<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>      Bornan-2-one (camphor, synthetic)
      (CAS reg no: 76-22-2)
      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/018, The Hague, 13 November 2001
018-1
</pre>

====================================================================== Einde pagina 1 =================================================================

<br><br>====================================================================== Pagina 2 ======================================================================

<pre>      Preferred citation:
      Health Council of the Netherlands: Committee on Updating of Occupational
      Exposure Limits. Bornan-2-one (camphor, synthetic); Health-based
      Reassessment of Administrative Occupational Exposure Limits. The Hague:
      Health Council of the Netherlands, 2001; 2000/15OSH/018.
      all rights reserved
018-2
</pre>

====================================================================== Einde pagina 2 =================================================================

<br><br>====================================================================== Pagina 3 ======================================================================

<pre>1     Introduction
      The present document contains the assessment of the health hazard of
      bornan-2-one 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 A Spooren, Ph.D., and H Stouten, M.Sc. (TNO
      Nutrition and Food Research, Zeist, the Netherlands).
           The evaluation of the toxicity of bornan-2-one has been based on the review
      by the American Conference of Governmental Industrial Hygienists (ACG99).
      Where relevant, the original publications were reviewed and evaluated as will be
      indicated in the text. In addition, literature was retrieved from the online data
      bases Medline, Toxline, and Chemical Abstracts covering the period 1966 to 26
      April 1999 (19990426/UP), 1965 to 29 January 1999 (19990129/ED), and 1967 to 24
      April 1999 (19990424/ED; vol 130, iss 18), respectively, using the following key
      words: camphor and the CAS registry numbers 76-22-2, 464-49-3, or 464-48-2.
      HSDB and RTECS, data-bases available from CD-ROM, were consulted as well
      (NIO99, NLM99). The final literature search has been carried out in April 1999.
           In April 2001, the President of the Health Council released a draft of the
      document for public review. The committee received no comments.
2     Identity
       name                      :   bornan-2-one
       synonyms                  :   camphor a , 2-bornanone, 2-camphanone,
                                     2-keto-1,7,7-trimethylnorcamphane,
                                     1,7,7,-trimethylnorcamphor,
                                     1,7,7-trimethylbicyclo(2.2.1)heptan-2-one,
                                     2-oxo-1,7,7-trimethyl-bicyclo[2.2.1]heptane
       molecular formula         :   C10H16O
       structural formula        :
       CAS reg no                :   76-22-2 (DL-camphor)
                                     464-49-3 (D-camphor)
                                     464-48-2 (L-camphor)
       a
             Name used in this document
018-3 Bornan-2-one (camphor, synthetic)
</pre>

====================================================================== Einde pagina 3 =================================================================

<br><br>====================================================================== Pagina 4 ======================================================================

<pre>3     Physical and chemical properties
       molecular weight              :     152,23
       boiling point                 :     204 oC
       melting point                 :     180 oC
       flash point                   :     66 oC (closed cup)
       vapour pressure               :     at 20 oC: 24 Pa
       solubility in water           :     insoluble
       log P octanol/water           :     3.04 (estimated)
       conversion factors            :     1 ppm = 6.34 mg/m 3
       (20 oC, 101.3 kPa)                  1 mg/m 3 = 0.16 ppm
      Data from ACG99, NLM99, http://esc.syres.com
      Synthetic DL-camphor is a colourless to translucent or white crystalline
      substance with a characteristic aromatic odour. A natural form, derived from the
      gum of the camphor tree, is optically active. Otherwise, the natural and the
      synthetic material appear to be identical. Odour thresholds ranging from 0.018 to
      16 ppm (0.11-100 mg/m3) have been reported.
4     Uses
      Camphor is used as a plasticiser for cellulose esters and ethers, in explosives,
      varnishes, lacquers, insecticides, moth and mildew preventives, tooth powder,
      pharmaceuticals, flavourings, embalming substances, cosmetics, and
      pyrotechnics. It is also used as a chemical intermediate (ACG99).
5     Biotransformation and kinetics
      There were no data on the kinetics of camphor following exposure by inhalation.
            Without providing details, it was stated that following ingestion of pure
      camphor or of alcoholic solutions, absorption is quite rapid, and constant from
      oil preparations. Camphor is slowly absorbed from subcutaneous or
      intramuscular depots (Ric93).
            Gas chromatographic/mass spectrometry analysis of urine from two men
      having ingested 6-10 g camphor showed the presence of 6 metabolites. It was
      concluded that the main metabolic pathways are hydroxylation in the 3-, 5-, 8-,
018-4 Health-based Reassessment of Administrative Occupational Exposure Limits
</pre>

