<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>Monocrotophos
(CAS No: 6923-22-4)
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/073, The Hague, 22 september 2003
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<pre>Preferred citation:
Health Council of the Netherlands: Committee on Updating of Occupational
Exposure Limits. Monocrotophos; Health-based Reassessment of Administrative
Occupational Exposure Limits. The Hague: Health Council of the Netherlands,
2003; 2000/15OSH/073.
all rights reserved
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<pre>1     Introduction
      The present document contains the assessment of the health hazard of
      monocrotophos 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 prepared by JAGM van Raaij, Ph.D. and WK de Raat, Ph.D.
      (OpdenKamp Registration & Notification, Zeist, the Netherlands) and J Krüse,
      Ph.D. (Kinetox, Vleuten, the Netherlands).*
          The evaluation of the toxicity of monocrotophos has been based on reviews
      published in the ‘Handbook of pesticide toxicology’ (Gal91) and by the
      American Conference of Governmental Industrial Hygienists (ACG99). Where
      relevant, the original publications were reviewed and evaluated as will be
      indicated in the text. In addition, in December 1999, literature was searched in
      the on-line databases Toxline, Medline, Chemical Abstracts, covering the period
      of 1965-1966 until December 1999, and using the following key words:
      monocrotophos and 6923-22-4. Data from unpublished studies were generally
      not taken into account. Exceptions were made for studies that were summarised
      and evaluated by international bodies such as the Food and Agricultural
      Organization/World Health Organization (FAO/WHO: Joint Meeting of the FAO
      Panel of Experts on Pesticides Residues on Food and the Environment and the
      WHO Expert Group on Pesticides Residues - JMPR) (FAO92, FAO94, FAO96).
      Use was also made of reviews prepared by the Health, Safety and Environment
      Division, Shell, The Hague, the Netherlands (SIP85) and the Crop Protection
      Division, Ciba-Geigy Ltd, Basel, Switzerland (Skr94).
          In October 2002, the President of the Health Council released a draft of the
      document for public review. Comments were received from the following
      individuals and organisations: J Soave (Health and Safety Executive, London,
      England).
          An additional search in Toxline and Medline in April 2003 did not result in
      information changing the committee’s conclusions.
*      Current address: OpdenKamp Registration & Notification, Zeist, the Netherlands.
073-3 Monocrotophos
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<pre>2     Identity
      name                   :    monocrotophos
      synonyms               :    phosphoric acid, dimethyl [1-methyl-3-(methylamino)-3-oxo-1-propenyl] ester;
                                  (E)-phosphoric acid dimethyl ester, ester with 3-hydroxy-N-methylcrotonamide;
                                  3-(dimethoxyphosphinyloxy)-N-methyl-cis-crotonamide; dimethyl 2-methylcar-
                                  bamoyl-1-methylvinyl phosphate, Azodrin, Nuvacron
      molecular formula      :    C7H14NO5P
      structural formula     :
      CAS number             :    6923-22-4
3     Physical and chemical properties
      molecular weight        :   223.2
      boiling point           :   At 0.07 Pa:125oC
      melting point           :   54-55oC
      vapour pressure         :   3 x 10-4 Pa
      solubility in water     :   miscible
      Log Poctanol/water      :   -0.22
      conversion factors      :   not applicable
      Data from ACG99, Gal91, Rob99, Tom97.
      The pure compound consists of colourless hygroscopic crystals. The commercial
      product is a reddish-brown to dark brown clear viscous liquid with a mild ester
      odour, which eventually forms a semisolid to solid mass through crystallisation
      (commercial product). The compound is unstable in low molecular weight
      alcohols and glycols. It is stable in ketones and higher molecular weight alcohols
      and glycols and when stored in glass and polyethylene containers (Gal91). It is
      relatively stable at acidic and neutral pH values, but it is hydrolysed in alkaline
      solutions (Rob99).
073-4 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>4     Uses
      Monocrotophos is a systemic insecticide and acaricide belonging to the vinyl
      phosphate group. It controls pests on a variety of crops, such as cotton, rice, and
      sugarcane. It is used to control a wide spectrum of chewing and sucking insects
      and also mites (ACG99, Bur94).
            According to the database of the Dutch Pesticide Authorisation Board
      (CTB)*, monocrotophos is at present not registered for its use as an active
      ingredient in pesticides in the Netherlands. In the USA, monocrotophos as an
      active ingredient is no longer contained in any registered product, and, thus, the
      Office of Pesticide Programs of the US Environmental Protection Agency has
      characterised monocrotophos as ‘cancelled’ in its Pesticide Registration Status
      (EPA98) implying that no toxicological review for a reregistration eligibility
      decision will be prepared.
5     Biotransformation and kinetics
      Human data
      In a dermal absorption study,14C-labelled monocrotophos was applied on the
      forearms of 6 human volunteers in a quantity of 4 µg/cm2 .The material remained
      non-occluded on the skin for 24 hours. After 5 days, 15% of the radioactivity
      administered was excreted in the urine. The maximum excretion rate was at
      24-48 hour after the start of application and amounted on average 0.18% of the
      applied dermal dose per hour, from which an absorption rate was calculated of
      7.3 ng/cm2/hour. However, skin absorption was reported to be incomplete
      because much of the applied compound was lost from the skin surface by
      washing, evaporation, or the gradual exfoliation of outer layers of the stratum
      corneum (Fel74). It was also shown that 37% of a 14C-labelled intravenous dose
      of 1 microCurie was excreted in the urine within 24 hours and 68% within 120
      hours. The half-life of excretion was 20 h (Fel74).
            In 2 field studies, the absorption of monocrotophos into the body during
      spraying was assessed by measurement of the concentration of the metabolite
      dimethyl phosphate (DMP) in urine of field workers. Observations during
      spraying showed the presence of skin exposure, but inhalation of spray mist was
      negligible. Urinary levels ranging from 0.02 to 1.9 mg monocrotophos
*      at: http://www.ctb-wageningen.nl/geel.html.
073-5 Monocrotophos
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<pre>      equivalents/24 hour were reported in one study (Kum86) and from 0.6 to 19 mg
      over a 3-day exposure period in the second study (Sit90). The levels
      corresponded to maximal tentative oral doses of 4.2 mg (Kum86) and 42 mg
      (Sit90), respectively. In the latter study, the average half-life of elimination of
      DMP from the body was 18 h.
      Animal data
      In rabbits, dermal absorption was demonstrated by application of unlabelled
      material to the midshoulder area, using the inhibition of blood cholinesterase as a
      measure for absorption (Fos71). The metabolic fate of monocrotophos has been
      investigated in a variety of animal species, such as rats, rabbits, and goats. Rats
      that received an oral dose of 1.0 mg/kg bw [32P]-monocrotophos excreted 67%
      and 5% of the radioactivity in urine and faeces, respectively (Men65). Similar
      percentages were found following oral administration of N-[14C-methyl]-
      monocrotophos (Men65). In a later study, Wistar albino rats, given a single oral
      dose of 2 mg/kg bw of [3-14C]-monocrotophos, excreted 83%, 3%, and 6% of the
      administered dose in the urine, in the faeces, and as expired 14CO2, respectively,
      within 96 hours. A very large portion (>90%) of the radiocarbon excreted within
      96 hours was produced during the first 24-hour period following administration
      (Lee87). The main mechanism of biotransformation of monocrotophos was
      hydrolysis of the P-O vinyl linkage, to give dimethyl phosphate (DMP) and N-
      methylacetoacetamide as major metabolites. The latter was further
      biotransformed into metabolites 3-hydroxy-N-butyramide and 14CO2 (Lee87).
