<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>Cyanamide and calcium cyanamide
(CAS No: 420-04-2, 156-62-7)
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/133 The Hague, November 9, 2004
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<pre>Preferred citation:
Health Council of the Netherlands: Committee on Updating of Occupational
Exposure Limits. Cyanamide and calcium cyanamide; Health-based
Reassessment of Administrative Occupational Exposure Limits. The Hague:
Health Council of the Netherlands, 2004; 2000/15OSH/133.
all rights reserved
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<pre>1             Introduction
              The present document contains the assessment of the health hazard of cyanamide
              and calcium cyanamide 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 MA Maclaine Pont, MSc (Wageningen
              University and Research Centre, Wageningen, the Netherlands).
                   In August 2000, literature was searched in the databases Toxline, Medline,
              and Chemical Abstracts, starting from 1981, 1966, and 1992, respectively, and
              using the following key words: cyanamide, carbimide, carbodiimide,
              cyanoamine, cyanogen amide, cyanogen nitride, hydrogen cyanamide, N-
              cyanoamine, calcium cyanamide, 156-62-7, 420-04-2, and 6860-10-2. Data of
              unpublished studies were generally not taken into account. Exceptions were
              made for studies that were summarised and evaluated by the German MAK
              committee (Gre02). The final literature search was carried out in September
              2003.
                   In October 2003, the President of the Health Council released a draft of the
              document for public review. Comments were received from the following
              individuals and organisations: A Aalto (Ministery of Social Affairs and Health,
              Tampere, Finland). These comments were taken into account in deciding on the
              final version of the document.
2             Identity
Name                          :  cyanamide                            cyanamide, calcium salt (1:1)
Synonyms                      :  amidocyanogen; carbimide;            calcium cyanamid; calcium carbimide;
                                 carbodiimide; hydrogen cyanamide; N- Alzodef, Dormex, Temposil
                                 cyanoamine; cyanogenamide; alzogur
molecular formula             :  CH2 N2                               CaCN2
structural formula            :  H2N-CN                               CaN-CN
CAS number                    :  420-04-2                             156-62-7
Data from: ACG99a, ACG99b, How92.
133-3         Cyanamide and calcium cyanamide
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<pre>3                 Physical and chemical properties
                                      cyanamide                                calcium cyanamide
molecular weight                  :   42.04                                    80.10
boiling point                     :   at 0.07 kPa: 83oC                        sublimes at 1150-1200oC
melting point                     :   45-46oC                                  ca. 1340oC (decomposes)
flash point                       :   140.6oC (open cup)                       not available
vapour pressure                   :   at 20oC: 0.5 Pa                          not applicable
solubility in water               :   at 15oC: soluble (77.5 g/100 mL)         insoluble (decomposes)
log Poctanol/water                :   - 0.82 (experimental); -0.81 (estimated) -0.20 (estimated)
conversion factors                :   at 20oC, 101.3 kPa: 1 ppm = 1.75 mg/m3   at 20oC, 101.3 kPa: 1 ppm = 3.3 mg/m3
                                                            1 mg/m3 = 0.57 ppm                     1 mg/m3 = 0.30 ppm
Data from: Bud96, Lid99, NLM02, http://www.syrres.com/esc/est_kowdemo.htm.
                  Cyanamide, as the undiluted material, is a colourless deliquescent, almost
                  odourless crystalline solid. It is commonly used as a 25% liquid solution. Pure
                  calcium cyanamide is a non-volatile, non-combustible, white crystalline solid.
                  Commercial calcium cyanamide is a crystalline grey material or a powder,
                  containing small amounts of calcium carbide and other contaminants, such as
                  carbon, calcium hydroxide, calcium oxide, calcium carbonate, and sulphides,
                  oxides, and nitrides of silicon, iron, and aluminium (ACG99a, ACG99b).
                      Cyanamide is weakly acidic and hygroscopic. It is a highly reactive
                  chemical, which can polymerise explosively if the liquid solution evaporates to
                  dryness. Cyanamide can be stabilised in acidic solutions such as phosphoric acid,
                  sulphuric acid, boric acid, or acetic acid, and by storage at low temperature. The
                  compound decomposes upon heating or burning, forming nitrogen dioxide,
                  ammonia and hydrogen cyanide. It reacts vigorously with strong acids, strong
                  bases, and strong oxidising agents (ACG99a, Gre02, NLM02).
