<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>Benzenethiol
(CAS No: 108-98-5)
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/095 The Hague, March 30, 2004
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<pre>Preferred citation:
Health Council of the Netherlands: Committee on Updating of Occupational
Exposure Limits. Benzenethiol; Health-based Reassessment of Administrative
Occupational Exposure Limits. The Hague: Health Council of the Netherlands,
2004; 2000/15OSH/095.
all rights reserved
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<pre>1     Introduction
      The present document contains the assessment of the health hazard of
      benzenethiol 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 AAE Wibowo, Ph.D. (Coronel Institute, Academic
      Medical Centre, Amsterdam, the Netherlands).
           In December 1997, literature was searched in the databases Medline,
      Embase, and Chemical Abstracts starting from 1966, 1988, and 1970,
      respectively, and using the following key words: benzenethiol, thiophenol,
      phenyl mercaptan, and 108-98-5. HSELINE, CISDOC, MHIDAS, NIOSHTIC
      (covering the period 1985/87 until 1997), and Poltox (Toxline, Cambridge Sc
      Abstr, FSTA) (covering information until 1994), databases available from CD-
      ROM, were consulted as well. 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. No comments were received.
2     Identity
      name                   :   benzenethiol
      synonyms               :   thiophenol; phenylthiol; phenylmercaptan; mercaptobenzene
      molecular formula      :   C6H6S
      structural formula     :
      CAS number             :   108-98-5
095-3 Benzenethiol
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<pre>3     Physical and chemical properties
      molecular weight      :    110.2
      boiling point         :    168oC
      melting point         :    -15oC
      flash point           :    50oC (closed cup)
      vapour pressure       :     at 19oC: 0.13 kPa
      solubility in water   :    not soluble
      log Poctanol/water    :    2.52
      conversion factors    :    at 20oC, 101.3 kPa: 1 mg/m3 = 0.22 ppm
                                                     1 ppm = 4.59 mg/m3
      Data from ACG99, NLM01.
      Benzenethiol is a colourless liquid with an offensive, garlic-like odour. Air odour
      thresholds as low as 0.004 (0.9 ppb) (Amo83) and 0.001 mg/m3 (0.3 ppb)
      (Rut86) have been reported. In an odour threshold study, a benzenethiol
      concentration of 3.2 mg/m3 (0.72 ppm) was characterised as ‘putrid’, while no
      and very faint odour were reported at 0.000022 and 0.0012 mg/m3 (0.005 and 0.3
      ppb), respectively (Kat30).
4     Uses
      Benzenethiol is used as a chemical intermediate for polymers and in the
      production of pesticides and pharmaceuticals. The compound is approved for use
      as a food additive under certain specified conditions (ACG99, NLM01).
5     Biotransformation and kinetics
      From a dermal LD50 of 300 mg/kg bw in rats (see Section 6) (Fai58), the
      committee concludes that benzenethiol can be absorbed through the skin.
           The committee did not find other quantitative or qualitative data on
      absorption.
      Following single oral administration of doses of 35S-labelled benzenethiol of 6
      mg/kg bw to rats (n=2/sex), methylphenylsulphone, o- and p-hydroxy-
      methylphenylsulphone, conjugates of these hydroxy derivatives, and traces of
      methylphenylsulphoxide were identified in urine collected for 60 hours. Based
      on their own and other information, the authors suggested that, in vivo,
095-4 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>      benzenethiol undergoes S-methylation to methylphenylsulphide, followed by
      oxidation to successively its corresponding sulphide, sulphoxide, and sulphone,
      and then hydroxylation of the sulphone ring and conjugation of the hydroxy
      derivatives (McB69).
6     Effects and mechanism of action
      Human data
      Katz and Talbert performed a series of experiments to study odour thresholds of
      amongst others certain thiols including benzenethiol by exposing subjects to
      vapour concentrations ranging from ‘1 part in 10 to 1 part in 1013’ for various
      periods. In addition to the determination of odour intensities, nasal and eye
      irritation were noted. The 6 volunteers involved described the odour of
      benzenethiol as very disagreeable and repulsive, and experienced a choking
      sensation in the throat, mucosal irritation, and headache. Eye, nose, and throat
      irritation occurred immediately after exposure, the eyes remaining irritated for
      hours. Already ‘one inhalation’ (not further specified) of benzenethiol at a
      concentration of 3.2 mg/m3 (0.7 ppm) caused headache and irritation (Kat30).
      The committee did not find other human data on the toxic effects of
      benzenethiol.
      Animal data
      Irritation and sensitisation
      In male and female rats exposed to concentrations of benzenethiol of 1100, 1560,
      and 2680 mg/m3 (242, 343, 590 ppm) for one hour, ocular oedema and erythema
      and slight nasal discharge were reported (Bul69a). In male rats (n=7) and male
      mice (n=13), immediate irritation, as evidenced by preening, salivation, and
      lachrymation, was seen after starting exposure to a saturated atmosphere of
      benzenethiol (Haz51)*.