      Another metabolic route is N-demethylation giving the N-hydroxymethyl
      derivative and O-dealkylation giving des-O-methylmonocrotophos (Bul66,
      Men65, Rob99). N-demethylated metabolites are highly active inhibitors of
      acetylcholinesterase, thus having toxicological significance (Rob99). Following
      an intraperitoneal dose of 5 mg/kg bw of 32P-monocrotophos, 40% of the dose
      was excreted in the urine within 24 hours as DMP, 20% as N-
      hydroxymethylmonocrotophos, and 10% as des-O-methylmonocrotophos
      (Bul66).
          In summary, the mechanisms involved in the absorption, distribution,
      metabolism, and elimination of monocrotophos seem to be largely species
      independent. In the initial biotransformation, 3 different metabolic reactions
      occur: hydroxylation of the N-methyl group, demethylation of the O- or N-
      methyl group, and hydrolysis of the phosphate-vinyl linkage. Excretion is
      predominantly in the urine, typically 70 to 90 % of the dose, and usually less than
073-6 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>      10% is voided with the faeces and expired as CO2. Monocrotophos may therefore
      contribute to the carbon pool and may thus, via de novo synthesis of endogenous
      compound, lead to non-monocrotophos-related 14C-residues in tissues. The
      highest concentrations of residues have been found in the liver and the kidneys
      (Muc94).
6     Effects and mechanism of action
      Human data
      Cases of poisoning with monocrotophos have occurred following gross spillage
      of an emulsifiable concentrate formulation, unintended ingestion, or by suicidal
      intent. A 19-year-old male splashed about 570 mL of an emulsifiable concentrate
      formulation on his bare chest and arms, washed it off with water, and continued
      working. Symptoms, becoming manifest 28 hours after exposure, were muscular
      weakness, blurred vision, chest pain, and blackouts. Clinical recovery, after
      treatment, occurred within 48 hours. Whole blood cholinesterase (ChE) activity
      was inhibited by 90% 1.5 days after exposure and returned slowly reaching to
      normal values 8 weeks after the incident (Sim69). Several cases of poisoning
      with monocrotophos have been described in Sri Lanka. In one patient, dermal
      exposure occurred due to spraying while in the second case, poisoning was due
      to ingestion with a suicidal intent. Patients showed neurological effects
      manifested as muscle weakness in those innervated by the cranial nerves,
      paralysis of cranial nerves, and respiratory difficulty. The times to onset and the
      durations of the effects were 1 to <4 and 16 to 18 days, respectively (Sen87). A
      third case in Sri Lanka reported respiratory distress and weakness of limbs in a
      man after accidental dermal exposure to a 60% monocrotophos concentrate. He
      recovered 16 days after the exposure. However, his plasma ChE levels were still
      within 37.5-50% of normal on the 20th day (Pei88). The 3 cases did not yield
      evidence of nerve degeneration. In a review of 20 human cases of poisoning with
      monocrotophos (including the 3 mentioned above), cases of delayed neuropathy,
      which may lead to irreversible nerve damage, have not been reported (Sch94).
          Several field studies were carried out to assess the health implications
      following application of monocrotophos. Monocrotophos (Nuvacron) was
      applied to cotton by aerial spraying and cholinesterase (ChE) activities were
      measured in the blood of pilots, engineers, and field workers. Whole blood ChE
      activities in some cases were inhibited by more than 60%, but no compound-
      related clinical signs or symptoms were observed (Rao79, Rao80, Ull79). Two
073-7 Monocrotophos
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<pre>      studies have been reported in workers following application of monocrotophos
      (Azodrin) to cotton and rice, respectively. Application to cotton was carried out
      by hand-held ULV (ultra low volume application), using a formulation of 20%
      monocrotophos in a mixture of a glycol and a glycol ether. On average 4 or 10 L
      per person per day was sprayed on one or 2 consecutive days. Absorption of
      monocrotophos was confirmed by the presence in the urine of the metabolite
      DMP. No clinical signs or symptoms of intoxication or significant inhibition of
      acetylcholinesterase (AChE) activity in red blood cells were observed. However,
      significant inhibition of plasma ChE up to 59% of pre-exposure value was
      measured. Below a 24-hour urinary DMP excretion of 650 µg monocrotophos
      equivalents, no significant whole blood, plasma, or red blood cell ChE inhibition
      was observed. Furthermore, at 24-hour urinary DMP levels up to 1.9 mg
      monocrotophos equivalents, corresponding to a tentative oral dose of 4.2 mg
      monocrotophos (0.06 mg/kg bw), no significant inhibition of red blood cell ChE
      activity occurred (Kum86).
          In another report, 21 applicators had sprayed Azodrin on rice cultures for 3
      consecutive days. Average ChE activities at the end of the third day were
      inhibited by 22% of pre-exposure value in whole blood and by 41% in plasma.
      However, average red blood cell AChE activity had not been affected. The
      median total amount of DMP excretion in the urine of the 21 sprayers
      corresponded to a tentative oral dose of 11 mg monocrotophos, i.e., 3.7 mg (0.05
      mg/kg bw/day) (Sit90).
          In a study with volunteers, monocrotophos (in capsules) was given daily for
      28 days to 3 groups of 6 people. Doses were 0, 3.6, and 5.7 µg/kg bw. No signs
      of poisoning were recorded, and red blood cell AChE and liver enzyme activities
      remained unaffected. Plasma ChE activity in the low-dose group decreased
      slowly during the first 18 days, reaching a mean inhibition of 15%. During the
      following 10 days of dosing, no further decrease in the activity occurred. In the
      high-dose group, a mean plasma ChE inhibition of 24% (range 12-29%) was
      reached after 28 days, and a tendency toward a steady state started to develop.
      Two weeks after cessation of exposure, plasma ChE activity had not yet returned
      to baseline levels. In a previous pilot study, a group of 8 subjects received 15
      µg/kg bw/day for 8 days and then, after a 3-day pause, for 4 more days. Plasma
      ChE was inhibited by 51%, but even then, no effect on red blood cell AChE was
      observed. In the absence of effects on red blood cell AChE, 5.7 µg/kg bw is the
      NOAEL for humans in this study (Ver77).
073-8 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>              Animal data
              Irritation and sensitisation
              A 4-hour occlusive irritation test in rabbits revealed that monocrotophos was
              slightly irritating to the skin. In rabbits, monocrotophos was also found to be
              slightly irritating to the eyes (Skr94). Monocrotophos had no sensitising
              properties in guinea pigs (Skr94).
              Acute toxicity
              Results of some acute lethal toxicity tests are summarised in Table 1.