4                 Uses
                  Cyanamide is used as a chemical intermediate for dicyandiamide in melamine
                  manufacture. It is also used in fumigants, metal cleaners, refining of ores,
                  production of synthetic rubber, and in chemical synthesis (ACG99a).
                      Calcium cyanamide is commercially used as raw material for the
                  manufacture of calcium cyanide and dicyandiamide. It is also used in the
                  desulphurisation of some types of speciality steels. The product is no longer used
                  as a defoliant, fertiliser, or herbicide (ACG99b). According to the database of the
133-4             Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>      Dutch Pesticide Authorisation Board (CTB)*, neither cyanamide nor calcium
      cyanamide are permitted in the Netherlands for use as an active ingredient in
      pesticides.
           Both compounds were introduced in Canada, Europe, and Japan in 1956 as
      new pharmacological adjuncts with few side effects in the treatment of
      alcoholism. Its use, however, is restricted in some countries, including the USA
      (Kaw97). It is sold either as a aqueous solution (stabilised with citric acid) or as a
      slow-release tablet, with various trade-names, such as Abstem, Colme, Dormex
      and Temposil (Bri80, Bri83, God94, Kaw97).
5     Biotransformation and kinetics
      Human data
      Cyanamide
      To study dermal penetration, the inner side of the 2 forearms (16 cm2/arm) of 6
      male human volunteers were treated with 10 mg cyanamide for 6 hours, under
      occlusion (total dose: 20 mg per person). On average, 17.7 mg cyanamide was
      still present on the patches, indicating that maximally 2.3 mg of cyanamide
      (11.5% of the dose) was available for dermal absorption. Of this amount, 7.7%
      was excreted in the urine as the metabolite N-acetylcyanamide. A maximum
      dermal absorption rate of 12 µg/cm2/ hour was calculated (Mer91a).
           The kinetics of cyanamide were studied in male human volunteers (n=4/
      group), given single oral doses of 0.3, 1.0, or 1.5 mg cyanamide/kg bw. Mean
      peak cyanamide concentrations in plasma (197-1706 g/L) were achieved at 10.5
      to 15.5 minutes after administration. Mean cyanamide elimination half-lives
      from the plasma were 40, 77, and 62 minutes, respectively. Absorption was not
      complete, the mean oral bioavailability being 53 and 70% at doses of 0.3 and 1.0
      mg/kg bw, respectively. In another experiment, male human volunteers (n=4/
      group) received single intravenous infusions of 0.1, 0.3, 0.6, or 1 mg cyanamide/
      kg bw for 20 minutes. The mean elimination half-lives from the plasma were 42,
      44, 52, and 52 minutes, respectively (Oba91).
           After oral administration of 0.25 mg cyanamide/kg bw to male human
      volunteers, approximately 35 and 40% were excreted in the urine as N-
      acetylcyanamide within 12 and 48 hours after administration, respectively. No
      significant changes were found in the cyanide concentrations in the blood or in
*     at: http://www.ctb-wageningen.nl.
133-5 Cyanamide and calcium cyanamide
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<pre>      the thiocyanate concentrations in the urine, indicating that cyanamide is not
      metabolised to cyanide (Mer91a).
      Calcium cyanamide
      At pH 5, the approximate pH of moist on human skin, 92-98% of calcium
      cyanamide was converted into cyanamide within 2.5 minutes. At 22oC, 95-100%
      was converted within 10 minutes (Mer91b). Under simulated human gastric
      conditions (at pH 1.15 and 37oC), calcium cyanamide was hydrolysed to
      cyanamide to the extent of 92% within 1 hour (Loo81).
