<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>Strychnine
(CAS No: 57-24-9)
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/111, The Hague, March 30, 2004
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<pre>Preferred citation:
Health Council of the Netherlands: Committee on Updating of Occupational
Exposure Limits. Strychnine; Health-based Reassessment of Administrative
Occupational Exposure Limits. The Hague: Health Council of the Netherlands,
2004; 2000/15OSH/111.
all rights reserved
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<pre>1     Introduction
      The present document contains the assessment of the health hazard of strychnine
      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 C de Heer, Ph.D. and H Stouten, M.Sc. (TNO Nutrition and Food
      Research, Zeist, the Netherlands).
           The evaluation of the toxicity of strychnine has been based on the review by
      the American Conference of Governmental Industrial Hygienists (ACGIH)
      (ACG91). Where relevant, the original publications were reviewed and evaluated
      as will be indicated in the text. In addition, in April 1997, literature was searched
      in the on-line databases Medline, Cancerlit, and Toxline starting from 1966,
      1963, and 1965, respectively, and using the following key words: strychnine and
      57-42-9.
           In March 2000, the President of the Health Council released a draft of the
      document for public review. The committee received comments by the following
      individuals and organisations: P Wardenbach, Ph.D. (Bundesanstalt für
      Arbeitsschutz und Arbeitsmedizin, Dortmund, Germany) and L Whitford
      (Health and Safety Executive, London, England). These comments were taken
      into account when deciding on the final version of the document.
           An additional search in Toxline and Medline in October 2003 did not result
      in information changing the committee’s conclusions.
2     Identity
      name                          :    strychnine
      synonyms                      :    strychnidin-10-one, strychinos
      molecular formula             :    C21H22N2O2
      structural formula:           :
      CAS number                    :    57-24-9
111-3 Strychnine
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<pre>3     Physical and chemical properties
      molecular weight         :      334.40
      boiling point            :      at 101.3 kPa: decomposes (at 0.67 kPa: 270oC)
      melting point            :      287oC
      flash point              :      not available
      vapour pressure          :      at 20oC: 0 kPa
      solubility in water      :        insoluble (at 20oC: 15 mg/100 mL)
      log Poctanol/water       :      1.93 (experimental); 1.85 (estimated)
      conversion factors       :      not applicable
      Data from ACG91, NLM03.
      Strychnine is a non-combustible, colourless, odourless, bitter-tasting crystalline
      solid. It is an alkaloid that is isolated from the dried seeds of Strychnos nux-
      vomica and other Strychnos (Loganiaceae) species (Muh86).
           The pH of a saturated strychnine solution is 9.5 (Muh86).
4     Uses
      Strychnine salts (nitrate, sulphate, phosphate) have been used as rodenticides, in
      poisoned grain and other baits for larger wild animals, and to destroy birds.
      Further, its use in medicine, as an adjunct in the treatment of non-ketotic
      hyperglycaemia, impotence, and sleep apnoea, and in veterinary medicine has
      been reported (ACG91, Ray91, Yam92). Nowadays, in the USA, it is used only
      for laboratory, research, and restricted (i.e., only for below-ground, bait
      applications to control pocket gophers) pesticide purposes (EPA96, Ros00).
      Strychnine is reported to have been found as an adulterant in street drugs such as
      amphetamines, heroin, and cocaine and as trace ingredient in certain
      homeopathic remedies (Flo99, Woo02).
           According to the database of the Dutch Pesticide Authorisation Board
      (CTB)*, strychnine is at present not permitted in the Netherlands for use as an
      active ingredient in pesticides. The ‘Geneesmiddelen Repertorium’, an overview
      of information on pharmaceutical specialties registered by the Dutch Medicines
      Evaluation Board, did not list strychnine-containing products**.
*     At: http://www.ctb-wageningen.nl.
**    At: http://www.geneesmiddelenrepertorium.org.
111-4 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>5     Biotransformation and kinetics
      While the serum of healthy subjects does not contain strychnine in detectable
      amounts, significant, endogenous amounts were found in patients with epilepsy,
      Parkinson’s disease, and manic-depressive psychosis (Kum02).