           Fairchild and Stokinger found that instillation of 0.1 mL of the compound
      into the conjunctival sac of one eye of each of 3 rabbits produced moderate to
      severe redness, chemosis, and discharge for 3 to 4 days post-treatment. Diffuse
*     The (theoretic) concentration in saturated air in ppm can be calculated using the formula: (vapour pressure in
      Pa x 106 ppm)/105 Pa. Using a vapour pressure of 260 Pa (at 25oC (NLM01); temperature of inhalation chamber
      was ca. 24oC), the committee estimates that these animals could have been exposed to, at most, 2600 ppm or
      (roughly) 12,000 mg/m3)
095-5 Benzenethiol
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<pre>      corneal opacities occurred in 2 rabbits on the fourth day, involving three-quarters
      of the cornea (Fai58).
      In an acute dermal toxicity study, 18-hour covered application of amounts of
      undiluted benzenethiol of 0.5 and 1.0 mL/kg (ca. 540 and 1080 mg/kg bw) to the
      clipped abdominal skin of rabbits (n=3/group) caused moderate to marked
      irritation generally accompanied by oedema, pigmentation, desquamation,
      coriaceous appearance, and necrosis. The effects generally deteriorated during
      the 8-day observation period and were still present at terminal sacrifice. Similar
      applications of 0.1 mL (ca. 110 mg/kg bw) for 5 successive days caused mild
      irritation as well as oedema, escharosis, coriaceous appearance, and necrosis. At
      sacrifice on day 11, all skins were ‘normal’ (Haz51). In another acute dermal
      toxicity study, application of doses of benzenethiol of 134-538 mg/kg to the
      clipped back skin of rabbits caused some inflammatory reaction that disappeared
      in 24 to 48 hours (Fai58). In a third study, application of 200 or 2000 mg/kg bw
      of neat benzenethiol to the skin of rabbits (n=4/group) caused severe skin burns
      classified as third degree (Bul69b). Benzenethiol was stated to be strongly
      irritating to the skin of guinea pigs after a 24-hour-covered contact (Rou68).
           The committee did not find information on the possible skin sensitisation by
      benzenethiol.
      Acute toxicity
      When male and female rats were exposed to benzenethiol concentrations of
      1100, 1560, and 2680 mg/m3 (242, 343, 590 ppm) for one hour, mortality was
      observed in 0/10, 3/10, and 10/10 animals, respectively, resulting in an LC50 of
      1900 mg/m3 (418 ppm). Mortality intervals were 2-18 and 0.5-5 hours at the mid
      and high concentration, respectively. At the low level, acute depression was seen
      during the exposure time, while the higher levels produced dyspnoea, gagging,
      fasciculation, and cyanosis. Upon gross post-mortem examinations, no
      abnormalities were observed in the animals exposed to 1100 mg/m3 (242 ppm) or
      in the survivors exposed to 1560 mg/m3 (343 ppm). The treatment-related deaths
      exhibited haemorrhagic areas in the lungs (Bul69a). All male rats (n=7) and male
      mice (n=13) exposed to a saturated atmosphere of benzenethiol died within 40
      and 55 minutes, respectively (see also footnote in Section ‘Irritation and
      sensitisation’) (Haz51).
           Fairchild and Stokinger performed acute toxicity studies in which
      benzenethiol was administered by inhalation, dermal application, oral intubation,
      and intraperitoneal injection. The 4-hour LC50 values were ca. 150 and 130
095-6 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>      mg/m3 (33 and 29 ppm) for (Wistar-derived) rats and (Swiss-derived) mice,
      respectively, for a 15-day observation period. The dermal LD50 values,
      determined 4-8 hours after application to the clipped backs of the animals, were
      300 and 134 mg/kg bw for rats and rabbits, respectively. In rats, the oral LD50
      value was 46.2 mg/kg bw, determined 24 hours after administration (vehiculum:
      ethanol), while the intraperitoneal LD50 for a 15-day observation period was 9.8
      mg/kg bw (25.2 mg/kg bw when determined 24 hours after injection).
      Symptomatology following lethal and maximum sublethal concentrations or
      doses was fairly uniform and included restlessness, increased respiration,
      incoordination, muscular weakness, skeletal muscle paralysis, heavy to mild
      cyanosis, lethargy and/or sedation, respiratory depression followed by coma and
      death, in cases of lethal doses. At macroscopic and microscopic post-mortem
      examination of the animals dying after these single exposures, generally, no
      lesions were seen. Animals surviving near-lethal oral or intraperitoneal doses and
      sacrificed 20 days after treatment frequently showed microscopic kidney and
      liver lesions. Animals dying several hours after being exposed to high
      concentrations of benzenethiol vapours had mild to severe hyperaemia of the
      trachea and the lungs. Generally, mice were more susceptible than rats (Fai58).
          Eight days following 18-hour covered dermal application of an amount of
      benzenethiol of 0.5 mL/kg (ca. 540 mg/kg) to 3 rabbits, gross post-mortem
      examination showed slightly pale kidneys in one, a slightly granular liver in
      another, and red-coloured lungs and irritated intestines in the third rabbit.
