<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>Resorcinol
(CAS No: 108-46-3)
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/139 The Hague, November 9, 2004
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<pre>Preferred citation:
Health Council of the Netherlands: Committee on Updating of Occupational
Exposure Limits. Resorcinol; Health-based Reassessment of Administrative
Occupational Exposure Limits. The Hague: Health Council of the Netherlands,
2004; 2000/15OSH/139.
all rights reserved
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<pre>1     Introduction
      The present document contains the assessment of the health hazard of resorcinol
      by the Committee on Updating of Occupational Exposure Limits, a committee of
      the Health Council of the Netherlands. The first draft of this document was
      prepared by C de Heer, Ph.D. (TNO Nutrition and Food Research, Zeist, the
      Netherlands).
           The evaluation of the toxicity of resorcinol has been based on the review by
      the American Conference of Governmental Industrial Hygienists (ACG98).
      Where relevant, the original publications were reviewed and evaluated as will be
      indicated in the text. In addition, in December 1998, literature was retrieved from
      the on-line databases Medline, Toxline, and Chemical Abstracts starting from
      1966, 1965, and 1990, respectively, and using the following key words:
      resorcinol, 3-hydroxyphenol, 1,3-benzenediol, and 108-46-3.
           In July 2000, the President of the Health Council released a draft of the
      document for public review. Comments were received from the following
      individuals and organisations: P Ashford (Resorcinol Task Force).
           An additional search in Toxline and Medline in September 2004 did not
      result in information changing the committee’s conclusions.
2     Identity
       name                       :    resorcinol
      synonyms                   :    1,3-benzenediol; m-benzenediol; m-dihydroxybenzene;
                                      1,3-dihydroxybenzene; m-hydroquinone; m-hydroxyphenol;
                                      3-hydroxyphenol; m-dioxybenzene; resorcine
      molecular formula          :    C6H6O2
      structural formula         :
      CAS number                 :    108-46-3
139-3 Resorcinol
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<pre>3     Physical and chemical properties
      molecular weight                 :   110.11
      boiling point                    :    276-280oC (volatilises at lower temperature)
      melting point                    :   109-111oC
      flash point                      :    127oC (closed cup); 165oC (closed cup)
      vapour pressure                  :    at 25oC: 0.03 Pa
      solubility in water              :    very soluble (at 20oC: 140 g/100mL)
      log Poctanol/water               :    0.80-0.97 (experimental); 0.79-1.03 (estimated)
      conversion factors               :    at 20oC, 101.3 kPa: 1 ppm = 4.59 mg/m3
                                                                 1 mg/m3 = 0.22 ppm
      Note: Most processes involving resorcinol involve elevated temperatures, at which
      resorcinol is a vapour. In other cases, it almost immediately becomes a resorcinol-water
      aerosol, because of its hygroscopic nature.
      Data from ACG98, BUA93, NLM04, http://www.syrres.com/esc/est_kowdemo.htm.
      The white crystals of resorcinol have a sweetish taste and may turn pink on
      exposure to air and light or on contact with iron (ACG98).
4     Uses
      Resorcinol is used primarily in the manufacture of tyres and other rubber goods.
      Likewise, it is used in the manufacture of resorcinol-formaldehyde resins used in
      tyre building as well as in adhesives used for bonding structural wood laminates.
      To a lesser extent, resorcinol is used as a medical ingredient in various over-the-
      counter pharmaceutical skin creams, as a bacterial and fungicidal ointment, and
      in cosmetics (hair tonics and dyes).*
5     Biotransformation and kinetics
      In F344 rats, resorcinol is quickly absorbed by the gastrointestinal tract and then
      rapidly metabolised and excreted. There was no significant sex difference.
      Twenty-four hours following an oral dose of 112 mg/kg bw containing 14C-
      labelled resorcinol, 91-93% of the administered dose was excreted in the urine
      and 1-2% was detected in the faeces. The remaining radioactivity was distributed
      among various tissues with no indication of bioaccumulation in any single tissue.
*     P Ashford, Resorcinol Task Force, personal communication.
139-4 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>      Much of the material excreted in bile underwent enterohepatic circulation to be
      eventually excreted in the urine. The major metabolite present in the urine was
      the monoglucuronide conjugate (approximately 70%). Additional metabolites
      included a monosulphate conjugate, a mixed sulphate-glucuronide conjugate,
      and a diglucuronide conjugate (a minor metabolite). Essentially the same results
      were obtained after a single dose of 225 mg/kg bw or daily doses of 225
      mg/kg bw for 5 consecutive days (Kim87).
          Following subcutaneous administration of a single dose of 50 or 100
      mg/kg bw 14C-labelled resorcinol to male CD rats, radioactivity was rapidly lost
      from plasma with approximately 90% being cleared in the first 2 hours.
      Elimination was biphasic with half-lives of 18-21 minutes and 9-11 hours,
      respectively. Twenty-four hours after dosing of 10 mg/kg bw, 94% was excreted
      in the urine and <0.5% in the faeces, primarily (84%) as a glucuronide conjugate.
      Resorcinol equivalents were rapidly distributed to major tissues, but showed no
      tendency to accumulate. Daily subcutaneous administration of 100 mg/kg bw for
      14 or 30 days did not affect the kinetics of resorcinol (Mer82).
          After a 2-week daily topical application of 20 mL 2% resorcinol in a
      hydroalcoholic vehicle to 3 human volunteers (2 times/day, 6 days/week, 150
      µg/cm2 per application) to 2600 cm2 of the body surface, 0.5-2.9% of the applied
      dose was detected in 24-hour urine as glucuronide or sulphate conjugates. No
      information was provided on the remaining part of the dose. Based on the urinary
      excretion in humans, the flux was calculated to be 0.37 µg/cm2/h. In in vitro tests
      using excised full-thickness human skin, a flux of 0.86 µg/cm2/h was established
      after application of 390 µg/cm2 (Yeu83). In another study, skin uptake of
      resorcinol (1.2-2% in solution) by human skin was found to be 0.02 µg/cm2/h
      (Lun92). Because of the limited validation of in vitro studies on dermal
      absorption, the committee considers the flux value of 0.37 µg/cm2/h established
      in the human volunteer study the most relevant for the assessment of the health
      hazard.
