<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>Sulphuryl difluoride
(CAS No: 2699-79-8)
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/141 The Hague, November 9, 2004
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<pre>Preferred citation:
Health Council of the Netherlands: Committee on Updating of Occupational
Exposure Limits. Sulphuryl difluoride; Health-based Reassessment of
Administrative Occupational Exposure Limits. The Hague: Health Council of the
Netherlands, 2004; 2000/15OSH/141.
all rights reserved
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<pre>1     Introduction
      The present document contains the assessment of the health hazard of sulphuryl
      difluoride 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 I Gubbels-van Hal, M.Sc. (NOTOX BV,
      ‘s-Hertogenbosch, the Netherlands).
           The evaluation of the toxicity of sulphuryl difluoride has been based on
      reviews published by the American Conference of Industrial Hygienists
      (ACG99), the US Environmental Protection Agency (EPA92), and Nitschke and
      Eisenbrandt in the ‘Handbook of Pesticide Toxicology’ (Nit01). Where relevant,
      the original publications were reviewed and evaluated as will be indicated in the
      text. In addition, in September 1999, literature was searched in the databases
      Toxline, Medline, and Chemical Abstracts, covering the periods 1965 until
      September 1999, 1966 until September 1999, and 1967 until September 1999,
      respectively, and using the following key words: 2699-79-8. The final literature
      search was carried out in Toxline and Medline in October 2003.
           In October 2003, the President of the Health Council released a draft of the
      document for public review. Comments were received from the following
      individuals and organisations: R Billington (Dow AgroSciences, Abingdon,
      UK). These comments were taken into account in deciding on the final version of
      the document.
2     Identity
      name                       :  sulphuryl difluoride
      synonyms                   :  sulphuryl fluoride; sulphuryl difluoride; sulfuryl fluoride;
                                    sulfur difluoride dioxide; sulfonyl fluoride; sulfuric
                                    oxyfluoride vikane, vikane fumigant
      molecular formula          :  F2O2S
      structural formula         :  -
      CAS number                 :  2699-79-8
      Data from ACG99, NLM01.
141-3 Sulphuryl difluoride
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<pre>3     Physical and chemical properties
      molecular weight             :    102.06
      melting point                 :   -136oC
      boiling point                 :   -55oC
      flash point                  :    not available
      vapour pressure               :   at 21oC: 1700 kPa
      solubility in water          :    750 mg/L
      log Poctanol/water            :   0.41 (estimated)
      conversion factors            :   20oC, 101.3 kPa: 1 ppm = 4.25 mg/m3
                                                         1 mg/m3 = 0.24 ppm
      Data from ACG99, NLM01, http://www.syrres.com/esc/est_kowdemo.htm.
      Sulphuryl difluoride is a colourless, odourless, non-flammable gas (ACG99).
4     Uses
      Sulphuryl difluoride is an inorganic gas fumigant used to control a wide variety
      of household pests, including cockroaches, rodents, clothes moths, bedbugs,
      drywood termites, and carpet beetles. Due to the fact that it has no odour,
      chlorpicrin, an irritant gas, is added as a warning material (ACG99, Nit01). For
      structural fumigation, the building to be fumigated is covered with large vinyl
      tarpaulins, sealing the building. The fumigant is introduced into the unoccupied
      house via a tube or hose, and fumigators leave the site. Documented air
      concentrations for sulphuryl difluoride during this operation varied from 16,150-
      161,500 mg/m3 (3800-38,000 ppm) of house area, and concentrations within 0.6
      m of the tarpaulins during the opening process in houses were up to 106 and
      1063 mg/m3 (25-250 ppm), respectively (Ang86).
           According to the on-line database of the Dutch Pesticide Authorisation Board
      (CTB)*, sulphuryl difluoride is at the present not permitted for its use as an
      active ingredient in pesticides in the Netherlands.
5     Biotransformation and kinetics
      In humans, the normal background levels for plasma fluoride range between 0.01
      and 0.2 mg/L. Fluoride levels in the blood of 2 individuals exposed to unknown,
*     at: http://www.ctb-wageningen.nl.
141-4 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>      but lethal concentrations of sulphuryl difluoride were 50 mg/L (24 to 36 hours
      post-mortem) and 20 mg/L (ante-mortem), respectively (Sch86).
          Serum fluoride levels have been elevated compared to control values in
      several experimental species, including mice, rats, rabbits, and dogs, following
      acute or subchronic exposure to sulphuryl difluoride (Eis89, Nit86, Nit91,
      Nit93).
      The biotransformation and kinetics of sulphuryl difluoride were studied in F344
      rats exposed to concentrations of 35S-labelled compound of 127,5 and 1275
      mg/m3 (30 and 300 ppm), for 4 hours, and reported in an abstract. Sulphuryl
      difluoride was rapidly absorbed. The pulmonary absorption was 11-14%*.
      Maximum concentrations of radioactivity in plasma and red blood cells occurred
      near the end of the 4-hour exposure period. The radioactivity was cleared from
      the plasma and red blood cells with initial halve-lives of 2.5 and 1-2.5 hours after
      exposure to 127.5 and 1275 mg/m3 (30 and 300 ppm), respectively. The terminal
      half-life of radioactivity was 2.5-fold longer in red blood cells than in plasma.
      The radiolabel was rapidly excreted, mainly via the urine. Radiochemical
      profiles of blood and urine did not indicate presence of parent compound in the
      blood and suggested initial hydrolysis into fluorosulphate, with release of
      fluoride, and subsequent hydrolysis into sulphate, with release of another
      fluoride. Analysis of tissues 7 days post-exposure, the end of the experiment,
      showed an even distribution among tissue, which was ascribed to incorporation
      of radiolabelled S into amino acids. The lungs had the highest level of
      radioactivity and also the nasal turbinates had detectable levels. Red blood cell
      levels were still elevated. Of the non-respiratory tissues, highly perfused tissues
      such as spleen and kidneys had the higher 35S concentrations (Men03).
6     Effects and mechanism of action
      Human data
      A 30-year-old male was hospitalised after exposure to sulphuryl difluoride
      containing 1% chloropicrin for about 4 hours under conditions of limited
      ventilation. Although not measured at the time of exposure, the concentration of
      sulphuryl difluoride was assumed to be at least 21 mg/m3 (5 ppm). Effects
      experienced consisted of nausea, vomiting, crampy abdominal pain, and pruritis.
      He was found to have reddened conjunctivae and pharyngeal and nasal mucosa,
*     R Billington, Dow AgroSciences, Abingdon, UK; personal communication.
141-5 Sulphuryl difluoride
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<pre>      diffuse rhonchi, and paraesthesia of the lateral border of the right leg up to 4 days
      after exposure. On the day of hospitalisation, a low serum potassium
      concentration was measured, which was normalised after 2 days. One day after
      admission, qualitative analyses of serum fluoride was positive, serum lactate
      dehydrogenase was normal, but serum alkaline phosphatase and serum
      phosphorus levels were below their lower normal limits. After being released
      from hospital on the 4th day after admission, he remained complaining about
      scratching of the throat, flatulence, and difficulty in reading. Serum biochemistry
      results were within normal levels on day 9 after admission (Tax66).