      Following similar application of 1 mL (ca. 1080 mg/kg bw), one animal died
      within 24 hours, but the cause of death could not be determined because of
      advanced autolysis. At necropsy of the two other rabbits, pale and granular liver
      were seen in both animals as well as pale kidney and almost black spleen in one
      animal. The author did not indicate whether these effects should considered to be
      treatment related (Haz51). No mortality, signs of toxicity, or gross organ
      abnormalities were seen in 4/4 rabbits dermally treated with a single dose of 200
      mg/kg bw. Following application of 2000 mg/kg bw, all 4 animals died between
      0.5 and 1.5 hours post-treatment, exhibiting extreme excitation and cyanosis
      (Bul69b). In guinea pigs, dermal application of an amount of benzenethiol of 2
      mL/kg (ca. 2160 mg/kg bw) caused deaths within 24 hours but no mortality
      occurred at dose of ca. 700 mg/kg bw (i.e., 0.65 mL/kg) (no more data
      presented) (Rou68).
          Given in polyethylene glycol 200 by stomach tube to male and female
      Sprague-Dawley rats (n=7/sex/group), the oral LD50 was determined to be ca. 65
      mg/kg bw for both males and females. During the 14-day observation period,
      there was no mortality at a single dose of ca. 54 mg/kg bw (i.e., 0.05 mL) while
095-7 Benzenethiol
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<pre>      9/16 animals died within 1 hour following administration of the next higher dose
      of ca. 81 mg/kg bw (i.e., 0,075 mL). Apart from some slight body weight
      depression, no signs of toxicity or organ abnormalities (gross post-mortem
      examination) was seen at doses of ca. 27 and 54 mg/kg bw. At doses of ca. 81
      mg/kg bw and above, there were depression and laboured respiration, starting 5
      to 30 minutes after dosing, and congested livers, kidneys, and adrenals and lung
      erythema in the treatment-related deaths (Hor66). Without presenting further
      information, the oral LD50 in rats was stated to be less than 50 mg/kg bw
      (Rou68). In male albino mice, single doses of 200, 300, or 500 mg/kg bw (in
      Wesson oil) caused mortality in 3/13, 8/13, and 13/13 animals, resulting in an
      oral LD50 of 267 mg/kg bw. In the low-dose group, animals died 5-7 days post-
      administration; in the mid- and high-dose group, all and 85% of the animals,
      respectively, within one day following administration. At all doses, there was
      depression with evidence of diarrhoea and some increased or irregular
      respiration. At 500 mg/kg bw, incoordination was also seen. Post-mortem
      examination results included no abnormalities in the survivors of the low-dose
      group, pale kidneys in the survivors of the mid-dose group, and haemorrhagic
      lungs, speckled and blanched livers, irritated intestines, and slightly granulated
      kidneys in the succumbed animals of the high-dose group (Haz51).
          The committee notices the discrepancy between the oral LD50 in rats of 46.2
      mg/kg bw (i.e., a dose that would kill 50% of the animals within 24 hours)
      reported above (Fai58) and the findings in the developmental toxicity studies in
      which repeated dosing of 50 mg/kg bw did not induce any mortality (Geo94).
      Repeated-dose toxicity
      Apart from a 4-day inhalation study, a 3-week intraperitoneal study, and the
      reproduction toxicity studies discussed below, no information was available on
      the effects (including potential carcinogenicity) of repeated exposure to
      benzenethiol or benzenethiol vapours.
          Male rats (n=7) and mice (n=12) were exposed to benzenethiol vapours that
      were obtained by diluting air saturated with benzenethiol in such a way that
      ‘3.2% of the atmosphere within the chamber was saturated with benzenethiol
      vapour’*. Exposure was for 6 hours the first day, and for 8 hours daily on each of
      the 3 succeeding days, and terminal sacrifices were scheduled 3 days later. While
      7 mice were found dead before starting the second exposure - the cause of death
*     Based on the assumptions and calculations presented in the footnote under Section ‘Irritation and sensitisation’,
      exposure could have been to a concentration as high as roughly 85 ppm or 400 mg/m3.
095-8 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>      was suggested to be cannibalism -, a second group of 13 mice was added. Among
      the rats, 2 died (during the night and 3 days, respectively, after the final
      exposure). During exposure, signs of irritation (preening, lachrymation, marked
      salivation), unthrifty appearance, lethargy, and decreased water and food
      consumption were observed. Post-mortem examination of the 2 deceased rats
      showed haemorrhagic lungs, marked intestinal irritation, and mottled livers and
      kidneys. In the surviving animals, gas-filled and irritated stomachs and
      intestines, congested and pale brown kidneys, small spleens, mottled livers, and
      markedly irritated eyes were seen while the lungs were unaffected. Two out of
      the 5 mice surviving the first exposure day, died during the second day, 2 during
      the fourth day, and one at post-exposure day 3. During exposure, effects
      observed were similar to those seen in rats. At autopsy, there were haemorrhagic
      lungs, marked intestinal irritation, and spotted kidneys and livers. In the added
      mouse group, one animal died after first exposure, 4 during or after the third
      exposure, and 6 during the 3-day period between the last exposure and terminal
      sacrifice. The effects seen in these animals and in those 2 that were terminally
      sacrificed were similar to those seen in the other mouse group (Haz51).