      Animal data
      Cyanamide
      In an unpublished dermal penetration study, 14C-labelled cyanamide was applied
      to the unoccluded skin of rats (12.5 cm2) at doses of 0.1, 1.0, or 10 mg/animal for
      0.5, 1, 2, 4, 10, or 24 hours. The peak concentrations of cyanamide in blood were
      achieved at 24 hours after application of 0.1 mg and at 10 hours after application
      of 1.0 or 10 mg. The 24-hour urinary excretion was 0.93, 1.7 or 7.7% of the
      administered doses at 0.1, 1.0, or 10 mg, respectively; the 24-hour excretion in
      faeces was less than 0.2%. Twenty-four hours after application, the amount of
      radioactivity retained in the skin and in the carcass was 20 and 0.1- 4% of the
      administered doses, respectively. From these data, it was calculated that the 24-
      hour dermal absorption of radioactivity was 1.8%, 2.8%, or 11.1% at doses 0.1,
      1.0, or 10 mg, respectively (SKW89a).
          Following administration of a single oral (gavage) dose of aqueous
      cyanamide of 2 mg/kg bw to Sprague-Dawley rats, the peak concentration of
      cyanamide in plasma (mean concentration: 0.39 mg/L) was achieved within 5
      minutes; the mean plasma elimination half-life was 27 minutes. The mean
      bioavailablity was 69%. Following oral administration of 4 mg/kg bw to beagle
      dogs, the peak plasma concentration (mean level: 2.3 mg/L) was reached within
      33 minutes; the mean elimination half-life was 62 minutes, the mean
      bioavailability 65% (Oba89). Single intravenous injections of 2 or 35 mg
      cyanamide/kg bw into rats resulted in mean elimination half-lives of 33 and 57
      minutes, respectively; in beagle dogs given intravenous injections of 1, 2, or 4
      mg cyanamide/kg bw, they were 39, 47, and 61 minutes, respectively (Oba86,
      Oba89).
          In rats, the kinetics of cyanamide were studied in fasting and non-fasting
      animals, given an oral dose of 35 mg/kg bw. No significant differences were
      found between the bioavailability in fasted animals (mean: 93.3%) compared
133-6 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>      with non-fasting animals (mean: 85.5%). However, the peak cyanamide plasma
      concentrations were reached much faster in fasted animals (mean: 6.3 minutes)
      compared to non-fasting animals (mean: 14.7 minutes), indicating retardation of
      drug absorption (Oba86). When 14C-labelled cyanamide was administered
      intraperitoneally to rats (10 µC/kg bw), 93.9% of the radioactivity was excreted
      in the urine and 1.4% as expired CO2 within 6 hours (Dei76).
          In an unpublished biokinetic and metabolism study, 4 groups of rats (n=5/
      sex/group) were given 14C-labelled cyanamide. Group 1 received a single
      intravenous dose of 1 mg/kg bw, groups 2 and 3 received single oral doses of 1 or
      20 mg/kg bw, respectively, and group 4 received oral doses of 1 mg non-
      radiolabelled cyanamide/kg bw for 14 days, followed by a single oral dose of 1
      mg/kg bw of 14C-labelled cyanamide. In all groups, the amount of radioactivity
      recovered within 7 days was at least ca. 99% of the administered dose, most of it
      within 12-24 hours after administration. The radioactivity excreted in urine,
      faeces, and expired air (as 14CO2) amounted to 67-98, 2.8-15, and 1.5-10.5% of
      the administered dose, respectively. Rats in groups 3 and 4 excreted less CO2
      compared to rats in groups 1 and 2, probably due to saturation of metabolism of
      cyanamide into CO2. At post-administration day 7, rats in groups 1 and 2
      retained traces of radioactivity in the blood (ca. 0.5-0.9%) and the liver (ca. 0.3-
      1.2%), but not in the gonads (<0.02%) while the carcass contained 2.9- 4.4%.
      Smaller amounts of radioactivity were found in the tissues after rats given 20
      mg/kg bw. The bioavailability was 100% or 95% for rats given an oral dose of 1
      or 20 mg/kg bw, respectively. Most of the urinary radioactivity (32 to 61% of the
      dose) was present as the metabolite N-acetylcyanamide. Three other metabolites,
      of unknown identity, were excreted in amounts of 1.6-14, 6.5-8.9%, and 3.2-
      4.8%, respectively (SKW93).
