insoluble
log Poctanol/waterc                        6.28        5.93           6.42           5.33           4.98            5.47
conversion factors          not applicable
a
     Number in superscript represents the atmospheric pressure in kPa at which the presented value was determined.
b
     Temperature not given.
c
     All estimated values.
Data from ACG99, Bud96, Cas95a, Gri73, Rob99, Tom97, http://www.syrres.com/esc/est_kowdemo.htm.
                  Pyrethrum is a viscous brown resin or solid (ACG99). Pyrethrins are very
                  unstable in light and air, with loss of insecticidal activity. The preparation of
                  concentrations containing high amounts of pyrethrins (>80%, prepared by
                  extracting OR with nitropyrene) leads to lack of stability, and it is therefore not
                  practised commercially. Pyrethrins I and II must be stored in glass wrapped in
                  metal foil, sealed in polythene, at a temperature of about -25°C (Ray91).
4                 Uses
                  Pyrethrum is a non-systemic insecticide with contact action. It has some
                  acaricidal activity. It is used for the control of a wide range of insects and mites
                  in public health and on domestic and farm animals and for the control of chewing
                  and sucking insects and spider mite on fruit, vegetables, field crops, ornamentals,
                  glasshouse crops, and house plants. It is normally combined with synergists, e.g.,
                  piperonyl butoxide, which inhibit detoxification in insects.
                      Pyrethrins have been used extensively for the control of human body lice,
                  and are still effective for control of head lice (Ray91).
                  The biological activities of the pyrethrum constituents depend on the structural
                  characteristics of the acid and alcohol components. Pyrethrins I and II are
                  considerably more potent than the cinerins and jasmolins. The chrysanthemates
138-5             Pyrethrum (pyrethrins)
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<pre>      (pyrethrin I series) are generally more potent killing agents, while the pyrethrates
      (pyrethrin II series) are more potent knock-down agents (Cas80).
      Pyrethrins are often mixed with organophosphates, carbamates, chlorinated
      pesticides, or rotenone. The following formulation types are in use: fogging
      concentrate, emulsifiable concentrate, aerosol dispenser, wettable powder,
      dispersible concentrate, and ultra-low volume liquid. Pyrethrum-containing
      products can be liquids (sprays, aerosols, shampoos, or lotions), semi-solids
      (creams and ointments), solids (mosquito coils), powders, and dusts (Tom97).
      The usual household formulation contains about 0.5% active pyrethrum (Ray91).
      According to the database of the Dutch Pesticide Authorisation Board (CTB)*,
      pyrethrins are at present registered in the Netherlands for use as an active
      ingredient in insecticides for specified applications. The ‘Geneesmiddelen
      Repertorium’, an overview of information on pharmaceutical specialties
      registered by the Dutch Medicines Evaluation Board, did not list pyrethrum- or
      pyrethrins-containing products**.
5     Biotransformation and kinetics
      The committee did not find quantitative data on the respiratory absorption of
      pyrethrins in humans or experimental animals.
           The in vivo dermal absorption of pyrethrin was studied by spreading
      [14C]pyrethrin to the ventral forearm of 6 male volunteers and washing it off after
      30 minutes. The commercial formulation used contained 0.3% pyrethrin.
      Concentrations applied amounted to 5.5 µg pyrethrin/cm2. Hardly any
      radioactivity was detected in the urine samples until day 2. At this day, excretion
      of radioactivity peaked (ca. 0.4% of the dose applied). Thereafter, excretion
      levels decreased through day 7 (ca. 0.2%), the end of the experiment. The
      calculated half-life for urinary 14C excretion was 50 hours. Based on the 7-day
      cumulatively excreted radioactivity and urinary excretion data from rhesus
      monkeys injected with [14C]pyrethrin, Wester et al. calculated that 1.9 (±1.2)% of
      the dose applied was absorbed through the skin (Wes94).
           When male Sprague-Dawley rats were given an oral (gavage) dose of 3
      mg/kg bw of [3H]-pyrethrin I or [3H]-pyrethrin II (label in the 6’-methyl and the
      5’-methylene groups of the cyclopentenolone ring, i.e., the alcohol moiety),
*     at: http://www.ctb-wageningen.nl.
**    at: http://www.geneesmiddelenrepertorium.nl/nefarma/.
138-6 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>      30.2% or 33.0% of the doses were excreted in the urine and 41% or 30.7% in the
      faeces, respectively, within 100 hours after administration. Most of the
      radioactivity (74-76%), excreted in the urine within 100 hours was produced
      during the first 20 hours after administration. When mice or rats received single
      doses of 1 to 5 mg/kg bw of radiolabelled 14C-pyrethrin I (label in the
      cyclopropane carboxy group, i.e., the acid moiety), 52 or 46% of the doses were
      excreted in urine and 1.0 and 0.3% as 14CO2, respectively, within 48 hours after
      administration. With the 14C-label in the methoxy position of pyrethrin II, rats
      excreted 7% of the label in the urine and 53% as 14CO2 within 48 hours after
      administration. It is concluded that the methoxycarbonyl group of pyrethrin II is
      largely hydrolysed in rats to a carboxyl group (Cas71, Ell72a).
           The metabolism of the pyrethrins I and II in rats, as found in these early
      studies, is shown in Figure 1 (see Annex I). By oxidation of the 10-methyl group
      in the acid moiety of pyrethrin I, a carboxylic acid is formed via an alcohol and
      an aldehyde metabolite. The same metabolite is formed after hydrolysis of the
      methoxycarbonyl group of pyrethrin II. This carboxylic acid metabolite is further
      biotransformed by oxidation of the alcohol side chain of pyrethrins I or II, to give
      a 10’,11’-dihydrodiol (14-21% of the dose), which was partly conjugated with
      glucuronic acid or sulphate (3.9-6.2% of the dose) prior to excretion. In addition,
      a 8’,11’-dihydrodiol was formed (3.3-4.4% of the dose). The identified products
      all retained the cyclopropane ester linkage. All these metabolites were present in
      both urine and faeces. The faeces, but not the urine, contained some
      unmetabolised compound (4-18% of the dose) (Cas71, Ell72a, Ell72b, Rob99).
           In a later unpublished study, under the auspices of the Pyrethrin Joint
      Venture, a consortium of major pyrethrum-manufacturing and -formulating
      companies, rats were given 14C-labelled pyrethrins I in single oral doses of 10
      mg/kg bw (males and females), 50 mg/kg bw (females), or 100 mg/kg bw
      (males). The peak concentration of radiolabel in blood occurred between 5 and 8
      hours after administration. The mean percentage of administered radiolabel
      excreted in urine, for the various dosing regimens, was 32-47% in males and
      50-57% in females, whereas in faeces 55-71% was found in males and 50-52% in
      females. Radiolabel was found in all tissues analysed, with the highest level
      found in the fat of females. The elimination half-life of pyrethrins I in the urine
      was 5-7 hours. Following repeated doses of pyrethrins (10 mg/kg bw/day;
      number of treatments not given), no accumulation of radioactivity in tissues
      occurred in animals of each sex. Identification of metabolites confirmed the
      findings of previous published studies, i.e., oxidation of the double bonds
      forming diols and of the methyl groups forming carboxylic acids. The major
      metabolite in urine was chrysanthemum dicarboxylic acid. A second pathway
138-7 Pyrethrum (pyrethrins)
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<pre>      involved hydrolysis of the ester bond of the methoxycarbonyl group to form the
      corresponding acid and alcohol (Sel95).