====================================================================== Einde pagina 4 =================================================================

<br><br>====================================================================== Pagina 5 ======================================================================

<pre>      and 9-position, and subsequent oxidation to a corresponding ketone and
      carbonic acid. No conjugated alcohols were detected, and only a glucuronidated
      carbonic acid was found (Köp82). From a case of intentional intoxication, in
      which camphor was detected in umbilical cord blood, the amniotic fluid, and fetal
      tissues (brain, liver, kidneys), it was seen that camphor can cross the placenta
      (Rig65).
      The toxicokinetics of DL-camphor after dermal application were studied in
      B6C3F1 mice and F344 rats. Single (3 dose levels) or repeated (7 days) doses were
      administered to male and female rats and mice; application sites were not
      occluded but either protected or unprotected from grooming (method of
      protection could not be derived from the available data). Single doses were
      approximately 40, 167, and 348 mg/kg for rats and approximately 176, 428, and 935
      mg/kg for mice. Analyses concerned only DL-camphor, metabolites were not
      looked for. The experiments showed that approximately 70% of an uncovered
      dermally applied dose was lost in male rats due to volatilisation. A similar
      percentage lost by volatility was assumed for female rats and for mice, although
      the surface area and the dose volume administered were different for mice and
      rats. Less than 1% was recovered from the application site after 24 hours,
      indicating that the remaining 30% had penetrated into the skin.* Plasma kinetics
      after dermal and intravenous administration were compared for determination of
      the bioavailability. In mice, DL-camphor given as a single intravenous injection
      (47 mg/kg) was rapidly eliminated from the plasma to undetectable levels after 3
      hours. After single dermal application, the t ½ ranged from 66 to 112 min and from
      104 to 131 min for male and female mice, respectively. A dose-proportional
      increase in plasma concentration, although not linear, was observed after single
      dermal administration. A large apparent volume of distribution after dermal
      application was suggestive of an extensive tissue distribution. Elimination of
      DL-camphor appeared to be slower in mice (studied in males only) when the
      application site was protected from grooming, although plasma AUC was not
      changed. Mean plasma peak concentrations were higher after single versus
      repeated administration (studied in males only). In rats, a biphasic elimination
      was observed after a single intravenous dose (approximately 6.7 mg/kg).
      DL-Camphor was still detectable 10 hours after administration. After single
      dermal application, the t ½ ranged from 161 to 303 min and from 94 to 246 min for
*     Camphor was recovered in volatiles traps. The possible contributions of volatility from exhaled camphor
      after absorption was studied in a separate intraperitoneal experiment. The appendix in which the
      methods used to measure camphor loss from the dermal application site was not present in the copy of
      the study report sent to the committee.
018-5 Bornan-2-one (camphor, synthetic)
</pre>

====================================================================== Einde pagina 5 =================================================================

<br><br>====================================================================== Pagina 6 ======================================================================

<pre>      male and female rats, respectively. Dose proportionality (not linear) was
      observed after single dermal administration. Unlike in mice and in male rats,
      protection from grooming was found to affect bioavailability in female rats. In
      protected animals, 2-4% of the effective dermal dose (corrected for the 70% loss
      due to volatility) was bioavailable versus 7-8% in unprotected animals. Plasma
      kinetics were comparable for single versus repeated dermal exposure in both male
      and female rats (Gri96, Spa97).
      Urinary excretion data from experiments in rabbits and dogs suggest that
      metabolism of camphor occurs either by hydroxylation of a methylene group (in
      conjunction with cytochrome P-450) or by reduction of the oxo group (Ric93,
      Rob69). In rabbits (n=5), ca. 59, 44, and 33% of single oral doses of 290-533 mg
      D-, 290-426 mg L-, and 122-259 mg DL-camphor/kg bw were excreted in the urine
      as glucuronides of 5-endo-hydroxycamphor and 3-endo-hydroxycamphor,
      borneol, and trace amounts of isoborneol. The proportions of borneol, 3-endo-
      and 5-endo-hydroxycamphor were 1.00:0.88:2.80 and 1.00:2.4:5.00 for D- and
      L-camphor, respectively (Rob69). According to Leibman and Ortiz, the analytical
      method applied by Robinson and Hussain was incapable of separating endo-
      and exo-isomers. In in vivo (one rabbit, one dog) experiments, the former authors
      found D-camphor to be metabolised to 3-hydrocamphor (probably endo) and
      both 5-endo- and 5-exo-hydroxycamphor. In in vitro (rabbit and rat liver
      preparations) experiments, interconversion of the 5-hydroxy isomers via
      2,5-bornanedione is possible. In addition, borneol and some small amounts of
      isoborneol were formed in rabbits (Lei73).
          Significant increases in activities of cytochrome P450, cytochrome b 5, aryl
      hydrocarbon hydroxylase, and glutathione S-transferase were found in the livers
      of female mice (Swiss; n=8) given daily doses of 300 mg/kg/bw camphor by
      gavage, for 20 days, while this was not seen after repeated dosing of 50 or 150
      mg/kg bw (Ban95).
6     Effects and mechanism of action
      Human data
      Little is known about the risk of occupational exposure to camphor. The
      committee did find only one report, on a survey in a camphor-packaging plant. In
      this survey, concentrations of camphor dust and vapour up to ca. 200 mg/m3
      were found in a first sampling period. The industrial hygienists involved
018-6 Health-based Reassessment of Administrative Occupational Exposure Limits
</pre>