      Absorption
      Strychnine is rapidly absorbed from the gastrointestinal tract, mucous
      membranes, and parental sites of injection. Ingested strychnine is absorbed
      primarily from the intestine (ACG91, NLM03). Dermal absorption may occur as
      well as was indicated by a case of non-fatal poisoning of a woman wiping up a
      strychnine spill with a cloth soaked in a diluted sodium hypochlorite solution
      (which converted the strychnine salt into the free base that is more efficiently
      absorbed through the skin) (Gre01).
      Distribution
      Once absorbed, strychnine rapidly leaves the blood stream. There is very little
      protein binding. In poisonings, the blood will usually contain more than 2 mg/L,
      the liver more than 4 mg/kg (McB73). At autopsy following fatal poisoning of
      humans and dogs, the highest concentrations were found in the blood, liver, bile,
      kidney, and stomach, with much lower levels detected in muscle and brain
      (Bla84, Niy73, Ray91). In cases of fatal ingestion, strychnine was detected in
      blood (at levels ranging from 0.4-61 mg/L), brain (0.5-66 mg/kg), spinal cord
      (0.1-1.9 mg/L), kidney (0.1-106 mg/kg), liver (0.3-515 mg/kg), bile (9-11 mg/L),
      spleen (11.8 mg/kg), skeletal muscle (trace-2.3 mg/kg), urine (0.5-33 mg/L), and
      stomach content (1-3000 mg) (Cin99, Mar00, Oli79, Ros00). Generally,
      although strychnine acts principally on the spinal cord, it is not concentrated
      there. Strychnine was detected in blood, urine, and gastric contents following
      non-fatal ingestion (Ray91).
          Analysis of strychnine levels in stomach contents and liver tissue from 44
      dogs that died after manifesting typical signs of strychnine poisoning showed
      that these levels were not related to each other (Hat68).
111-5 Strychnine
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<pre>      Metabolism
      Strychnine metabolism occurs largely by the hepatic microsomal enzyme
      system, where up to 80% of the dose is oxidised. Biotransformation rates in liver
      microsomal preparations of rats were 64-144 µg/g liver/hour, whereas in guinea
      pig liver slices, rates of 387-649 µg/g liver/hour have been reported (Ray91). In
      rats given strychnine in the drinking water at doses of 0.15 mg/mL for 5 days,
      profound induction of cytochrome P450 isoenzymes CYP2B1 and CYP2B2 was
      found. The maximal increase was attained after 3 days of administration. In
      addition, strychnine induced some glutathione S-transferase and UDP-
      glucuronosyltransferase activities (Fuj94).
          Urinary metabolites identified in vivo in rats after subcutaneous injection of
      doses of strychnine of 0.5 mg/kg bw were strychnine N-oxide (M-1), 21α,22α−
      dihydroxy-22-hydrostrychnine (M-11), 21α,22β-dihydroxy-22-hydrostrychnine
      (M-12), 2-hydroxystrychnine (M-2), strychnine 21,22-epoxide (M-3), and 16-
      hydroxystrychnine (M-7) (see Annex I). The major metabolite of strychnine in
      vivo in rats was M-3 (Ogu89).
          The in vitro metabolism of strychnine was studied in 9000g supernatant
      fractions of rat and rabbit livers. The metabolism was markedly inhibited by
      cytochrome P450 inhibitors, but only slightly by a microsomal FAD-containing
      monooxygenase inhibitor, methimazole. Five metabolites formed in vitro with
      rabbit liver were identified as 2-hydroxystrychnine (M-2), strychnine N-oxide
      (M-1), 21α,22α -dihydroxy-22-hydrostrychnine (M-11), strychnine 21,22-
      epoxide (M-3), and 11,12-dehydrostrychnine (M-13). Although M-2 was the
      major of the characterised metabolites (15%), whereas all other metabolites
      accounted for less than 1%, this may be of limited relevance because almost 85%
      of metabolites were not identified (Mis85).
          Primary metabolism of strychnine was also examined in vitro in liver
      microsomes of mice, rats, guinea pigs, rabbits, and dogs. Six out of 8 metabolites
      were identified, i.e., strychnine N-oxide (M-1), 2-hydroxystrychnine (M-2),
      strychnine 21,22-epoxide (M-3), 22-hydroxystrychnine (M-5), 16-
      hydroxystrychnine (M-7), and 18-oxostrychnine (M-8) (Tan90, Tan91a).