      In a comparative in vitro study, the metabolism of all 6 natural pyrethrins was
      investigated, using both rat and mouse liver microsomes. Pyrethrin I, cinerin I,
      and jasmolin I were oxidised at the 10-, 10’-, and 11’-methyl groups, the 7’- and
      10’-methylene groups, the 7,8- and 8’,9’-double bonds, and particularly at the
      10’,11’-double bond of pyrethrin I. Microsomal oxidases of the rat were more
      selective than of the mouse in hydroxylating the pyrethrins I at the 10-position
      versus oxidation at the other sites. Epoxidation of these double bonds yields
      7,8-, 8’,9’-, and 10’,11’-epoxy derivatives. Epoxides from the alcohol moiety
      metabolites readily form dihydrodiols, i.e., the 8’9’-dihydrodiol from cinerin I-
      8’,9’-epoxy and the 10’,11’- and 8’,11’-dihydrodiols (which are major
      metabolites in vivo; see above) from pyrethrin I-10’,11’-epoxy. In total, 13-18
      metabolites were identified. The pyrethrins II have one major metabolite in
      common with the corresponding pyrethrins I, since oxidation of the 10-methyl
      group of the pyrethrins I give the same carboxylic acid, formed on hydrolysis of
      the methoxycarbonyl group of pyrethrins II. The acid moiety of the pyrethrins II
      is resistant to oxidation, except at a 5- or 6-methyl substituent, whereas the
      alcohol moieties undergo the oxidation reactions anticipated from the findings on
      the pyrethrins I. No hydrolysis of the cyclopropane ester bond of any of the 6
      pyrethrins has been reported (Cas95b, Cla90).
      The toxicity of the pyrethrins is attributable to a combination of the effects of the
      parent ester and the metabolites generated. The ease of oxidative metabolism of
      pyrethrins contributes to, or accounts for, their low toxicity to mammals.
      Hydrolysis of the methoxycarbonyl ester group of the acidic side chain of
      pyrethrin II to a carboxylic group proceeds faster than oxidation of the 10-methyl
      group of pyrethrin I, which may explain the higher toxicity of pyrethrin I than
      pyrethrin II in rats, and also the larger proportion of pyrethrin I excreted
      unchanged in the faeces (Cas71, Cas95b, Ell72a, Ell72b). The relative rates of
      microsomal oxidation are similar for pyrethrin I, pyrethrin II, cinerin I, and
      cinerin II (Sod77).
138-8 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>6     Effects and mechanism of action
      Human data
      Irritation and sensitisation
      Allergic dermatitis and asthma are the usual health effects observed in workers
      exposed to pyrethrum dust or powder. Case reports of adverse respiratory effects
      attributed to pyrethrins, such as asthma-like attacks and anaphylactic reactions,
      indicate that these responses often occur in individuals with a history of asthma.
           In 2 recent cases, death associated with allergic reactions to dog shampoos
      containing pyrethrins has been reported. The first case dealt with an 11-year-old
      asthmatic girl who washed her dog with shampoo containing 0.2% pyrethrin.
      Within 10 minutes, she suffered a severe asthmatic attack and died within 3
      hours, despite medical treatment. The cause of death was listed as ‘respiratory
      arrest secondary to acute asthmatic attack’, pathological findings being
      consistent with the literature on pathological changes in acute asthma (Wag00).
      In the second case, a 37-year-old female with a 10-year history of mild asthma
      developed severe shortness of breath within 5 minutes after beginning to wash
      her dog with a shampoo containing 0.06% pyrethrin. She went into
      cardiopulmonary arrest and died a short time later, despite efforts to revive her.
      Post-mortem examination revealed pulmonary findings consistent with reactive
      airway responses (Wax94). In another report concerning a shampoo containing
      natural pyrethrins (0.3%), a non-fatal case of a 43-year-old woman with a history
      of asthma and ragweed allergy, who experienced an anaphylactoid reaction after
      self-medication for the treatment of head lice was described. Within one hour
      after application, she had periorbital oedema. The next morning, she also
      complained of shortness of breath, chest tightness, dysphagia, and numbness in
      the extremities, and she became unresponsive during transport to the hospital.
      After 4 days of medical treatment, the patient was discharged (Cul88). No data
      on exposure or on the purity of pyrethrum extracts (see below) used in the
      shampoos were reported in either study.
           Pulmonary interstitial fibrosis and pneumonia in a 24-year-old woman, who
      applied approximately 2.5 cans of a pyrethrum-based insecticide every week for
      6 months, have been ascribed to pyrethrum hypersensitivity. She complained
      about increasing fatigue, pain on the chest, cough, and laboured breathing.
      Furthermore, the serum IgG, IgM, and IgE levels were substantially increased.
      Skin testing demonstrated type 1 and 3 hypersensitivity reactions. Chest X-ray,
138-9 Pyrethrum (pyrethrins)
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<pre>       spirometry, and lung biopsy showed symptoms indicative for hypersensitivity
       lung disease. Cessation of usage of the insecticide resulted in disappearance of
       the symptoms (Car77). A 24-year-old man presented to an emergency
       department with stinging sensation on the nasal and upper pharyngeal mucosa,
       rhinorrhoea, moderate shortness of breath, cough, severe nausea, and diffuse
       abdominal cramping associated with repeated vomiting, tingling sensation in
       both hands, dizziness, and fatigue. Thirty minutes prior to the onset of
       symptoms, he had sprayed his dog and the floor of his enclosed, unventilated
       bedroom with a flea-killing spray containing 0.15% pyrethrins and rubbed the
       spray into the dog’s fur with ungloved hands. Upon medical treatment,
       symptoms disappeared within 2 hours with the exception of a feeling of fatigue
       (Pat88). In an older study, 7 out of 14 patients, who showed adverse reactions to
       intradermal tests with pyrethrum extracts, developed a mild nose and throat
       discomfort following inhalation exposure to pyrethrum aerosol. None of the
       patients developed asthma and there were no delayed reactions (Zuc65). Some of
       the less purified pyrethrum extracts may contain allergens that cause rhinitis and
       asthma (Mor82). However, no thorough investigation of the substances
       responsible for the adverse respiratory responses has been conducted (FAO00).
       Reported skin effects in older studies were a mild erythematous, vesicular
       dermatitis with papules in moist areas and intense pruritus. Oedema and cracking
       develop in severe cases, particularly of the face, lips, and eyelids. Other effects
       were rhinitis, asthma, and temporary numbness of the tongue and lips. Hot
       weather or severe perspirating increase the susceptibility to pyrethrum dermatitis
       (Cas80, Mar41, McC21, Ram30, Seq36). Ointments that were applied as
       mosquito repellents, containing 40% colourless concentrate of pyrethrum,
       caused a high incidence of sensitisation leading to dermatitis in 9.7% of the men
       and 25.9% of the women who applied the cream on a daily basis (Lor47). A 41-
       year-old farmer, who used pyrethrin and endosulfan, developed erythematous
       papular lesions on the face, the dorsum of the hands, and the posterior part of the
       neck 2 days after use. Histological examination of the skin demonstrated
       perivascular infiltrates of lymphocytes and necrosis of basal keratinocytes. Patch
       tests with pyrethrum (2%) were positive (Bra95). Baer demonstrated that 6 out of
       200 patients, allergic to ragweed pollen, evaluated for contact dermatitis or other
       skin diseases, developed contact dermatitis or other skin diseases following
       exposure to pyrethrum (Bae73).