Table 1 Summary of some acute lethal toxicity studies for monocrotophos in mammals.
exposure route (duration) vehiculum               species (strain)    sex           LC50/LD50    reference
           a                                                                                3
inhalation    (4 h)                               rat                 not given     63 mg/m      NIO02
             (1 h)b                               rat                 not given     80 mg/m3     Sac73
                  b                                                                         3
             (1 h)                                rat                 not given     94 mg/m      Sac73
             (1 h)c                               rat                 not given     169 mg/m3    New78
intratracheal                                     rat                 not given     4.5 mg/kg bw NIO02
dermal                     xylene                 rat (Sherman)       male          126 mg/kg bw Gai69
                           xylene                 rat (Sherman)       female        112 mg/kg bw Gai69
                           propylene glycol       rat                 not given     135 mg/kg bw New78
                           none                   rabbit              not given     709 mg/kg bw She63
                           water                  rabbit              not given     420 mg/kg bw She64
                           water                  rabbit              not given     336 mg/kg bw Hur69
                           DMSO                   rabbit              not given     223 mg/kg bw She64
                           xylene                 rabbit              not given     149 mg/kg bw She64
oral                       peanut oil             rat (Sherman)       male          18 mg/kg bw  Gai69
                           peanut oil             rat (Sherman)       female        20 mg/kg bw  Gai69
                           propylene glycol       rat                 male          35 mg/kg bw  New78
                           propylene glycol       rat                 female        20 mg/kg bw  New78
                           water                  rat                 not given     5.7 mg/kg bw Bro70
                           peanut oil             rat                 not given     13 mg/kg bw  She63
                                                  rat                 not given     8 mg/kg bw   NIO02
                           peanut oil             mouse               not given     10 mg/kg bw  She63
                                                  mouse               not given     15 mg/kg bw  NIO02
073-9         Monocrotophos
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<pre>                       aqueous                rabbit           not given   45 mg/kg bw         Hur70
                       carboxymethylcellulose
a
   Aerosols.
b
   Droplet size <7 µm.
c
   Droplet size <3 µm.
           When rats (n=10/sex/group) were exposed to air saturated with vapours from
           technical monocrotophos (purity: not given), for 1 hour, no mortality, clinical
           signs, body or organ weight changes, or gross or microscopic abnormalities were
           observed (observation time: 14 days) (New64, She95a).
                Occlusive 24-hour dermal exposure of rats during 24 hours, using different
           vehicles and monocrotophos formulations, resulted in LD50's between 135 and
           1028 mg/kg bw (Skr94). Semi-occlusive exposure of rats yielded an LD50 value
           >2000 mg/kg bw for the active ingredient and a value >500 mg/kg bw for
           Nuvacron 40 SCW formulation (Skr94).
                Several acute oral toxicity studies were specifically focussed on the possible
           neurotoxic effects.
                The effect of monocrotophos on brain AChE, red blood cell AChE, and
           serum ChE activity was reported in several studies. Inhibition of brain AChE
           (87%), red blood cell AChE (72%), and serum ChE (80%) activity was observed
           in female Crl:CD rats, 2 hours after treatment with a single oral dose of 3 mg/kg
           bw. Recovery of inhibited cholinesterases to approximately 30% inhibition
           occurred within 24 hours after treatment. In the same study, rats were given
           single oral doses of 0, 0.01, 0.03, 0.1, 0.3, or 1.0 mg/kg bw by gavage. Brain
           AChE, red blood cell AChE, and plasma ChE activities were equally sensitive to
           inhibition by moncrotophos. The NOAEL for this effect was 0.1 mg/kg bw,
           based on >20% inhibition of brain AChE activity at higher dose levels (Pot94).
           Male and female Wistar rats, treated with monocrotophos at a dose of 0.96
           mg/kg bw by oral intubation, showed decreased red blood cell AChE activity by
           12.8 and 16.2% in males and females, respectively. Brain Mg2+-ATP-ase
           activities were significantly inhibited by 14% in males. Brain Ca2+-ATPases were
           inhibited about 40% in both males and females (Sid93). The enzyme kinetics of
           the inhibition of brain AChE activity in rats was studied following a single oral
           LD50 dose of 20 mg/kg bw monocrotophos. Both the degree of AChE inhibition
           and the enzyme kinetics were determined 1, 3, 5, or 7 days after treatment. AChE
           activity showed maximum inhibition on day 1, with a significant recovery at day
           3. However, the activity was inhibited again at day 5, followed by a recovery at
           day 7. Enzyme kinetics of the inhibition of brain AChE differed between in vivo
073-10     Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>       and in vitro studies, demonstrating that the toxic properties based on in vitro
       studies may not be extrapolated to in vivo studies (Rao92).
           The acute behavioural toxicity of monocrotophos was assessed in Albino
       mice and Wistar rats (n=5/group), given doses of 1, 2, and 4 mg/kg bw by
       intragastric intubation. Observed effects at all dose levels were reduced
       locomotor activity, hypothermia, and reduced ability of trained mice to ride on a
       rotating rod (Man95). In an acute neurotoxicity test, 14 adult hens received 2 oral
       doses of 6.7 mg/kg bw monocrotophos with an interval of 3 weeks. The hens
       were pre-treated with atropine sulphate and pralidoxime chloride to protect from
       the acute effects of monocrotophos. Nine hens did not survive the treatment. In
       the others, no signs of delayed neurotoxicity were detected. Histological
       examination did not reveal neuropathological changes. All hens treated with a
       positive control (tri-o-tolyl phosphate) developed ataxia and had lesions in the
       sciatic nerve and spinal cord (Owe78).
           Other published acute toxicity studies were focussed on biochemical effects
       of the compound. Hepatic and extrahepatic glutathione (GSH) depletion and
       glutathione-S-transferase (GST) inhibition were observed in different tissues of 6
       male albino rats, given a single oral dose of 0.96 mg/kg bw monocrotophos
       (Sid90). Adult male albino rats (n=6/group), given a single oral dose of 2 mg/kg
       bw monocrotophos, developed hyperglycaemia and showed a decrease of liver
       glycogen content 12 hours after administration. A reversed effect was found in
       the next 12 hours: a hypoglycaemia developed accompanied by an increase of
       glycogen content in the liver. No changes with respect to pre-exposure values
       were reported for lactic acid, pyruvic acid and protein concentrations in the liver
       (Sha98). Dose-related decreased cytochrome P450 levels have been observed in
       the liver, lung, kidney, and brain of rats, treated with single oral doses of
       monocrotophos (0, 0.96, 1.23, 3 mg/kg bw). Cardiac and splenic cytochrome
       P450 concentrations were, however, increased. This study suggested organ
       specificity in modulating the microsomal cytochrome P450 content of hepatic
       and extrahepatic tissue (Sid92).
       Subacute and subchronic toxicity
       Monocrotophos (60% w/v formulation) applied to the intact or abraded, occluded
       skin of rabbits, at doses of 20 and 40 mg/kg bw/day, 6 hours/day, 5 days/week,
       for 3 weeks, was mildly irritating. No clinical signs of toxicity were recorded.
       Cholinesterase activities were not determined (Doy65).
073-11 Monocrotophos
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<pre>           In a 4-week dermal study in rats, technical monocrotophos was applied at
       doses of 0.2, 1, 10, and 100 mg/kg bw/day under semi-occlusive dressing, a
       NOEL of 1 mg/kg bw was established. This NOEL was based on inhibition of
       red blood cell and brain AChE and cholinergic signs of toxicity at 10 mg/kg bw
       and above (no more data presented) (Hag92).
       The behavioural tolerance to monocrotophos was studied in male Wistar rats
       following oral administration of monocrotophos at an initial dose of 9 mg/kg bw,
       followed by 16 daily doses of 6 mg/kg bw. Observed signs of toxicity were
       tremors, sweating, salivation, and uncoordinated movements. The animals
       developed behavioural tolerance, which was evident by the disappearance of
       signs while dosing continued. Brain AChE and butyryl (plasma) ChE activities
       were inhibited and brain acetylcholine content elevated up to day 7, followed by
       recovery towards normal activities. ChE activities correlated well with the
       appearance and disappearance of the mainly cholinergic signs. The authors
       concluded that behavioural tolerance to monocrotophos developed despite
       changes in brain AChE and acetylcholine levels (Swa92).