      Significant differences in metabolic profiles were observed among the above
      species, although the indicated metabolites were detected in all species (with the
      exception of M-3 in rabbits). M-7 was the main metabolite in mice and rats, M-2
      in guinea pigs and rabbits, and M-1 in dogs. M-3 and M-8 were minor
      metabolites (Tan90). This latter finding contrasts with the in vivo data obtained
      in rats, where M3 was identified as a major metabolite (Ogu89). The metabolic
      activity in guinea pig liver microsomes was much higher than those of other
111-6 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>      species. Except for dogs, there seemed to be a fairly good inverse correlation
      between the observed metabolic activity and the acute toxicity data on strychnine
      reported elsewhere (Tan90).
          The N-oxide metabolite (M-1) can readily be reduced to the parent
      compound and M-7 by human intestinal flora under anaerobic conditions
      (ElM93).
          Animals treated with phenobarbital or other microsomal enzyme inducers
      metabolised strychnine faster than untreated animals. Phenobarbital treatment
      resulted in increased formation of especially M-2 and M-1 strychnine
      metabolites, but also of other oxidative metabolites. Similar increases, albeit to a
      lesser extent, were observed after 3-methylcholanthrene treatment (Tan91b).
          The metabolites did not appear to contribute to the toxicity of strychnine but
      to detoxification (Ogu89, Tan90).
          Female rats showed more pronounced responses to strychnine than males.
      This sex difference was due to a difference in the rate of metabolism of
      strychnine in the liver, as male rats oxidised strychnine about 2.5 times faster
      than female rats; castration abolished the observed difference in metabolism and
      toxicity. In mice, no clear sex differences were noted in metabolism of
      strychnine (Kat74).
          A metabolism scheme is presented in Figure 1 (Annex I).
      Excretion
      The urinary and faecal excretions of radioactivity in rats subcutaneously dosed
      with [3H]-strychnine at 0.5 mg/kg bw, were approximately 30% and 65% of the
      dose in 7 days, respectively. Almost 80% of the radioactivity was excreted
      within 24 hours. Approximately 6% and 3% were excreted unchanged in urine
      and faeces, respectively (Ogu89).
          In humans, a variable amount (1-20%) was excreted unchanged in the urine,
      depending on the amount ingested (Hei92, Muh86, Sga73, Smi90, Yam92).
      Seventy percent of the excretion of the unchanged parent compound occurs in
      the first 6 hours. Trace concentrations persist in urine for up to 5 days after
      ingestion (ACG91, Ray91). Strychnine is very stable and may be found in
      cadavers exhumed many years after death (Muh86).
          At 1 hour after fatal ingestion, no strychnine was detected in urine. Serial
      serum strychnine levels detected at 0.5, 8, 22, 35, and 43 hours decreased from
      3.8 to less than 0.1 mg/L, and this was best described by a (non-linear) single
      compartment model with saturating (Michaelis-Menten) elimination. Assuming
      100% absorption, the following parameters were calculated: absorption rate
111-7 Strychnine
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<pre>      constant (ka=2.68/h), absorption half-life (T½ a=15.5 min), maximum elimination
      rate (Vmax=3.71 mg/kg/h), Michaelis constant (km=1.46 mg/L), and volume of
      distribution (Vd=13 L/kg). When absorption is less complete, then Vd would be
      proportionally less (Hei92). Two other reports described a first-order kinetics of
      elimination from the blood in humans after oral ingestion of strychnine (Edm86,
      Pal97). In the first study, 19 serial serum samples were obtained from 4 to 53
      hours post-ingestion. The elimination after oral ingestion (peak strychnine level
      1.6 mg/L at 4-hour post-ingestion) was found to be consistent with first-order
      kinetics, with an elimination half-life of 10 h (Edm86). In the second study, 18
      serial serum samples were obtained from 20 minutes to 51 hours post-ingestion.
      The highest serum strychnine concentration was 2.1 mg/L and occurred 3 hours
      after ingestion. Disappearance from the blood was best described by first-order
      kinetics, with an elimination half-life of 15.9 hours (Pal97).
      Together, the results indicate that strychnine is readily metabolised and rapidly
      excreted into the urine and faeces (Ogu89).