           Several investigations have been undertaken to isolate and characterise the
       allergen responsible for the dermal reactions. When purified pyrethrum extracts
       were tested on 106 patients allergic to pyrethrum flowers, only a few subjects
138-10 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>       reacted positive. However, all subjects showed positive skin reactions to
       unrefined pyrethrum (Zuc65). When 200 people (177 woman and 23 men) were
       patch tested with a 1% water dispersion of pyrethrins, no evidence of primary
       skin irritancy or of sensitisation was found (FAO71, Gri73). A patient, who was
       reported to be allergic to pyrethrum flowers, reacted positively in a 48-hour
       closed patch test with 0.1% w/v pyrethrosin, a sesquiterpene lactone present in
       pyrethrum powder, and weakly positive to 2% w/v pyrethrin II. Negative
       responses were obtained with pyrethrin I, cinerin I and II, and jasmolin I and II
       (Mit72). It is highly unlikely that pyrethrosin, or other allergic impurities, are
       present in commercial refined pyrethrum extracts (Hea69).
           The committee concludes that the refined pyrethrum extracts do not induce
       skin allergies when tested on sensitive subjects, and that the dermal effects in the
       early literature are not relevant to an assessment of refined pyrethrins.
       Acute toxicity
       Apart from the data on allergic dermatitis and asthma presented above, the
       committee found only very little information on effects following acute
       accidental or incidental exposure of humans to pyrethrins. This information is
       limited to 2 cases both reported at the end of the 19th century. One case
       concerned a 2-year-old child dying after eating about 15 grams (‘half an ounce’)
       of an insect powder. The other case was an 11-month-old infant whose mouth,
       nostrils, and entire face were accidentally covered with pyrethrum powder. This
       infant immediately showed pallor, intermittent convulsions, vomiting, collapse,
       redness by pain when pulled up by the hands, refusal to nurse, feeble and slow
       heart sounds, and laboured respiration. After carefully washing the face and
       mucous membranes and abundant vomiting, induced by an emetic, the infant
       essentially recovered within 1.5 hours, except for a slight inflammation of the
       conjunctivae and extreme redness of the lips and the tongue (Ray91). When
       pyrethrins were used as an anthelmintic, the recommended dose was 20 mg for
       adults given daily for 3 days, with no apparent adverse effects (Ray91). The
       acute human oral lethal dose has been estimated to be between 700 and 2100
       mg/kg bw (Gos84, Leh39).
       Interaction with the endocrine system
       A purified pyrethrum extract with a total pyrethrin content of 20% was tested in
       vitro for its ability to interact with androgen binding sites in human genital skin
       fibroblasts and with sex hormone binding globulin (SHBG) in human plasma.
138-11 Pyrethrum (pyrethrins)
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<pre>       Pyrethrins showed competitive binding to the human androgen receptor and to
       SHBG, indicating potential androgenic or anti-androgenic activity. Though the
       activity of natural pyrethrins was higher than that of synthetic pyrethroids, the
       hormonal activity was relatively weak. According to the authors, huge amounts
       would be required to induce an effect in vivo (Eil90).
       Animal data
       Irritation and sensitisation
       Application of pyrethrins to the skin of albino rabbits produced only minimal
       skin irritation (Rom91a, Sch95). Undiluted pyrethrum extract produced mild
       conjunctival irritation to the eyes of albino rabbits during the first 48 hours after
       application. The irritation disappeared within 72 hours after application. No
       corneal opacity or iritis was observed (Bie91, Sch95). In older studies, various
       pyrethrum grades were found to be slightly irritating to the skin and eyes of
       rabbits (Car50, Mal68). Pyrethrins (purity: 86%) did not cause local reactions,
       when rubbed into the skin of rats in amounts of 50 mg daily for 30 days
       (Amb51).
       Pyrethrins were not sensitising to the skin of guinea pigs, with a modified
       Buehler test (Rom91b, Sch95). Other studies in female guinea pigs demonstrated
       that a refined pyrethrum extract, used in aerosol fly killers, did not evoke an
       allergic response. Pyrethrins I and II were also negative in these studies (Ric72,
       Ric73).
       Acute toxicity
       The results of acute lethal toxicity tests, using ‘pale’ or ‘nitropyrene’ pyrethrum
       extracts are summarised in Table 1. Results are expressed in mg total pyrethrins
       per kg body weight.
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<pre>Table 1 Summary of acute lethal toxicity studies for pyrethrum extracts in mammals.
exposure route           species (sex)         purity (%          grade             LC50/ LD50       reference
(duration)                                     pyrethrins)
inhalation      (4 h)    rat (males, females) 57.6%               not specified     3400 mg/m3       Hof91, Sch95
                (1 h)    rat                   not specified      not specified     >20 mg/m3        Gri73
                (30 min) rat (females)         not specified      not specified     >6200 mg/m3      Car50
dermal                   rabbit                57.6%              not specified     >2000 mg/kg bw   Gab91, Sch95
                         rabbit                ca. 20%            ‘pale’            >5000 mg/kg bw   Mal68
                         rabbit                ca. 80%            ‘nitropyrene’     >19800 mg/kg bw  Mal68
                         rat                   ca. 20%            ‘pale’            >1500 mg/kg bw   Mal68
                         rat                   ca. 80%            ‘nitropyrene’     >5400 mg/kg bw   Mal68
oral                     rat (males)           57.6%              not specified     2370 mg/kg bw    Gab92, Sch95
                         rat (females)         57.6%              not specified     1030 mg/kg bw    Gab92, Sch95
                         rat                   ca. 20%            ‘pale’            584 mg/kg bw     Mal68
                         rat                   ca. 60%            ‘pale’            710 mg/kg bw     Gri73
                         rat                   ca. 60%            ‘pale’            1440 mg/kg bw    Bon73
                         rat                   ca. 80%            ‘nitropyrene’     715-900 mg/kg bw Mal68
                         rat                   ca. 80%            ‘nitropyrene’     >1400 mg/kg bw   Ver72
                         mouse                 ca. 20%            ‘pale’            796 mg/kg bw     Mal68
                         mouse                 ca. 80%            ‘nitropyrene’     285-308 mg/kg bw Mal68
                         mouse                 ca. 80%            ‘nitropyrene’     786 mg/kg bw     Mal68
intraperitoneal          rat                   ca. 20%            ‘pale’            189 mg/kg bw     Mal68
                         rat                   ca. 80%            ‘nitropyrene’     208-798 mg/kg bw Mal68
                         mouse                 ca. 20%            ‘pale’            185 mg/kg bw     Mal68
                         mouse                 ca. 80%            ‘nitropyrene’     160-452 mg/kg bw Mal68
intravenous              rat                   ca. 80%            ’nitropyrene’     5 mg/kg bw       Ver72
             In summary, the inhalation 4-hour LC50 was 3400 mg/m3 for rats, the dermal LD50
             values were greater than 1500 and 5000 mg/kg bw for rat and rabbits,
             respectively, and the oral LD50 values varied from 584 to 2400 mg/kg bw for rats,
             and from 285 to 796 mg/kg bw for mice. Variations in LD50 values are suggested
             to be due to variations in the components in the extracts and the concentrations of
             pyrethrum in the dosing solutions (Ray91). Female rats are more sensitive to the
             acute effects of pyrethrum extracts than male rats (Cas95a, Gab92).
             Administration via the intravenous route is by far the most toxic, probably
             because the target organ (nerve synapses) is reached before metabolism occurs
             (Gri73).
                  After acute inhalation, oral, or parenteral exposure, signs of intoxication were
             hyperactivity, increased respiratory rate, muscular tremors, ataxia,
             incoordination, and convulsions (Car50, Mal68, Sch95). No-effect levels for
             clinical signs following acute oral dosing were 710 and 320 mg/kg bw for males
             and females, respectively. The inhalation no-effect level was 690 mg/m3 (Sch95).