          George et al. stated that in studies preliminary to a developmental study in
      rats, no signs of toxicity were observed in pregnant rats treated with 20
      mg/kg bw/day on gestational days 6 through 15 or in non-pregnant rats given up
      to 40 mg/kg bw/day, for 6 consecutive days. At 50 mg/kg bw/day for 6
      consecutive days, there was a 7% body weight decrease in non-pregnant rats (no
      more data presented) (Geo94). In similar studies in rabbits, pregnant animals
      were given 0.5, 1, 2, 5, or 10 mg/kg bw/day on gestational days 6 through 19,
      while non-pregnant animals were treated with 20, 40, or 50 mg/kg bw/day for 14
      consecutive days. In none of the groups, effects on body weight were observed.
      Doses up to 40 mg/kg bw/day did not induce clinical signs. At 50 mg/kg bw/day,
      1 or 2 non-pregnant rabbits were slightly sedated post-dosing on 2 days during
      the dosing period, and one of these animals died (on treatment day 10). Exposure
      of pregnant animals to 50 mg/kg bw starting on gestational day 6 caused
      excessive maternal toxicity. Six out of 13 animals died during the first treatment
      week, and the experiment was terminated by sacrificing the remaining animals at
      gestational day 14 (Nav94).
          In a reproduction toxicity study using a continuous breeding protocol,
      parental rats (Spraque-Dawley; n=20/sex/group) were exposed to daily
      (7 days/week) oral (gavage) doses of benzenethiol of 9, 18, and 35 mg/kg bw, for
      1 week housed individually and subsequently for 16 weeks housed as breeding
      pairs during which period animals were allowed to produce several litters.
      Thereafter (at day 112), pairs were separated. After rearing and weaning the final
095-9 Benzenethiol
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<pre>       litter, a crossover mating trail (in which high-dose males and females were paired
       with untreated females and males), and subsequent rearing and weaning, the F0
       animals were sacrificed and post-mortem investigation was performed on the
       first 10 living animals/sex/group. Animals were kept exposed until sacrifice, i.e.,
       males until study days 198-199 and females until day 217. In this part of the
       study, mortality was observed in 0, 1, and 2 males and 4, 2, and 5 females of the
       low-, mid-, and high-dose group, respectively, while there were no deaths in the
       control groups. Of these, one mid-dose male, one high-dose male, and one high-
       dose female died as a result of gavage errors and one low-dose and one high-dose
       female animal as a result of parturition difficulties; the cause of death of the other
       animals could not be determined. Clinical signs were observed in control and
       treated groups but at relatively low incidences (<20% per group) and without
       dose-related differences. Throughout this part of the study, body weights of male
       animals of the high-dose group were 7-15% less than those of controls while no
       effect on body weight was seen in high-dose females. At necropsy, absolute and
       relative liver and kidney weights were increased in all dose groups: relative liver
       weights of the low-, mid-, and high-dose animals by 20, 35, and 50 %,
       respectively, in males and by 11, 18, and 36%, respectively, in females; relative
       kidney weights by 30, 53, and 104%, respectively, in males and by 8, 5, and
       20%, respectively, in females. Gross and microscopic post-mortem observations
       included a treatment-relatedly increased incidence of enlarged and pitted kidneys
       in male animals, increased incidences of renal tubular degeneration (30, 35, and
       40%, respectively) in male and female animals, and centrilobular hepatocellular
       hypertrophy in mid- and high-dose male and in all treated female groups. In the
       F1 litter, selected from litters born after week 17 and, after a weaning period,
       exposed to the same dose levels as their respective parents for ca. 10 weeks,
       similar effects on body weight and liver and kidney were observed (Wol96a,
       Wol96b). From this study, the committee concludes that oral dose levels as low
       as 9 mg/kg bw/day (the lowest level tested) caused effects on liver and kidney
       (increased absolute and relative weights; renal tubular regeneration; centrilobular
       hepatocellular hypertrophy) of rats.
            In the intraperitoneal study, 6 rats were given 9 injections of 3.5 mg/kg bw as
       a 2% v/v solution in ethanol over a 3-week period. One rat died on the seventh
       day. The remaining animals did neither show significant weight losses nor other
       signs of toxicity. Upon necropsy, fibrous thickening of the splenic capsule due to
       irritation caused by the repeated injections, enlargement of the spleen,
       hyperaemia of the adrenal medulla, and some mild kidney lesions were seen
       (Fai58).
095-10 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>       Mutagenicity and genotoxicity
       Benzenethiol was negative when tested in S. typhimurium strains TA100 with
       and without metabolic activation and TA98 with metabolic activation (not tested
       without S9) at concentrations of 25 to 500 µg/plate. Concentrations greater than
       25 µg/plate caused poor survival in these tests (Lav79).
           The committee did not find other data on the mutagenic and genotoxic
       potential of benzenethiol.
       Reproduction toxicity
       The potential fertility and reproductive effects of benzenethiol were assessed in
       Sprague-Dawley rats using the continuous breeding protocol. The compound
       was administered by gavage (vehicle: corn oil) at daily (7 days/week) doses of 9,
       18, or 35 mg/kg bw to 20 animals/sex/group. Rats were individually housed for
       one week and then cohabited for 16 weeks. During cohabitation, litters were
       euthanised after evaluation on post-natal day 1. Litters born after week 17 were
       reared until post-natal day 21, and selected weanlings were administered the
       same dose levels as their respective parents. On post-natal day 81 (+10 days), F1
       animals were cohabited within groups for one week and necropsied following
       delivery of the litters. Both in the parental F0 and F1 animals, toxicity was seen
       at all dose levels: increased absolute and relative liver and kidney weights and
       histological lesions at 9 mg/kg bw/day (see above under ‘Repeated-dose
       toxicity’).