          Three cases of suicide by exposure to sulphuryl difluoride were reported. In
      one case, a 29-year-old man was found dead in his apartment, which had been
      fumigated with sulphuryl difluoride the previous day. In the second case, a
      22-year-old man was found dead next to an open sulphuryl difluoride container
      in a warehouse. Both men were found dead with bloody froth covering their
      mouth, and both had faecal soiling suggestive of parasympathetic stimulation.
      Post-mortem examination revealed congestion of the mucosa of the respiratory
      tract and the lungs. In one of these cases, the serosa were dotted with petechiae.
      A third case concerned a 19-year-old Arabic woman who was found unconscious
      after re-entry in her residence on the afternoon of the fumigation. Upon arrival in
      the hospital, she was alert, responsive, coughing, and complaining of chest
      discomfort. She appeared to be hypotensive. After 6 hours, she became
      hyperexcitable, hyperventilated, and developed tachycardia. A few hours later,
      she died after developing carpopedal tetany and cardiac dysrhythmias. The main
      autopsy finding was pulmonary oedema, with congestion and petechiae of the
      visceral pleura. Blood fluoride concentrations were 50 mg/L (24 to 36 hours
      post-mortem) and 20 mg/L (ante-mortem) in cases 1 and 3, respectively (Sch86).
          Two other fatalities have been reported for an elderly couple, who returned to
      their home approximately 5-8 hours after their house was ventilated to remove
      sulphuryl difluoride, remaining after a 24-hour fumigation of their home. The
      man died after one day. Symptoms included dyspnoea, restlessness, cough, and
      seizure followed by cardio-pulmonary arrest. The wife experienced weakness,
      nausea, vomiting, dyspnoea, intermittent chills, and anorexia. In hospital, severe
      hypoxaemia and diffuse pulmonary infiltrates were seen. Four days later, she
      died after ventricular fibrillation (Nuc87).
          In an overview of 1065 cases of confirmed occupational illnesses and
      injuries, potentially related to pesticides, 5 cases of systemic poisoning were
      ascribed to due to exposure to sulphuryl difluoride in California in 1986. No
      further details were given (Edm87).
141-6 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>          A retrospective investigation was carried out on 24 workers in soil and
      structure fumigation in California, using sulphuryl difluoride as a fumigant
      during 80% or more of the applications (mean: 92%; the other fumigant being
      methyl bromide). Personal air samples in the breathing zone of 6 fumigators after
      application of approximately 16,000 mg/m3 (3800 ppm) of house area were on
      average 22 mg/m3 (5 ppm) (2-hour TWA) with a maximum of 37 mg/m3 (8.7
      ppm). Workers were subjected to neurobehavioural testing, including tests on
      motor activity, nerve conduction velocity, grip strength, eye-hand coordination,
      sensory aspects (tactile sensitivity, eye-movements and vision, noise-stimulus
      effects), and cognition (memory, association and discrimination). Comparison
      with a reference group (n=29), which mostly has sedentary and less strenuous
      jobs and differed with respect to age, race, educational level, and use of alcohol,
      prescription drugs, and illegal drugs, did not show any statistically significant
      difference in results of any of about 70 tests (Ang86).
          A cross-sectional study was conducted, in south Florida (USA), on 123 male
      structural fumigation workers, engaged in the application of sulphuryl difluoride
      and/or methyl bromide. A referent group, consisting of 120 males, was recruited
      by asking the fumigators to identify a male friend or neighbour who was of
      similar age and had never worked with or been poisoned by pesticides. Only 11
      workers in this group had been working with sulphuryl difluoride only, the rest
      with both sulphuryl difluoride and methyl bromide. The mean application time
      was less than 2 hours/day. The median lifetime duration of employment in
      sulphuryl difluoride fumigation was 2.85 years (range: 0.11-20.5 years) and in
      methyl bromide fumigation 1.2 years (range: 0-22 years). Based on personal
      airborne sampling results of another cohort of fumigation workers conducted in
      1991, it was expected that air concentrations to sulphuryl difluoride over the year
      preceding examination were far below 20 mg/m3 (5 ppm) and in most cases even
      below the analytical limit of detection. Participants in the investigation were
      subjected to standardised questionnaires, tests of neurological function, and a
      physical examination. Sulphuryl difluoride employment was associated with a
      significantly reduced performance on the Pattern Memory test, while there was
      no impairment in the other memory-related tests (Pattern Memory recall time,
      Symbol Digit, Symbol Digit recall score, Serial Digit Learning score) and on
      olfactory testing compared to the reference group. In addition, fumigation
      workers had significantly reduced performance on tests in median nerve function
      (nerve motor conduction velocity; Santa Ana Dexterity Test of the dominant
      hand - a non-computerised test of psychomotor function), but these peripheral
      nerve effects were likely caused by ergonomic stresses rather than with sulphuryl
      exposure (Cal98). The committee notices methodological limitations of the study
141-7 Sulphuryl difluoride
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<pre>      design and of some of the tests used. Also, no more statistically significant
      positive findings (less than 10%) were observed than would be expected given
      the large number comparisons made. Further, concomitant exposure to methyl
      bromide, a neurotoxic compound, cannot be excluded. Therefore, the committee
      is of the opinion that the results of this study are better explained by bias,
      confounding, or change than by exposure to sulphuryl chloride and that they are
      not indicative of any neurotoxic potential.
          In another case-control study, no increased risk of developing brain tumours
      was found for workers working with vikane in termite treatment (Pog97).
      Animal data
      Acute toxicity
      The 4-hour LC50 values of sulphuryl difluoride were 4769 and 4212 mg/m3 (1122
      and 991 ppm) in male and female Fischer 344 rats, respectively. Macroscopic
      and microscopic examination revealed primarily changes in the upper and lower
      respiratory tract and, in addition, liver, kidney, heart, and spleen effects (Mil80).
      The 1-hour LC50 values were 15,853 and 12,835 mg/m3 (3730 and 3020 ppm) for
      male and female Sprague-Dawley rats, respectively (Ver77). In B6C3F1 mice,
      the 4-hour inhalation LC50 values were between 1700 and 2550 mg/m3 (400 and
      600 ppm) for both males and females, and in CD-1 mice, 2805 and 2729 mg/m3
      (660 and 642 ppm) for males and females, respectively (Nit89, Nit90). In an
      older study, it was reported that rabbits were less sensitive and mice more
      sensitive to acute effects of sulphuryl difluoride than rats. When rats (n=5-15)
      and rabbits (n=1-5) were exposed during 60 minutes to 8500-42,500 mg/m3
      (2000-10,000 ppm) and mice (n=10-20) to 4250-21,250 mg/m3 (1000-5000
      ppm), symptoms observed consisted of convulsions and flat body posture. Cause
      of death was blockage of the respiratory muscles. Macroscopic examinations
      showed congestion of the lungs and haemorrhageous alveolitis (Tru73).