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<pre>       Microscopic and macroscopic examination of rats exposed by inhalation
       revealed moderate congestion of lung tissue at approximately 6200 mg/m3 for 30
       minutes(Car50) and discoloured and oedematous respiratory tissues at 3400 mg/
       m3 for 4 hours (Hof91). Following dermal application, rabbits showed slight
       erythema and very slight oedema (Gab91). Oral administration caused
       haemorrhagic lungs, tan to yellow fluid in the lower gastro-intestinal tract, and
       muzzle and genital staining (Gab92).
       Oral LD50 values of pyrethrin I and II in rats were between 260 and 420 mg/kg
       bw and greater than 600 mg/kg bw, respectively (Cas71). This difference is due
       to the differences in the metabolism of pyrethrins I and II (see Chapter 5). The
       intravenous LD50 of pyrethrin I in rats was 5 mg/kg bw (Ver72).
       In an unpublished acute neurotoxicity study, under auspices of the Kenya
       Pyrethrum Information Centre, Sprague-Dawley rats (n=15/sex/group) received
       single oral doses of pyrethrum extract (purity: 57.6% total pyrethrins) by gavage,
       at doses of 0, 40, 125, or 400 mg/kg bw for males and 0, 20, 63, or 200 mg/kg
       bw/day for females. Mortality was observed in 5 males and 2 females of the
       high-dose group. At this dose, neurological signs of toxicity were tremors,
       wetness of the urogenital area, salivation, perinasal encrustation, exaggerated
       startle response, decreased grip strength, hind-leg splay, and increased body
       temperature. Tremors were also seen in females at 63 mg/kg bw. Behavioural
       effects (increased motor activity and decreased rearing and ambulation) were
       observed at the high- and mid-dose levels in males and at the top dose in females.
       Microscopic examination of the sciatic nerve revealed not dose-related scattered
       degenerating nerve fibres or myelin sheets in a few animals. The NOAEL was 20
       mg/kg bw/day (Her93).
       Short-term toxicity
       Sherman strain rats (12 males, 15 females) received 85 inhalation exposures to
       pyrethrum extract at an aerosol concentration of approximately 23 mg
       pyrethrins/m3 for 41 days. One 30-minute exposure/day was given during the
       first week and 2 daily 30-minute exposures thereafter. Mortality, body weight
       gain, and relative liver and kidney weights were not different from the control
       group. No treatment-related macroscopic or microscopic changes were observed
       (Car 50). In a similar experiment conducted by the same authors, in which rats
       received 42 exposures within 31 days, 30 minutes/day, effects were a significant
       decrease in number of neutrophils, accompanied by a significant increase in
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<pre>       number of lymphocytes, and a significant decrease in relative kidney weights.
       No treatment-related macroscopic or microscopic changes were observed
       (Car50).
           In an unpublished inhalation study, under the auspices of the Pyrethrin Joint
       Venture, groups of 15 Charles River rats of each sex were exposed to a liquid
       aerosol of pyrethrum extract (purity: 57.6% total pyrethrins) at concentrations of
       0, 38, 68, 230, or 830 mg pyrethrins/m3, 6 hours/day, 5 days/week, for 13 weeks.
       The average mass median aerodynamic diameter (MMAD) of the aerosol
       particles was 2.7 µm. One death, potentially related with exposure, was observed
       in the high-concentration group. Signs of toxicity were laboured breathing,
       hyperactivity, excess lachrymation, and tremors. Irritation of the respiratory tract
       was observed at 68 mg/m3 and above. Body weights, body weight gains, and
       food consumption were decreased in both males and females exposed to 230 and
       830 mg/m3. Anaemia was observed in males at the 3 highest and in females at the
       highest exposure level, with significant decreases in haemoglobin levels,
       haematocrit, and erythrocyte counts. Other effects at the high exposure level
       were an increase in white blood cell counts in females, and decreased total
       protein and globulin concentrations in the serum of male animals. Liver weights
       were increased at 830 mg/m3. Microscopic examination revealed treatment-
       related changes in the larynx, nasoturbinates, nasopharynx, and lungs. They were
       observed in all groups, including the control group, but were more pronounced in
       the pyrethrin-exposed groups, especially in the high-concentration group
       (New92, Sch95). Based on anaemia in male animals, the committee concludes
       that 38 mg/m3 is a NOAEL for systemic effects, while this level might have
       induced local effects in the respiratory tract.
           When dogs (n=5) were fogged with a 1 L pyrethrum extract (0.25%) in
       kerosine, producing an aerosol concentration of 562 mg pyrethrins/m3, 20
       minutes/day, for 4 consecutive days (4 exposure periods of 5 minutes, with a 7-
       10 minute pause between each period), effects were a significant increased
       number of reticulocytes and a reduced haematocrit at 7 days after the beginning
       of exposure. White blood cell and platelet counts remained unaffected. However,
       additional to these effects, splenectomised dogs also showed erythroid
       hyperplasia in the bone marrow, with a reversal of myeloid:erythroid ratio and a
       reduction in platelet counts (Lor72). Griffin calculated that the applied
       concentration was 11,000 times higher than that received by someone spraying a
       room (Gri73).
           In another study, 3 dogs were given 40 30-minute aerosol exposures of
       approximately 23 mg pyrethrins/m3 during 26 days. No significant changes were
       observed in body weight gain or haematological tests. Two pyrethrin-exposed
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<pre>       dogs developed minor congestion of the lungs, but this effect was unlikely
       related to pyrethrin exposure, as it also ocurred in one control animal (Car50).
       Rabbits (n=15) received a dermal application of 0 or 10 mg pyrethrins/kg bw for
       15 days, with a 2-day rest after the 5th and the 10th administration. The occluded
       skin was exposed for 6-8 hours, after which the gauze was removed and the
       exposed area washed. No treatment-related effects were observed (Gri73).
           In an unpublished dermal study, under the auspices of the Kenya Pyrethrum
       Information Centre, a 25% (w/v) mixture of pyrethrum extract (purity: 57.6%
       total pyrethrins) in corn oil was administered to the skin of New Zealand rabbits
       (n=5/sex/dose level), at doses of total pyrethrins of 0, 100, 300, or 1000 mg/kg
       bw/day, 5 days/week, for 3 weeks. The application sites were occluded during
       the 6-8-hour exposure. Several animals in the treated groups showed very slight
       to well-defined erythema of the skin at the application site, but this effect was not
       dose-related. Microscopic examination of organs and tissues did not show
       treatment-related abnormalities. The NOAEL for systemic effects was 1000
       mg/kg bw/day, the highest dose tested (Gol92, Sch95).
       Sherman strain rats (n=6) received pyrethrum extract (20% total pyrethrins) via
       the diet at a dose level equivalent to 50 mg pyrethrins/kg bw/day, for 14 days.
       Mean body weight gain was significantly decreased and mean absolute and
       relative liver weights were significantly increased, compared with control
       animals. Microscopic examination revealed occasional enlarged hepatocytes,
       occasional vacuolated cytoplasm, and occasional cytoplasmic inclusions. These
       changes were intensified when rats received doses of combined pyrethrins and
       piperonyl butoxide (Kim68).
       When male Sprague-Dawley rats (n=4/group) were given pyrethrum extract
       (20%) at doses equivalent to 85, 200, or 500 mg pyrethrins/kg bw/day by gavage
       for 15 days, a statistical significant dose-related increase in relative liver weight
       was observed at the 2 higher levels and a statistical significant increase in the
       activity of several drug metabolising enzymes at all dose levels. Treatment at 500
       mg/kg bw/day for 4 days resulted in increased activities of cytochrome P450 and
       NADPH-dependent cytochrome c reductase to 141% and 197% of control levels.