====================================================================== Einde pagina 6 =================================================================

<br><br>====================================================================== Pagina 7 ======================================================================

<pre>      experienced very slight (transient) eye irritation, a strong odour of camphor, and
      a (transient) olfactory fatigue during the first survey during which they
      themselves were exposed to levels of ca. 30 to 40 mg/m3. The workers
      complained of similar symptoms. Due to exposure-reducing measures,
      concentrations were lowered to 3 to 3.5 mg/m3 in a second sampling period,
      during which the hygienists noticed a slight odour of camphor only. After
      exposure-reducing measures had been introduced, 6 workers of which only 2
      were actually exposed at that time were examined physically and interviewed.
      Apart from moderate inflammation of nose and throat in 4 of them, there were no
      significant findings. Besides shortness of breath on stair climbing and numbness
      in fingers in a rather heavy worker with an elevated blood pressure level, only
      symptoms concerning nose and throat were reported with relatively low
      frequency (i.e., 1 or 2) (Gro69).
           According to information cited by Flury and Zernike, headache was reported
      in celluloid workers — which were also exposed to other compounds such as
      acetone and amyl acetate — as well as one fatal case resulting from inhalation of
      the vapour of heated camphor with marked rigidity of the jaw muscles as the
      major symptom. According to cited other authors, camphor vapours may induce
      intoxications characterized by dyspnea and coma and that long-term exposure
      may cause significant disfunctioning, especially of the heart (Flu31).
      Most data on the toxicity of camphor are from its incidental or accidental use as a
      drug.
           Negative results were obtained when camphor in 10% petrolatum was patch
      tested in two cases who had shown acute eczema following topical application of
      a camphor-containing spray (Agu94).
           The human lethal oral dose of camphor is estimated to be between 50 to 500
      mg/kg bw. In children, 1 gram of camphor can be lethal (Gib89, Nav92a).
      Symptoms of camphor poisoning can usually be seen within 15-30 minutes after
      ingestion and include nausea, vomiting, and epigastric distress. Neurologic
      changes from camphor ingestion include anxiety, confusion, depression,
      headache, dizziness, twisting of facial muscles, hallucinations, and, in case of
      severe poisoning, convulsions, and coma (Com94, Sie86).
           Autopsy results indicate that camphor can damage the liver (fatty deposits),
      kidney (swelling of the proximal tubules), and the brain (neuronal death) (Sie86,
      Sko77, Smi54). The fetus is also at risk for camphor poisoning since camphor
      crosses the placenta and the ability of the fetus to conjugate camphor’s
      metabolites to glucuronic acid is low (Nav92a, Sie86). Camphor has occassionally
018-7 Bornan-2-one (camphor, synthetic)
</pre>

====================================================================== Einde pagina 7 =================================================================

<br><br>====================================================================== Pagina 8 ======================================================================