          Beagle dogs, given a single dose of 14C-labelled cyanamide of 1.7 mg/kg bw,
      excreted 67-83 and 80-90% of the radioactivity in the urine within 27 and 120
      hours after administration, respectively. When the same dose was injected
      intravenously, 62 and 75% of the radioactivity was excreted in the urine within
      27 and 120 hours, respectively. About 87% of the urinary radioactivity excreted
      between 0 and 27 hours was present as the metabolite N-acetylcyanamide, and
      11% as unchanged cyanamide. N-acetylcyanamide was also found to a large
      extent (no quantitative data given) in the urine of rats and rabbits, given single
      intravenous doses of 42 and 75 mg/kg bw, respectively. The acetylation reaction
      is catalysed by an acetyl-S-CoA-dependent hepatic N-acetyltransferase, which
      capacity is variable among different species, with dogs, and possibly also slow
      acetylator-phenotype rabbits, exhibiting the lowest activity (Shi84).
133-7 Cyanamide and calcium cyanamide
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<pre>          In rats given single oral doses of unlabelled cyanamide of 10 mg/kg bw, an
      average of 42.7 and 45.6% of the dose was excreted in the urine as N-
      acetylcyanamide within 22 and 48 hours, respectively (Mer91a).
      The ability of a cyanamide metabolite to inhibit the activity of hepatic aldehyde
      dehydrogenase (ALDH), an enzyme involved in the biotransformation of
      ethanol, is thought to be an important step in the mechanism of the alcohol-
      deterrent effect of cyanamide (see Section 6). N-acetylcyanamide did not inhibit
      purified preparations of ALDH, indicating that another, yet unidentified
      metabolite of cyanamide, is the ALDH blocking agent (Shi84).
      Calcium cyanamide
      After a single oral dose of 7 mg calcium cyanamide/kg bw (equals 3.68 mg
      cyanamide/kg) to rats, the peak plasma cyanamide concentration was achieved at
      60 minutes after administration. No cyanamide residues were detected in the
      liver (Bri83).
      In vitro data
      In an unpublished in vitro dermal penetration study, 6 µL of cyanamide solutions
      of 27 g/L or 544 g/L were applied on 0.64 cm2 human skin for 6 hours. The
      amounts absorbed were 34 and 80% at the low and high concentration,
      respectively. The rate of absorption was faster at the high than at the low
      concentration (SKW00).
          In an unpublished in vitro dermal penetration study, 6 µL of cyanamide
      solutions of 27 g/L or 544 g/L were applied on 0.64 cm2 of rat skin for 6 hours.
      The amounts absorbed were 26 and 75% at the low and the high concentration,
      respectively. The rate of absorption was faster at the high than at the low
      concentration (SKW00).
133-8 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>6     Effects and mechanism of action
      Human data
      Cyanamide
      A few case studies of skin sensitisation have been reported, most of them related
      to the use of cyanamide as a therapeutical medicine. A 61-year-old man, treated
      with cyanamide for alcoholism during 2 years, started to develop erythematous
      scaly skin lesions. He reacted positively to patch tests with 0.1-5% aqueous
      solutions of cyanamide (Aba99). Of 7 patients who were treated for alcoholism
      with cyanamide daily during their stay in a clinic, 6 developed exfoliate
      dermatitis, and one a lichen-planus-like skin eruption. All subjects had positive
      patch tests with cyanamide at concentrations ranging between 0.001% and 1%
      (Kaw97). Three persons, who worked in hospitals and had handled many drugs,
      among which cyanamide (Colme), for treatment of alcoholic patients, developed
      erythema and oedema on the hands and also facial dermatitis. All reacted
      positively to patches containing 0.1 to 5% aqueous solutions of cyanamide
      (God94). In an earlier case report, a 35-year-old woman, who had given a
      cyanamide (Colme) solution to her husband as treatment for alcoholism for 4
      months, developed redness and swelling on the back of her hand, marked
      oedema of the tip of her nose, and small papules on her plate and lips. She
      reacted positively to a patch with 1 and 10% Colme solution (0.6 and 6 g
      cyanamide/L, respectively) (Fer82). A 32-year-old man, who had handled
      numerous medicines, developed erythemato-squamous dermatitis. He reacted
      positively to patches containing 0.1 to 5% aqueous solution of cyanamide
      (Con81). A case of eczematous dermatitis with diffuse symmetrical involvement
      of the face, including the eyelids, the region under the chin, and the retroauricular
      folds, was reported in a worker 20 days after starting as a supervisor of the
      synthesis of phosphorylcreatine. Symptoms disappeared when away from the
      workplace, with the aid of medical treatment, but developed again when
      returning to work on the same job. Patch testing showed positive responses to
      phosphorylcreatine as well as to dibenzyl phosphite and cyanamide, both used as
      reagents in phosphorylcreatine synthesis (Fot03). In 2 older case reports,
      dermatitis and positive patch tests were described in a worker following
      occupational exposure to lead cyanamide (Bla75), and in a chemist who worked
      with several chemicals, among which cyanamide (Cal70). No allergic skin
      reactions were observed in 29 workers engaged in cyanamide and calcium
133-9 Cyanamide and calcium cyanamide
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<pre>       cyanamide manufacture upon patch testing with a 0.5% aqueous solution of
       cyanamide (Mer91b).