          Trace amounts of resorcinol equivalents were detected in the liver of female
      hairless Wistar rats 4 days after a single dermal application of 1.5% resorcinol in
      hair dye solution, whereas no resorcinol was detected in the thyroid gland. No
      other organs were examined for the presence of resorcinol (Tso92).
          In in vitro experiments, the steady state permeability coefficient (Kp) was
      found to be 0.00024 cm/h for resorcinol in aqueous solutions through human
      skin (Rob77).
139-5 Resorcinol
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<pre>6     Effects and mechanism of action
      Human data
      A survey of 180 men employed in work involving resorcinol revealed that none
      complained of irritation or discomfort at exposure levels of 10 ppm (Fli76).
          The lowest oral dose reported to be lethal for humans was 29 mg/kg bw
      (NIO04).
          In a study on 42 workers in a tire-manufacturing plant, the presence of
      dermatitis has been directly correlated with exposure to the processes involving
      resorcinol use (Abb89). With positive results reported in 0.1 to 2.1% of patch-
      tested patients, resorcinol sensitisation appeared to be rare despite the
      widespread use of resorcinol in acne preparations, hair tonics, cosmetics, dyeing,
      and printing (Bar96, Fis82, Fro93, Gue92, Ket70, Lan87, Mar78, Mas93, Pec92,
      Ser92, Sus79, Tar95, Vil91, Wad81).
          Upper and lower respiratory tract inflammatory disease and conjunctivitis
      developed in 210 out of 600 repeatedly exposed workers, following introduction
      of a new resorcinol-containing thermosetting resin into a rubber tire carcass
      stock formulation. The respiratory tract disease resulted from delayed
      hypersensitivity reactions. doPico et al. did not identify the aetiological chemical
      agent (doP75). Rubber workers (n=52) reported no adverse effects following
      prolonged exposure to concentrations of resorcinol of 0.3 mg/m3 (Gam76).
          In humans, resorcinol affected (observed primarily after clinical use of
      resorcinol- containing ointments) the central nervous system (with symptoms
      such as dizziness, trembling, cramps, and shortness of breath) as well as on red
      blood cells (methaemoglobinaemia, haemolytic anaemia, haemoglobinuria).
      Effects on the thyroid have also been reported after prolonged exposure. In
      addition, exogenous ochronosis, chronic myxoedema, and cyanosis have been
      associated with resorcinol exposure (ACG98, Blo85, Bon95, Kat77, Lun92,
      Pas78, Tus96, Wüt70). Human pathology reports from poisoning include
      siderosis of the spleen and kidney tubule damage (All94, Ric92).
          Cutaneous application may result in local hyperaemia, dermatitis, oedema,
      corrosion, and loss of superficial layers of the skin. This may also be associated
      with enlargement of regional lymph nodes (NLM04).
          In a case-control study in ordnance(munition)-factory workers, exposure
      histories of 32 (out of 33) previously diagnosed as haematologically abnormal
      (criteria: neutropenia, decreased platelet count, macrocytosis MCV, and
      increased percentage macrocytosis) were compared with 322 (out of 345)
139-6 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>      controls with normal values. An odds ratio of 2.9 (95% confidential interval: 0.9-
      9.2; not statistically significant) was observed for haematological abnormalities
      based on 4 cases with ‘low’ (not further specified) levels of resorcinol exposure
      out of 29 male workers with ‘abnormal’ blood values compared with 15 males
      with resorcinol exposure out of 282 males with normal blood values (Wes97).
      The number of cases was very small, 25/29 cases were exposed to
      trinitrotoluene, which is known to induce haematology effects, and the
      apparently low (but not specified) levels of exposure to resorcinol. Therefore, the
      committee cannot assess whether resorcinol is capable of inducing haematology
      effects.
           Some occupational groups (e.g., embalmers, rubber workers, and oil refinery
      workers) appear to have an elevated risk of brain tumours (Tho86). Although
      exposure to phenolic compounds (including resorcinol) is indicated, the
      committee cannot adequately evaluate risks due to any single exposure because
      of the small number of tumours observed and the occurrence of combined
      exposures.
           Topical application of 20 ml 2% resorcinol (2 times/day, 6 days/week; equal
      to 150 µg/cm2 per application) for 4 weeks to 2600 cm2 of the body surface (daily
      dose 12 mg/kg bw/day) to 3 human volunteers did not result in significant
      changes in any thyroid function examined (T3, T4, T7, and TSH) or
      haematological parameters (Yeu83).
      Animal data
      Irritation and sensitisation
      Dermal application of 0.5 g resorcinol moistened with saline to the intact and
      abraded skin of rabbits for 24 hours resulted in no perceptible to moderate
      irritation and no perceptible irritation to necrosis, respectively (primary irritation
      index of 4.4). In an acute dermal toxicity test, high dermal doses (1-7.95 g/kg or
      2.5-19.3 g total dose; amount per cm2 not specified) resorcinol caused irritation
      and necrosis in a dose-related response (Fli76). In another study, no response was
      observed during the 72-hour observation period following topical application of
      a 2.5% (w/v) resorcinol preparation (volume not indicated) (Llo77). Aqueous
      solutions of 0.1-10% resorcinol were not irritating to guinea pigs in a screening
      study (Bra86).
           Instillation of 0.1 g resorcinol into the eyes of rabbits caused discomfort,
      conjunctivitis, and corneal ulcerations that were not reversible (BUA93, Fli76).
      A 2.5% (w/v) resorcinol preparation instilled into the eyes of New Zealand
139-7 Resorcinol
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<pre>      White rabbits resulted in transient mild conjunctival inflammation, not persisting
      for more than 24 hours (Llo77).
          Throat sprayings with 1% resorcinol in water in rats and guinea pigs (3 times/
      day for 2 weeks) resulted in irritation of the throat during spraying. Recovery
      was seen after cessation of exposure, and no gross evidence of respiratory
      damage was observed after a 10-week observation period (Fli76).
          Resorcinol was sensitising when tested in the guinea pig maximisation test
      performed according to OECD guideline 406, but not in the open epicutaneous
      test (BUA93). Resorcinol was not photoallergenic to guinea pigs (Bra86).