<pre>      been used intentionally to induce abortion with varying results (see e.g., Gos84,
      Rab97). However, no increase in malformation rates were found in a study on
      birth defects due to use of drugs during pregnancy. Out of the study group of
      50,282 mother-child pairs, 168 women reported to have used camphor during
      lunar months 1-4. Of these, 10 had given birth to infants with malformations
      which was less than expected. In the group of 763 women who had used
      camphor at anytime in pregnancy, 13 malformed children were observed while
      13.65 were expected (Hei77).
      Animal data
      Irritation
      The committee did not find experimental animal data on the potential irritating or
      sensitising effects of camphor.
      Single exposure
      Exposure to 1300 mg/m3 (200 ppm) of camphor, for 5-10 minutes, was reported to
      induce in mice amongst others restlessness, dyspnoea, dizziness, coma,
      convulsions, and, eventually, death from respiratory arrest (Flu31). Exposures of
      400 to 1760 mg/m3 (65-280 ppm), for 3 hours, were lethal to mice causing central
      nervous system injury (Izm82). Single exposure of unknown duration to 6 mg/m3
      (1 ppm) was stated to affect severely the heart function of mice and rabbits (no
      more data presented) (Heu13).
           Smith and Margolis cited minimal lethal oral doses of 2000 and 1800 mg/kg
      bw for rabbits and guinea pigs, respectively. In their own experiments in rabbits
      (n=1/dose), single oral (gavage) doses of 1600 mg/kg bw and higher were lethal
      (dose range: 1000 to 4000 mg/kg bw). Tonic and clonic convulsions were seen in
      all animals within 5 to 40 minutes after administration. At autopsy, congestion
      and small focal haemorrhages were seen in the stomach (but may have been due
      to trauma from the stomach tube). No lesions were found in the brain, kidneys,
      lungs, liver, heart, pancreas, and the spleen (Smi54).
           Following intraperitoneal injection, a minimal lethal dose of 900 mg/kg bw
      was reported in rats. Doses of 400 and 550 mg/kg bw induced convulsions in 50
      and 100% of the rats, respectively (Sam39). Based on a series of experiments in
      which mice were given 1, 2, or 3 intraperitoneal injections of 300-400 mg/kg bw,
018-8 Health-based Reassessment of Administrative Occupational Exposure Limits
</pre>

====================================================================== Einde pagina 8 =================================================================

<br><br>====================================================================== Pagina 9 ======================================================================

<pre>      the authors stated that the LD 50 was ca. 300 mg/kg bw. At autopsy, no
      significant lesions were seen in the animals given a single injection (Smi54).
          For subcutaneous administration, a minimal lethal dose of 2200 mg/kg bw
      was reported in mice (ACG99).
      Repeated exposure
      No data from toxic effects in experimental animals following repeated inhalation
      exposure were found.
          Convulsions and lesions in the brain similar to those found in human lethal
      cases were seen in mice given 2 or 3 intraperitoneal injections of 300-400 mg/kg
      bw (interval between dosing: 24 hours), and sacrificed 36 hours to 4 days after
      the first injection (Smi54).
          Referring to a paper in Italian (dated 1936), it was stated that chronic
      experimental exposure to camphor induced fatty alteration in the liver and the
      kidneys (no more data presented) (Smi54).
      Carcinogenicity
      Application of 3 drops of 0.3-3.0% acetone solutions of camphor to the back skin
      of mice, once a week, for 1 year, concurrently with 5% croton oil (once/week, for
      1 year; time space between croton oil and test substance application 3-4 days;
      vehicle: acetone) induced skin papillomas in 2 out of the 110 treated mice
      compared with 2/160 treated with croton oil alone. The first tumour appeared at
      month 6, the second between month 6 and 9; the first tumour in the croton oil
      group was seen at month 5. Treatment appeared to be very toxic: survival
      numbers were 21, 9, 4, and 2 (the 2 tumour-bearing animals) at 3, 6, 9, and 12
      months, respectively (for crotonoil: 86, 58, 33, 13) (Gra53). [The committee
      noticed that the way the study was presented suggests that dosing was adjusted
      because of irritation of the skin and that no control group treated with acetone
      alone was included].
          In a short-term study primarily aimed at the induction of lung tumours in a
      pulmonary-tumour-prone strain, intraperitoneal injections — 3 times a week, for 8
      weeks — of total doses of D-camphor (vehiculum: tricaprylin) of 3600 or 18,000
      mg/kg bw (i.e., doses of 150 and 750 mg/kg bw per injection, resp) into male and
      female A/He mice (n=15/sex/group) did not induce statistically significant
      increases of the number of mice with lung tumours or in the number of lung
      tumours per mouse. At week 24, the end of experiment, survival rates were 11/15
018-9 Bornan-2-one (camphor, synthetic)
</pre>

====================================================================== Einde pagina 9 =================================================================

<br><br>====================================================================== Pagina 10 ======================================================================