       When animals were treated with 500 mg/kg bw/day for 4, 7, or 17 days, the
       increases in relative liver weight and in activities of drug metabolising enzymes
       reached already a plateau at day 4. Liver weights and enzyme activities returned
       to normal within 7 days after cessation of treatment. The LOAEL was 85 mg/kg
       bw/day, based on hepatic enzyme induction (Spr73).
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<pre>           Female or male rats (n=5/sex) were fed ‘pale’ pyrethrum extract via the diet,
       at dose levels equivalent to of 911 or 704 mg pyrethrins/kg bw/day, respectively,
       for 5 weeks. No clinical signs of toxicity were reported. Macroscopic
       examination revealed prominent Peyer’s patches in the ileum of one male and
       one female. No further details were provided (Hun72).
           In an unpublished oral study, under the auspices of the Pyrethrum Joint
       Venture, Charles River CD rats (n=15/sex/group) received pyrethrum extract
       (purity: 57.6% total pyrethrins) via the diet at dose levels equivalent to 0, 17, 57,
       170, 590, or 1200 mg pyrethrins/kg bw/day for males and 0, 22, 74, 220, 710, or
       1400 mg/kg bw/day for females, for 13 weeks. In the high-dose group, 1 male
       and 12 females died during the first week of the study. Signs of toxicity were
       tremors, hyperactivity, increased respiration rate, convulsions, and decreased
       defecation. Most signs were seen only during the first 2 weeks of the study. Other
       effects at the 170 mg/kg bw/day were decreased body weight gains, food
       consumption, haemoglobin levels, haematocrit, and erythrocyte count and
       increased liver and kidney weights. Macroscopic examination showed a dose-
       related enlargement and congestion of the liver in both sexes at the 2 highest
       doses. Microscopic examination revealed treatment-related small focal or
       multifocal areas of tubular degeneration and regeneration in the renal cortex in
       animals at 170 (males) or 220 mg/kg bw/day (females) and above. The NOAEL
       was 57 mg/kg bw/day, based on effects on liver, kidney, and erythrocytes at
       higher dose levels (Gol88a, Sch95).
           In an unpublished oral study, under the auspices of the Pyrethrum Joint
       Venture, Charles River CD-1 mice (n=15/sex/group) received pyrethrum extract
       (purity: 57.6% total pyrethrins) via the diet at dose levels equivalent to 0, 47,
       160, 460, or 1600 mg pyrethrins/kg bw/day for males, and 0, 56, 200, 580, or
       1800 mg/kg bw/day for females, for 13 weeks. In the high-dose group, 4 males
       and 2 females died on day 2. Signs of toxicity included tremors, dilated pupils,
       altered activity, laboured breathing, and cold to touch. No treatment-related
       clinical signs were observed in the other groups. Body weights and food
       consumption remained unaltered. At the 2 highest dose levels, absolute and
       relative liver weights were significantly increased in both sexes, and congestion
       of the liver was observed. Microscopic examination showed hepatocellular
       hypertrophy at the 3 highest dose levels. The NOAEL was 47 mg/kg bw/day,
       based on effects on the liver (Gol88b, Sch95).
           Beagle dogs (n=6) were fed pyrethrum extract (purity not given) at a dose
       level equivalent to approximately 165 mg pyrethrins/kg bw, for 90 days. Signs of
       toxicity were tremors, ataxia, laboured respiration, and salivation, mainly in the
       1st month of the experiment. Appetite was poor during the first week, but
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<pre>       improved thereafter. Slight body weight loss was observed, but results of
       haematological, biochemical, and urine tests were comparable to controls. No
       treatment-related microscopic changes were seen, apart from slight centrolobular
       vacuolation in the liver (Gri73).
            In an unpublished oral study, under the auspices of the Pyrethrum Joint
       Venture, beagle dogs (n=2/sex/group) received pyrethrum extract (purity: 57.6%
       total pyrethrins) via the diet at dose levels equivalent to 0, 18, 30, 86, or 170
       mg/kg bw/day for males and 0, 19, 29, 94, or 200 mg/kg bw/day for females, for
       8 weeks. At the high dose, 1 male and both females died. Clinical signs observed
       at the 2 highest dose levels included inappetence, ataxia, tremors, and impaired
       limb function. Animals in the high-dose group had decreased body weight gains
       and food consumption, anaemia, alterations in electrolytes, and increased liver
       enzyme (ALAT and ASAT) activities. At 86 mg/kg bw/day, males showed
       decreased haemoglobin, haematocrit, and erythrocyte values compared to the
       controls. Liver weight increases occurred in both males and females at 30 mg/kg
       bw/day and higher and 29 mg/kg bw/day and higher, respectively. There were no
       treatment-related microscopic or macroscopic lesions at any dose level. The
       NOAEL was 18 mg/kg bw/day (Gol88c, Sch95).
            In another unpublished dog study, under the auspices of the Pyrethrum Joint
       Venture, beagles (n=4/sex/dose level) received pyrethrum extract (purity: 57.6%
       total pyrethrins) via the diet at dose levels equivalent to 0, 2.6, 14, or 66 mg
       pyrethrins/kg bw/day for males and 0, 2.8, 14, or 75 mg/kg bw/day for females
       for 52 weeks. No mortality was reported and no signs of toxicity observed in any
       dog at any dose level. Mean body weights of treated animals were similar to
       those of controls. Food consumption was lower in animals of the high- and mid-
       dose groups during the first 2 week only. Effects in the high-dose females were
       increased white blood cell counts, segmented neutrophil counts, and serum
       alanine aminotransferase (ALAT). In high-dose males, haemoglobin
       concentration, haematocrit, and erythrocyte counts were decreased and absolute
       and relative liver weights increased. Macroscopic and microscopic examination
       did not reveal treatment-related abnormalities. The NOAEL was 14 mg/kg
       bw/day, based on haematological and liver effects (Gol90a, Sch95).
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<pre>             A summary of short-term toxicity studies with pyrethrum is shown in Table 2.
Table 2 Summary of short-term toxicity studies for pyrethrum.