      Acute and subacute toxicity
      In an inhalation toxicity test in female Wistar rats, resorcinol-water aerosol
      concentrations up to 7800 mg/m3 for a 1-hour period and up to 2800 mg/m3 for
      an 8-hour period caused no deaths or lesions attributable to inhalation of the
      aerosol at gross autopsy (Fli76). In contrast, 1-hour exposure to 160 mg/m3 was
      reported to be lethal to rats (not further information) (NIO04). The dermal LD50
      for (male) rabbits was 3360 mg/kg (Fli76). Rat oral LD50 values ranged from
      202 to 980 mg/kg bw (All94, BUA93, Fli76, Llo77, Woo51). Oral LD50 values
      for mice and guinea pigs were found to be 200-500 mg/kg bw and 370 mg/kg bw,
      respectively (All94, NIO04, Woo51). The primary signs of resorcinol
      intoxication include initial stimulation of the central nervous system followed by
      depression, renal glomerular and tubular degeneration, central hepatic necrosis,
      myocardial depression, pruritis, and reddening of the skin (ACG98, Fli76). The
      subcutaneous LD50s were 450 and 213 mg/kg bw in rats and mice, respectively
      (BUA93). Dogs died following intravenous injections of 0.7-1.0 g/kg bw
      (All94). The intraperitoneal LD50 in mice was 215 mg/kg (BUA93).
          In subacute inhalation studies, no toxic effects (not further specified) were
      noted in rats, guinea pigs, and rabbits exposed to resorcinol concentrations of 34
      mg/m3 (8 ppm), 6 hours/day, for 2 weeks, and then maintained for several
      months with periodic sacrifices (Fli76).
          Daily topical application of 1 or 3% resorcinol in vaseline to the ears and
      flanks of male Pirbright guinea pigs for up to 14 days resulted in concentration-
      dependent acanthosis, hypergranulosis, hyperkeratosis, and in the ear epidermis
      also in papillomatosis. Keratinocyte proliferation was induced in treated skin
      areas (Win77). Toxicity to rats was not observed after dermal application of an
      ointment containing 12.5% resorcinol, 2 times daily for 3 weeks (not further
      specified) (Bra86).
139-8 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>          In rats, intravenously injected resorcinol (24.5 mg) led to a decrease in
      thyroidal radioiodine uptake and labelled iodothyronine/iodotyrosine ratio. A
      2-week study in rats revealed increased thyroid weights, decreased T4 plasma
      levels, and a decreased T4 half-life after dietary exposure to 5% resorcinol
      (estimated intake 5 g/kg bw/day assuming a 150 g body weight) (Ber79). After
      F344/N rats (n=5/sex/group) received 12 daily oral (gavage) doses of resorcinol
      (vehicle: water) of 0, 27.5, 55, 110, 225, or 450 mg/kg bw, 5 days/week, over 17
      days, tachypnoea and hyperexcitability ensued within 30 minutes of dosing and
      resolved within 2 hours in those animals given 55 mg/kg bw/day and higher
      (NTP92). Exposure of B6C3F1 mice (n=5/sex/group) to 0, 37.5, 75, 150, 300, or
      600 mg/kg bw/day by intubation, 5 days/week, over 17 days, resulted in death of
      4/5 males and 5/5 females in the highest dose group and death of 1/5 males in the
      300-mg/kg dose group. Clinical signs, including prostration and tremors, started
      within 30 minutes after dosing of 150 mg/kg bw and lasted 1-2 hours (NTP92).
      Feeding of 0-260 mg/kg bw/day for 4 weeks did not induce mortality, clinical
      abnormalities, histological changes, or body weight effects in resorcinol-exposed
      rats (n=10). Relative adrenal weights were decreased in all exposed animals
      (Bra86).
          Thyroid uptake of labelled iodine was not affected in rats given a single
      subcutaneous dose of resorcinol (not further specified). Daily subcutaneous
      administration of 15 mg/kg bw resorcinol for up to 69 days resulted in moderate
      thyroid hyperplasia (Bra86).
          Subcutaneous exposure of CD rats to 55, 88, 140, 220, and 350 mg/kg bw
      resulted in slight tremors, progressing to moderate to marked tonic clonic
      convulsions within 10 minutes after dosing of 140 mg/kg bw or more. Complete
      recovery of these symptoms occurred within 1-1.5 hours. No gross signs of
      toxicity were observed after exposure to 55 and 88 mg/kg bw (Mer82). In
      another study, subcutaneous injection of 154 mg/kg bw resorcinol in rats
      produced myxoedema and goitre. A similar injection of 50 mg/kg bw failed to
      produce any such disturbance in rat thyroid. In contrast, a temporary reduction of
      iodine uptake in the thyroid was noted in rats subcutaneously exposed to 5
      mg/kg bw resorcinol (ACG98, Lun92).
          The dose producing myoclonic convulsions in 50% of urethane-anaesthetised
      male Sheffield mice following intraperitoneal administration of resorcinol, was
      101 mg/kg bw (Ang72).
139-9 Resorcinol
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<pre>       Subchronic toxicity
       When F344/N rats (n=10/sex/group) were given oral (gavage) doses of 0, 32, 65,
       130, 260, or 520 mg/kg bw resorcinol, 5 days/week, for 13 weeks, 10/10 females
       and 8/10 males given the highest dose died. All male dose groups displayed
       increased absolute and relative adrenal weights, albeit without a clear dose-
       response relationship. Increased absolute and relative liver weights were seen at
       doses >65 mg/kg bw/day in females and at >130 mg/kg bw/day in males. There
       was no clear dose-response relationship. No other clinical signs, macroscopic or
       microscopic lesions, or changes in clinical chemistry parameters were seen in
       those rats that survived to the end of the study (NTP92). When B6C3F1 mice
       (n=10/sex/group) were given oral (gavage) doses of 0, 28, 56, 112, 225, or 420
       mg/kg bw/day, 5 days/week, for 13 weeks, 7/10 mice of each sex given the
       highest dose experienced dyspnoea, prostration, tremors, and then died. Absolute
       and relative adrenal gland weights were reduced significantly in all dose groups,
       although no dose-response relationship was observed. No other changes were
       recorded (NTP92). Effects on the thyroid gland were not addressed in the 13-
       week NTP studies in rats and mice.