<pre>       in high-dose males and 14/15 in high-dose females, low-dose males, and
       low-dose females. No abnormalities were reported in the liver, kidneys, spleen,
       thymus, intestine, and salivary and endocrine glands at necropsy (Sto73).
       Mutagenicity and genotoxicity
       Camphor was negative when tested both with and without adding a metabolic
       activating system from induced rat livers in S. typhimurium strains TA1535, TA
       1538, TA98, and TA100 (concentration range: 4-2500 µg/plate; solvent: DMSO)
       (And78). In a separate test using strains TA97a, TA98, TA100, and TA102,
       results were negative as well (concentration range: 50-2500 µg/plate; solvent:
       ethanol) (Gom98). According to NTP*, D-camphor was negative in a
       Salmonella-test and in a chromosome aberrations test (no details available).
            Camphor (tested as a 10% solution in ethanol) did not induce mitotic arrest or
       anaphase abnormalities in a grasshopper embryo assay (Lia83).
            A single intraperitoneal injection of 76 mg/kg bw to mice (Swiss; n=4) caused
       a statistically significant increase in the frequency of SCE in bone marrow (3.70
       SCE/metaphase vs 2.76 and 2.89 in untreated and vehicle-treated controls) in an
       experiment designed to examine the influence of camphor-pretreatment on the
       SCE induction by γ -irradiation (Goe89).
       Reproduction toxicity
       When 0, 100, 400, or 800 mg D-camphor/kg bw/day was administered by gavage
       to pregnant rats (Sprague-Dawley; n=26-29/group) on gestational days 6
       through 15, maternal toxicity (hypoactivity during the first treatment days,
       increased water consumption, decreased food intake, decreased body weight
       gain during the treatment period, increased relative and absolute liver weights)
       was observed in the animals of the mid- and high-dose group, while no such
       effects were seen at 100 mg/kg bw. No effect on fetal growth, viability, or
       morphological development was found in any of the treated groups (Nav92a). In
       a separate study, administration by gavage of doses of D-camphor of 0, 216, 464,
       or 1000 mg/kg bw to pregnant rats (Sprague-Dawley; n=20/group), on gestational
       days 6 through 17, did neither result in evidence of embryotoxic or teratogenic
       effects. Some maternal toxicity was seen including salivation and reduced food
       intake in the mid- and high-dose group and more pronounced signs such as
       clonic convulsion, piloerection, reduced motility, and reduced body weight gain
*      http://ntp-server.niehs.nih.gov/htdocs/Results_Status/Resstatc/464493.html
018-10 Health-based Reassessment of Administrative Occupational Exposure Limits
</pre>

====================================================================== Einde pagina 10 =================================================================

<br><br>====================================================================== Pagina 11 ======================================================================

<pre>       in the high-dose group. At necropsy, ulceration of (the cardiac region of) the
       stomach was seen in 2 and 5 dams of the mid- and high-dose group, respectively
       (Leu97).
           In pregnant rabbits (n=26/group) given D-camphor at oral (gavage) doses of
       0, 50, 100, or 400 mg/kg bw/day on gestational days 6 through 19, no maternal
       toxicity (mortality, body weight, body weight gain, clinical signs, liver weights)
       was found in any of the experimental groups, but maternal weight gain tended to
       decrease with increasing dose during the treatment period. No effect on fetal
       growth, viability, or morphological development was seen in any of the treated
       groups (Nav92b). In a separate study, administration by gavage of doses of
       D-camphor of 0, 147, 316, or 681 mg/kg bw to pregnant rabbits (Himalayan;
       n=12/group), on gestational days 6 through 18, did neither result in evidence of
       embryotoxic or teratogenic effects. Maternal toxicity including reduced food
       intake, and body weight gain was seen in the high-dose group. Histological
       examination did not reveal any changes in any of the treatment groups (Leu97).
           A single intraperitoneal injection of 100 mg/kg bw to 8-week-old male mice
       (strain A; n=5) caused statistically significant decreases in the number of resting
       primary spermatocytes when counted 2, 4, and 6 days after treatment. By day 8,
       these numbers did not differ from those from control animals in this experiment
       which was not aimed at the effects of camphor on reproductive organs but
       designed to examine the influence of camphor-pretreatment on effects of
       γ-irradiation in less vascularized and hypoxic tissues (Goe85).
7      Existing guidelines
       The current administrative occupational exposure limit (MAC) for bornan-2-one
       (camphor) in the Netherlands is set at 12 mg/m3 (2 ppm), 8-hour TWA.
           Existing occupational exposure limits for camphor in some European
       countries and in the USA are summarised in the annex.
8      Assessment of health hazard
       The committee did not find data on the kinetics of camphor following inhalation
       exposure. Experiments in rats and mice showed that bioavalibility was low and
       independent of sex and species following uncovered skin application.
       Approximately 70% appeared to be lost by volatilization. Absorption from the
       gastrointestinal tract is rapid. Camphor was found to be metabolised by
       hydroxylation at several positions and subsequent oxidation to corresponding
018-11 Bornan-2-one (camphor, synthetic)
</pre>

====================================================================== Einde pagina 11 =================================================================

<br><br>====================================================================== Pagina 12 ======================================================================