           A 29-year-old Hispanic worker experienced hypotension, vertigo, nausea,
       puffiness of the face, and hypokalaemia, without exposure to alcohol, while
       spraying kiwi trees hydrogen cyanamide stabilised with phosphoric acid (Les98).
       Calcium cyanamide
       In the older German literature, 11 cases were reported of farmers who allegedly
       died after application of ‘Kalkstickstoff’, used as an agricultural product. The
       main ingredients were calcium cyanamide (60%) and calcium oxide (15%). In 5
       of the cases, the victims probably had consumed alcohol on the day of
       application. Within the first days after application, symptoms were irritation of
       the mucous membranes of the throat, trachea, or bronchi, with a rapid
       deterioration of the health of the patient. Death followed generally with an
       unspecific cause, diagnosed, e.g., as a complication of an infection, a disease of
       the gastrointestinal tract, or a disease of the respiratory or circulatory system
       (Hau53). The effects of ‘Kalkstickstoff’ on the mucous membranes were likely
       caused by the calcium oxide in the product (Sch81). In another case, a causal
       connection between exposure to calcium cyanamide and the death of a farmer, 8
       days after application of calcium cyanamide was doubtful, according to the
       author (Olk58). A more recent case is described of a 34-year-old housewife with
       alcohol dependence, who started vomiting, lost consciousness, and died after she
       took more than 20 mL of a 1% calcium cyanamide solution, together with an
       alcoholic beverage containing about 129 g of ethanol (Koj97).
           The health effects of exposure to calcium cyanamide were investigated in a
       cross-sectional study on 65 workers who had been employed for 5 to 41 years in
       a ‘Kalkstickstoff’-producing plant. At the time of the study, the airborne
       concentrations of calcium cyanamide in different units of the plant, measured
       with static air monitoring, varied between 0.23 and 8.4 mg/m3. The workers were
       divided into 3 groups: group 1 comprised 18 workers employed in units of the
       plant where exposures were higher than 2.5 mg/m3, group 2 24 workers
       employed in units with exposures between 1 and 2.5 mg/m3, and group 3 23
       workers employed in units where exposures were below 1 mg/m3. There were no
       differences in age, duration of employment, and alcohol use between the 3
       groups. The medical examination did not reveal diseases or health impairments
       related to exposure to calcium cyanamide. Special attention was given to the skin
       and mucous membranes, the respiratory system, the gastro-intestinal tract, the
       urogenital tract, the central and peripheral nervous system, the coronary and
       circulatory system, the thyroid gland, as well as to complications of infections.
133-10 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>       The main effects of calcium cyanamide exposure were vasomotoric disturbances
       after drinking alcohol, leading to flushing, i.e., redness of the head, the neck, and
       the upper part of the body, often combined with tachycardia and dyspnoea. The
       percentages of workers who had experienced this effect during their employment
       were 83, 79, and 74% in group 1, 2, and 3, respectively, and the frequency of
       occurrence of the effect per year (median) 8, 9, and 15, respectively. According
       to the authors, the possible cause of the effect is exposure to high levels of
       calcium cyanamide dust during cleaning operations, combined with heavy
       drinking during the weekends (Sch81). The committee concluded that a
       connection between this so-called antabuse effect of workers and potential
       exposure to calcium cyanamide air levels could not be demonstrated in this
       study.