           As to male fertility indices, there were only a decreased epididymal sperm
       motility (by 5-6%) in the F0 mid- and high-dose group and a decreased right
       caudal epididymis weight in the high-dose group. However, this did not affect
       pregnancy outcome as was confirmed in a separate, crossover mating trial in
       which naive females were mated with high-dose males. Treatment did not affect
       fertility in the F0 females. In the male F1 generation, right testis weights were
       increased in the mid- and high-dose groups and, upon histological examination
       of the left testes, an increased incidence of inhibited spermiation (of the stage
       VIII-X tubules) was found in all treated groups. However, this did not affect
       pregnancy outcome. There were no fertility effects in F1 females.
           As to the developmental aspects of this study, exposure of the F0 generation
       did not induce effects other than small, not clearly dose-related decreases in
       adjusted live pup weight by 4 (p<0.05) and 6% (p<0.05) in the low- and high-
       dose groups, respectively, and in the number of live pups by 7% (not significant)
       in the high-dose group. The females were the affected sex, since at the crossover
095-11 Benzenethiol
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<pre>       mating trial to determine the affected sex, the pups born to high-dose females
       (mated with untreated males) weighed 8-9% less than pups from untreated males
       and females, while no effects were observed in litters from benzenethiol-treated
       males and untreated females. In the F1 mating trial, no developmental effects
       were seen except for statistically significant decreases in mean live F2 pup
       weight by 9% and 12% in the mid- and high-dose groups, respectively. However,
       the statistical significance disappeared when adjusting for litter size. In addition,
       the females in these 2 dose groups littered about half a day earlier than the
       control group which may account for the pup weight decreases (Wol96a,
       Wol96b). The committee concludes that, in this study, the NOAELs for maternal
       and developmental toxicity were <9 and 35 mg/kg bw/day, respectively. The
       NOAELs for male and female fertility effects are <9 and 35 mg/kg bw,
       respectively.
       The developmental toxicity of benzenethiol (purity: >99%) was examined in
       Sprague-Dawley rats (n=25/group) and New Zealand White rabbits (n=15-26/
       group). Rats were given oral (gavage) doses of 0, 20, 35, or 50 mg/kg bw/day on
       gestational days 6 through 15 (vehicle: corn oil). At 50 mg/kg bw, there was
       maternal toxicity as indicated by mortality (in 4/25), persistently decreased body
       weight and body weight gain, decreased food consumption during the treatment
       period, and, at necropsy on gestational day 20, decreased gravid uterine weights
       and increased relative and adjusted liver weights. Kidney weights were not
       affected. In the 2 other dose groups, there was a transient decrease in maternal
       body weight gain and food consumption during the first dosing period
       (gestational days 6-9). After dosing, rooting behaviour indicative of aversion to
       the taste or smell of the test substance was seen in all treatment groups. This
       behaviour was most prevalent and had an earlier onset at the mid and high doses
       and subsided after dosing was completed. At developmental toxicity evaluation,
       no significant differences between treated and control groups were found in the
       average number of corpora lutea per litter, the number of implantation sites per
       litter, the percent pre-implantation loss per litter, the percent late fetal deaths per
       litter, or in the incidence of visceral and skeletal malformations or variations.
       Embryo and fetal effects observed included post-implantation loss, decreased
       live litter size, decreased fetal body weight per litter, and an increased incidence
       of external malformations in the high-dose group and reduced female fetal body
       weight in the mid-dose group (Geo94, Geo95). The committee concludes that in
       this rat study, the NOAEL for developmental toxicity is 20 mg/kg bw/day, based
       on decreased female fetal body weights. The committee could not set a maternal
095-12 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>       NOAEL since maternal body weight gain was affected in the first few treatment
       days at 20 mg/kg bw/day, the lowest dose tested.
            Rabbits were given benzenethiol (in corn oil) at oral (gavage) doses of 0, 10,
       30, or 50 mg/kg bw/day (replicate I) or 0, 10, 30, or 40 mg/kg bw (replicate II) on
       gestational days 6 through 19. Because of excessive mortality (46%) during the
       first treatment week of replicate I, the 50 mg/kg bw/day group was untimely
       terminated and replaced in the second replicate by 40 mg/kg bw/day. At sacrifice
       on day 30, a total of 24, 18, 20, and 9 pregnant animals of the control, 10, 30, and
       40 mg/kg bw-group, respectively, were evaluated. In the maternal animals, one
       animal of the 10 and one of the 30 mg/kg bw/day-group died during the study.