exposure species                 dose levels         exposure      critical effect          NOAEL               reference
route      (strain, number, sex)                     duration
inhalation rat                   0, 23 mg/m3         31-41 d, 30-  effects on white blood LOAEL: 23 mg/m3       Car50
           (Sherman;                                 60 min/d      cells, kidney
           12 males, 15 females)
           rat                   0, 38, 68, 230, 830 13 w, 5 d/w   anaemia                  38 mg/m3            New92,
           (Charles River ;      mg/m3                             effects on upper         LOAEL: 38 mg/m3     Sch95
            n=15/sex/group)                                        respiratory tract, lungs
           dog                   0, 562 mg/m3        4 d, 20 min/d anaemia                  LOAEL: 562 mg/m3    Lor72
           (n=5)
           dog                   0, 23 mg/m3         26 d, 30-60   none identified          23 mg/m3            Car50
           (n=3)                                     min/d
dermal     rabbit                0, 10 mg/kg bw      15 d          none identified          10 mg/kg bw         Gri73
           (n=15)
           rabbit                0, 100, 300, 1000 21 d            none identified          1000 mg/kg bw       Gol92,
           (New Zealand;         mg/kg bw                                                                       Sch95
            n=5/sex/group)
oral       rat                   0, 50 mg/kg bw      14 d          liver enlargement        LOAEL: 50 mg/kg bw Kim68
           (Sherman; n=6/
           group)
           rat                   0, 85, 200, 500     3w            liver enlargement        NOAEL: 200 mg/kg bw Spr73
           (Sprague-Dawley; mg/kg bw                               enzyme induction         LOEL: 85 mg/kg bw
           n=4/group)
           rat                   0 ,704 (males), 911 5 w           effects on ileum         LOAEL: 704 mg/kg bw Hun72
                                 (females) mg/kg bw
           rat                   0, 1200 (males),    13 w          effects on liver,        57 mg/kg bw         Gol88a,
           (Charles River CD; 1400 (females)                       kidneys, erythrocytes                        Sch95
           n=15/sex/group)        mg/kg bw
           mouse                 0, 1600 (males),    13 w          effects on liver         47 mg/kg bw         Gol88b,
           (Charles River CD-1; 1800 (females)                                                                  Sch95
           n=15/sex/group)       mg/kg bw
           dog                   0, 165 mg/kg bw     90 d          clinical signs           LOAEL: 165 mg/kg bw Gri73
           (beagle; n=6)
           dog                   0, 170 (males), 200 8 w           increased absolute liver NOAEL: 18 mg/kg bw Gol88c,
           (beagle; n=2/sex/     (females) mg/kg bw                weight                                       Sch95
           group)
           dog                   0, 66 (males), 75   52 w          effects on liver, white 14 mg/kg bw          Gol90a,
           (beagle; n=4/sex/     (females) mg/kg bw                blood cells; anaemia                         Sch95
           group)
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<pre>       Long-term toxicity and carcinogenicity
       Rats (n=12/sex/group) were fed pyrethrum extract via the diet at doses
       equivalent to 10, 50, and 250 mg total pyrethrins/kg bw/day for 2 years. No
       treatment-related effects were observed on mortality or growth of the animals.
       Microscopic examination revealed slight liver damage, characterised by bile duct
       proliferation and focal necrosis at the 2 highest dose levels. There was no
       evidence for the induction of treatment-related tumours. No further information
       was given. The NOAEL was 10 mg/kg bw (Cas80, FAO65, Leh65).
           In an unpublished toxicity and carcinogenicity study, under the auspices of
       the Pyrethrum Joint Venture, Charles River CD rats (n=60/sex/group) received
       diets containing pyrethrum extract (purity: 57.6% total pyrethrins) at dose levels
       equivalent to 0, 4, 43, or 130 mg pyrethrins/kg bw/day for males and 0, 5, 56, or
       170 mg/kg bw/day for females, for 104 weeks. No treatment-related mortality or
       signs of toxicity were observed. Animals in the high-dose group showed
       decreased body weights (7-10%) during the first 78 weeks of the study, together
       with a slight decrease in food consumption. No treatment-related
       ophthalmological abnormalities or changes in organ weights and haematology or
       urinanalysis parameters were found. Males in the high-dose group had
       substantially increased serum transaminase levels during the study. At the high-
       dose, the incidence of hepatocellular adenomas was statistically significantly
       increased in females, but no increased incidence of hepatocellular carcinomas
       was found. The incidence of hyperplasia of the thyroid was found to be enhanced
       in a dose-related fashion, but the increase was not statistically significant. At the
       2 highest dose levels, the incidences of follicular adenomas of the thyroid in
       males and females were higher than the upper range seen in historical controls. A
       statistically significantly increased incidence, compared with control animals,
       was only observed in high-dose females. No statistically significantly increased
       incidence of follicular carcinomas was observed at any dose level, compared
       with controls. Macroscopic examination of the skin showed a slight, dose-
       related, increased incidence of cystic lesions in males, which was not statistically
       significant. Microscopic examination revealed a statistically significantly higher
       incidence of keratoacanthomas in males at the high dose. The authors concluded
       that the increased incidences of liver and thyroid tumours and of
       keratoacanthomas of the skin were treatment-related effects, but threshold
       phenomena. Macroscopic or microscopic results of non-neoplastic lesions were
       not reported. The NOEL was 4 mg/kg bw/day, based on an increased incidence
       of follicular adenomas of the thyroid at higher dose levels (Gol90b, Sch95).
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<pre>           In another unpublished carcinogenicity study, under the auspices of the
       Pyrethrum Joint Venture, Charles River CD-1 mice (n=60/sex/group) received
       diets containing pyrethrum extract (purity: 57.6% total pyrethrins) at dose levels
       equivalent to 0, 14, 350, or 690 mg pyrethrins/kg bw/day for males and 0, 17,
       410, or 830 mg/kg bw/day for females, for 18 months. At the high dose, 1 male
       and 1 female animal died during the first week. No other treatment-related
       mortality occurred, and survival was similar in the control and treated groups.
       Animals in the high-dose group exhibited hyperactivity during the first week of
       the study only. No treatment-related effects on body weight or food consumption
       were found. Macroscopic examination showed increased absolute and relative
       liver weights and discoloured dark livers at the 2 highest dose levels.
       Microscopic examination revealed vacuolar fatty change in the livers at these
       doses. The incidence of nodules and masses in the lungs appeared to be slightly
       increased in high-dose animals. Microscopic examination showed statistically
       significantly increased incidences of alveolar bronchiolar adenomas in females at
       the high dose and of alveolar bronchiolar carcinomas in males at the mid- and
       high-dose levels, compared with control animals. The authors concluded that
       these tumours had a threshold exposure level and that the NOAEL of the study
       was 14 mg/kg bw/day (Gol90c, Sch95).
       Mutagenicity and genotoxicity
       In vitro tests:
       • Gene mutation assays. Pyrethrins did not induce reverse mutations in E. coli
           WP2 Try-, in a test without metabolic activation. Concentrations of
           pyrethrins tested were not given (Ash72). Tests for inverse mutations were
           negative in various S. typhimurium strains (TA98, TA100, TA1535, TA1537,
           TA1538) and in E. coli WP2hcr, in the presence or absence of metabolic
           activation by a rat liver microsomal S9 preparation (Mor83). In a later
           unpublished study, under auspices of the Pyrethrum Joint Venture, tests for
           reverse mutations in S. typhimurum TA98, TA100, TA1535, T1537, and
           TA1538 were negative at concentrations up to 8772 µg/plate (as total
           pyrethrum extract, containing 57.6% total pyrethrins), with and without
           metabolic activation (San89, Sch95).
       • Cytogenicity assays. In an unpublished study, under auspices of the
           Pyrethrum Joint Venture, pyrethrum extract (purity: 57.6% total pyrethrins)
           did not induce an increased incidence in the frequency of chromosomal
           aberrations in Chinese hamster ovary cells, in the presence or absence or
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<pre>            metabolic activation, at concentrations ranging from 0.005 to 0.32 µL/mL
            (Put89, Sch95).
       •    Other mutagenicity assays. In an unpublished study, under auspices of the
            Pyrethrum Joint Venture, pyrethrum extract (purity: 57.6% total pyrethrins)
            did not increase unscheduled DNA synthesis in rat primary hepatocytes at
            concentrations between 0.03 and 1µL/mL (Cur89, Sch95).
       The committee did not find data from in vivo genotoxicity tests on pyrethrum.
       Reproduction toxicity
       In a 2-generation reproduction toxicity study, rats (n=18) were given pyrethrum
       extract via the diet at a dose level equivalent to approximately 250 mg
       pyrethrins/kg bw/day, starting 3 weeks prior to first mating. After weaning the
       first litter, they were mated again. The only reported effect was significantly
       reduced body weights of F1 and F2 weanlings. This treatment did not result in
       effects on the reproductive performance of the parents (Wei66).