           Wistar rats (n=8/sex/group) were fed technical monocrotophos at doses
       equivalent to 0, 0.005, 0.025, 0.05, 0.5, or 5 mg/kg bw/day, for 5 weeks. Food
       and body weight gain were reduced at the 2 highest dose levels and (not
       specified) clinical signs of intoxication were observed at the top dose.
       Histological changes in the liver and the kidneys were observed at the highest
       dose only. Brain and red blood cell AChE, and plasma ChE activity were
       inhibited by more than 20-30% at dose levels starting at 0.025 mg/kg bw/day and
       0.05 mg/kg bw, respectively. The NOAEL in this 5-week oral rat study was
       0.005 mg/kg bw (McA79).
           In an experiment to study the reversibility of ChE activity, technical
       monocrotophos (purity: 78.8%) was fed to 5-week-old Wistar rats (n=30/sex/
       group; controls: n=60/sex) at dose levels equivalent to 0, 0.005, 0.0125, 0.025,
       0.1, and 0.4 mg/kg bw/day. The animals in each dose group were divided into 3
       subgroups. Rats in subgroup A were treated for 8 weeks, rats in subgroup B for
       13 weeks, and rats in subgroup C were treated for 8 weeks, and then given
       control diets during a 5-week recovery period. A small decrease in body weight
       gain was observed at 0.4 mg/kg bw/day. A small decrease in brain AChE activity
       (5% inhibition compared to control level) was already observed at 0.005 mg/kg
       bw/day. Biologically significant ChE inhibitions (>20%) were measured at 0.025
       mg/kg bw/day and above for red blood cell AChE and plasma ChE activity, and
       at 0.1 and 0.4 mg/kg bw/day for brain AChE activity. In the males and females of
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<pre>       the group receiving 0.4-mg/kg bw/day, brain AChE, red blood cell AChE, and
       plasma ChE activities were reduced by 72-75%, 84-86%, and 51-79%,
       respectively. Continuation of treatment in subgroup B beyond 8 weeks did not
       inhibit ChE activities further. At the end of the recovery period of subgroup C,
       plasma ChE was comparable to or exceeded control values. The recovery of red
       blood cell and brain AChE activities was incomplete, still being inhibited by
       approximately 30% at 0.4 mg/kg bw/day. Other toxicological effects than ChE
       inhibition were not investigated in this study. In the absence of biologically
       significant ChE inhibitions, the NOAEL was 0.0125 mg/kg bw/day (Hen81).
           Long-Evans rats were given technical monocrotophos (purity: not given) in
       the diet at dose levels of 0, 0.025, 0.075, 0.75, 2.25, and 6.75 mg/kg bw/day, for
       12 weeks. The number of animals of each sex in each dose group was 42, 30, 30,
       42, 12, and 12, respectively. At the top dose, all rats exhibited tremors; body
       weight gain was reduced and liver and kidney weights were increased but no
       histological effects were observed. Haematology values were unaffected in all
       dose groups. From 2 weeks onwards, brain AChE activity was significantly
       inhibited at 0.075 mg/kg bw/day and above, but remained within the normal
       range at 0.025 mg/kg bw/day. After a 4-week recovery period, AChE activity in
       the higher dose groups had returned to control levels. The NOAEL in this 12-
       week oral rat study was 0.025 mg/kg bw/day based on cholinesterase inhibition
       (no more data presented) (She64).
           In a 90-day study, weanling Wistar rats (n=10/sex/group) received daily
       doses of 0, 0.3, 0.6, and 1.2 mg/kg bw/day of monocrotophos (purity: 70%) by
       intragastric intubation. Blood samples were collected at 15, 30, 60, and 90 days
       after the beginning of the study. At the top dose, mortality was reported in both
       males and females. Growth retardation was observed at all dose levels. Whole
       blood ChE levels decreased over time at all dose levels in males, but in females,
       no further inhibition was observed beyond day 15 in the groups fed 0.6 and 1.2
       mg/kg bw/day. At termination, no clear dose-effect relationship was seen for
       inhibition of whole blood ChE and brain AChE activities in males. The average
       suppression levels of whole blood ChE and brain AChE activities (all dose
       levels) were 22% and 33% of control levels, respectively. In contrast, female rats
       showed a dose-related inhibition of whole blood ChE and brain AChE activities.
       Levels ranged from 73 to 34% and from 72 to 56% of control levels,
       respectively, at day 90. Dose-related histological effects were reported in liver
       and kidneys (Jan90). Because of the inconsistencies in the outcome of
       cholinesterase results, the committee has doubts on the reliability of this study.
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<pre>            Mice (n=8/sex/group) were fed daily dose levels equivalent to 0, 0.005,
       0.025, 0.05, 0.5, and 5 mg/kg bw of technical monocrotophos (purity: not given),
       for 5 weeks. General health and physical appearance of the mice were not
       affected. Ocular or haematology changes did not occur. Food and body weight
       gain were reduced at the top dose only. Histological changes of the kidneys and
       the adrenal glands were also observed at 5 mg/kg bw. Plasma ChE was inhibited
       in females at 0.05 mg/kg bw/day (by 30%) and above, and in males at 0.5 mg/kg
       bw (by 80%) and above. Inhibition of red blood cell and brain AChE activities
       was found at 0.5 (by 60%) and 5 mg/kg bw (by 70-90%). The NOAEL in this
       5-week oral mouse study was 0.025 mg/kg bw based on cholinesterase inhibition
       (Hen79).
            Beagle dogs (6-9-month old) were fed diets containing technical
       monocrotophos (purity: not given) at dose levels equivalent to 0, 0.0125, 0.0375,
       0.375, 1.125, and 3.375 mg/kg bw, for 12 weeks. Dose groups up to 0.375 mg/kg
       bw/day consisted of 4 animals per sex, 2 of which were allowed to recover
       during a 4-week exposure-free period. The 2 highest dose groups consisted of 2
       animals per sex. From week 9 onwards, the concentration in the high-dose group
       was raised stepwise to 13.5 mg/kg bw/day and to 27 mg/kg bw/day during an
       extra 13th exposure week, after which these animals were killed. Body weights
       were reduced only in the highest dose group after the first increase in dosing (to
       6.75 mg/kg bw/day). At termination of the study, brain AChE, red blood cell
       AChE, and plasma ChE activities were inhibited by more than 50% in the
       animals of the highest dose group. At 0.0375 mg/kg bw, these activities were
       inhibited by less than 20% while they were comparable to pre-treatment levels at
       0.0125 mg/kg bw. In the dogs that were allowed to recover, ChE levels returned
       to pre-treatment values. Haematology, clinical chemistry and histological
       examination did not show abnormalities related to treatment with
       monocrotophos. The NOAEL in this 12-week oral dog study was 0.0125 mg/kg
       bw based on cholinesterase inhibition (She64, She65b).