          The 4-hour dermal LC50 of sulphuryl difluoride vapour in rats was greater
      than 40,800 mg/m3 (9600 ppm). The only clinical effects were
      chromodacryorrhea and faecal soiling. There was no evidence of body tremors.
      Macroscopic or microscopic examination of skin and brain did not reveal
      treatment-related changes (Bra90).
           The acute oral LD50 of sulphuryl difluoride was 100 mg/kg bw in both rats
      and guinea pigs (Lew96).
          In a study, designed to understand the mode of action of sulphuryl difluoride,
      male rats (n=5/group) were exposed to ca. 17,000, 42,500, 85,000, or 170,000
141-8 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>      mg/m3 (4000-40,000 ppm) until incapacitation (i.e., not longer capable of
      walking on a rotating activity wheel), after which exposures were terminated. A
      dose-related decrease in the time to incapacitation was observed as the sulphuryl
      difluoride exposure increased. At the 2 highest concentrations, rats were
      incapacitated within 12 minutes and died within 10 minutes after terminating
      exposure. At 42,500 or 17,000 mg/m3, incapacitation was observed within 18 or
      46 minutes, respectively, and the survival times were 61 or 150 minutes after
      incapacitation occurred, respectively. Symptoms observed consisted of clinging
      to the floor or side and ride the wheel rather than walk. The rats made postural
      adjustments, while clinging to the screen, to remain in an upward position. Rats
      exposed to the 3 highest concentrations developed cyanosis shortly after
      exposure occurred. Tonic convulsions were observed during exposure in 3 out of
      5 animals in the lowest concentration group, but after exposure in most animals
      of the other groups. Pulmonary congestion appeared to contribute significantly to
      the death of the animals. According to Nitschke et al., the responses observed
      were probably related to fluoride toxicity. Pre-treatment with calcium gluconate
      (a known fluoride ion antagonist) increased the survival in rats at 17,000 mg/m3,
      but not at 42,500 mg/m3. However, there was no apparent protection against
      convulsions. At both exposure concentrations, rats had increased serum fluoride
      levels and decreased serum cholinesterase and magnesium levels, which were
      statistically significant in a dose-related fashion, either with or without pre-
      treatment with calcium gluconate. Administration of calcium gluconate resulted
      in about 10% increase in serum calcium levels, but did not affect fluoride or
      magnesium levels. Pre-treatment with phenobarbital was effective in decreasing
      the effects of exposure to the lowest exposure concentration. All 5 animals
      survived without any evidence of convulsions (Nit86).
          Exposure of female rats to 0, 425, or 1275 mg/m3 (0, 100, 300 ppm)
      sulphuryl difluoride for 2 consecutive days (6 hours/day) did not result in any
      changes in a functional observational test battery, grip performance, landing foot
      splay, motor activity, and a battery of electrodiagnostic tests, including flash
      evoked potentials, somatosensory evoked potentials, and auditory brainstem
      responses, when compared to pre-exposure performance (Alb93).
      Subacute and subchronic toxicity
      Fischer 344 rats (n=5/sex/group) were exposed to concentrations of sulphuryl
      difluoride of 0, 425, 1275, and 2550 mg/m3 (0, 100, 300, 600 ppm), 6 hours/day,
      5 days/week, for 2 weeks. At the high exposure, all male and 4 female rats died
      after a period of reduced activity and lethargy. These rats had severe kidney
141-9 Sulphuryl difluoride
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<pre>       lesions, including papillary necrosis, dilation of collecting ducts, and reduced
       basophilic cytoplasm, and patchy segments in the epithelial cells of the
       descending proximal tubules. Respiratory effects observed in these animals
       consisted of pulmonary oedema and/or haemorrhage or fibrin within the alveoli
       (with thrombi in the capillaries). Other observations included visceral
       congestion, stomach erosion, metastatic mineralisation, hypertrophy of the
       adrenal cortex, and necrosis and depletion of the lymphoid tissue in thymus,
       spleen, and lymph nodes. The one surviving female animal had a significantly
       decreased body weight at the end of the study and kidney effects similar to those
       found in the animals that died, as well as debilitation and dehydration,
       significantly increased relative heart and kidney weights, significantly decreased
       thymus weight, elevated urea nitrogen levels, glucosuria, significant increase in
       mean total white blood cell counts, inflammation and multifocal ulceration of the
       nasal mucosa with bronchoalveolar inflammation and myeloid hyperplasia of the
       bone marrow. Among the male and female animals of 1275-mg/m3 group,
       papillary hyperplasia and hyperplasia of the collecting ducts and a significant
       increase in the mean total white blood cell counts became apparent. In the
       females, significantly increased relative kidney and heart weights and
       significantly decreased thymus weights (both absolute and relative) were seen. In
       the low-exposure group, there was only a significant increase in the mean total
       white blood cell counts in females, which was not of toxicological significance.
       The NOAEL was 425 mg/m3 (Eis89).
           In a subsequent 13-week study, rats (n=10/sex/group) were exposed to
       sulphuryl difluoride concentrations of 0, 127.5, 425, and 1275 mg/m3 (0, 30, 100,
       300 ppm), 6 hours/day, 5 days/week. No treatment-related deaths were reported.
       In rats exposed to 1275 mg/m3, effects seen consisted of a significantly decreased
       body weight gain, vacuolisation of area of the caudate-putamen nuclei (no
       further specification), decrease in microscopic protein droplets (α2µ-globulin) in
       the convoluted tubules of the kidney (males only), hyperplasia of the renal
       collecting ducts (females only), significantly decreased urinary gravity (males
       only), pale foci on the pleural surface of the lungs (subpleural histiocytosis),
       inflammation of the nasal, respiratory, and olfactory mucosa with mucopurulent
       exudate in the nasal passages, and mottled teeth (dental fluorosis). Serum
       fluoride levels were increased compared to control animals, but the difference
       was not statistically significant. Apart from mottled teeth (dental fluorosis) in
       rats exposed to 425 mg/m3 (100 ppm), no effects were observed in the animals
       exposed to 425 and 127.5 mg/m3 (100 and 30 ppm) (Eis89).