            Some 10 years later, another occupational health study was conducted in the
       same factory on 2 groups of workers, engaged in the manufacture of cyanamide
       and calcium cyanamide. Group 1 comprised 31 males and 1 female, who had
       been employed for 1.5-35 years. Dermal exposure to (calcium) cyanamide,
       assessed by quantification of the amount of cyanamide on both hands of the
       workers, varied from 0.2 to 140 mg (mean: 17 mg; median: 5 mg). Patch tests on
       the workers did not reveal any case of allergy to cyanamide. Examination of the
       health status of these persons, including haematological tests, thyroid function
       tests (serum triiodothyronine, T3; serum thyroxine, T4; serum thyroid-stimulating
       hormone, TSH), or urine analyses did not reveal abnormalities. However, most
       of the workers had experienced the antabuse effect after drinking alcohol. The
       incidence of these effects varied largely, and no correlation was found with the
       amount of alcohol consumption. The effect was also experienced after
       consumption of cola, coffee, spices, and analgesics. In the 30 workers of group 2
       (duration of employment not given), total absorption of (calcium) cyanamide via
       all routes of exposure was measured by determination of the concentration N-
       acetylcyanamide in urine samples, collected at the end of the 8-hour shift.
       Concentrations, expressed as cyanamide equivalents, varied from, <0.01 to 4.1
       mg/L (mean: 1.1 mg/L; median: 0.2 mg/L). The estimated cyanamide uptake
       during the workshift, calculated from these urinary levels, ranged from <0.01 to
       15 mg/day (mean: 4.0 mg/day; median: 0.7 mg/day). Airborne cyanamide levels
       were not reported (Mer91b). In a subsequent study, 21 male workers from the
       calcium cyanamide-production unit of the same factory were examined
       specifically for effects on thyroid and gonadal function. A control group
       comprised 9 males, not occupationally exposed to calcium cyanamide. Thyroid
       function was examined by determination of serum concentrations T3, T4, TBG
       (thyroxine-binding globulin), and TSH. Gonadal function was examined by
133-11 Cyanamide and calcium cyanamide
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<pre>       determination of serum concentrations FSH (follicle-stimulating hormone), LH
       (luteinising hormone), and testosterone. Internal exposure to calcium cyanamide
       was assessed by determination of the concentration N-acetylcyanamide in urine
       samples, collected at the end of the 8-hour shift. Concentrations, expressed as
       cyanamide equivalents, ranged from <0.01 to 11.54 mg/L (mean: 2.1 mg/L;
       median 1.2 mg/L), demonstrating appreciable absorption of calcium cyanamide.
       All control persons had urinary levels below the limit of detection (<0.01 mg/L).
       The calculated cyanamide uptake varied from <0.04 to 43 mg/day (mean: 8.0
       mg/day; median: 4.6 mg/day). No statistically significant abnormalities were
       found in any of the thyroid or gonadal laboratory tests in exposed workers
       compared to the control group. No other work-related health disturbances were
       found in any of the workers in the calcium cyanamide production plant. Airborne
       cyanamide levels were not reported (Mer93). The committee concludes that
       mean daily absorption of approximately 0.1 mg cyanamide/kg bw, or 0.2 mg
       calcium cyanamide/kg bw, via all routes of exposure, in workers engaged in
       calcium cyanamide processes, does not induce effects on the thyroid or the
       gonadal function of the workers.
           In several, mainly Spanish studies, specific hepatocyte lesions have been
       reported in patients with chronic alcoholism, who were taking cyanamide as a
       therapeutic medicine at daily doses of 20 to 180 mg, for 1 to 13 months. These
       lesions consist of distinctive cytoplasmatic ‘inclusion bodies’, similar to those
       observed in Lafora’s disease, and to the ground-glass hepatocytes observed in
       type B hepatitis infections. ‘Inclusion bodies’ consist of glycogen, secondary
       lysosomes, and degenerated organelles. In addition, portal and periportal
       inflammation, as well as portal fibrotic lesions have been observed in patients
       with ‘inclusion bodies’ (Bru86, Mor84, Vaz80, Vaz83, Tho81). Apparently, these
       cytoplasmatic liver changes develop only by simultaneous intake of cyanamide
       and alcohol, but not of cyanamide alone (Yok95). Further, this effect is probably
       specific for plain cyanamide, because only scarce cases of this hepatic lesion
       have been reported in countries, where the medicine is used in its calcium form
       (Val89).