            In a prolonged feeding study, beagle dogs (n=3/sex/group) received
       monocrotophos at levels equivalent to 0, 0.004, 0.04, and 0.4 mg/kg bw/day, for
       106 weeks. ChE activities were not reduced at and below 0.04 mg/kg bw/day, but
       significant inhibition occurred at 0.4 mg/kg bw/day (inhibition of plasma ChE
       and RBC AChE by more than 50%). A satellite dose group (n=2/sex) given 2.5
       mg/kg bw/day was started after 52 weeks until the end of the study. During the
       first weeks of dosing, signs of toxicity (salivation, tremor, diarrhoea, body
       weight loss) were observed, and plasma ChE and erythrocyte AChE were
       inhibited by more than 50%. Brain AChE activity was inhibited by 60% in 2 out
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<pre>       of 4 dogs. Mortality rate, clinical signs, body weights, heart rate, blood pressure,
       haematology, blood chemistry, brain AChE, urinalysis, organ weights,
       ophthalmoscopy, gross pathology, and histopathology were evaluated but no
       effects other than those mentioned above were reported. The NOAEL of this
       study was 0.04 mg/kg bw/day for cholinesterase inhibition and 0.4 mg/kg bw/
       day for other toxic effects (Jon66, Jon67a). [The committee notes that actual
       levels may have been considerably lower since diet analysis at week 15 and 40
       showed deviations from above presented nominal values of up to 60% due to
       compound instability].
           In a subchronic neurotoxicity study in hens (Cofal/Marek; n=10/group),
       animals were dosed daily with 0, 0.03, 0.1, and 0.3 mg/kg bw/day, for 96 days.
       The high dose was raised to 0.5 mg/kg bw/day on day 79. Tri-o-cresyl phosphate
       (7.5 mg/kg bw/day, raised to 10 mg/kg bw/day on day 79) was used as a positive
       control. Body weights were slightly decreased in the high-dose and in the
       positive control group. Brain weight was increased in the high-dose group only.
       Plasma ChE was inhibited dose dependently in all groups receiving
       monocrotophos by 15 and 47% in the low- and high-dose group, respectively.
       However, neither changes in red blood cell AChE, nor clinical signs of delayed
       neurotoxicity, nor neuropathological changes were observed in any of the groups
       receiving monocrotophos. The positive control showed typical signs of
       neurotoxicity (not specified) (Bec81).
       Haematological effects in mice were studied following weekly intraperitoneal
       doses of Nuvacron (0.8 mg/kg bw), for 6 weeks. Significant decreases in
       haemoglobin concentration, red blood cell count, platelet count, haematocrit, and
       erythrocyte sedimentation rate were found, while clotting time was prolonged
       and white blood cell count was increased. Neutrophil and basophil counts were
       increased and lymphocyte count decreased. In addition, bone marrow depression
       and splenic hyperplasia were observed (Gup82). The author also reported
       increased concentrations of brain neurotransmitters (e.g., acetylcholine,
       epinephrine, dopamine) and a decrease in AChE activity of the brain (Gup84).
       The results of various subacute and subchronic toxicity studies in experimental
       animals are summarised in Table 2. In nearly all studies, inhibition of brain or red
       blood cell AChE is the critical effect.
073-15 Monocrotophos
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<pre>Table 2 Summary of subacute and subchronic dermal and oral toxicity studies for monocrotophos.
exposure    species                     dose levels              exposure critical effecta        NOAEL (mg/kg reference
route       (strain; number; sex)       (mg/kg bw/d)             duration                         bw/d)
dermal      rabbit                      20, 40                   3w         clinical signs        20               Doy65
            (‘albino’; n=10/sex/group)
            rat                         0.2, 1, 10, 100          4w         BAChE, RAChE          1                Hag89
            (not given)
oral        rat                         6 (1st d: 9)             17 d       behaviour             6                Swa92
            (Wistar; male)
            rat                         0, 0.005, 0.025, 0.05, 5 w          BAChE, RAChE          0.005            McA79
            (Wistar; 8/sex/group)       0.5, 5
            rat                         0, 0.005, 0.0125, 0.025, 8-13 w     BAChE, RAChE          0.0125           Hen81
            (Wistar; n=30/sex/group;    0.1, 0.4
            controls: n=60/sex)
            rat                         0, 0.025, 0.075, 0.75, 12 w         BAChE                 0.025            She64
            (Long-Evans; n=12-42/sex/ 2.25, 6.75
            group)
            rat                         0, 0.3, 0.6, 1.2         90 d       BAChE, liver effects, LOAEL: 0.3       Jan90
            (Wistar; n=10/sex/group)                                        kidney effects
            mouse                       0, 0.005, 0.025, 0.05, 5 w          BAChE, RAChE          0.025            Hen79
            (CD; n=8/sex/group)         0.5, 5
            dog                         0, 0.125, 0.375, 1.125, 13 w        BAChE, RAChE          0.125            She64;
            (beagle; 2-4/sex/group)     3.375                                                                      She65
            dog                         0, 0.004, 0.04, 0.4b     106 w      BAChE, RAChE          0.04b            Jon66;
            (beagle; n=3/sex/group)                                                                                Jon67a
            hen                         0, 0.03, 0.1, 0.3        96 d       neurotoxicity, RAChE 0.3               Bec81
            (Cofal/Marek; n=10/group)
a
     BAChE= brain AChE; RAChE= red blood cell AchE.
b
     Actual levels might have been considerably lower since diet analysis at week 15 and 40 showed deviations from nominal
     values of up to 60% due to compound instability.
              In summary, subacute or subchronic exposure of rats, mice, dogs, and rabbits to
              monocrotophos caused inhibition of brain, red blood cell, and/or plasma ChE
              activities and cholinergic symptoms. The committee considers a NOAEL of
              0.0125 mg/kg bw/day, based on biologically significant inhibition of brain and
              red blood cell AChE in rats. Subchronic oral exposure of rats to monocrotophos
              may also cause dose-dependent liver and kidney damage (LOEL: 0.3 mg/kg bw).
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<pre>       Chronic toxicity and carcinogenicity
       In a 2-year study, rats (Charles River; n=25/sex/group) were given technical
       monocrotophos (purity: not given) in dietary levels equivalent to 0, 0.05, 0.5, and
       5 mg/kg bw/day. However, actual levels may have been considerably lower since
       diet analysis at week 15 and 40 showed deviations from above presented nominal
       values of up to 60% due to compound instability. In the high-dose group, signs of
       toxicity, reduced body weight gain accompanied by reduced food intake in males
       only, and, in females only, decreased absolute liver, gonads, thyroid, and
       pituitary gland weights were observed. No other changes were seen at post-
       mortem gross and microscopic examination. Plasma ChE and red blood Cell
       AChE activities were inhibited in the mid-dose group by more than 50% from
       week 6 onwards but were not affected on the low-dose group (no data given for
       the high dose group). Brain AChE activities measured at the end of the study did
       no show significant changes in the low-dose group (no data given for the 2
       higher dose groups) (Jon66, Jon67b).
           In a 2-year study with Wistar rats (n=85/sex/group), the animals received
       technical monocrotophos (purity: 78.7%) in dietary concentrations equivalent to
       0.0005, 0.0015, 0.005, 0.05, and 0.5 mg/kg bw/day. The control group comprised
       170 rats of each sex. At 0.5 mg/kg bw, survival, body weight gain, and feed
       consumption were reduced. No changes were found in haematology and in
       clinical chemistry test results. There was no evidence of carcinogenic effects,
       and no gross and microscopic lesions attributable to treatment were found. Brain
       AChE, red blood cell AchE, and plasma ChE activities were reduced throughout
       the study by up to 75, 85, and 80%, respectively, at 0.5 mg/kg bw, and by up to
       30, 50, and 30, respectively, at 0.05 mg/kg bw. At and below 0.005 mg/kg bw,
       ChE activities remained within the normal range. The NOAEL for inhibition of
       brain and red blood cell AChE and plasma ChE activities was therefore 0.005
       mg/kg bw/day; the NOAEL for reduced body weight gain and feed consumption
       was 0.05 mg/kg bw/day (Bro83).