           Because of the neurological effects seen in acute and 2-week studies,
       additional groups of rats (n=7/sex/group) were included in the above-discussed
141-10 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>       13-week study to evaluate the neurological function following exposure to
       sulphuryl difluoride (at concentrations of 127.5, 425 and 1275 mg/m3). After 8-9
       weeks, epidural electrodes were implanted into the skull of the animals. A
       battery of neurological tests was conducted on all animals at 12 hours after the
       end of the 13-week exposure, except on 2 animals/sex of the high-exposure and
       control groups, which were allowed to recover for approximately 2 months for
       the assessment of an auditory brainstem response. Body weight gain was reduced
       in males and females of the high-exposure group. Dental fluorosis was seen in all
       animals in the mid- and high-exposure groups. No effects were seen in a
       functional observation test battery and hind limb grip strength testing in any of
       the exposure groups. In the high-exposure male and female groups,
       electrophysiological data collected 42 to 48 hours after the last exposure showed
       a significant increase in the latency time to flash and somatosensory evoked
       responses and to auditory brainstem response. Cortical flicker fusion was slightly
       altered in high-concentration males and females. No effect on caudal nerve
       action potentials was seen at any treatment. At 425 mg/m3, flash evoked potential
       and auditory brainstem response were slightly, but significantly altered
       (significance was attributed to females). At necropsy, pale foci on pleural
       surfaces, vacuolisation in the caudate putamen (not further specified), nasal
       tissue inflammation, mild multifocal inflammation of the lungs, hyperplasia of
       renal collecting ducts (females only), and a decrease in protein droplets in the
       cortical tubules of the kidney (males only) were seen in high-concentration
       animals. At 425 mg/m3, pale foci on pleural surfaces were reported for one male
       and one female. No brain lesions were found at this exposure level. Auditory
       brainstem responses and brain histology were within normal limits in the 2
       animals/sex of the high-exposure group after an 8-week recovery period,
       indicating that the effects were, at least to a great extent, reversible. The NOAEL
       for neurological effects was 127.5 mg/m3 (30 ppm) (Mat88).
           In a 2-generation inhalation reproduction toxicity study (see also Section
       ‘Reproduction toxicity’), parental (F0) rats (Sprague-Dawley; n=30/sex/group)
       were exposed to concentrations of sulphuryl difluoride of 0, 21, 85, or 637.5
       mg/m3 (0, 5, 20, 150 ppm), 6 hours/day, 5 days/week, prior to meeting, i.e., 10
       weeks, and 6 hours/day, 7 days/week during mating, gestation, and lactation, i.e.,
       another 10 weeks. No treatment-related mortality or clinical signs of toxicity
       were observed in any of the exposure groups. Statistically significant decreases
       in body weight were seen in the high-concentration group only: in the male
       animals from day 14 through the end of the exposure period and in the females
       from day 14 to day 56 and during gestational days 7-14 and 1-21 and lactation
       days 1, 4, and 7. At post-mortem macroscopic examinations, there were dental
141-11 Sulphuryl difluoride
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<pre>       fluorosis (‘dark lower incisors’) in 27/30 males and 29/30 females of the high-
       concentration group and multiple, round, pale or grey foci in the lungs in 30/30
       males and 18/30 females of the high-concentration group and in 5/30 males of
       the mid-concentration group. Microscopically, lesions of the lungs and brain
       were observed. The lung lesions consisted of aggregates of alveolar
       macrophages, which showed a dose-related increase in incidence and severity
       and which were graded as ‘very slight’ (i.e., 1 to 3 small aggregates), ‘slight’ (3
       to 6 usually larger aggregates), and ‘moderate’ (more than 6 large aggregates).
       These aggregates were observed in 3 (all ‘very slight’), 5 (all ‘very slight’), 11
       (10 ‘very slight’; 1 ‘slight’), and 30 (6 ‘very slight’; 17 ‘slight’; 7 ‘moderate)
       males of the control, low-, mid-, and high-concentration group, respectively, and
       in 7 (all ‘very slight’), 10 (9 ‘very slight’; 1 ‘slight’), 19 (all ‘very slight’), and 30
       (1 ‘very slight’; 16 ‘slight’; 13 ‘moderate’) females of the control, low-, mid- and
       high-concentration group, respectively. Especially in the animals of the high-
       concentration group, the presence of these aggregates was accompanied by
       chronic inflammation (graded ass ‘very slight’ in 9 males and 19 females and as
       ‘slight’ in 5 males and 6 females). The brain lesions were limited to the high-
       concentration group and consisted of bilaterally symmetrical vacuolation of the
       caudate putamen myelinated fiber tracts in 11 males (graded as ‘very slight’) and
       14 females (‘slight’). Based on the increased incidence of aggregates of alveolar
       macrophages, the (parental) NOAEL was placed at 21 mg/m3 (5 ppm) (Bre92,
       Bre93).
       When mice (CD-1; n=5/sex/group) were exposed to sulphuryl difluoride at
       concentrations of 0, 127.5, 425, or 1275 mg/m3 (0, 30, 100, 300 ppm), 6
       hours/day, 5 days/week, for 2 weeks, all males and 4 females of the high-
       exposure group died during the second week. Clinical signs were tremors and
       body weight loss. Microscopic examination revealed vacuolation in the
       cerebellum and/or medulla in the high-and mid-exposure groups. The NOAEL
       was 127.5 mg/m3 (30 ppm) (Nit95).
           In an unpublished 13-week study, CD-1 mice (n=14/sex/group) were exposed
       to 0, 4.25, 127.5, or 425 mg/m3 (0, 10, 30, 100 ppm), 6 hours/day, 5 days/week.
       At the highest concentration, a 10% decrease in body weight was observed in
       both males and females. No treatment-related changes in haematology, clinical
       chemistry, organ weight, or gross pathology were observed. Serum fluoride
       levels were significantly increased in a dose-related fashion in the mid-and high-
       exposure groups (males and females). Microscopic examination revealed effects
       on the brain and the thyroid gland in males and females exposed to 425 mg/m3.
       Changes in the cerebrum consisted of slight vacuolation in the external capsule
141-12 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>       and the caudate putamen. Vacuolation was also observed in the thalamus/
       hypothalamus region of these animals. Microscopic changes in the thyroid gland
       were characterised by very slight hypertrophy of the follicular epithelial cells
       associated with a decrease in the amount of colloid present. The NOAEL was
       127.5 mg/m3 (30 ppm) (Nit93).
       When New Zealand white rabbits (n=3/sex/group) were exposed to sulphuryl
       difluoride at concentrations of 0, 425, 1275, and 2550 mg/m3 (0, 100, 300, 600
       ppm), 6 hours/day, 5 days/week, for 2 weeks, 2 females of the high-exposure
       group were euthanised after they were found with fractures of the tibia and
       vertebra, respectively. For one of these females, this fracture resulted from a
       convulsion. The only other clinical sign observed in males and females of the
       high-exposure group consisted of hyperactivity. Slightly decreased body weights
       were observed in some rabbits. At necropsy, effects on the respiratory tract
       (moderate inflammation of nasal mucosa with mucopurulent exudate in the nasal
       cavities; inflammation of the trachea in a few animals; acute inflammation of
       bronchi and bronchioles in the female survivor), the nervous system
       (vacuolisation in globus pallidus and basal nuclei in the putamen; effects on
       myelinated tracts; malacia with gliosis and demyelination (no more detailed
       description provided), and the liver (decreased weight, - not specified - altered
       cytoplasmic homogeneity of liver cells) were seen, as well as decreased serum
       albumin and lymphoid hyperplasia in mediastinal lymph nodes and the spleen.