       No consistent clinical signs were observed. Maternal relative food consumption
       during the end of the dosing period tended to be lower in the animals given 30
       and 40 mg/kg bw/day, but food consumption before and after treatment did not
       differ from that in controls. In these groups, there was a transient dose-dependent
       decrease in maternal body weight gain during gestational days 12 through 15 (the
       same period in which the largest reductions in food consumption occurred),
       reaching statistically significance in the mid- and high-dose group. Overall
       maternal body weight gain during the dosing period (gestational days 6-19)
       tended to be lower in the treated animals. Because of the inconsistent nature and
       small size (generally less than 5%) of these body weight reductions, overall
       maternal weight gain during gestation and corrected weight gain did not differ
       across groups. At necropsy, gravid uterine weight, liver, and (right) kidney
       weights were not affected. Apart from a statistically significant increase in the
       percentage of female fetuses with variations per litter (mainly extra or
       rudimentary lumbar ribs) of the 40 mg/kg bw/day group, no differences between
       treated groups and controls were found in the developmental toxicity end points
       examined (Geo95, Nav94). The committee concludes that in this rabbit study, the
       NOAEL for developmental toxicity is 30 mg/kg bw/day, based on an increased
       incidence in the percentage of female fetuses with variations per litter (mainly
       extra or rudimentary lumbar ribs). The committee could not set a maternal
       NOAEL since maternal body weight gain was dose-dependently decreased
       during gestational days 12-15.
       In vitro studies
       In vitro experiments in human red blood cells have shown that benzenethiol can
       induce methaemoglobin formation (Amr89) and this group of compounds (e.g.,
       aliphatic, aromatic, and heterocyclic thiols and disulphides) are described as
095-13 Benzenethiol
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<pre>       haemolytic agents (Mun89). There is no information whether it also occurs in
       vivo.
7      Existing guidelines
       The current administrative occupational exposure limit (MAC) for benzenethiol
       in the Netherlands is 2 mg/m3 (0.5 ppm), 8-hour TWA .
            Existing occupational exposure limits for benzenethiol in some European
       countries and the USA are summarised in the annex.
8      Assessment of health hazard
       The committee did not find qualitative data on the oral or inhalation absorption
       of benzenethiol. Although benzenethiol can be absorbed through the skin as
       indicated by a dermal LD50 value of 300 mg/kg bw in rats, no quantitative
       information was found. Following oral administration of labelled benzenethiol to
       rats, methylphenylsulphone, o- and p-hydroxy-methylphenylsulphone,
       conjugates of these hydroxy derivatives, and traces of methylphenylsulphoxide
       were identified in urine collected for 60 hours. This suggests that benzenethiol
       may undergo S-methylation to methylphenylsulphide, followed by oxidation to
       successively its corresponding sulphide, sulphoxide, and sulphone, and then
       hydroxylation of the sulphone ring and conjugation of the hydroxy derivatives.
            Apart from an old study reporting headaches and eye, nose, and throat
       irritation in volunteers at ‘one inhalation’ of a concentration of 3.2 mg/m3 (0.7
       ppm), the committee did not find data on the effects of exposure to benzenethiol
       in man.
            Liquid benzenethiol was very irritating to the eyes and skin of experimental
       animals. The committee could not assess the irritating potential of benzenethiol
       in experimental animals because only relatively high (>1000 mg/m3) or poorly
       documented levels were used.
            Acute toxicity studies showed rather varying results. In rats, the 1-hour LC50
       was 1900 mg/m3 (418 ppm), while 4-hour LC50 values were much lower: ca. 140
       mg/m3 (30 ppm) in both rats and mice. Dermal LD50 values of 300 and 134
       mg/kg bw were reported for rats and rabbits, respectively, although in other
       rabbit experiments, no mortality occurred at doses of 200 or 540 mg/kg bw.
       Following oral administration, the LD50 in rats, determined 24 hours after
       treatment, was 42.6 mg/kg bw while in acute (with a 14-day observation period)
       and developmental studies, all rats survived doses up to 50 mg/kg bw. However,
       dose-response curves may be steep since in the aforementioned acute
095-14 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>       experiment, a single dose of ca. 81 mg/kg bw caused the death of 9/16 animals
       within one hour. In mice, the oral LD50 was 267 mg/kg bw. When administering
       doses of 50 mg/kg bw/d to pregnant rabbits during organogenesis, 6/13 animals
       died with 5 days.
           Apart from oral developmental toxicity studies, the committee did not find
       data from relevant repeated-dose toxicity studies. In one of these studies, which
       used a continuous breeding protocol, parental rats were given daily doses of 0, 9,
       18, and 35 mg/kg bw for about 200 consecutive days, during which period
       several litters were produced and reared and weaned. In this study, no NOAEL
       could be established since liver and kidney effects (increased absolute and
       relative weights; renal tubular regeneration; centrilobular hepatocellular
       hypertrophy) were found in the parental animals at 9 mg/kg bw, the lowest level
       tested.
           Apart from a negative result in a mutagenicity test in S. typhimurium strains
       TA100 (with and without metabolic activation) and TA98 (tested with metabolic
       activation only), the committee did not find data from mutagenicity or
       genotoxicity studies on benzenethiol.