           Exposure of cross-bred rats (F1 from 1.0 BD IX x 0.1 WELS/Fohm) to
       0.004% resorcinol in drinking water for 12 weeks (calculated intake: 0.04
       mg/mL x 35 mL/day x 0.275 kg bw = 5 mg/kg bw/day), resulted in significantly
       increased mean epithelial cell height and significantly decreased mean follicle
       diameter upon histometrical evaluation of the thyroid gland. Seffner et al.
       interpreted these findings as a precursor phase of goitre. No other effects were
       studied. In these experiments, resorcinol was added as a control whilst studying
       humic acid effects on the thyroid (Sef95). In another study, similar exposure (5
       mg/kg bw/day) for 30 days had resulted in significant enlargement of the thyroid
       gland and decreased T3 and T4 levels in Wistar rats (Coo85).
           Multiple subcutaneous daily doses of 100 mg/kg bw (2x50) for 14 or 30 days
       to male Sprague-Dawley rats did not result in overt signs of toxicity or adverse
       changes in body weight gain, organ weights, thyroid function (serum T3, T4),
       several haematological parameters (number of red blood cells, haemoglobin,
       haematocrit) and clinical chemistry parameters examined, and histology
       (Mer82).
           Topical application of hair dye solutions containing 2% resorcinol (and 23
       other ingredients) and mixed with 6% H2O2 to male and female New Zealand
       rabbits for 13 weeks (1 hour, 2 times/week, 0.5 mL/kg bw) did not result in toxic
       effects (normal body weight gain, normal urinalysis). The only observation was a
       slight thickening of treated skin (Bra86, review, original report not available).
139-10 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>           Thus, the adrenals, the liver, and the thyroid were identified as the target
       organs for subchronic exposure to resorcinol. Exposure of rats to resorcinol at 5
       mg/kg bw/day through drinking water for 12 weeks resulted in histopathological
       changes in the thyroid (considered to be a precursor phase of goitre). No NOAEL
       for these effects was derived.
       Chronic toxicity and carcinogenicity
       The National Toxicology Program has completed and peer-reviewed a gavage
       study of resorcinol. The substance, dissolved in water, was administered at oral
       (gavage) doses of 0, 112, or 225 mg/kg bw/day to rats (F344/N; n=60/sex/group)
       and mice (B6C3F1; n=60/sex/group), 5 days/week, for 104 weeks. Because of
       high mortality in the high-dose female rats (16 by week 22), the female rat study
       was restarted using doses of 0, 50, 100, or 150 mg/kg bw/day. At 15 months,
       interim evaluations were performed on 10 animals/species/sex/group. In rats,
       clinical signs, including ataxia, prostration, salivation, and tremors, started
       shortly after exposure, lasted for 0.5-1 hour, and became more pronounced at the
       end of each 5-day treatment period. They were seen in the 2 male dose groups
       and in females given 100 and 150 mg/kg bw. Due to high early mortality in the
       high-dose males, animals from this group were not evaluated at 15 months.
       Instead, 10 high-dose males that died or were killed moribund near month 15
       were considered part of the 15-month interim evaluation. As in the female
       animals dying following administration of doses of 225 mg/kg bw, no gross or
       microscopic lesions were observed in these high-dose male animals. In male rats,
       body weights were decreased in the high-dose group throughout the study, being
       10-15% lower than those in controls from week 87 to study termination. The
       survival rate in the high-dose group was decreased as well. Survival rate and
       body weights of low-dose males were similar to those of controls. In female rats,
       body weights in the high-dose group were lower than those of controls during
       most of the study, being 11-14% lower from week 95 to study termination. Mean
       body weights of the mid-dose females were slightly lower (4-7%) than those of
       controls in the final ca. 20 weeks of the study while those of the low-dose group
       were similar to those of controls. Survival rates were decreased in high-dose
       female rats, because of early deaths occurring between weeks 30 and 60, while in
       the mid- and low-dose female groups, they were similar to those in controls. At
       the interim evaluation, there were no treatment-related changes in absolute and
       relative organ weights, in haematology or clinical chemistry values, or in the
       incidences of neoplastic or non-neoplastic gross and microscopic lesions in any
       of the treated groups, when compared to controls, apart from a statistically
139-11 Resorcinol
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<pre>       significantly increased relative liver weight in high-dose females. At the terminal
       evaluation, no increase in the incidence of any neoplastic or non-neoplastic
       lesion was found in any of the treated rat groups when compared to controls. In
       mice, clinical signs of toxicity including recumbency and tremors occurred for a
       short period after dosing in all treated mice groups. Survival rates in the treated
       groups were similar to the survival rate of the control mice. Apart from decreased
       body weights in high-dose female mice (by 10-15% from week 85 to study
       termination), no effects on body weights were observed. When compared to
       controls, there were no treatment-related changes in absolute and relative organ
       weights or in haematology or clinical chemistry values at the interim evaluation
       and no increases in the incidence of any neoplastic or non-neoplastic gross and
       microscopic lesion in any of the treated groups at the interim or terminal
       evaluation (NTP92). Based on this study, the committee concludes that
       resorcinol was not carcinogenic in rats or mice following long-term exposure to
       oral doses of 225 mg/kg bw/day. Based on clinical signs observed after
       administration of doses of 100 mg/kg bw and more, the committee concludes that
       50 mg/kg bw is a NOAEL. For mice, the committee could not establish a
       NOAEL since clinical signs were seen in both males and females at 112
       mg/kg bw, the lowest dose tested.
           Skin painting of female Swiss mice (n=50/dose) with 0.02 ml of 5%, 25%, or
       50% solutions of resorcinol in acetone twice weekly for 100 weeks did not result
       in statistically significant increased numbers of skin or other tumours when
       compared to untreated or vehicle-treated controls (Ste74).
           A twice-weekly topical application of 0.02 mL 5% to 50% resorcinol to the
       inner ear of New Zealand White rabbits for 180 weeks failed to induce local or
       distant tumours or to cause any compound-related toxicity (Ste77).