       The latter effects were considered to be a haematopoietic reaction on the
       inflammation of the respiratory tract. In the animals exposed to 1275 mg/m3,
       there were slightly decreased body and liver weights in some animals, moderate
       inflammation of nasal mucosa with mucopurulent exudate in the nasal cavities in
       most animals, and - probably - similar haematopoietic responses as found in the
       high-exposure group. No effects were seen in the animals exposed to 425 mg/m3
       (100 ppm), which was considered to be the NOAEL of the study (Eis89).
            In a subsequent 13-week study, rabbits (n=7/sex/group) were exposed
       initially to 0, 127.5, 425 and 2550 mg/m3 (0, 30, 100, 300 ppm), 5 days/week, 6
       hours/day, but clinical effects seen in high-exposure animals (posterior paralysis
       attributing to a fractured vertebra in 1 female and convulsions in 1 male and 1
       female) caused reduction of the concentration to 1275 mg/m3 after 9 days,
       leading to a 90-day time-weighted average concentration of ca. 1432 mg/m3 (337
       ppm). The female with posterior paralysis was euthanised. After the decrease of
       the exposure level, no further clinical signs were observed. A dose-related
       decrease of body weight gain throughout the study period was seen in animals
       exposed to the high and mid concentrations, reaching statistical significance in
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<pre>       high-exposure males only. Absolute and relative liver weights were significantly
       decreased in female rabbits of the high-exposure group, and absolute liver weight
       in male rabbits at 425 mg/m3. At the high concentration, brain lesions seen in
       both males and females consisted of microscopic changes in the area of the
       putamen, globus pallidus, and the internal and external capsule of the cerebrum,
       malacia, and slight vacuolisation accompanied by gliosis and endothelial cell
       hypertrophy. Moderate vacuolation of the cerebrum was seen in a single female
       at 425 mg/m3. Treatment-related inflammation of the nasal mucosa with
       mucopurulent exudate and hypertrophy and hyperplasia of respiratory epithelium
       were observed in the respiratory tract of all high-exposure rabbits. Degeneration
       of olfactory epithelium was associated with the inflammation in 2 males and 3
       females of the high-exposure group. White blood cell counts for male rabbits
       exposed to 1432 mg/m3 were significantly increased. Serum fluoride levels were
       significantly increased in a dose-related fashion in all treatment groups,
       compared with the controls. The NOAEL was 127.5 mg/m3 (30 ppm) (Eis89).
       In beagle dogs (n=1/sex/group) exposed to concentrations of 0, 127.5, 425, or
       1275 mg/m3 (0, 30, 100, 300 ppm), 6 hours/day, 5 days/week, for 2 weeks,
       clinical signs observed at the high concentration were infrequent intermittent
       episodes of tremors and tetany in both dogs, beginning with the 5th exposure.
       These effects were rapidly reversible when exposure was terminated and even
       during the exposure period. Body weight loss was observed in the female animal.
       Serum fluoride levels of dogs exposed to the 2 highest concentrations were
       increased 2- to 4-fold compared with the control values. No changes were
       observed in serum calcium levels. There were no exposure-related changes in
       haematology, organ weights, or gross pathology in any of the treated groups.
       Microscopic examination revealed inflammatory changes in the nasal turbinates
       of dogs exposed to the high concentration. No abnormalities were seen in tissues
       from the cerebral cortex, brainstem, cerebellum, and medulla oblongata. The
       NOAEL was 425 mg/m3 (100 ppm) (Nit91).
           In a subsequent unpublished study, groups of beagle dogs (n=4/sex/group)
       were exposed to concentrations of 0, 127.5, 425, or 850 mg/m3 (0, 30, 100, 200
       ppm), 6 hours/day, 5 days/week, for 13 weeks. On exposure day 19, one high-
       exposed dog showed tremors, tetany, salivation, and incoordination at 75 minutes
       after the beginning of exposure. These effects were reversible and were not
       observed during the remainder of the study. At the end of the study, the mean
       body weights of male and female dogs were slightly reduced at the highest
       concentration. There were no treatment-related changes in haematology, clinical
       chemistry, organ weight, or gross pathology. Microscopic examination revealed a
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<pre>       single small bilaterally symmetrical focal change in the putamen of the midbrain
       of one male and one female dog, exposed to the highest concentration. This
       change was characterised by vacuolation, gliosis, perivascular cuffing, and
       hypertrophy of endothelial cells. No other treatment-related microscopic changes
       were observed. The NOAEL was 425 mg/m3 (100 ppm) (Nit92).
           An unpublished 1-year toxicity study was conducted with beagle dogs
       (n=4/sex/group) exposed to concentrations of 0, 85, 340, or 850 mg/m3 (0, 20,
       80, 200), 6 hours/day, 5 days/week. In the high-exposure group, a decrease in
       body weight was observed leading to morbidity and death (not further specified).
       At approximately 9 months of exposure, high-exposed animals started to show
       clinical signs, including laboured breathing, shallow and rapid respiration, and
       pale and blue mucous membranes, eventually leading to death. No treatment-
       related clinical signs were observed in the dogs exposed to 85 or 340 mg/m3.
       Gross examination of the high-exposure dogs revealed dark-coloured lungs that
       appeared to be consolidated. No macroscopic abnormalities were seen in any of
       the low- and mid-exposure groups. Microscopic changes in the high-exposure
       dogs were noted in the lungs, brain, thyroid, and canine teeth, and in the lungs
       and canine teeth of the dogs exposed to 340 mg/m3. The pulmonary changes
       were a chronic active inflammation that primarily involved the peripheral
       regions of the lung. An increased number of alveolar macrophages was observed
       in scattered alveoli. In the more advanced stages of inflammation, these foci
       apparently increased in size, and hypertrophied type II pneumocytes were
       observed. In the more severe cases, a focal thickening of the pleura and
       interalveolar septae was observed as well. In dogs exposed to 340 mg/m3, a very
       slight increase in the aggregate of alveolar macrophages was observed, with
       several dogs showing a very slight degree of chronic active inflammation. In the
       brain of 5 out of the 8 high-exposure dogs, a focus of malacia was noted. No
       other brain abnormalities were found in any of the treated groups compared with
       the controls. Effects found in the thyroid gland consisted of slight hypertrophy of
       the follicular epithelium in the high-exposure dogs. There were no exposure-
       related effects noted in dogs exposed to the lowest level, and consequently the
       NOAEL was 85 mg/m3 (20 ppm) (Qua93a).