6     Effects and mechanism of action
      Human data
      Strychnine produces excitation at all levels of the nervous system by selectively
      and competitively blocking the post-synaptic action of the inhibitory
      neurotransmitter glycine. This leads to increased neuronal activity such that any
      sensory stimuli may produce exaggerated reflex arcs, leading to muscular
      spasms, convulsions, or respiratory muscle paralysis (Hei92, Yam92). Early
      symptoms of poisoning occurring within 15-30 min include tremors, slight
      twitching, and stiffness of face and legs. Painful convulsions subsequently
      develop. All sensation is heightened. Convulsive seizures become more frequent
      and death eventually occurs from exhaustion or anoxia during a tetanic seizure.
      Few patients survive more than 5 episodes of convulsions with respiratory arrest
      causing death. Lactic acidosis, renal failure, hyperthermia, and rhabdomyolysis
      occur as secondary effects arising from the severe spasms. In addition, exposure
      to strychnine may lead to photophobia, muscular rigidity, stiffness in joints,
      hysteria, myalgia, lassitude, and headache. Finally, the occurrence of abnormal
      eye movements (horizontal and vertical nystagmus) has been reported (ACG91,
      Bla82, Edm86, Gon90, Hei92, Nis95, Osw77, Per85, Ric94, Smi90, Spa90,
      Tei70, Yam92).
111-8 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>           In human beings, 15-30 mg of strychnine usually proves lethal, but deaths
      have been reported from as little as 5-10 mg, and survival after a dose of 3750
      mg (ACG91, Niy73, Ray91, Ric94). Children may be more susceptible to
      strychnine than adults (ACG91, Ray91). The latter observation contrasts with
      animal data (Hun89). There is a wide individual variability in the manifestations
      of poisoning, as both people surviving doses as large as 3.75 g and people dying
      within 15 minutes after ingestion of 3.4 g (with no signs of the classic spasms or
      convulsions) have been reported (ACG91).
           In accidental, suicidal, or homicidal poisonings with strychnine, toxic doses
      usually produce some muscular tightness and fasciculations. Movements may be
      abrupt and vomiting may occur. With a fatal dose, only 10-20 minutes elapse
      from the time of ingestion to the onset of symptoms, and death occurs in about
      40 minutes (DiP81). Within 15-30 minutes after ingestion, generalised
      convulsions occur that may be clonic initially but quickly become tonic. Patients
      given doses of 5 to 7 mg reported a tightness of their muscles, especially those of
      the neck and jaws; individual muscles, especially those of the little fingers, may
      twitch (Ray91).
           Pathological findings are entirely non-specific. They usually consist of
      petechial haemorrhages and congestion of the organs, indicating combined
      action of severe convulsions and anoxia (Per85, Ray91).
           At autopsy, necrosis was observed throughout the brain probably as a result
      of hypoxic damage (Hei92). Histologically, a human autopsy liver containing
      108 mg/kg strychnine showed an intense formation by lipofuscin pigment
      throughout the liver parenchyma together with small-droplet hyaline change. It
      was suggested that high levels of strychnine in the liver may result in death
      without evidence of physical struggle, whereas low levels result in a delayed
      death probably accompanied by the physical responses commonly attributed to
      strychnine poisoning (Oli79).
           Full recovery from strychnine poisoning was observed after 7-10 days
      (Nis95). In contrast, after recovery from strychnine ingestion, other patients
      suffered from 70% loss of visual acuity together with a left hemiparesia. This is
      considered secondary to severe acidaemia and prolonged hypoxia (Gon90).
      Animal data
      Irritation of tissues and sensitisation was stated not to be associated with
      strychnine (Ray91), but no data were available. Oral LD50 values reported in rats
      ranged from 2.35 to 16 mg/kg bw (ACG91, Ric94). In mice and dogs, oral LD50
      values were 2 and 0.5-1.1 mg/kg bw, respectively (Ric94, Sga73).