            In an unpublished 2-generation reproduction toxicity study, under auspices of
       the Pyrethrum Joint Venture, groups of 28 male and 28 female Charles River rats
       received diets containing pyrethrum extract (purity: 57.6% total pyrethrins) at
       doses equivalent to 0, 10, 100, or 300 mg pyrethrins/kg bw/day, for a minimum
       of 77 days before mating. The same number of weanlings from the F1b litters
       was treated for a minimum of 95 days before mating. For both parental groups,
       treatment was continued through gestation and lactation. No signs of toxicity or
       effects on body weight or food consumption were observed in parental animals
       of the F0 generation. However, parental animals of the F1 generation showed
       reduced body weights and reduced food consumption at the 2 highest doses. At
       these levels, body weights were also significantly reduced at birth and during
       lactation for F1 and F2 offspring of each sex. No other reproductive effects were
       observed. No treatment-related effects were observed on male and female
       fertility indices, gestation lengths, litter size, numbers of viable and stillborn
       pups, and pup survival and growth during lactation. The NOAEL for parental
       and reproductive toxicity was 10 mg/kg bw/day (Sch89, Sch95).
       In a developmental toxicity study, pregnant Wistar rats (n=20/group) received
       pyrethrum (purity: 20% total pyrethrins) in corn oil by gavage at doses of 10, 20,
       or 30 mg pyrethrins/kg bw/day, on days 6-15 of gestation. On day 22 of
       pregnancy, the dams were killed and subjected to macroscopic examination.
       Fetuses were weighed and examined for viability and for external, visceral, and
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<pre>       skeletal abnormalities. No mortality or signs of toxicity were noted. Maternal
       body weight gain did not significantly differ among treated and control groups.
       There was a statistically significant increase in the proportion of resorptions in
       all dose groups, without any significant difference in the mean number of
       corpora lutea, total implants, live fetuses per dam, or fetal weight. According to
       the authors, this difference was due to the unusual low incidence of resorptions in
       the control group (3% vs. 6% normal). The proportion of fetuses with skeletal
       abnormalities was significantly increased in the mid- and high-dose groups, but
       no difference was seen in the incidence of skeletal defects such as extra ribs,
       missing or fused sternebrae, or delayed ossification of sternebrae. The incidence
       of external or visceral defects in the treated groups was not significantly greater
       than in the control group. In this study, 30 mg/kg bw, the highest dose tested, was
       a NOAEL for maternal and developmental toxicity (Khe82).
            In another, unpublished, developmental toxicity study, under auspices of the
       Pyrethrum Joint Venture, pregnant Charles River rats (n=25/group) received
       pyrethrum extract (purity: 57.6% total pyrethrins) at doses of 0, 5, 25, or 75 mg
       pyrethrins/kg bw/day by gavage, on days 6-15 of gestation. On day 20 of
       gestation, fetuses were removed by Caesarean section. No mortality, treatment-
       related signs of toxicity, or changes in body weight gains were observed in any of
       the animals in any of the groups. Maternal ovarian and uterine examination did
       not show abnormalities, and no treatment-related changes were observed in fetal
       external examination and in fetal internal soft tissue and skeletal examinations at
       any dose tested. The NOAEL for both maternal and developmental toxicity was
       75 mg/kg bw/day, the highest level tested (Cas95a, Sch87a).
            In a developmental study, pregnant rabbits (n=9/group) were given daily oral
       doses of pyrethrum extract at doses of 0 and 90 mg pyrethrins/kg bw/day, on
       days 8-16 of gestation. Of 4 rabbits per dose level, pups were delivered by
       Caesarean section on day 30, and the remainder were delivered by normal
       parturition. No effects were noted on the number and weight of fetuses,
       implantation sites, or on gross external and internal examination. Two control
       pups and 1 treated pup had a deformed front paw, and 1 treated pup had a missing
       caudal vertebrae. It was concluded that pyrethrum did not induce teratogenic
       effects in rabbits (Wei66).
            In an unpublished developmental study, under auspices of the Pyrethrum
       Joint Venture, pregnant New Zealand rabbits (n=16/group) were given pyrethrum
       extract (purity: 57.6% total pyrethrins) at doses of 0, 25, 100, or 250 mg
       pyrethrins/kg bw/day by gavage, on days 7-19 of gestation. On day 29 of
       gestation, fetuses were removed by Caesarean section. One doe at the high dose
       aborted on day 28 of gestation. Signs of toxicity included excessive salivation,
138-23 Pyrethrum (pyrethrins)
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<pre>       arched head, and laboured breathing at the high dose on days 18 and 19 of
       gestation. Reduced body weights were observed in does at the 2 highest dose
       levels. Macroscopic and microscopic examination did not show changes related
       to treatment in any of the animals in any of the groups. No abnormalities were
       found in mean numbers of total implantations, post-implantation losses, and
       viable fetuses, and in fetal body weights or sex distribution. No treatment-related
       fetal malformations were observed. The NOAEL for maternal toxicity was 25
       mg/kg bw/day, and the NOAEL for developmental toxicity was 250 mg/kg
       bw/day, the highest dose tested (Sch87b, Sch95).
7      Existing exposure limits
       The current administrative occupational exposure limit (MAC) for pyrethrum in
       the Netherlands is 5 mg/m3, 8-hour TWA.
            Existing occupational exposure limits for pyrethrum in some European
       countries and in the USA are summarised in
       Annex II.
8      Assessment of health hazard
       The health hazard assessment of pyrethrum is based to a large extent on a
       toxicology review issued by the FAO/WHO Joint Meeting on Pesticide Residues
       for recommendation of an acceptable daily intake (ADI) and a toxicology review
       published in ‘Pyrethrum Flowers’ (Cas95a). Toxicity data presented in these
       reviews are obtained mainly from unpublished studies, conducted for registration
       purposes and sponsored by a consortium of companies, manufacturing or
       marketing the product.
            The most likely routes of exposure of workers to pyrethrum are inhalation of
       aerosols or direct contact with the pyrethrum extract or a formulation. No data is
       available of the percentage of uptake of the compound through the lungs or
       through the skin. In view of the low acute and short-term dermal toxicity, the
       committee concludes that skin penetration is low. This is in accordance with the
       negligible absorption of the synthetic pyrethroid cypermethrin, following
       application on the skin of a human volunteer (Ead88). Following oral
       administration, the extent of absorption of pyrethrins I and II ranges from 70 to
       close to 100%. Peak levels of pyrethrins or metabolites in blood were reached
       between 5 and 8 hours after administration, and the half-life of elimination was
       approximately 6 hours. Pyrethrins are rapidly and extensively metabolised by rat
       and mouse liver microsomes. Major metabolic pathways involve oxidation of the
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<pre>       double bond and/or methyl groups, resulting in about 63 metabolites for
       pyrethrins I and II. Hydrolysis of the cyclopropane ester bond, found with
       synthetic pyrethroids, has not been demonstrated. There is no evidence of
       accumulation of the compound in any of the tissues.
           Most reported human health effects associated with exposure to pyrethrum
       were allergic dermatitis and asthma. These allergic reactions are believed to be
       due to impurities no longer present in the currently purified extracts. However,
       recently, death has been reported in 2 asthmatic female subjects, allegedly
       exposed to pyrethrum extracts of unknown purity in dog shampoo. No cases of
       inadvertent acute poisoning of spray-men or factory workers have been
       documented. Accidental oral or dermal exposure to high doses of pyrethrins can
       cause a temporary numbness of the tongue and lips.