       Chronic toxicity and carcinogenicity
       Groups of Fischer 344 rats (n=50/sex/group) were exposed to sulphuryl difuoride
       at concentrations of 0, 21, 85, and 340 mg/m3 (0, 5, 20, 80 ppm), 6 hours/day, 5
       days/week, for 24 months. Simultaneously with this core study, satellite groups
       of 15 rats/sex/exposure level were included that were sacrificed after 12 months
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<pre>       for the assessment of general toxicity (haematology, clinical chemistry,
       urinalysis, organ weights, and macroscopic and microscopic examination) and
       neurotoxicity (functional observation battery, motor activity, and microscopic
       examination of nervous system tissues in 5 animals/sex/group; see below:
       Spe94). In the core study, mortality of rats in the treated groups was similar to the
       control group during the first 16 months, but thereafter strongly increased in the
       high-exposure group. At the end of the 24 months, mortality amounted to 18, 22,
       and 50 males and 13, 12, and 50 females, in the low-, mid-, and high-exposure
       groups, respectively, vs. 21 males and 25 females in the control group. Causes of
       death included normal age-related diseases for the animals of the control and the
       low- and mid-exposure groups. For the high-exposure group, most deaths were
       related to chronic renal disease. In the high-exposure group, body weights were
       significantly decreased in males and females after 400 to 500 days exposure.
       Haematology parameters were considered to be within normal ranges at the
       different sampling times (at 19 and 21 months). Main changes in clinical
       chemistry parameters were significant increases in urinary specific gravity and in
       serum urea nitrogen, creatinine, and phosphorus, and significant decreases in
       total protein, albumin, and chloride in high-exposure rats. The committee
       considered these changes related to or secondary to the renal disease observed in
       these animals. In the satellite study, the only change was a decrease in serum
       albumin levels of rats exposed to the highest concentration for 12 months.
       Relative kidney and liver weights of male rats were significantly increased in this
       group. At necropsy (both in the satellite and the core groups), the target organs
       for sulphuryl difluoride toxicity in high-exposure animals appeared to be the
       kidney, the lungs, and the teeth (dental fluorosis). Microscopic examination
       revealed only a slight degree of chronic progressive glomerulonephropathy in
       high-exposure male and female animals after 12 months. However, kidney
       changes had progressed to severe or very severe chronic progressive
       glomerulonephropathy in rats exposed to the highest concentration for 24
       months. Along with these kidney changes, secondary changes, such as
       hyperparathyroidism and mineralisation of many tissues were observed. In the
       lung, slight aggregates of alveolar macrophages were noted in the satellite group,
       but were not considered to significantly impair pulmonary function. These
       changes were not increased in severity after 24 months of exposure. Macroscopic
       and microscopic dental effects were seen in the upper incisor teeth of both males
       and females exposed to the high concentration for 12 or 24 months. In addition,
       after 24 months, a very slight fluorosis of the teeth of male rats exposed to 84
       mg/m3 was found. There was no increase in the incidence of any tumour in male
       or female rats in any of the treated groups compared with the control animals.
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<pre>       Both in the 12-month and 24-month study, the NOAELs were 21 (5 ppm) (based
       on slight dental fluorosis) and 85 mg/m3 (20 ppm) (based on lung and renal
       injury), for male and female rats, respectively (Qua93b).
           In the separate 12-month neurotoxicity study, no treatment-related effects
       were found in the functional observation battery or motor activity, and no
       treatment-related abnormalities in the microscopic examination. The NOAEL for
       neurotoxic effects was 340 mg/m3 (80 ppm) (Spe94).
       Groups of CD-1 mice (n=50/sex/group) were exposed to concentrations of
       sulphuryl difluoride 0, 21, 85 and 340 mg/m3 (0, 5, 20, 80 ppm), 6 hours/day, 5
       days/week, for 18 months. A separate satellite group of 10 mice/sex/exposure
       level was included in the study for blood sampling and necropsy after 12 months.
       In the core study, mortality was comparable for exposed and control groups,
       except for the females of the high-exposure group (males: 23/50, 20/50, 25/50,
       and 32/50; females: 18/50, 12/50, 20/50, and 36/50 at 0, 21, 85, 340 mg/m3,
       respectively). Body weights were significantly decreased in high-exposure males
       and females. No treatment-related effects were reported on clinical observations,
       haematology, clinical chemistry and organ weights (changes related to the
       decreased body weights only), and macroscopic examination. Microscopically,
       the main findings in high-exposure animals were a minimal vacuolation of the
       external capsule of the brain, but only in 1 animal in the area of the caudate
       putamen, and not in the amygdaloid regions (no more details given), and slight
       hypertrophy of the thyroid follicular epithelial cells. These findings proved to be
       less severe in the core group animals than in the satellite animals. All other
       microscopic changes were considered to be unrelated to sulphuryl difluoride
       exposure. There was no increased incidence of any tumour in any of the treated
       groups compared with controls. The NOAEL for both the 12 and 18 months
       studies was 84 mg/m3 (Qua93c).
       A summary of the results of short- and long-term toxicity studies in rats, mice,
       rabbits, and dogs is shown in Table 1.
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<pre>Table 1 Summary of short- and long-term inhalation toxicity studies for sulphuryl difluoride.
speciesa             dose levels         exposure      critical effect                                  NOAEL       reference
(strain)             (mg/m3)             durationb                                                      (mg/m3)
rat                  0, 425, 1275, 2550 2 weeks        lung, renal injury                               425         Eis89
(F344)
(F344)               0, 127.5, 425, 125 13 weeks       lung, nasal, renal injury; dental fluorosis      127.5       Eis89
(F344)               0, 127.5, 425, 1275 13 weeks      neurotoxicity study: electrophysiological        127.5       Mat88
                                                       effects in brain
(Sprague-Dawley) 0, 21, 85, 637.5        20 weeksc reproduction toxicity study: lung injury             21          Bre92,
                                                                                                                    Bre93
(F344)               0, 21, 85, 340      12 months     dental fluorosis                                 21 (male)   Qua93b
                                                       lung, renal injury                               85 (female)
(F344)               0, 21, 85, 340      12 months     neurotoxicity study: no adverse effects reported 340         Spe94
(F344)               0, 21, 85, 340      24 months     dental fluorosis                                 21 (male) Qua93b
                                                       lung, renal injury                               85 (female)
mouse                0, 127.5, 425, 1275 2 weeks       brain injury                                     127.5       Nit95
(CD-1)
(CD-1)               0, 42.5, 127.5, 425 13 weeks      brain, thyroid injury                            127.5       Nit93
(CD-1)               0, 21, 85, 340      12 months     brain, thyroid injury                            85          Qua93c
(CD-1)               0, 21, 85, 340      18 months     brain, thyroid injury                            85          Qua93c
rabbit               0, 425, 1275, 2550  2 weeks       lung, nasal, brain injury                        425         Eis89
(New Zealand)
(New Zealand)        0, 127.5, 425, 1432 13 weeks      lung, nasal, brain injury                        127.5       Eis89
dog                  0, 127.5, 425, 1275 2 weeks       nasal injury                                     425         Nit91
(beagle)
(beagle)             0, 127.5, 425, 850  13 weeks      brain injury                                     425         Nit92
(beagle)             0, 85, 340, 850     12 months     lung, brain, thyroid injury; dental fluorosis    85          Qua93
a
     Studies were performed using Fischer 344 rats, CD-1 mice, New Zealand white rabbits, and beagle dogs.
b
     6 hours/day, 5 days/week.
c
     6 hours/day, 5 days/week, for 10 weeks, then 6 hours/day, 7 days/week, for another 10 weeks.