           In a 2-year study, CD mice (n=77/sex/group) were fed technical
       monocrotophos (purity: 78.7%) at doses equivalent to 0.15, 0.30, 0.75, or 1.5
       mg/kg bw/day. The control group comprised 154 animals of each sex. A dose-
       related increase in the number of mice showing convulsions was seen. Survival,
       body weight gain, haematological parameters, and organ weights were not
       adversely affected. No gross or microscopic lesions, and no evidence of a
       carcinogenic effect were seen. Dose-related inhibition of brain AChE, red blood
       cell AChE, and plasma ChE was observed at all levels. A NOAEL could not be
073-17 Monocrotophos
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<pre>       established since at the lowest dose ChE activities were still inhibited by 30-35%
       (Bro82).
           In summary, long-term studies in mice and rats did not show evidence for a
       carcinogenic potential of monocrotophos. Brain AChE, red blood cell AChE, and
       plasma ChE were inhibited by monocrotophos in a dose-dependent manner. The
       overall 2-year rat oral NOAEL was 0.005 mg/kg bw based on inhibition of brain
       AChE and red blood cell AChE activities.
       Mutagenicity and genotoxicity
       Mutagenicity and genotoxicity assays comprised tests for the detection of gene
       mutations in bacteria, yeast, and mammalian cells (in vitro) and in vitro and
       in vivo cytogenicity and other genotoxicity assays.
       •   In vitro tests
           • Gene mutation assays. Tests for reverse mutations in S. typhimurium
              strains TA100, 1535, 1537, and 1538 were negative at concentrations up
              to 1 mg/plate (Sim77) and positive at concentrations up to 20 mg/plate
              (Hoo86, Mor83, San85, Wat82) in the presence and absence of metabolic
              activation. Positive results were also found in S. cerevisae D7 in
              concentrations up to 30 mg/mL (San85, Wat82). In E.coli WP2, gene
              mutation tests were negative at doses up to 10 mg/plate in the presence
              and absence of metabolic activation (San85, Sim77, Wat82).
              Monocrotophos induced gene mutations in cultured mouse lymphoma
              L5178Y cells at levels up to 1200 µg/mL in the presence or absence of
              metabolic activation (Jot80, San85, Wat82). The genotoxicity of a ‘farm-
              grade’ formulation of monocrotophos was studied in D. melanogaster
              using the wing mosaic test and the sex-linked recessive lethal test. At
              concentrations between 0.5-10 x 10-5%, the compound was genotoxic in
              both somatic and germ cells of Drosophila (Tri92), confirming findings in
              previous studies (San85, Wat82).
           • Cytogenicity assays. In cultured Chinese hamster ovary (CHO) cells,
              monocrotophos induced sister chromatid exchanges (SCE) at levels
              ranging from 25 up to 2000 µg/mL and chromosome aberrations at levels
              >200 µg/mL with and without metabolic activation (Lin87, San85,
              Wan87, Wat82). No chromosome aberrations were observed at doses
              between 9.8-78.1 µg/mL monocrotophos (Her92a). At concentrations
              between 1 and 10 µg/mL, Nuvacron induced a significant increase in the
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<pre>               frequencies of micronuclei in CHO cells (Pei96). In human lymphocyte
               cultures, increased frequencies of chromosome aberrations and SCEs
               were seen at monocrotophos concentrations of 0.05 and 0.1 µg/mL (in
               DMSO) and at >0.0125 µg/mL, respectively (Rup88). Chromosome
               aberrations were also observed in another study at monocrotophos
               concentrations between 0.001 and 10 µM (Vai82). A SCE test in cultured
               human lymphoid cells was positive at monocrotophos levels up to 2 µg/ml
               (Sob82).
            • Other genotoxicity assays. Positive results were seen in a mitotic-
               recombination assay in S. cerevisiae D3 and D7 at concentrations 10-50
               mg/mL in the presence or absence of metabolic activation (Mor80, San85,
               Sim77, Wat82). Monocrotophos induced DNA repair or unscheduled
               DNA synthesis (UDS) in cultured human fibroblasts at levels in the range
               of 10-4-10 mM, with and without metabolic activation (Sim77). Positive
               UDS results were also obtained in later studies (San85, Wat82). In a study
               on the alkylating properties of organophosphorus compounds, it was
               demonstrated that monocrotophos is a weak alkylating agent, e.g., 30
               times less potent than the standard alkylating agent methyl
               methanesulfonate. Monocrotophos might, therefore, form adducts with
               DNA in vitro (Bed72).
       • In vivo tests
       Male and female Swiss mice treated with single intraperitoneal doses of 1.25,
       2.5, and 5.0 mg/kg bw monocrotophos (Nuvacron-400) showed a significantly
       increased incidence of micronuclei in polychromatic bone marrow erythrocytes
       at the 2 highest dose levels (Pei96). Increased frequencies of micronuclei and
       chromosome aberrations were also observed in bone marrow cells of Swiss mice
       after 2 intraperitoneal doses of 1.5 and 2 mg/kg bw monocrotophos on 2
       consecutive days (Vai82). However, monocrotophos did not induce micronuclei
       in bone marrow cells of mice following 2 intraperitoneal doses in the range of
       2-8 mg/kg bw (Kir80) or following 5 intraperitoneal doses in the range of 1.25-5
       mg/kg bw. In the latter study, chromosome aberrations were induced by
       intraperitoneal administration, but no significant effects were detected when
       monocrotophos was given orally at doses of 5 mg/kg bw (Bhu88). No increased
       frequency of micronuclei was observed in bone marrow cells of mice treated
       with a single oral dose of 9 mg/kg bw (Her92b). In Wistar rats, monocrotophos
       induced chromosome aberrations in bone marrow cells following 2
       intraperitoneal doses of 2 mg monocrotophos/kg bw (interval 24 hours). At
073-19 Monocrotophos
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<pre>       lower doses, no aberrations were induced (Adh88). No increased frequency of
       chromosome aberrations was observed in bone marrow cells of Chinese hamsters
       after 2 oral doses up to 5.6 mg/kg bw, 24 hours apart (Str86). Dominant lethal
       effects were not observed in mice fed monocrotophos at levels equivalent to
       0.75, 1.5, and 3.0 mg/kg bw, for 7 days or 7 weeks (Wat82, Sim77). Hens given
       either intraperitoneal doses of 1.25, 2.5, and 5 mg/kg bw or an oral dose of 5
       mg/kg bw showed a significant increased frequency of chromosome aberrations
       and micronuclei in bone marrow cells and peripheral red blood cells (Bhu93). A
       significant increase in frequency of micronuclei was also observed in bone
       marrow cells and peripheral red blood cells of 1-week-old chicks, fed 5 mg
       monocrotophos/kg for 30 days (Jen92). A statistically significant, dose-related
       increase in mean comet tail length indicating DNA damage was seen in
       peripheral blood leukocytes 24 hours after treating male Swiss mice (n=6/group)
       with single (gavage) oral doses of 0, 0.046, 0.093, 0.186, 0. 373, and 0.746
       mg/kg bw. At 48 hours post-treatment, mean tail lengths were gradually
       decreased in all dose groups, but still statistically significantly increased while
       they returned to control levels at 72 hours post-administration indicating repair
       of damaged DNA (Mah02).