           The antabuse effect of calcium cyanamide, reported in the above studies, is
       due to interference of cyanamide with the hepatic biotransformation of ethanol,
       by inhibiting the hepatic enzyme ALDH (See Section 5). This results in an
       increased blood acetaldehyde level, which implicates unpleasant reactions,
       including peripheral cutaneous vasodilatation - manifested as flushing -,
       tachycardia, hypotension, headache, nausea, and vomiting (Sch81, Bri83); also,
       faintness and sweating are reported (Kaw97).
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<pre>           In several studies, the relationship between alcohol consumption and clinical
       responses in human subjects exposed to or receiving calcium cyanamide, has
       been investigated.
           As part of the above study on workers in a calcium cyanamide-producing
       plant (Sch81), 22 workers were asked to drink about 15 grams of alcohol, 1 to 7
       hours after the working shift. Modest, weak, and no flushing reactions were
       observed in 6, 7, and 9 workers, respectively. No correlation was found between
       flushing reaction and calcium cyanamide exposure. The same author conducted a
       study with human volunteers who were given 100 mg calcium cyanamide
       followed by 20 grams of alcohol. Flushing and tachycardia were observed 5
       hours after the alcohol consumption. The increase in acetaldehyde levels in blood
       was about 3 times the increase of a control group who did not ingest calcium
       cyanamide. Based on these studies, the authors calculated that the antabuse effect
       started with a daily intake of more than 25 mg calcium cyanamide (Sch81). The
       interindividual variability in the calcium cyanamide-alcohol interaction was
       studied in 4 volunteers who consumed 400 mg ethanol/kg bw, 10 hours after oral
       administration of 0.7 mg calcium cyanamide/kg bw (equals 0.37 mg cyanamide/
       kg bw). The peak acetaldehyde concentration in blood was achieved at about 30
       minutes after administration of alcohol, and ranged from 3.92 to 11.94 µg/mL
       (mean: 8.87 µg/mL). There was a statistically significant correlation between
       blood acetaldehyde concentrations and heart rate. The intraindividual variability
       was studied in 1 individual who drank 400 mg ethanol/kg bw, 12 hours after oral
       administration of 0.7 mg calcium cyanamide/kg bw, with one-week interval
       between the sessions. The peak acetaldehyde concentration in blood ranged from
       5.87 to 16 µg/mL. The coefficient of variation was 49.9% (Bri80). In another
       study, 4 male and 3 female volunteers were given an oral dose of 50 mg calcium
       cyanamide per person (equals 26.3 mg cyanamide per person), followed by an
       intravenous dose of 200 mg ethanol/kg bw 4 hours later. The peak acetaldehyde
       blood concentrations ranged from 12.2 to 185 µg/mL, which demonstrates that
       individual blood levels may vary a factor 15. The antabuse effect of calcium
       cyanamide started to occur at blood acetaldehyde levels between 30 and 50
       µg/mL. Flushing reaction and pulse rate appeared to correlate best with blood
       acetaldehyde levels (Joh92).
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<pre>       Animal data
       Irritation and sensitisation
       Cyanamide
       Cyanamide is severely irritating to the skin of rabbits, producing erythema,
       oedema and necrosis, when applied as a 50% aqueous solution under an
       occlusive patch for 4 hours (SKW82a). In another experiment, a 4-hour
       treatment of rabbit skin with a 50% aqueous solution under a semi-occlusive
       cover, caused erythema but only weak oedema (SKW89b). Cyanamide was a
       skin sensitiser in the standard guinea pig maximisation test of Magnusson-
       Kligman (SKW82b). However, no skin sensitisation was found when the Buehler
       test was used (SKW88a).
           Cyanamide was severely irritating, when 0.1 mL of 50% aqueous solution
       was instilled into the rabbit eye (SKW74, SKW91a).
       Calcium cyanamide
       Calcium cyanamide caused severe skin irritation, several days after application
       on rabbit skin for a 24-hours period under a polyethylene cuff, at doses of 5 or10
       mg/kg (ACG99b).