           Long-term toxicity and carcinogenicity studies on hair dyes containing 0.4-
       2% resorcinol in mice and rats did not reveal overt toxicity or carcinogenic
       effects following lifetime dermal application (Bra86, Bur75, IRDC79).
       Oral (gavage) administration of doses of resorcinol of 225 mg/kg bw/day, 5
       days/week, for 24 weeks to heterozygote p53-deficient mice (n=15/sex) did not
       induce increased tumour incidences (Eas98).
           In 18-month studies performed in two laboratories (in the USA and Japan,
       respectively) under identical test conditions, oral (gavage) administration of
       doses of 225 mg/kg bw, 5 days/week, to CB6F1 and hemizygote CB6F1-Tg
       rasH2 mice, which carry 5 to 6 copies of the intact human c-Ha-ras gene,
       induced small, not statistically significant increases in the incidence of lung
       tumours in both wild-type and transgenic animals in both experiments. Taken the
139-12 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>       results together, the incidences of carcinomas were 0/50 and 2/55 in transgenic
       males and females, respectively (vs. 1/24 and 0/25, respectively, in controls),
       while none was found in treated and control wild-type animals; incidences of
       adenomas were 4/50 and 4/55 in transgenic males and females, respectively (vs.
       1/24 and 0/25, respectively) and 3/51 and 1/56 in wild-type males and females,
       respectively (vs. 1/24 and 1/25, respectively). In the US, but not in the Japanese
       study, signs of hyperactivity and sporadic tremors were seen primarily in
       resorcinol-treated mice throughout the study. Lower body weights and body
       weight gains were seen in treated mice in the US study and in treated wild-type
       males in the Japanese study (Mar00).
           Dermal application of resorcinol doses of 225 mg/kg bw/day, 5 days/week,
       for 24 weeks, to the clipped skin of hemizygote Tg.AC mice (n=15/sex), which
       carry an activated H-ras oncogene, resulted in an increase in the incidence of
       squamous cell papillomas (males: 10/15 vs. 3/30 in controls, p<0.05; females:
       12/15 vs. 1/30, p<0.05). Further, the incidences of hyperplasia (in males and
       females) and of hyperkeratosis, inflammation, and sebaceous gland hyperplasia
       were statistically significantly increased when compared to controls. No
       systemic treatment-related lesions were observed. Eastin et al. could not discern
       whether the non-neoplastic skin lesions were secondary to the papillomas or had
       contributed in some way to their development. However, with another
       compound, viz., rotenone, non-neoplastic but no neoplastic skin reactions were
       observed (Eas98).
       Neither an increase in forestomach or urinary bladder epithelial cell turnover nor
       any treatment-related histological change could be detected in male Syrian
       golden hamsters (n=15) fed 0.25% resorcinol for 20 weeks (estimated intake 375
       mg/kg bw/day based on 100 g body weight and 15 mg/day food consumption).
       The thyroid was not studied (Hir86).
           Resorcinol failed to induce proliferative or pre-neoplastic lesions in stomach
       mucosa of male F344 rats upon dietary exposure to 0.8% resorcinol for 8 weeks.
       There were no effects of resorcinol treatment on body weight gain, food and
       water consumption (Shi90).
       Female ICR/Ha Swiss mice, simultaneously or sequentially exposed to
       benzo[a]pyrene and resorcinol (10 mg) by topical application on clipped dorsal
       skin for up to 55 weeks, revealed a partial (>50%) inhibition of benzo[a]pyrene
       carcinogenicity by resorcinol. It was concluded that resorcinol did not show
       cocarcinogenic or tumour-promoting activity in mouse skin (Duu76).
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<pre>            Groups of male Syrian hamsters received either saline or subcutaneous
       injections of 70 mg/kg bw N-nitrosobis(2-oxopropyl)amine (BOP), twice with a
       2 week interval, followed by a standard diet or diet containing 1.5% resorcinol
       from week 4 for a period of 16 weeks. At week 20, resorcinol-fed BOP-treated
       animals showed decreased numbers of pancreatic lesions (comprising
       carcinomas, atypical ductal hyperplasias, and ductal hyperplasias) when
       compared to those animals treated with BOP and fed a basal diet. There was no
       effect of resorcinol on the incidence of (pre)neoplastic lesions in the gall bladder
       or liver (nodules, adenomas, carcinomas). In the forestomach and glandular
       stomach a higher frequency of epithelial hyperplasias, but not of neoplastic
       lesions (such as papillomas, adenomas, carcinomas), was observed in resorcinol-
       treated and initiated animals when compared to initiated controls. Animals only
       treated with resorcinol for 16 weeks (not treated with BOP) displayed no effects
       on body weight gain or relative pancreas weights, but had significantly decreased
       relative liver weights (Mar91).
            In a study designed to evaluate the potential of resorcinol to act as a promoter
       of urinary bladder carcinogenesis, 6-week-old male F344 rats were given
       drinking water containing 0.05% N-butyl-N-(4-hydroxybutyl)-nitrosamine
       (BBN) for 2 weeks. The rats were then fed diets containing 0.2% resorcinol for
       21 additional weeks. No hyperplastic or papillomatous lesions were found in the
       bladders of BBN-initiated and resorcinol-fed rats (Miy85). In a comparable
       experimental setting, tumour initiation with 0.05% BBN in drinking water for 4
       weeks was followed by dietary exposure to 0.8% resorcinol for 32 weeks. Also
       in this study, no hyperplastic lesions, papillomas, or carcinomas were detected in
       the urinary bladder (Kur90).
            Tumour-promoting activity in the liver was studied in male F344 rats
       initiated with diethylnitrosamine (single intraperitoneal injection). Two weeks
       after initiation, animals were given a diet containing 20,000 ppm resorcinol for 6
       weeks (calculated intake 1.2 g/kg bw/day based on body weight of 250 g and
       food consumption of 60 g/kg/day). At 3 weeks after initiation, a 2/3 partial
       hepatectomy was carried out. Resorcinol did not induce an increase in
       glutathione S-transferase placental form positive foci in the regenerating liver,
       indicative of the absence of tumour-promoting activity in the liver (Has92).