       The committee concludes that monocrotophos is mutagenic both in in vitro and
       in vivo assays. However, apart from a positive result in a test indicative of DNA
       damage in mouse, oral genotoxicity studies in either mice or rats were negative.
       Reproduction toxicity
       Male Swiss Albino mice (n=9-10/group) were given monocrotophos (0, 0.9, 1.8,
       3.6 mg/kg) by intragastric intubation, for 5 days. The percentage of abnormal
       sperms increased with the dose from 2.1% in the control and low-dose groups to
       3.6 and 5.4% in the 2 higher dose groups (Kum88). When female virgin Swiss
       albino mice (n=10/group) were given oral doses of technical grade
       monocrotophos (purity: 75%) of 0, 1.6, 3.3, 6.6, 10, and 13 mg/kg bw/day, for 30
       days, dose-dependent decreases in the number of oestrus cycles and in the
       duration of pro-oestrus, oestrus, and metoestrus with concomitant increases in
       di-oestrus duration were found reaching statistically significance at doses of 3.3
       mgkg bw and above. Morphometric follicular analysis in 4 animals per group,
       showed dose-dependent decreases in the sizes and number of healthy follicles
       and increases in the sizes and number of atretic follicles, reaching statistically
       significance at doses of 6.6 mg/kg bw and higher. Statistically significant
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<pre>       decreased ovary and uterus weights were seen at 3.3 mg/kg bw and above and 10
       mg/kg bw and above, respectively. At the 2 higher dose levels, body weights
       were significantly decreased, while treatment did not cause changes in relative
       weights of liver, kidneys, adrenals, thymus, thyroid, spleen, and pituitary gland
       (Rao02).
            A 2-generation reproduction study was carried out in rats (13 male and 26
       female rats per dose group) that were given doses equivalent to 0, 0.005, 0.05,
       0.15, and 0.5 mg/kg bw via the diet. Parental effects noted before mating were
       lower body weights in the male rats of the F0 and F1 generation at 0.5 mg/kg bw,
       and small dark faecal pellets at 0.5 and 0.15 mg/kg bw. At 0.5 mg/kg bw/day, the
       mating, fertility, and gestation indices were not different among F0 groups, but
       the mating index of F1 males was lower compared to the control group.
       Gestation length was increased, but mean litter size, mean pup weight, and
       viability and lactation indices were significantly reduced. Three total litter losses
       were observed in both F1 and F2 generations. At 0.15 mg/kg bw, one total litter
       loss was observed in the F2 generation. In addition, mean pup weight and
       viability index were significantly reduced. F2 female weanlings showed higher
       kidney and liver weights at 0.15 and 0.5 mg/kg bw compared to the controls. A
       NOAEL of 0.05 mg/kg bw/day was established for parental and reproduction
       toxicity (Dix81).
            In another study, doses of 0, 0.3, 0.6, and 1.2 mg/kg bw/day were
       administered by gavage to female rats (n=10/group), for 2 weeks prior to mating
       with non-treated males. The female rats had dose-dependent lower body weights,
       lower resorptions, enlarged ovaries, and reduced fertility and parturition indices.
       These changes already started at 0.3 mg/kg bw. The gestation index was not
       affected. Pups showed also a dose-dependent reduction of average birth weight,
       average crown-rump length, and of viability and lactation indices at 0.3 mg/kg
       and higher. However, the average litter size was not affected in any of the groups
       (Adi94).
            In a developmental study, monocrotophos was given to pregnant Sprague-
       Dawley rats (number not specified) by gavage at doses of 0, 0.3, 1, and 2
       mg/kgbw/day, during days 6 to 15 of pregnancy. Dams were killed on gestation
       day 20. Maternal toxicity was evident by muscle tremors and twitching,
       listlessness, salivation, perianal urine-soaked fur, and crusty eyes at 2 mg/kg bw/
       day, and maternal body weight was reduced at 1 and 2 mg/kg bw/day. No
       compound-related effects on maternal reproduction parameters, i.e., number of
       corpora lutea, of implantations, of resorptions, and number of dead and viable
       fetuses, were found. At 2 mg/kg bw/day, fetuses had a decreased body weight, a
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<pre>       decreased crown-rump length, and delayed ossification of sternebrae, and at
       1and 2 mg/kg bw, the number of runt fetuses was increased. Fetal visceral
       examination did not reveal abnormalities. The findings in fetuses were
       considered to be secondary to maternal toxicity. Brain defects were observed in
       all groups but were considered unspecific and unrelated to the test compound.
       The NOAEL for maternal and developmental toxicity was 0.3 mg/kg bw
       (Bor83). In order to evaluate the relevance of the brain defects observed in the
       above study, a new study was performed in female rats that were given doses of
       0, 0.1, 0.3, 1, and 2 mg/kg bw during days 6 through 15 of gestation. The animals
       were killed on pregnancy day 20. Clinical signs of intoxication were seen in most
       animals at 2 mg/kg bw and tremors in one female at 1 mg/kg bw. Body weight
       gain was reduced at 2 mg/kg bw. There were no treatment-related necropsy
       findings. Pre- and post-implantation losses, mean litter size, mean fetal weight,
       and sex ratio were unaffected. No treatment-related external, visceral, and
       skeletal changes were found in fetuses. This study confirmed the conclusion that
       the brain defects observed in the preceding study were not related to treatment.
       This study confirmed the maternal NOAEL value of 0.3 mg/kg bw, and further, a
       NOAEL for developmental toxicity of at least 2 mg/kg bw was established
       (Fuc92).
            In a developmental toxicity in rabbits, the animals received oral doses of 0,
       0.1, 1, 3, or 6 mg/kg bw monocrotophos during days 6 through 18 of gestation.
       The animals were sacrificed at day 29 of gestation. Maternal effects observed at
       the top dose were mortality of 13 animals, weight loss, signs of cholinergic
       toxicity (such as hyperpnoea, tremor, ataxia, salivation, excitation, faecal
       changes, and constricted pupils). Necropsy revealed gastrointestinal ulceration
       and pulmonary oedema. At 3 mg/kg bw, diarrhoea and related faecal changes and
       transiently reduced body weights were seen. Average numbers of late resorptions
       were slightly increased, and mean live fetal weights and maternal uterine weights
       marginally reduced at 6 mg/kg bw. Average numbers of corpora lutea,
       implantations, early resorptions, litter size, dead fetuses, and fetal sex ratio were
       comparable among all groups. Fetuses did not show treatment-related
       malformations externally, in soft tissues, or in skeletal structures at any dose
       level. The maternal NOAEL was 1 mg/kg bw and the NOAEL for developmental
       toxicity 3 mg/kg bw (Dea87).
            In summary, these studies indicate that the overall NOAEL for reproduction
       toxicity in rats or rabbits is 0.05 mg/kg bw monocrotophos/day.
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<pre>7      Existing exposure limits
       The current administrative exposure occupational limit (MAC) for
       monocrotophos in the Netherlands is 0.25 mg/m3, 8-hour TWA.
           Existing occupational exposure limits for monocrotophos in some European
       countries and in the USA are summarised in the annex.
8      Assessment of health hazard
       The health hazard assessment of monocrotophos is based mainly on toxicology
       reviews issued by the FAO/WHO (Joint Meeting of the FAO Panel of Experts on
       Pesticides Residues on Food and the Environment and the WHO Expert Group
       on Pesticides Residues - JMPR) (FAO92, FAO94, FAO96), the Health, Safety,
       and Environment Division, Shell, The Hague, The Netherlands (SIP85), and the
       Crop Protection Division, Ciba-Geigy Ltd, Basel, Switzerland (Skr94). The
       toxicity profile in these reviews is obtained mainly from unpublished reports of
       toxicology studies conducted for registration purposes by the chemical
       companies manufacturing or marketing the compound.