           In a reproduction toxicity rat study according to a continuous breeding
       protocol at doses of 9, 18, and 35 mg/kg bw, no effects were found on female
       fertility. Although some male fertility indices, among which a decreased
       epididymal sperm motility (by 5-6%), were impaired, pregnancy outcome was
       not affected. Treatment did not cause changes in developmental endpoints. The
       committee concluded that, in this study, the NOAELs for maternal and
       developmental toxicity were <9 and 35 mg/kg bw/day, respectively. The
       NOAELs for male and female fertility effects are <9 and 35 mg/kg bw,
       respectively. In developmental toxicity studies in rats and rabbits, the committee
       could not set NOAELs for maternal toxicity since maternal body weight gains
       were affected at the lowest doses tested, viz., 20 mg/kg bw in rats and 10
       mg/kg bw in rabbits. Based on reduced female fetal body weight in rats and an
       increased incidence in the percentage of female fetuses with variations per litter
       (mainly extra or rudimentary lumbar ribs) in rabbits, the developmental
       NOAELs were 20 and 30 mg/kg bw in rats and rabbits, respectively.
           The committee could take the oral reproduction toxicity study in which
       repeated dosing of 9 mg/kg bw, the lowest dose tested, induced effects on liver,
       kidneys, and epididymal sperm motility as a starting point in deriving a health-
       based occupational exposure limit. After adjusting for continuous exposure (7
       days/week vs. 5 days/week for occupational exposure), and using a factor of 4
       for scaling from rat to human based on caloric demand and an overall assessment
       factor of 36 - to account for the absence of a NOAEL, intra- and interspecies
095-15 Benzenethiol
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<pre>       variation, and the differences between experimental conditions and the exposure
       pattern of the worker, and the preferred-value approach, the committee could
       recommend a health-based occupational exposure limit of 0.5 mg/m3. The
       committee is of the opinion that this level would protect workers from systemic
       effects. However, headache and irritation were found in volunteers after only
       very brief exposures to 3.2 mg/m3 (0.7 ppm) indicating that benzenethiol is very
       irritating, offensively smelling compound. Because of lack of additional human
       data, the committee is not able to estimate which level would protect workers
       from irritation and to recommend a health-based occupational exposure limit.
       The committee considers the toxicological database on benzenethiol too poor to
       justify recommendation of a health-based occupational exposure limit.
       Based on human (irritation) and experimental animal (systemic toxicity) data, the
       committee concludes that the current MAC value of 2 mg/m3, 8-hour time-
       weighted average, is too high.
       References
ACG99  American Conference of Governmental Industrial Hygienists (ACGIH). Phenyl mercaptan. In:
       TLVs® and other occupational exposure values - 1999. [CD-ROM]. Cincinnati OH, USA: ACGIH®,
       Inc, 1999.
ACG03a American Conference of Governmental Industrial Hygienists (ACGIH). Guide to occupational
       exposure values - 2003. Cincinnati OH, USA: ACGIH®, Inc, 2003: 107.
ACG03b American Conference of Governmental Industrial Hygienists (ACGIH). 2003 TLVs® and BEIs®
       based on the documentation of Threshold Limit Values for chemical substances and physical agents
       & Biological Exposure Indices. Cincinnati OH, USA: ACGIH®, Inc, 2003: 47.
Amo83  Amoore JE, Hautala E. Odor as an aid to chemical safety: odor thresholds compared with threshold
       limit values and volatilities for 214 industrial chemicals in air and water dilution. J Appl Toxicol
       1983; 3: 272-90.
Amr89  Amrolia P, Sullivan SG, Stern A. Toxicity of aromatic thiols in the human red blood cell. J Appl
       Toxicol 1989; 9: 113-8.
Arb02  Arbejdstilsynet. Grænseværdier for stoffer og materialer. Copenhagen, Denmark: Arbejdstilsynet,
       2002: 34 (At-vejledning C.0.1).
Bul69a Bullock CH. Acute inhalation LC50 study of thiophenol in male and female rats. Richmond CA,
       USA: Stauffer Chemical Co, Western Research Center, 1969; toxicology lab rep T-1403 (available
       from the National Technical Information Service, Springfield VA, USA; order no NTIS/
       OTS0557380).
095-16 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>Bul69b Bullock CH. Two level rabbit dermal toxicity screen of thiophenol. Richmond CA, USA: Stauffer
       Chemical Co, Western Research Center, 1969; toxicology lab rep T-1403 (available from the
       National Technical Information Service, Springfield VA, USA; order no NTIS/OTS0557379).
DFG03  Deutsche Forschungsgemeinschaft (DFG): Commission for the Investigation of Health Hazards of
       Chemical Compounds in the Work Area. List of MAK and BAT values 2003. Maximum
       concentrations and Biological Tolerance Values at the workplace Weinheim, FRG: Wiley-VCH
       Verlag GmbH & Co. KGaA, 2003; rep no 39.
EC04   European Commission: Directorate General of Employment and Social Affairs. Occupational
       exposure limits (OELs); http://europe.eu.int/comm/employment_social/h&s/areas/oels_en.htm.
Fai58  Fairchild EJ, Stokinger HE. Toxicologic studies on organic sulfur compounds. Am Ind Hyg Ass J
       1958; 19: 171-89.
Geo94  George JD, Price CJ, Marr MC, et al. Final report on the developmental toxicity of thiophenol (CAS
       #108-98-5) Sprague-Dawley rats (CDÒ) rats. Research Triangle Park NC, USA: National
       Toxicology Program, National Institute of Environmental Health Sciences, 1994; rep no TER-92133
       (available from the National Technical Information Service, Springfield VA, USA; order no PB94-
       155009).