           In experimental animals, pyrethrum extract was only minimally irritating to
       the skin and eyes and showed no potential for skin sensitisation. Based on the
       acute lethal toxicity studies with purified pyrethrum extract (57.6% total
       pyrethrins), the committee considers the extract as unlikely to present an acute
       health hazard. On the basis of signs of poisoning in mammals, the nervous
       system is the critical organ following acute exposure. The oral NOAEL for acute
       neurological disorders and behavioural effects was 20 mg/kg bw.
           In a 13-week inhalation toxicity study in rats, critical effects of exposure to a
       liquid aerosol of pyrethrum extract (57.6% pyrethrins) were anaemia and
       microscopic abnormalities in the upper respiratory tract and the lungs. The
       NOAELs for systemic and local effects were 38 mg/m3 and (possibly) <38
       mg/m3, respectively.
           Dermal application of pyrethrum extract (57.6% total pyrethrins) at doses up
       to 1000 mg/kg bw/day for 21 days caused no toxicity in rabbits. In short-term
       oral toxicity studies in rats, liver enlargement (NOAEL: 200 mg/kg bw/day) and
       hepatic enzyme induction (LOAEL: 85 mg/kg bw/day) were found in a 3-week
       study and effects on the liver, the kidneys, and anaemia in a 13-week study
       (NOAEL: 57 mg/kg bw/day). In mice, effects on the liver were observed in a
       13-week oral study (NOAEL: 47 mg/kg bw/day) and in dogs, effects on the liver
       and anaemia in a 52-week oral study (NOAEL: 14 mg/kg bw/day).
           In a 2-year oral toxicity and carcinogenicity study in rats, with dose levels of
       4-5, 43-56, and 170-250 mg/kg bw/day, a dose-related increased incidence of
       follicular adenomas of the thyroid was found in both sexes. The incidence was
       statistically significantly increased compared with the control group in the high-
       dose females only. High-dose females also showed a statistically significantly
       increased incidence of hepatocellular adenomas and high-dose males a
       statistically significantly increased incidence of benign skin tumours. The only
138-25 Pyrethrum (pyrethrins)
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<pre>       observed non-neoplastic effect was an increase in the activity of serum
       transaminases in high-dose males, indicating liver injury. In an 18-month oral
       study in mice, with dose levels of 14-17, 350-410, and 690-830 mg/kg bw/day, a
       statistically significantly increased incidence of alveolar bronchial adenomas
       was found in high-dose females and of alveolar bronchial carcinomas in males at
       the 2 highest dose levels. Non-neoplastic liver changes were seen in both sexes at
       the 2 highest dose levels. Pyrethrum extracts did not induce gene mutations,
       cytogenetic effects, or unscheduled DNA synthesis in in vitro assays, in the
       presence or absence of a metabolic activation system. The committee concluded
       that pyrethrins have no genotoxic or mutagenic potential, but no in vivo tests
       have been reported. In view of the absence of genotoxicity or mutagenicity of the
       pyrethrum extract and the stimulatory effect of pyrethrins on liver metabolism, as
       shown by the induction of cytochrome P450 enzymes in rats, the committee is of
       the opinion that the carcinogenicity in rats and mice is induced through a non-
       genotoxic mechanism, for which a threshold exposure level exists.
           In 2-generation reproduction toxicity studies in rats, the only reported effects
       were treatment-related reduced body weights of F0 parental animals and of pups
       at birth and during lactation of the F1 and F2 offspring. The NOAEL for parental
       and reproduction toxicity was 10 mg/kg bw/day. In two developmental toxicity
       studies in rats, no maternal or developmental toxicity was observed up to the
       highest doses tested (30 and 75 mg/kg bw/day, respectively). In rabbits, the
       NOAEL for maternal toxicity was 25 mg/kg bw/day and for developmental
       toxicity 250 mg/kg/day, the highest dose tested.
           The committee takes the 13-week inhalation study in rats, with a NOAEL for
       systemic effects of 38 mg/m3 as a starting point in deriving a health-based
       recommended occupational exposure limit (HBROEL). For the extrapolation to a
       HBROEL, the committee establishes an overall assessment factor of 27. This
       factor covers the following aspects: intra- and interspecies variation and
       differences between experimental conditions and the exposure pattern of the
       worker. Thus, applying this factor of 27 and the preferred-value approach, a
       health-based occupational exposure limit of 1 mg/m3 is recommended for
       pyrethrum. This HBROEL will protect workers from respiratory tract irritation
       as well and has a sufficient margin of safety concerning the effects observed in
       the 2-year oral rat study.
       The committee recommends a health-based occupational exposure limit for
       pyrethrum of 1 mg/m3, as the inhalable fraction, as an 8-hour time-weighed
       average (TWA). The committee notes that this value holds for pyrethrum purified
       from sensitising lactones.
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<pre>            Although quantitative data on skin absorption are lacking, acute lethal
       toxicity data do not suggest significant skin absorption*. Therefore, the
       committee does not recommend a skin notation.
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<pre>Wei66  Weir RJ. Reproduction study. Rats neopynamin and pyrethrin. Falls Church VA, USA: Hazleton
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Wes94  Wester RC, Bucks DAW, Maibach HI. Human in vivo percutaneous absorption of pyrethrin and
       piperonyl butoxide. Food Chem Toxicol 1994; 32: 51-3.
Zuc65  Zucker A. Investigation on purified pyrethrum extracts. Ann Allergy 1965; 23: 335-9.
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<pre>       Annex I
       Figure 1 Metabolism of pyrethrin I and II in orally treated rats (from Cas95b).
138-33 Pyrethrum (pyrethrins)
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<pre>              Annex II
Occupational exposure limits for pyrethrum in various countries.
country                                occupational               time-weighted       type of                notea    referenceb
- organisation                         exposure limit             average             exposure limit
                                       ppm         mg/m3
the Netherlands
- Ministry of Social Affairs and       -           5              8h                  administrative                  SZW04
Employment
Germany
- AGS                                  -           5c             8h                                                  TRG04
                                       -           20c            15 min
- DFG MAK-Kommission                   -           5c             8h                                         sens     DFG04
                                       -           10c            15 mind
Great-Britain
- HSE                                  -           5              8h                  OES                             HSE02
                                       -           10             15 min
Sweden                                 -           -                                                                  Swe00
Denmark                                -           5              8h                                                  Arb02
USA
- ACGIH                                -           5              8h                  TLV                    A4e      ACG04b
- OSHA                                 -           5              8h                  PEL                             ACG04a
- NIOSH                                -           5              10 h                REL                             ACG04a
European Union
- SCOEL                                -           5f             8h                  ILVg                            EC04
a
     S = skin notation; which means that skin absorption may contribute considerably to body burden; sens = substance can
     cause sensitisation.
b
     Reference to the most recent official publication of occupational exposure limits.
c
     Measured as the inhalable fraction of the aerosol.
d
     Maximum number per shift: 4, with a minimum interval between peaks of 1 hour.
e
     Classified in carcinogenicity category A4, i.e., not classifiable as a human carcinogen: agents which cause concern that
     they could be carcinogenic for humans but which cannot be assessed conclusively because of lack of data. In vitro or
     animal data do not provide indications of carcinogenicity which are sufficient to classify the agent in one of the other
     categories.
f
     In January 2003, SCOEL (SCOEL/SUM/95 final) recommended an occupational exposure limit for pyrethrum (purified
     from sensitising lactones) of 1 mg/m3.
g
     Listed among compounds for which OELs are already included in Commission Directives.
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