             Mutagenicity and genotoxicity
             • In vitro tests:
             Sulphuryl difluoride did not induce reverse mutations in S. typhimurium strains
             TA98, TA100, TA1535, and TA1537, with and without metabolic activation, at
             nominal concentrations of 1275, 4250, 12,750, 42,500, and 127,500 mg/m3 (300-
             30,000 ppm) (4 hours, 37°C) (Gol90a).
                  Sulphuryl difluoride did not increase unscheduled DNA synthesis in rat
             primary hepatocytes at concentrations ranging from ca. 867 to 4335 mg/m3 (204-
             1020 ppm) (Gol91).
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<pre>       • In vivo tests:
       Cytogenetic assays. No increased frequency of micronucleated polychromatic
       erythrocytes was observed in the bone marrow of mice, exposed to air
       concentrations of sulphuryl difluoride of ca. 0, 212.5, 744 or 2210 mg/m3 (0, 50,
       175, 520 ppm) (Gol90b)
       Reproduction toxicity
       In a 2-generation reproduction study, groups of 30 male and 30 female Sprague-
       Dawley rats were exposed to concentrations of sulphuryl difluoride of 0, 21, 85,
       or 637.5 mg/m3 (0, 5, 20, 150 ppm), 6 hours/day, 5 days/week, for 10 weeks for
       the F0 and 12 weeks for the F1 generation prior to mating, and 6 hours/day, 7
       days/week during mating, gestation, and lactation through 2 generations. Male
       and female F0 and F1 rats had significantly decreased body weights at 637.5
       mg/m3 during most of the pre-mating period, and female rats during gestation.
       Body weights were also decreased in F1 females during the lactation period, but
       an increase was seen in F0 females. No exposure-related effects were found on
       the F0 and F1 male or female conception index, fertility indices, length of
       gestation, time to mating, pup survival indices, or pup sex ratio. The number of
       F1 or F2 pups born dead or alive or the litter size was not significantly different
       between any of the exposed groups and the control group. In the high-exposure
       group, decreased body weights were observed in F1 and F2 pups throughout
       most of the lactation period. This effect was considered to be secondary to the
       decreased growth of female F0 and F1 rats during the pre-mating and gestation
       periods. The effect on pup weight in the high-exposure group was less severe in
       the F2 litters. Microscopic examination revealed an increased incidence of very
       slight to slight, bilaterally symmetrical, vacuolation of the caudate putamen
       myelinated fiber tracts in the brain of F0 and F1 male and female parental rats in
       the high-exposure group. Dental fluorosis was also observed in high-exposure
       parental animals. At a concentration of 85 mg/m3, F0 and F1 parental effects were
       limited to an increased incidence of aggregates of alveolar macrophages in the
       lung. No treatment-related abnormalities were found in macroscopic or
       microscopic examination of the reproductive organs. The parental NOAEL was
       21 mg/m3 (5 ppm) for males and females, the NOAEL for neonatal growth was
       85mg/m3 (20 ppm), and the NOAEL for reproductive toxicity and fertility was
       637.5 mg/m3 (150 ppm) (Bre92, Bre93).
           In a developmental toxicity, pregnant F344 rats (n=35-36/group) were
       exposed to sulphuryl difluoride concentrations of 106, 319, and 956 mg/m3
       (0, 25, 75, 225 ppm), 6 hours/day, on gestational days 6-15. No mortality was
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<pre>       observed and maternal effects were limited to an increased water consumption in
       high-exposure rats. Pregnancy rate, numbers of implantations and litter sizes, and
       fetal sex ratio in the exposed groups were not statistically significantly different
       compared with the control group. In the high-exposure group, a statistically
       significant increase in fetal body weight and fetal crown-rump length was found,
       which was not considered of toxicological significance. Teratological
       examination revealed a statistically significant increased incidence of bilobed
       thoracic vertebral centra in fetuses of dams exposed to 106 or 956 mg/m3 and of
       unfused thoracic vertebral centra at 319 mg/m3. However, no relationship with
       dose was apparent, and, therefore, the committee decided that these effects were
       of no toxicological significance. The NOAEL for maternal and developmental
       toxicity was 956 mg/m3 (225 ppm), the highest level tested (Han89).
           In another development study, groups of 28-29 inseminated New Zealand
       white rabbits were exposed to sulphuryl difluoride concentrations of 106, 319,
       and 956 mg/m3 (0, 25, 75, 225 ppm), 6 hours per day, on gestational days 6-18.
       Mortality was observed in 2/29, 1/28, and 3/29 rabbits of the low-, mid- and
       high-exposure group, respectively; 4 of these deaths were attributed to
       pneumonia, most probably pasteurellosis. No overt signs of maternal toxicity
       were observed, but, in the high-exposure group, animals lost weight during
       gestational days 9-19 (decrease statistically significant during days 12-15) and
       did not gain weight in the post-exposure period (gestational days 19-29). No
       effects on number of corpora lutea, number of implantation sites, and number of
       resorptions were found. Apart from decreases in body weight (by 14%) and in
       crown-rump length in fetuses of the high-exposure group, no treatment-related
       fetal effects (morphology, skeletal ossification) were seen in any of the exposed
       groups. The NOAEL for maternal and developmental toxicity was 319 mg/m3
       (75 ppm) (Han89).
7      Existing guidelines
       The current administrative occupational exposure limit (MAC) for sulphuryl
       difluoride in the Netherlands is 20 mg/m3 (5 ppm), 8-hour TWA.
           Existing occupational exposure limits in some European countries and the
       USA are summarised in the annex.
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<pre>8      Assessment of health hazard
       The health hazard assessment of sulphuryl difluoride is based to a large extent on
       a toxicology review in ‘The Handbook of Pesticide Toxicology’ (Nit01),
       describing numerous unpublished toxicology studies.
            The principal route of occupational exposure to sulphuryl difluoride is
       through inhalation. Increased fluoride concentrations found in the blood or urine
       of exposed humans indicated that at least part of the sulphuryl difluoride is
       metabolised into inorganic fluoride. In rats, exposed to concentrations of 35S-
       labelled compound of 127,5 and 1275 mg/m3 (30 and 300 ppm) for 4 hours, the
       pulmonary absorption was 11-14%. Radioactivity in plasma and red blood cells
       peaked near the end of the 4-hour exposure period and was rapidly cleared with
       initial half-lives of about 2.5 hours. The terminal half-life of radioactivity was
       2.5-fold longer in red blood cells than in plasma. The radiolabel was rapidly
       excreted, mainly via the urine. Radiochemical profiles of blood and urine did not
       indicate presence of parent compound and suggested hydrolysis into
       fluorosulphate and subsequently into sulphate releasing fluoride in both steps.