Geo95  George JD, Price CJ, Navarro HA, et al. Developmental toxicity of thiophenol (THIO) in rats and
       rabbits. Toxicologist 1995; 15: 160 (abstract).
Haz51  Hazleton L. Acute oral, acute and chronic dermal and vapor toxicity study of thiophenol. Falls
       Church VA, USA: Hazleton Laboratories, 1951 (available from the National Technical Information
       Service, Springfield VA, USA; order no NTIS/OTS0557378).
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       Western Research Center, 1966; toxicology lab rep T-924 (available from the National Technical
       Information Service, Springfield VA, USA; order no NTIS/OTS0557377).
HSE02  Health and Safety Executive (HSE). EH40/2002. Occupational Exposure Limits 2001. Sudbury
       (Suffolk), England: HSE Books, 2002: 13.
Kat30  Katz SH, Talbert EJ. Intensities of odors and irritating effects of warning agents for inflammable and
       poisonous gases. Washington DC, USA: Dept of Commerce, Bureau of Mines, 1930; technical paper
       480; cited in NIO78.
Lav79  Lavoie E, Tulley L, Fow E, et al. Mutagenicity of aminophenyl and nitrophenyl ethers, sulfides and
       disulfides. Mutat Res 1979; 67: 123-31.
McB69  McBain JB, Menn JJ. S-methylation, oxidation, hydroxylation and conjugation of thiophenol in the
       rat. Biochem Pharmacol 1969; 18: 2282-5.
Mun89  Munday R. Toxicity of thiols and disulfides: involvement of free-radical species. Free Radic Biol
       Med 1989; 7: 659-73.
Nav94  Navarro HA, Price CJ, Marr MC, et al. Final report on the developmental toxicity of thiophenol
       (CAS #108-98-5) in New Zealand white (NZW) rabbits. Research Triangle Park NC, USA: National
       Toxicology Program, National Institute of Environmental Health Sciences, 1994; rep no TER-92134
095-17 Benzenethiol
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<pre>       (available from the National Technical Information Service, Springfield VA, USA; order no PB94-
       201183).
NIO78  US National Institute for Occupational Safety and Health (NIOSH). Criteria for a recommended
       standard. Occupational exposure to n-alkane mono thiols, cyclohexanethiol, and benzenethiol.
       Cincinnati OH, USA : US Dept of Health, Education, and Welfare, Public Health Service, Center for
       Disease Control, NIOSH, 1978; DHEW (NIOSH) Publication No 78-213.
NLM01  US National Library of Medicine (NLM), ed. Thiophenol. In: Hazardous Substances Data Bank
       (HSDB) (last revision date benzenethiol file: 16 May 2001); http://toxnet.nlm.nih.gov.
Rou68  Roudabush RL. Toxicity and health hazard summary for benzenethiol. Rochester NY, USA: Eastman
       Kodak company, 1969 (available from the National Technical Information Service, Springfield VA,
       USA; order no NTIS/OTS0510336).
Rut86  Ruth JH. Odor thresholds and irritation levels of several chemical substances: a review. Am Ind Hyg
       Assoc J 1986; 47: A-142-51.
Swe00  Swedish National Board of Occupational Safety and Health. Occupational exposure limit values and
       measures against air contaminants. Solna, Sweden: National Board of Occupational Safety and
       Health, 2000; Ordinance AFS 2000:3.
SZW03  Ministerie van Sociale Zaken en Werkgelegenheid (SZW). Nationale MAC-lijst 2003. The Hague,
       the Netherlands: Sdu, Servicecentrum Uitgevers, 2003: 18.
TRG00  TRGS 900. Grenzwerte in der Luft am Arbeitsplatz; Technische Regeln für Gefahrstoffe. BArbBl
       2000; 2.
Wol96a Wolfe GW, Delaney JC, Chapin RE. Final report on the reproductive toxicity of thiophenol (CAS
       #108-98-5) administered by gavage to Sprague-Dawley rats. Research Triangle Park NC, USA:
       National Toxicology Program, National Institute of Environmental Health Sciences, 1996; rep no
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095-18 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>              Annex
Occupational exposure limits for benzenethiol in various countries.
country                                occupational           time-weighted          type of exposure    notea    referenceb
- organisation                         exposure limit         average                limit
                                       ppm        mg/m3
the Netherlands
- Ministry of Social Affairs and       0.5        2           8h                     administrative               SZW03
Employment
Germany
- AGS                                  -          2           8h                                                  TRG00
- DFG MAK-Kommission                   -          -                                                               DFG03
Great-Britain
- HSE                                  0.5        2.3         8h                     OES                          HSE02
Sweden                                 -          -                                                               Swe00
Denmark                                0.5        2.3         8h                     OEL                          Arb02
USA
- ACGIH                                0.5c       -           8h                     TLV                          ACG03b
- OSHA                                 -          -                                                               ACG03a
- NIOSH                                0.1        0.5         15 min; ceiling        REL                          ACG03a
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..
c
     Intended to be changed for 2003 to 0.1 ppm, with a skin notation.
095-19        Benzenethiol
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<pre>095-20 Health-based Reassessment of Administrative Occupational Exposure Limits</pre>

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<br><br>