            In another study, 6-week-old F344 rats were given a single gavage dose of
       150 mg/kg of N-methyl-N’-nitro-N-nitrosoguanidine (MNNG). A week later, the
       rats were administered diets containing 0.8% resorcinol for an additional 51
       weeks. Resorcinol exhibited no tumour-promoting activity in the forestomach
       and glandular stomach (Hir89). In male F344 rats, the incidence of lung tumours,
       initiated by a 2-weeks treatment with 0.1% N-bis(2-hydroxypropyl)nitrosamine
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<pre>       (in drinking water), was not affected by supplementation of the diet with 0.8%
       resorcinol for 30 weeks. Quantitative analysis of numbers and areas of lesions
       per unit area of lung section revealed an inhibitory effect of resorcinol.
       Resorcinol did not affect the incidence of neoplastic lesions in the thyroid gland,
       urinary bladder, and kidney (Has90).
           In contrast, male F344 rats initiated with 3 intraperitoneal injections of
       methyl-N-amylnitrosamine over a 2-week period, followed a week later by
       administration of a diet containing 0.8% resorcinol for 49 weeks, showed
       significantly increased incidences of oesophageal squamous cell carcinomas
       (59%) and lingual squamous cell papillomas (50%) when compared to controls
       receiving the nitrosamine alone (incidence: 0 and 9%, respectively) (Yam89).
       In summary, resorcinol did neither induce tumours in mice and rats following
       oral exposure nor in mice and rabbits following dermal exposure. Tumour-
       promotion activity was concluded in 1 out of 7 studies. In this study, resorcinol
       exposure significantly increased the incidence of oesophageal squamous cell
       carcinomas initiated by methyl-N-amylnitrosamine. In experiments in which
       doses of 225 mg/kg bw were administered by gavage or dermally to various
       types of genetically altered mice for 24 weeks or 18 months, there were only
       small, not statistically significant increases in the incidence of lung adenomas in
       male and female CB6F1-Tg rasH2 mice orally dosed for 18 months.
           The committee concludes from the NTP-study that the overall NOAEL for
       chronic toxicity of resorcinol in rats was 50 mg/kg bw/day. At the higher doses
       (100 and 150 mg/kg bw/day), acute clinical signs indicative of an effect on the
       central nervous system occurred.
       Mutagenicity and genotoxicity
       •   In vitro tests:
           • Gene mutation assays. Resorcinol (tested up to 5 mg/plate) did not induce
               gene mutations in any of several strains of S. typhimurium and E. coli,
               with or without metabolic activation (Bra81, BUA93, Cre81, Cre85,
               Flo80, Haw83, NTP92, Pro81, Sha80). However, in the presence of S9
               mix, a pH-dependent positive response was observed in the SD510 strain
               of S. typhimurium TA98 and in E. coli B/r WP2 trp-hcr-. Mutagenicity
               was highest at pH 3.0, decreased with increasing pH, and was no longer
               observed at pH>5.0 (Hos91). Gocke et al. produced positive results in S.
               typhimurium TA1535 (with S9; without S9 negative) and TA100 (without
               S9; with S9 negative) but only on a so-called ZLM medium, but not on a
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<pre>              Vogel-Bonner medium. Tests in strains TA1537, TA1538, and TA98 were
              negative (Goc81).
              Tested in the absence of metabolic activation only, resorcinol induced a
              significant increase in the number of trifluorothymidine-resistant colonies
              of L5178Y mouse lymphoma cells (McG88, NTP92).
              No induction of sex-linked recessive lethal mutations was observed in
              germ cells of adult male D. melanogaster given resorcinol in the feed,
              whereas equivocal results were obtained following injection (Fou94,
              NTP92). Feeding of 55 mM in sucrose did not induce sex-linked recessive
              lethal mutations in the Basc test with D. melanogaster (Goc81).
          • Cytogenicity assays. Resorcinol (only tested in the absence of metabolic
              activation) failed to induce SCE in cultured hamster V79 cells (Wil81) or
              human peripheral blood lymphocytes (BUA93, Dar83, Jan86).
              Contradictory results were obtained with resorcinol in the SCE assay in
              CHO cells (BUA93, Gal85, Gal87, NTP92). It was also positive, with and
              without S9, in tests for induction of chromosomal aberrations in Chinese
              hamster lung fibroblasts (Sak85) and Chinese hamster ovary (CHO) cells
              (Sti81, Gal85, Gal87, NTP92, Sti91), although negative results in CHO
              cells were also reported (Dar83). Chromosomal aberrations were not
              found after treatment of human diploid fibroblasts with resorcinol
              (Dar83), but resorcinol was reported to induce chromosomal aberrations
              in cultured human amniotic cells and peripheral blood lymphocytes
              (Dar83, Sch82).
          • Other assays. Resorcinol was negative in an unscheduled DNA synthesis
              test with primary rat hepatocytes (Pro81).
              Resorcinol did not induce an SOS response in S. typhimurium strain
              TA1535/pSK1002, with or without S9 (Nak87).
              It failed to induce DNA strand breaks in mammalian cells or in isolated
              DNA (Kaw89, Miu00, Yam85, Wal92).
       •  In vivo tests:
          Despite the positive responses observed with resorcinol in vitro, results from
          all reported in vivo tests for genotoxicity were negative. Treatment of mice
          with resorcinol did not induce micronuclei in bone marrow cells (tested up to
          300 mg/kg bw) (Bra86, Dar83, Goc81, Pas86, Wil81), inhibition of DNA
          synthesis in testicular cells (100 mg/kg, single oral dose) (Sei77), or sperm
          abnormalities (55-220 mg/kg, intraperitoneal administration) (Wil81). In rat
          bone marrow, negative results were obtained in tests for induction of
          micronuclei (Hos77) and SCE (1-100 mg/kg, oral and intraperitoneal
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<pre>            administration, and 0.2-200 mg/kg, dermal application) (Bra81, Bra86).
       •    Other tests:
            Resorcinol failed to induce in vitro transformation of human diploid
            fibroblasts and Syrian hamster kidney fibroblasts (Pur78).
       Despite the positive results in some in vitro genotoxicity tests, the committee
       concludes that resorcinol is not a genotoxic compound.