       Analysis of tissues 7 days post-exposure showed a rather even distribution
       among tissue, which was ascribed to incorporation of radiolabelled sulphur into
       amino acids, with the highest levels of radioactivity in the lungs, still elevated
       levels in the red blood cell, and detectable levels in the nasal turbinates. Of the
       non-respiratory tissues, highly perfused tissues such as spleen and kidneys had
       the higher 35S concentrations.
            Several fatalities have been published in humans exposed to the compound
       after re-entry in their fumigated homes. Signs of toxicity were seizures, tetany,
       and cardiac rhythm disturbances. Post-mortem examination revealed visceral
       congestion and pulmonary oedema. Two studies on structural fumigation
       workers did not show evidence of neurotoxic effects due to occupational
       exposure to sulphuryl fluoride.
            The committee did not find experimental animal data on skin or eye
       irritation, or on skin sensitisation. Based on the results of acute lethal toxicity
       studies in test animals, the committee considers the compound as harmful after
       inhalation, and as unlikely to present an acute health hazard after dermal
       exposure. Rats exposed to 17,000 mg/m3 (4000 ppm) were incapacitated within
       45 minutes; although exposure was terminated, they died about 2.5 hours later.
       Sulphuryl difluoride did not induce neurotoxicity in rats exposed 6 hours/day, for
       2 consecutive days to concentrations up to 1275 mg/m3 (300 ppm).
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<pre>           In short- or long-term studies in rats, mice, rabbits, and dogs, the target
       organs after exposure to sulphuryl difluoride were the respiratory tract and the
       brain. In addition, renal effects were observed in Fischer 344 (but not in Sprague-
       Dawley) rats, effects on the thyroid in mice and dogs, and dental fluorosis -
       which the committee considers as a biomarker of fluoride exposure rather than a
       toxicological effect - in rats and dogs. The NOAELs were:
       • 21 mg/m3 (5 ppm) for (parental) rats, based on lung lesions of minor severity
           and incidence in a 2-generation reproduction toxicity study (6 hours/day, 5
           days/week, for 10 weeks, then 6 hours/day, 7 days/week, for another 10
           weeks);
       • 85 mg/m3 (20 ppm) for female rats, based on renal and lung injury and dental
           fluorosis in a 24-month study (6 hours/day, 5 days/week);
       • 85 mg/m3 (20 ppm) for mice, based on brain injury and effects on the thyroid
           in an 18-month study (6 hours/day, 5 days/week);
       • 85 mg/m3 (20 ppm) for dogs, based on lung and brain injury, thyroid effects,
           and dental fluorosis in a 12-month study (6 hours/day, 5 days/week);
       • 127.5 mg/m3 (30 ppm) in rabbits, based on effects on the brain and the
           respiratory tract in a 13-week study (6 hours/day, 5 days/week).
           In vitro and in vivo tests for mutagenicity or genotoxicity were negative, and
       no evidence of carcinogenicity was found in 18- and 24-month studies in mice
       and rats, respectively.
           In a 2-generation reproductive toxicity study in rats, the NOAELs for
       parental and reproduction toxicity were 21 and 85 mg/m3 (5 and 20 ppm),
       respectively, on the basis of effects on the respiratory tract in parental males and
       females and reduced body weights of pups throughout most of the lactation
       period, respectively. In developmental toxicity studies, no effects indicative of
       maternal or developmental toxicity were seen in rats at concentrations up to 956
       mg/m3 (225 ppm), the highest level tested. In rabbits, slight fetotoxicity
       (decreased weight and crown-rump length) and maternal toxicity (weight loss)
       were seen at 956 mg/m3 (225 ppm) but not at 319 mg/m3 (75 ppm).
           From the above-presented data, the committee concludes that, generally, the
       various toxicity studies do not show remarkable differences concerning effects
       and effect levels between the species (rat, mouse, rabbit, dog) tested, apart from
       21 mg/m3 (5 ppm) for the minor lung lesions. These lesions were seen in the
       2-generation reproduction study in parental animals exposed to 85 mg/m3 (20
       ppm), 6 hours/day, 5 days/week for 10 weeks and 6 hours/day, 7 days/week for
       another 10 weeks, but not in rats, mice, and dogs exposed to 84 mg/m3 (20 ppm)
       for 5 days/week for much longer exposure times of 12 to 24 months. The
       committee considers these lung lesions to be due to the continuous exposure of 7
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<pre>       days/week in the second half of this study. Since workers are exposed 5
       days/week, the committee prefers to use the animals studies with 5-days/week
       exposure schedules in deriving a health-based occupational exposure limit
       (HBROEL), and concludes that 85 mg/m3 (20 ppm) is the overall NOAEL to be
       taken as a starting point. For the extrapolation to a HBROEL, an overall
       assessment factor of 9, covering intra- and interspecies variation, is established.
       Thus, applying this factor and the preferred value approach, a health-based
       occupational exposure limit of 10 mg/m3 (2.4 ppm) is recommended for
       sulphuryl difluoride.
       The committee recommends a health-based occupational exposure limit for
       sulphuryl difluoride of 10 mg/m3 (2.4 ppm), as an 8-hour time-weighted average
       (TWA).
       References
ACG99  American Conference of Governmental Industrial Hygienists (ACGIH). Sulfuryl fluoride. In: TLVs®
       and other occupational exposure values - 1999. [CD-ROM]. Cincinnati OH, USA; ACGIH®, 1999.
ACG04a American Conference of Governmental Industrial Hygienists (ACGIH). Guide to occupational
       exposure values - 2004. Cincinnati OH, USA: ACGIH®, 2004: 133.
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<pre>              Annex
Occupational exposure limits for sulphuryl difluoride in various countries.
country                          occupational                time-weighted       type of         notea referenceb
- organisation                   exposure                    average             exposure limit
                                 ppm          mg/m3
the Netherlands
- Ministry of Social Affairs and 5            20             8h                  administrative        SZW04
Employment
Germany
- AGS                            -            21             8h                                        TRG04
- DFG MAK-Kommission             -            -                                                        DFG04
Great-Britain
- HSE                            5            21             8h                  OES                   HSE02
                                 10           42             15 min
Sweden                           -            -              8h                                        Swe00
Denmark                          5            20             8h                                        Arb02
USA
- ACGIH                          5            -              8h                  TLV                   ACG04b
                                 10           -              15 min              STEL
- OSHA                           5            20             8h                  PEL                   ACG04a
- NIOSH                          5            20             10 h                REL
                                 10           40             15 min              STEL                  ACG04a
European Union
- SCOEL                          -            -                                                        EC04
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.
141-27        Sulphuryl difluoride
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<pre>141-28 Health-based Reassessment of Administrative Occupational Exposure Limits</pre>

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