           Workers can be exposed to monocrotophos through inhalation of aerosols or
       by direct skin contact with a formulation of the compound. Skin absorption has
       been demonstrated by detection of large amounts of the metabolite dimethyl
       phosphate (DMP), excreted in the urine of sprayers following 3-day
       monocrotophos application. The maximum dermal absorption is estimated to be
       0.18% of the dose per hour, 24-48 hours after application. The extent of
       absorption following oral intake is 90-100% in the rat. Following absorption, the
       compound is rapidly metabolised into breakdown products (e.g., DMP), which
       are mainly excreted in the urine. There is no evidence of accumulation of the
       compound in any of the tissues.
           Human case studies show a high acute toxicity of monocrotophos following
       accidental exposures. Effects observed in these studies were typical cholinergic
       symptoms such as reversible nerve weakness, paralysis, and respiratory
       difficulty. Two field studies on occupational exposure during application of
       monocrotophos on crops showed no compound-related clinical signs of
       intoxication or inhibition of red blood cell AChE activity. However, serum ChE
       was inhibited up to 59% of pre-exposure levels. Estimated dose levels were on
       average equivalent to an oral intake of 0.05 mg/kg bw/day. In a human volunteer
       study, oral intake of 0.0057 mg/kg bw/day for 28 days produced inhibition of
073-23 Monocrotophos
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<pre>       serum ChE (24%), but AChE activity in red blood cells remained unaffected and
       no cholinergic symptoms were observed. The NOAEL for inhibition of red blood
       cell AChE is >0.006 mg/kg bw/day. The committee concludes that in humans,
       red blood cell AChE is much less sensitive to inhibition by monocrotophos than
       plasma ChE. In addition, the rate of recovery of inhibited serum ChE in humans
       in slow in comparison to test animals.
           Based on results of acute lethal toxicity studies in test animals and case
       reports in humans, the committee considers the compound as very toxic after oral
       and respiratory exposure, and as toxic after dermal exposure. Monocrotophos did
       not cause neurological changes indicative of acute delayed neurotoxicity. No
       significant systemic effects have been reported in short- or long-term toxicity
       studies in test animals, except liver and kidney injury in one short-term study in
       which rats were given high oral doses of monocrotophos. However, these studies
       showed inhibition of plasma ChE and of red blood cell and brain AChE in dogs,
       rats, and mice. These cholinesterases have approximately the same sensitivity for
       inhibition by monocrotophos in these species. NOAELs for brain and red blood
       cell AChE inhibition were 0.04 mg/kg bw for dogs (2-year oral study), 0.005
       mg/kg bw for rats (2-year feeding study), and <0.15 mg/kg bw for mice (2-year
       feeding study). Monocrotophos caused gene mutations in vitro and cytogenetic
       effects both in vitro and in vivo. The induction of mutations is in accordance
       with its weak DNA alkylating potency. In mammals, cytogenicity effects were
       found if monocrotophos was given by intraperitoneal injections; apart from a
       positive result in a Comet assay suggesting - repairable - DNA damage in mouse
       leukocytes, studies following oral administration were negative. Carcinogenicity
       studies in rats and mice did not show a treatment-related increase in tumour
       incidence. The committee concludes that the positive genotoxic effects of
       monocrotophos were thus not reflected in carcinogenicity. Monocrotophos was
       not embryotoxic or teratogenic. At doses below those causing parental toxicity,
       reproduction performance was not affected. The overall NOAEL associated with
       reproduction toxicity was 0.05 mg/kg bw/day.
           Based on the above data, the committee concludes that the mechanism of
       toxicity of monocrotophos in mammals is through inhibition of AChE activity in
       nerve tissue. The committee identifies inhibition of AChE in brain tissue as the
       most sensitive adverse toxic effect of monocrotophos in animal studies,
       occurring at dose levels that are lower than those causing other toxic effects. In
       human beings, for obvious reasons, brain AChE cannot be measured. Instead, red
       blood cell AChE, being the same molecular target for inhibition by
       organophosporus pesticide as brain AChE, is used as a surrogate for brain AChE
073-24 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>       in assessing the human health risk of exposure to monocrotophos (Jey94).
       Studies in experimental animals showed that red blood cell AChE and brain
       AChE are equally sensitive for inhibition by monocrotophos, and it may be
       assumed that this is also the case in humans.
       The committee takes the NOAEL of 0.006 mg/kg bw/day, derived from the 28-
       day human volunteer study, as a starting point in establishing a health-based rec-
       ommended occupational exposure limit (HBROEL). Since workers are exposed
       for 5 days a week, this NOAEL from a continuous study (i.e., 7 days a week) is
       adjusted by multiplying with a factor of 7/5 resulting in a no-adverse-effect level
       (NAEL) of 0.008 mg/kg bw. For extrapolation to a HBROEL, an overall assess-
       ment factor of 3, covering intraindividual variation, is used. This results in a
       NAEL for humans of 0.003 mg/kg bw/day. Assuming a 70-kg worker inhales 10
       m3 of air during an 8-hour working day, and a retention of 100%, and applying
       the preferred value approach, a health-based occupational exposure limit of 0.02
       mg/m3 is recommended for monocrotophos.
       The committee recommends a health-based occupational exposure limit for
       monocrotophos of 0.02 mg/m3, as an 8-hour time-weighted average (TWA).
       Because monocrotophos can be absorbed through the skin in significant
       amounts, the committee recommends a skin notation.
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       cells of Drosophila. Mutat Res 1992; 278: 23-9.
Ull79  Ullmann L, Phillips J, Sachsse K. Cholinesterase surveiilance of aerial applicators and allied workers
       in the democratic Republic of the Sudan. Arch Environ Contam Toxicol 1979; 8: 703-12.
073-31 Monocrotophos
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<pre>Vai82  Vaidya VG, Patanakar N. Mutagenic effect of monocrotophos- An insecticide in mammalian test
       systems. Indian J Med Res 1982; 76: 912-7.
Ver77  Verberk MM. Incipient cholinesterase inhibition in volunteers ingesting monocrotophos or
       mevinphos for one month. Toxicol Appl Pharmacol 1977; 42: 345-50.
073-32 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>              Annex
Occupational exposure limits for monocrotophos 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   -             0.25              8h                 administrative       S           SZW03
Employment
Germany
- AGS                              -             0.25c             8h                                      S           TRG00
- DFG MAK-Kommission               -             -                                                                     DFG02
Great Britain
- HSE                              -             -                                                                     HSE02
Sweden                             -             -                                                                     Swe00
Denmark                            -             0.25              8h                                                  Arb02
USA
- ACGIH                            -             0.25c             8h                 TLV                  S, A4d      ACG03b
- OSHA                             -             -                                                                     ACG03a
- NIOSH                            -             0.25              10 h               REL                              ACG03a
European Union
- SCOEL                            -             -                                                                     EC03
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 inhalable fraction.
d
     Classified in carcinogen 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
     studies do not provide indications of carcinogenicity which are sufficient to classify the agent into one of the other
     categories.
073-33        Monocrotophos
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<pre>073-34 Health-based Reassessment of Administrative Occupational Exposure Limits</pre>

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