       Reproduction toxicity
       Daily oral (gavage) administration of doses of 125, 250, or 500 mg/kg bw to
       pregnant Sprague-Dawley rats from gestational days 6 to 15 caused a slight
       reduction in maternal weight gain at 500 mg/kg bw (dose level not adjusted for
       pup weights). It was not embryotoxic nor did it have any effect on the numbers of
       litters produced or did it cause any fetal abnormalities or malformations (DiN85).
       Similarly, resorcinol was not embryotoxic or teratogenic in pregnant rats and
       rabbits given daily oral (gavage) doses of 0, 40, 80, or 250 (gestational days 6-
       15) and of 0, 25, 50, or 100 mg/kg bw (gestational days 6-18), respectively
       (Bra86, Spe86; only abstract available for evaluation).
            Pregnant Sprague-Dawley rats, exposed to single oral doses of 0, 100, 333,
       667, or 1000 mg/kg bw on gestational day 11, did not show evidence of maternal
       toxicity within 72 hours after dosing. No developmental toxicity was observed in
       the offspring (Kav90).
            A series of hair dyes containing 1-2% resorcinol were negative in teratology
       and reproduction toxicity studies in rats and rabbits (Bra86). Dermal application
       of 0.5 mL hair dye formulation to mice (2 out of 3 formulations tested contained
       1.7% resorcinol), twice a week from 4 weeks prior to mating through the mating
       and gestation periods, did not result in overt signs of maternal toxicity. There was
       no evidence of teratogenic effects. Evaluation of the ossification data, however,
       suggested a retarding effect of the formulations on the ossification process. In
       addition, slightly lower fetal weights were noted in all formulation-treated
       groups, although mean crown-rump distances were comparable to controls
       (Hog77). Because all formulations had similar effects, and one of them did not
       contain resorcinol, the committee considers the effects observed on ossification
       and fetal body weights not likely due to resorcinol exposure.
            Resorcinol was embryotoxic for 3-day-old chicken embryos with an ED50 of
       2.4 µmol/egg, whereas the LD50 for embryo-mortality in this system was 2.7
       µmol/egg (Kor83).
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<pre>            In in vitro tests, resorcinol inhibited rat embryo limb cell differentiation
       (ED50: 56 mg/mL) at concentrations not affecting cell survival. It did not affect
       rat embryo midbrain cell differentiation in vitro (Fli88).
            Thus, resorcinol did not induce developmental toxicity, but induced maternal
       toxicity (slight decrease in body weight gain) in rats at 500 mg/kg bw/day.
       Other studies
       In isolated rabbit tracheas, ciliary movements on tracheal epithelial cells
       decreased after 42-45 minutes of exposure to 625 mg/m3 resorcinol (BUA93).
            Resorcinol was found to stimulate glycogen synthesis and inhibit glycolysis
       in isolated rat hepatocytes (Agi97, Sch95).
            In vitro, resorcinol inhibited porcine thyroid peroxidase (50% inhibition at
       0.3 nmol/L (33 ng/mL)). In porcine thyroid slices, resorcinol inhibited both
       thyroidal uptake of 125I and its incorporation into tyrosine to form iodotyrosines,
       which are the precursors of active thyroid hormones (Coo85).
            In a study on the role of GSH depletion in hydroquine-induced development
       of γ-glutamyltranspeptidase (GGT)-positive enzyme-altered foci in rat liver
       hydroquinone and other benzene derivatives, among which resorcinol, were
       studied. GGT-positive cells in enzyme-altered foci are often assumed to represent
       initiated or pre-malignant cells in the liver. Resorcinol was found not to deplete
       GSH and clear effects of resorcinol on the development of enzyme-altered foci
       were not observed (Ste89).
7      Existing guidelines
       The current administrative occupational exposure limit (MAC) for resorcinol in
       the Netherlands is 45 mg/m3 (10 ppm), 8-hour TWA.
            Existing occupational exposure limits for resorcinol in some European
       countries and in the USA are summarised in the annex.
8      Assessment of health hazard
       Resorcinol is readily absorbed from the gastrointestinal tract and, in a suitable
       solvent, is readily absorbed through the (human) skin (estimated flux 0.37
       µg/cm2/h). The compound is metabolised extensively to glucuronide and/or
       sulphate conjugates, and excreted primarily in the urine. It has little potential for
       bioaccumulation. Sex differences were not observed.
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<pre>           A survey of 180 workers revealed that none complained of irritation or
       discomfort at exposure levels of 10 ppm (45 mg/m3) resorcinol. Prolonged
       exposure of 52 rubber workers to <0.3 mg/m3 resorcinol in air caused no adverse
       effects. There are virtually no data from which to determine a dose-response
       relationship for occupational exposure to resorcinol.
           Based on acute lethal toxicity data in experimental animals, the committee
       conciders resorcinol to be of low toxicity following inhalation and dermal
       exposure and as harmful following oral exposure. Resorcinol is irritating to eyes
       and skin and may cause sensitisation by skin contact.
           In subacute inhalation studies, no toxic effects were noted in rats, guinea
       pigs, and rabbits exposed to resorcinol at 34 mg/m3 (8 ppm), 6 hours/day, for 2
       weeks, and then maintained for several months with periodic sacrifices.
           Rats orally exposed to resorcinol dissolved in water at 0-450 mg/kg bw, over
       17 days, displayed tachypnoea and hyperexcitability at dose levels of >55 mg/kg
       bw/day. No effects were observed after exposure to 27.5 mg/kg bw/day. In mice,
       a similar oral exposure to 0-600 mg/kg bw/day resorcinol resulted in clinical
       signs including prostration and tremors in animals dosed >150 mg/kg. No toxic
       effects were noted in mice exposed to 37.5 and 75 mg/kg bw/day.