<pre>       ketones and carbonic acid or by reduction of the keto group. Human data
       indicated that camphor may cross the placenta.
           The committee did not find relevant data concerning effects following
       long-term ocupational exposure. Symptoms of poisoning following incidental
       and accidental oral exposure included effects on the gastointestinal tract and the
       nervous system. At autopsy of lethal cases, effects on kidneys, liver, and brain
       were observed. Oral doses of 50 to 500 mg/kg bw were found to be lethal to
       adults.
           The committee did not find experimental data on the potential irritation and
       sensitisation of camphor. Inhalation of concentrations of 400 to 1760 mg/m3
       (65-280 ppm), for 3 hours, induced effects on the central nervous system and
       mortality in mice. Minimum lethal oral doses of 1600 and 2000 mg/kg bw were
       reported for rabbits and guinea pigs, respectively. In the rabbits that died from
       exposure to camphor, only gross effects on the stomach were seen at autopsy.
       Single doses of 1000 mg/kg bw induced convulsions. The committee did not find
       data on LC50 or LD 50 values.
           Apart from oral teratogenicity studies and a dermal and intraperitoneal
       carcinogenicity study, the committee did not find data on the effects of camphor
       following repeated exposure. Considering the flaws in the carcinogenicity
       studies (high initial mortality in the dermal study; intraperitoneal injection as a
       less relevant route of administration, short duration, and lung tumours as an
       endpoint in a lung-tumour sensitive strain of mice in the intraperitoneal study),
       the committee feels that these studies are not informative with respect to the
       potential carcinogenicity of camphor. Camphor did not induce mutations when
       tested in vitro in bacteria (S.typhimurium) but caused a small but statistically
       significant increase in the frequency of SCE in bone marrow of intraperitoneally
       injected mice.
           Camphor did not induce reproduction toxicity in rats and rabbits when
       administered by gavage during organogenesis at oral doses up to 1000 and ca.
       700 mg/kg bw, respectively. Maternal toxicity was seen at doses of 400 and ca.
       700 mg/kg bw in rats and rabbits, respectively.
       The committee considers the toxicological data base on camphor too poor to
       justify recommendation of a health-based occupational exposure limit.
       The committee concludes that there is insufficient information to comment on the
       level of the present MAC-value.
018-12 Health-based Reassessment of Administrative Occupational Exposure Limits
</pre>

====================================================================== Einde pagina 12 =================================================================

<br><br>====================================================================== Pagina 13 ======================================================================

<pre>       References
ACG99  American Conference of Governmental Industrial Hygienists (ACGIH). Camphor, synthetic.
       In: TLVs ® and other occupational exposure values - 1999. [CD-ROM]. Cincinnati OH, USA;
       ACGIH® , Inc, 1999.
ACG00  American Conference of Governmental Industrial Hygienists (ACGIH). Guide to occupational
       exposure values - 2000. Cincinnati OH, USA: ACGIH® , Inc, 2000: 19.
ACG01  American Conference of Governmental Industrial Hygienists (ACGIH). 2001 TLVs ® and
       BEIs® . Threshold Limit Values for chemical substances and fysical agents. Biological
       Exposure Indices. Cincinnati OH, USA: ACGIH® , Inc, 2001: 20.
Agu94  Aguirre A, Oleaga JM, Zabala R, et al. Allergic contact dermatitis from Reflex® spray.
       Contact Dermatitis 1994; 30: 52-3.
And78  Anderson D, Styles JA. An evaluation of six short-term tests for detecting organic chemical
       carcinogens. Appendix II. The bacterial mutation test. Br J Cancer 1978; 37: 924-30.
Arb00a Arbejdstilsynet. Grænseværdier for stoffer og materialer. Copenhagen, Denmark:
       Arbejdstilsynet, 2000; At-vejledning C.0.1.
Arb00b Arbetarskyddstyrelsen. Hygieniska gränsvärden och åtgärder mot luftföroreningar.
       Solna,Sweden: National Board of Occupational Safety and Health, 2000; Ordinance AFS
       2000/3.
Ban95  Banerjee S, Welsch CW, Rao AR. Modulatory influence of camphor on the activities of
       hepatic carcinogen metabolizing enzymes and the levels of hepatic and extrahepatic reduced
       glutathione in mice. Cancer Lett 1995; 88: 163-9.
CEC00  Commission of the European Communities (CEC). Commission Directive 2000/39/EC of 8
       June 2000 establishing a first list of indicative occupational exposure limit values in
       implementation of Council Directive 98/24/EC on the protection of the health and safety of
       workers from the risks related to chemical agents at work. Official Journal of the European
       Communities 2000; L142 (16/06/2000): 47-50.
Com94  Committee on Drugs. Camphor revisited: Focus on toxicity. Pediatrics 1994; 94: 127-8.
DFG01  Deutsche Forschungsgemeinschaft (DFG): Commission for the Investigation of Health
       Hazards of Chemical Compounds in the Work Area. List of MAK and BAT values 2001.
       Maximum concentrations and biological tolerance values at the workplace. Weinheim, FRG:
       Wiley-VCH, 2001: 33 (rep no 37).
Flu31  Flury F, Zernicke F. Campher. In: Schädliche Gase, Dämpfe, Nebel, Rauch- und Staubarten.
       Berlin, FRG: Julius Springer, 1931: 451-2.
Gib89  Gibson DE, Moore GP, Pfaff JA. Camphor ingestion. Am J Emerg Med 1989; 7: 41-3.
Goe85  Goel HC, Surinder Singh, Adhikari JS, et al. Radiomodifying effect of camhpor on the
       spermatogonia of mice. Jpn J Exp Med 1985; 55: 219-23.
018-13 Bornan-2-one (camphor, synthetic)
</pre>