111-9 Strychnine
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<pre>            Intraperitoneal LD50 values were 0.9-2.8 mg/kg bw in rats and 1.4-1.8 mg/kg
       bw in mice (ACG91, Lam68). There was no difference in intraperitoneal toxicity
       between the sulphate, benzoate, salicylate, and o-nitrobenzoate expressed in
       terms of their alkaloid content (Ray91). Subcutaneous LD50 values of 1.2-4.0,
       0.47, and 0.46 mg/kg bw have been reported for rats, mice, and dogs,
       respectively. Strychnine was more toxic to female than to male rats after oral,
       subcutaneous, or intraperitoneal administration, a difference that has been
       attributed to a higher rate of metabolism in males. Intravenous LD50 values were
       as low as 0.57-0.96 and 0.39 mg/kg bw in rats and guinea pigs, respectively
       (ACG91, NLM03, Ray91, Ric94, Sei82).
            The circadian toxicity of strychnine (sulphate) was evaluated at 6-hour
       intervals in male Ha/ICR mice, previously conditioned on a 12-hour light (from
       08.00 to 20.00 h) and 12-hour darkness schedule in a controlled environment.
       The highest acute lethality was observed in animals exposed during the light
       phase (at 18.00 h), whereas the lowest toxicity was observed in animals exposed
       during the dark phase (dose resulting in 50% acute lethality 1.57±0.12 and
       1.84±0.20 mg/kg bw, respectively) (Pie77).
            In vitro [3H]-strychnine binding was decreased by 38 and 34% in the medulla
       and spinal cord, respectively, of 24-month-old rats compared to 2-month-old
       rats. Comparison of these age groups after intraperitoneal injection of strychnine
       of 1.75 mg/kg bw showed that senescent animals had a higher incidence of
       seizures and mortality (with faster onset times) compared to young animals
       (seizures 6/8 vs. 0/8, mortality 5/8 vs. 0/8). These differences may be attributed
       to age-related changes in glycinergic neurotransmission (Hun89). The findings
       contrast with data on strychnine poisoning in humans.
            The ED50* for convulsions is remarkably close to the LD50. In male COBS-
       CDI mice, the intraperitoneal LD50 was 1.34 mg/kg, whereas the intraperitoneal
       ED50 for both clonic and tonic convulsions was 1.24 mg/kg bw (Mac77).
       Following single subcutaneous administration of strychnine doses of 0.75, 1.25,
       and 1.50 mg/kg bw to adult CBA mice, convulsions developed in 8/20, 19/20,
       and 21/21 animals, respectively, with an average latency time ranging from 6.1
       to 10.3 minutes. Death occurred in 4/20, 17/20, and 19/21 mice, respectively. No
       sex difference was observed (Man87). Strychnine, intraperitoneally administered
       at 0.5-4 mg/kg bw, dose-dependently produced tonic seizures in male ‘albino
       mice’. The strychnine seizures in mice were potentiated by enhancement of
       noradrenergic neurotransmission (Ama94).
*      ED50: dose at which a described effect is found in 50% of the exposed animals or at which the effect is changed by
       up to 50% compared to the control value.
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<pre>           The convulsing action of strychnine (0.25-4 mg/kg bw, intraperitoneal) was
       studied in 3- to 25-day-old rats. Generalised tonic-clonic seizures occurred in all
       age groups. The convulsing effects increased from day 3 to 18, and decreased
       again from day 25, as indicated by the incidence and latencies of seizures. Lethal
       effects did not occur before day 12 (Kub95).
           In rabbits, strychnine produces a continuous discharge of synchronous waves
       at 30 c/sec at the level of the spinal cord, the cerebellum, and the midbrain; only
       desynchronisation can be noticed in cortical leads (Lon83). Rabbits,
       anaesthetised with urethane and administered doses of strychnine of 400 µg/kg
       bw (route not specified), developed tonic-clonic convulsions. Afterwards, one-
       third of the animals displayed irreversible paralysis of the hind limbs due to
       transverse lesions. Microscopically, only limited degenerative changes were
       observed at 100 days after exposure (Jäg66).
           Injection of strychnine into the brain of cats caused convulsing effects in a
       laminar-specific manner. No effects of strychnine were noted in rats attempting
       to solve a stressful task in either terms of probability or rapidity. Intravenous
       administration to rats inhibited bethanechol-stimulated secretion in the stomach
       and was associated with convulsions. Inhibition did not occur in d-tubocurarine-
       paralysed animals (Ric94). In cats, the strychnine-sensitive synapses appeared to
       be limited only to a subset of cortical neurons driven by somatic inputs (Tre88).