           Subchronic oral (gavage) exposure of rats to 0-520 mg/kg resorcinol, 13
       weeks, resulted in increased absolute and relative liver and adrenal weights in
       rats given resorcinol at >65 mg/kg bw/day. No other clinical or histological signs
       or changes in clinical chemistry parameters were seen in those rats that survived
       to the end of the study. The no-observed adverse effect level (NOAEL) was
       found to be 32 mg/kg bw/day. In a similar experimental setting, mice were given
       0-420 mg/kg bw/day resorcinol or an equivalent amount of deionised water by
       gavage. Adrenal gland weights were reduced significantly in mice given >28
       mg/kg bw/day, but no other changes were recorded in animals exposed to dose
       levels of up to 225 mg/kg bw/day.
           Exposure of rats to 0.004% resorcinol in drinking water for 12 weeks
       (calculated intake 5 mg/kg bw/day) resulted in significantly increased mean
       epithelial cell height and significantly decreased mean follicle diameter upon
       histometrical evaluation of the thyroid gland. These findings were considered as
       a precursor phase of goitre. No other effects were studied. In another study,
       similar exposure (5 mg/kg bw/day) for 30 days had resulted in significant
       enlargement of the thyroid gland and decreased T3 and T4 levels in Wistar rats.
           Based on the available genotoxicity data, the committee concludes that
       resorcinol is not genotoxic.
           In 1992, the National Toxicology Program has completed and peer-reviewed
       a long-term gavage study of resorcinol. The substance was administered in water
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<pre>       by gavage to rats and mice. Clinical signs at doses >100 mg/kg bw starting
       shortly after exposure and lasting 0.5-1 hour, included ataxia, prostration,
       salivation, and tremors. The NOAEL for these effects was 50 mg/kg bw. At an
       interim kill after 15 months of exposure, no treatment-related differences in
       haemotology or clinical chemistry parameters, neoplastic or non-neoplastic
       lesions were observed. At the end of the study, body weights were lower in most
       of the highest dose groups. There was neither evidence of carcinogenicity in
       male or female rats and mice in this study nor in other studies in mice and rabbits
       following dermal exposure. Tumour-promotion activity was concluded in 1 out
       of 7 studies; in this study, resorcinol exposure significantly increased the
       incidence of oesophageal squamous cell carcinomas initiated by methyl-N-
       amylnitrosamine. In experiments in which doses of 225 mg/kg bw were
       administered by gavage or dermally to various types of genetically altered mice
       for 24 weeks or 18 months, there were only small, not statistically significant
       increases in the incidence of lung adenomas in male and female CB6F1-Tg rasH2
       mice orally dosed for 18 months.
           Based on studies with pregnant rats and rabbits, the committee concludes that
       resorcinol is not embryotoxic and teratogenic.
           The lowest dose level of resorcinol inducing adverse effects was 5 mg/kg
       bw/day and was observed in the 30-day and 12-week oral (drinking water)
       studies in rats. At this dose level, changes were noted in thyroid organ weights,
       and in serum T3 and T4 levels (30-day study), whereas histological effects were
       noted in the thyroid upon histometrical analysis (12-week study). Although
       thyroid histopathology was evaluated in the latter studies, no effects on the
       thyroid were found at higher dose levels in subacute, subchronic, and chronic
       oral studies performed in rats by the NTP (NOAEL 27.5, 32, and 50 mg/kg
       bw/day, respectively).
           The committee considers the NTP studies as well performed and attaches
       more importance to these studies then to the studies of Seffner et al. (Sef95) and
       Cooksey et al. (Coo85). The committee questions the relevance of the thyroid
       effects found by these authors. The chronic NOAEL of 50 mg/kg bw/day
       observed in the long-term NTP rat study is taken as the starting point for deriving
       a health-based occupational exposure limit (HBROEL). For the extrapolation to
       a HBROEL, a factor of 4 for allometric scaling from rats to humans, based on
       caloric demand, and an overall assessment factor of 9, covering intra- and
       interspecies variation, are applied, resulting in a no-effect level for humans of 1.4
       mg/kg bw. Assuming a 70-kg worker inhales 10 m3 during an 8-hour working
       day and a retention of 100%, and applying the preferred-value approach, a
       health-based occupational exposure limit of 10 mg/m3 is recommended for
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<pre>       resorcinol. The committee considers this HBROEL of 10 mg/m3 sufficiently low
       to protect against irritation by resorcinol. A ‘skin notation’ is not warranted.
       The committee recommends a health-based occupational exposure limit for
       resorcinol of 10 mg/m3 (2 ppm), as an 8-hour time-weighted average (TWA).
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       workers' urinary concentrates and raw materials. Br J Ind Med 1985; 42: 481-7.
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       treated with resorcinol. Mutat Res 1983; 124: 179-89.
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<pre>Fou94  Foureman P, Mason JM, Valencia R, et al. Chemical mutagenesis testing in Drosophila. IX. Results
       of 50 coded compounds tested for the National Toxicology Program. Environ Mol Mutagen 1994; 23:
       51-63.
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<pre>              Annex
Occupational exposure limits for resorcinol 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    10         45               8h                  administrative                 SZW04
Employment
Germany
- AGS                               10         45               8h                                                 TRG04
- DFG MAK-Kommission                -c         -c                                                       sens       DFG04
Great-Britain
- HSE                               10         46               8h                  OES                            HSE02
                                    20         92               15 min
Sweden                              10         45               8h                                      S          Swe00
Denmark                             10         45               8h                                                 Arb02
USA
- ACGIH                             10         -                8h                  TLV                 A4d        ACG04b
                                    20         -                15 min              STEL
- OSHA                              -          -                                                                   ACG04a
- NIOSH                             10         45               10 h                REL                            ACG04a
                                    20         90               15 min
European Union
- SCOEL                             10         45               ILVe                                               EC04
a
     S = skin notation; which means that skin absorption may contribute considerably to body burden; sens = substance can
     cause sensitisation.
b
     Reference to the most recent official publication of occupational exposure limits.
c
     Listed among compounds for which studies of the effects in man or experimental animals have yielded insufficient
     information for the establishment of MAK values.
d
     Classified in carcinogenicity category A4, i.e., not classifiable as a human carcinogen: agents which cause concern that
     they could be carcinogenic for humans but which cannot be assessed conclusively because of a lack of data. In vitro or
     animal studies do not provide indications of carcinogenicity which are sufficient to classify the agent into one of the other
     categories.
e
     Listed among compounds for which OELs are already included in Commission Directives.
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