====================================================================== Einde pagina 13 =================================================================

<br><br>====================================================================== Pagina 14 ======================================================================

<pre>Goe89  Goel HC, Surender Singh, Singh SP. Radiomodifying influence of camphor on
       sister-chromatid exchange induction in mouse bone marrow. Mutat Res 1989; 224: 157-60.
Gom98  Gomes-Carneiro MR, Felzenszwalb I, Paumgartten FJR. Mutagenicity testing of (±)-camphor,
       1,8-cineole, citral, citronellal, (-)-menthol and terpineol with the Salmonella/microsome
       assay. Mutat Res 1998; 416: 129-36.
Gos84  Gosselin RE, Smith RP, Hodge HC, et al (eds). Camphor. In: Clinical toxicology of
       commercial products. 5th ed. Baltimore MD, USA: Williams and Wilkins, 1984: III-84-6.
Gra53  Graffi A, Vlamynck E, Hoffmann F, et al. Untersuchungen über die geschwulstauslösende
       Wirkung verschiedener chemischer Stoffe in der Kombination mit Crotonöl. Arch
       Geschwulstforsch 1953; 5:110-26.
Gra86  Grant WM. Camphor. In: Toxicology of the eye. Springfield IL, USA: Charles C Thomas
       Publ, 1986: 173-4.
Gri96  Grizzle TB, Dix KJ, Handy RW. The toxicokinetics of d,l-camphor. Protocol RTI-524: The
       toxicokinetics of intravenously and dermally administered d,l-camphor (CAM) in male and
       female B6C3F1 mice and F344 rats. Research Triangle Park NC, USA: Research Triangle
       Institute, 1996.
Gro69  Gronka PA, Bobkoskie RL, Tomchick GJ, et al. Camphor exposure in a packaging plant. Am
       Ind Hyg Assoc J 1969; 30: 276-9.
Hei77  Heinonen OP, Slone D, Shapiro S. Birth defects and drugs in pregnancy. Littleton MA, USA:
       Publishing Science Group, Inc, 1977.
Heu13  Heubner W. Über die Wirkung des Dampfes von Campher und Camphen. Z Gesamte Exp
       Med 1913; 1: 268-81.
HSE01  Health and Safety Executive (HSE). EH40/2001. Occupational Exposure Limits 2001.
       Sudbury (Suffolk), England: HSE Books, 2001: 13.
Izm82  Izmerov NF, Sanotsky IV, Siderov KK. In: Toxicometric parameters of industrial toxic
       chemicals under single exposure. Moscow, Russia: Centre of International Projects, 1982:
       31-2.
Köp82  Köppel C, Tenczer J, Schirop T, et al. Camphor poisoning. Abuse of camphor as a stimulant.
       Arch Toxicol 1982; 51: 101-6.
Leu97  Leuschner J. Reproduction toxicity studies of D-camphor in rats and rabbits.
       Arzneimittelforsch 1997; 47: 124-8.
Lia83  Liang JC, Hsu TC, Henry JE. Cytogenetic assays for mitotic poisons. The grasshopper
       embryo system for volatile liquids. Mutat Res 1983; 113: 467-79.
Nav92a Navarro HA, Price CJ, Marr MC, et al. Developmental toxicity evaluation of d-camphor
       (CAS No. 464-49-3) administered by gavage to Sprague-Dawley (CD® ) rats on gestational
       days 6 through 15. Final study report and appendix. Research Triangle Park NC, USA:
       Research Triangle Institute, 1992; report available from National Technical Information
       Service, Springfield VA, USA, order no. NTIS/PB92-170034.
018-14 Health-based Reassessment of Administrative Occupational Exposure Limits
</pre>

====================================================================== Einde pagina 14 =================================================================