           In anaesthetised and paralysed dogs, administration of strychnine in
       cumulative doses of up to 0.1 to 0.2 mg/kg bw caused significant pressor, as well
       as positive inotropic and chronotropic effects on the heart, which were abolished
       by adrenergic blocking agents. The cardiovascular responses possibly were
       elicited by a central mechanism in contrast to the peripheral inhibitory action of
       strychnine on the sympathetic system (Sof76).
           Autopsy findings were usually entirely non-specific, reflecting only the
       presence of violent convulsions and anoxia. Congestion and small haemorrhages
       may be found in the brain and sometimes in the viscera (Ray91). Convulsive
       doses of strychnine (2.5 mg/kg bw strychnine sulphate, subcutaneously) caused a
       marked depletion of the neurosecretory material from the hypothalamic nuclei as
       well as from the neurohypophysis (Vij72).
           The biochemical mechanism of strychine poisoning is dependent upon
       inhibition of outward sodium ion flux in spinal nerves, manifest as increased
       cerebrospinal excitability, tetanic contractions of the diaphragm and striated
       muscles, sympathetic discharge (accounting for the tachycardia and
       hypertension), and death in respiratory arrest (ACG91).
           Individual subcutaneous injection of dogs and guinea pigs with strychnine at
       0.25 to 0.35 mg/kg bw every 3 to 7 days occasionally produced no increase of
111-11 Strychnine
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<pre>       reflexes but generally produced increased reflexes or tonic-clonic variable
       convulsions (ACG91).
           Based on maximally tolerated single doses, determined in a pilot experiment,
       of 8 and 2.5 mg/kg bw/day for males and females, respectively, male and female
       Sprague-Dawley/SIV rats (n=12/sex/group) were orally (gavage) exposed to
       strychnine (given as a 2% solution of strychnine hydrochloride in distilled water)
       at doses of 0, 5, and 10 or 0 and 2,5 mg/kg bw, respectively, for 28 days. Apart
       from haematological, blood chemistry, urinalysis, ophthalmological,
       macroscopic, and microscopic investigations, animals were submitted to a
       rotating rod test and an electrocardiography before and during treatment. Ten to
       20 minutes after each administration, the animals showed increased muscle tone
       and slight tremors gradually subsiding during the following hour. Mortality
       occurred in 1/12 and 5/12 male rats of the low- and high-dose group,
       respectively, and in 1/12 females. Animals died within 1/2 to 6 hours following
       administration showing tonic muscle contractions and respiratory paralysis and,
       at autopsy, pulmonary oedema and cyanosis. Comparison with control animals
       did not show treatment-related changes in body weight gains and food and water
       consumption or in any of the investigations performed (Sei82).
       The committee did not find further data on repeated-dose toxicity, including
       carcinogenicity or reproduction toxicity, of strychnine.
       Mutagenicity and genotoxicity
       Strychnine was stated to be negative in the gene mutation assay using S.
       typhimurium strains TA98, TA100, TA1537, and TA1538 (no reference or
       details presented (Wür91). It induced a dose-dependent increase in the frequency
       of Trp+ genetic duplications in S. typhimurium strain TS1121 (aroC321 hisG46),
       with very high frequencies at high doses. Doses that were recombinagenic did
       not cause increases in the frequency of base-pair substitution or frameshift
       mutations in the hisG46, hisD3052, or hisC3076 alleles in the same strain
       (Hof87). Strychnine was stated to have induced mitotic recombination and/or
       gene conversion in S. cerevisiae (unpublished results; no details presented)
       (Wür86).
           Strychnine did not induce sex-linked recessive lethal mutations or
       clastogenic effects in D. melanogaster germ cells (unpublished results; no details
       presented) (Wür86). In somatic Drosophila cells, it was negative in the white-
       ivory reversion assay when tested at one single dose of 1.14 mM (Wür91) while
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<pre>       positive results were obtained in he wing-spot assay in DNA repair-proficient
       larvae (Wür86).
            These results suggest that strychnine may be specifically recombinagenic,
       but not mutagenic.
7      Existing guidelines
       The current administrative occupational exposure limit (MAC) for strychnine in
       the Netherlands is 0.15 mg/m3, 8-hour TWA.