<br><br>====================================================================== Pagina 15 ======================================================================

<pre>Nav92b Navarro HA, Price CJ, Marr MC, et al. Developmental toxicity evaluation of d-camphor
       (CAS No. 464-49-3) administered by gavage to New Zealand White (NZW) rabbits on
       gestational days 6 through 19. Research Triangle Park NC, USA: Research Triangle Institute,
       1992; report available from National Technical Information Service, Springfield VA, USA,
       order no. NTIS/PB93-123784.
NIO99  National Institute of Occupational Safety and Health (NIOSH). Camphor. In: Registry of
       Toxic Effects of Chemical Substances (RTECS) [CD-ROM], issue July 1999. SilverPlatter
       International, 1999 (last update camphor file: July 1999).
NLM99  US National Library of Medicine (NLM). Camphor. In: Hazardous Substances Data Bank
       (HSDB) [CD-ROM], issue July 1999. SilverPlatter International, 1999 (last update camphor
       file: June 1999).
Rab97  Rabl W, Katzgraber F, Steinlechner M. Camphor ingestion for abortion (case report).
       Forensic Sci Int 1997; 89: 137-40.
Ric93  Richardson ML, Gangolli S, eds. C48 Camphor. In: The dictionary of substances and their
       effects. Cambridge, UK: Royal Society of Chemistry 1993: 76-7 (Vol 2).
Rig65  Riggs J, Hamilton R, Homel S, et al. Camphorated oil intoxication in pregnancy. Obstet
       Gynecol 1965; 25: 255-8.
Rob69  Robertson JS, Hussain M. Metabolism of camphors and related compounds. Biochem J 1969;
       113: 57-65.
Sam39  Sampson WL, Fernandez L. Experimental convulsions in the rat. J Pharmacol Exp Ther
       1939; 65: 275-80 (cited from ACG98 and Nav92b).
Sie86  Siegel E, Wason S. Camphor toxicity. Pediatr Clin North Am 1986; 33: 375-9.
Sko77  Skoglund RR, Ware LL, Schanberger JE. Prolonged seizures due to contact and inhalation
       exposure to camphor. Clin Pediatr 1977; 16: 901-2
Smi54  Smith A, Margolis G. Anatomical and pharmacologic study: Report of a fatal case —
       Experimental investigation of protective action of barbituates. Am J Pathol 1954; 30:
       857-69.
Spa97  Sparacino CM, , Collins BJ, Blake JC, et al. Toxicokinetics (TK) of intravenously and
       dermally administered d,l-camphor (CAM) in rats and mice. Toxicologist 1997; 36: 141.
Sto73  Stoner GD, Shimkin MB, Kniazeff AJ, et al. Test for carcinogenicity of food additives and
       chemotherapeutic agents by the pulmonary tumor response in strain A mice. Cancer Res
       1973; 33: 3069-85.
SZW01  Ministerie van Sociale Zaken en Werkgelegenheid (SZW). Nationale MAC-lijst 2001. The
       Hague, The Netherlands: Sdu, Servicecentrum Uitgevers, 2001: 18.
TRG00  TRGS 900. Grenzwerte in der Luft am Arbeitsplatz; Technische Regeln für Gefahrstoffe.
       BArbBl 2000; 2.
018-15 Bornan-2-one (camphor, synthetic)
</pre>

====================================================================== Einde pagina 15 =================================================================

<br><br>====================================================================== Pagina 16 ======================================================================

<pre>            Annex
Occupational exposure limits for camphor in various countries.
country                         occupational                   time-weighted type of exposure       notea     lit refb
-organisation                   exposure limit                 average         limit
                                ppm          mg/m 3
the Netherlands
- Ministry                      2            12                8h              administrative                 SZW01
Germany
- AGS                           2            13                8h                                             TRG00
- DFG MAK-Kom.                  2            13 c              8h              MAK                            DFG01
Great Britain
- HSE                           2            13                8h              OES                            HSE01
                                3            19                15 min
Sweden                          -            -                                                                Arb00b
Denmark                         2            12                8h                                             Arb00a
USA
- ACGIH                         2            -                 8h              TLV                  A4d       ACG01
- OSHA                          3            -                 15 min          STEL
- NIOSH                         -            2                 8h              PEL                            ACG00
                                -            2                 10 h            REL                            ACG00
European Union
- SCOEL                         -            -                                                                CEC00
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
     Substance still being evaluated or the available toxicological data are indequate for classification and, therefore,
     not placed in one of the peak exposure limitation categories yet
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
018-16      Health-based Reassessment of Administrative Occupational Exposure Limits
</pre>

====================================================================== Einde pagina 16 =================================================================

<br><br>