            Existing occupational exposure limits for strychnine in some European
       countries and in the USA are summarised in Annex II.
8      Assessment of health hazard
       Strychnine is rapidly absorbed from the gastrointestinal tract and mucous
       membranes. It concentrates primarily in the liver, where it is detoxified by
       oxidation by hepatic microsomal enzymes. Elimination from the blood is
       probably best described by first-order kinetics with an elimination half-life of 10-
       16 hours. It is rapidly excreted in urine and faeces (80% as metabolites, 1-20% as
       parent compound).
            There are no human data from which an inhalation exposure concentration-
       effect relation can be estimated for strychnine. There are no data on irritation and
       sensitisation.
            Strychnine is an acute convulsant poison acting at the level of the spinal cord
       in man and animals, but there is no evidence for cumulative toxicity. Doses as
       low as 5 mg have been fatal for man. The committee did not find data on acute
       toxicity after inhalation or dermal exposure. Acute lethal toxicity data from other
       routes indicate that strychnine is a very toxic compound. Oral LD50 values were
       2.35-16, 2, and 0.5-1.1 mg/kg bw in rats, mice, and dogs, respectively. Values
       found in rats, mice, dogs, or guinea pigs following intraperitoneal, subcutaneous,
       or intravenous administration were 0.9-2.8, ca. 0.5-4.0, and ca. 0.4-1 mg/kg bw,
       respectively. Strychnine was more toxic to female than to male rats after oral,
       subcutaneous, or intraperitoneal administration, a difference that has been
       attributed to a higher rate of metabolism in males.
            Administration via the drinking water of strychnine doses of 2.5
       mg/kg bw/day to female and of 5 and 10 mg/kg bw to male Sprague-Dawley rats
       caused transient increased muscle tone and slight tremors 10-20 minutes after
       each administration. Mortality occurred in 1/12 female and in 1/12 low-dose and
       5/12 high-dose male rats, animals showing tonic muscle contractions, respiratory
111-13 Strychnine
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<pre>       paralysis, pulmonary oedema, and cyanosis. In the surviving animals, no changes
       were seen at haematological, blood chemistry, urinalysis, ophthalmological,
       electrocariographic, macroscopic, and microscopic investigations and in a
       rotating rod test.
            Strychnine induced genetic duplications in S. typhimurium, in D.
       melanogaster, and in yeast. It was negative in the D. melanogaster white-ivory
       reversion test. It was negative in mutagenicity assays in S. typhimurium. These
       results suggest that strychnine may be specifically recombinagenic, but not
       mutagenic.
            There are no further data available on repeated-dose toxicity of strychnine,
       including carcinogenicity and reproduction toxicity.
       The committee considers the database on strychnine too poor to justify
       recommendation of a health-based occupational exposure limit.
       In view of the occurrence of deaths in humans at doses as low as 5 mg and the
       present MAC-value of 0.15 mg/m3, 8-hour TWA, (equivalent to a dose of 1.5 mg
       per day for workers, assuming a respiratory volume of 10 m3 per working day),
       the committee concludes that the present MAC-value may be too high.
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<pre>       Annex I
         Figure 1 Metabolism scheme for strychnine in rats (Mis85, Ogu89, Tan90, Tan91a).
111-19 Strychnine
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<pre>              Annex II
Occupational exposure limits for strychnine 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        -           0.15          8h                   administrative             SZW03
Employment
Germany
- AGS                                   -           0.15c         8h                                              TRG00
- DFG MAK-Kommission                    -           -d            8h                                              DFG03
Great-Britain
- HSE                                   -           0.15          8h                   OES                        HSE02
                                                    0.45          15 min
Sweden                                  -           -                                                             Swe00
Denmark                                 -           0.15          ceiling                                         Arb02
USA
- ACGIH                                 -           0.15          8h                   TLV                        ACG03b
- OSHA                                  -           0.15          8h                   PEL                        ACG03a
- NIOSH                                 -           0.15          10 h                 REL                        ACG03b
European Union
- SCOEL                                 -           -                                                             EC03
a
     S = skin notation; which mean 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
     The inhalable fraction of the aerosol.
d
     Listed among compounds for which studies of the effects in man or experimental animals have yielded insufficient
     information for the establishment of MAK values.
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