           It was irritating when 100 mg was instilled directly into the conjunctival sac
       of the eye of a rabbit (ACG99b).
       Acute toxicity
       Results of acute lethal toxicity tests with cyanamide and calcium cyanamide are
       summarised in Table 1.
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<pre>Table 1 Summary of acute toxicity studies in experimental animals.
                        exposure route              species               LD50/LC50           reference
                        (duration)                  (sex)
cyanamide               inhalation          (4 h)   rat (male, female)    >1000               SKW73a
                        dermal                      rabbit                590 mg/kg bw        Lew00
                                                    rabbit (male, female) 2100-3200 mg/kg bw  SKW73b
                                                    rabbit (male)         901 mg/kg bw        SKW88a
                                                    rabbit (female)       742 mg/kg bw        SKW88b
                                                    rat                   84 mg/kg bw         Lew00
                        oral                        rat                   125 mg/kg bw        Lew00
                                                    rat (male)            100-125 mg/kg bw    SKW73c
                                                    rat (female)          >175 mg/kg bw       SKW73a
                                                    rat (male, female)    223 mg/kg bw        SKW94
                        intraperitoneal             mouse                 200 mg/kg bw        Lew00
calcium cyanamide       inhalation          (4 h)   rat                   LCLo: 86 (4 hours)  Lew00
                        dermal                      rabbit                590 mg/kg bw        Lew00
                        oral                        rat                   158 mg/kg bw        ACG99b
                                                    rabbit                1400 mg/kg bw       ACG99b
                                                    mouse                 334 mg/kg bw        ACG99b
                                                    cat                   100 mg/kg bw        ACG99b
                        intravenous                 rat                   125 mg/kg bw        Lew00
                                                    mouse                 282 mg/kg bw        Lew00
                        intraperitoneal             mouse                 100 mg/kg bw        Lew00
            Cyanamide
            In an acute inhalation study, rats (n=5/sex) were exposed to 1 mg/m3 of a
            cyanamide aerosol for 4 hours. Particle sizes of the aerosol were 1.5 µm and
            below. No mortality was observed. Signs of toxicity were irritation of mucous
            membranes of the respiratory tract. Pathological examination did not show
            abnormalities (SKW73a).
                Following the acute oral and dermal studies, signs of toxicity were lethargy,
            lachrymation, miosis, tremor, unsteady gait, piloerection (SKW73b, SKW73c,
            SKW88a, SKW94). In addition, dermal application caused erythema, oedema,
            and necrosis of the skin (SKW73b).
                The effect of cyanamide on the levels of circulating ketone bodies was
            studied in fed and 18-hour fasted rats, that received a single intraperitoneal
            injection of 20 mg cyanamide/kg bw and were killed 4-hours later. Blood acetone
            levels were elevated 10-fold over controls, with a commensurate 5- to 7-fold
            increase in blood acetoacetate levels and a 2.5-fold increase in blood β-
            hydroxybutyrate concentrations (fed rat only). The threshold value required to
            elevate blood levels of ketone bodies was approximately 10 mg/kg bw. The
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<pre>       authors suggested that cyanamide caused a change in the rate of ketone body
       formation, as well as an inhibition of acetone metabolism. The latter effect is
       likely due to cyanamide-inhibition of the activity of ALDH (DeM88).
       Calcium cyanamide
       Rats given a single oral dose of 7 mg calcium cyanamide/kg bw (equals 3.7 mg
       cyanamide/kg), 30 minutes prior to an intraperitoneal dose of saline at 0, 48, and
       96 hours, showed an increased activity of liver enzymes aspartate
       aminotransferase (ASAT), alanine aminotransferase (ALAT), and glutamate
       dehydrogenase (GLDH) in blood, at 48 hours after the last dose of saline was
       given. No effect was found on the urinary concentrations of glucose, GLDH, N-
       acetyl-β-glucosaminidase (NAG), or coproporhyrin III, or on the urinary
       concentrations of any of the aldehydes investigated. However, calcium
       cyanamide caused a potentiating effect on the urinary excretion of several
       aldehydes in rats treated with diquat (Zwa99).
       Subacute and subchronic toxicity
       Cyanamide
       In an unpublished 2-week ‘nose-only’ inhalation study, Wistar male and female
       rats (n=5-8/sex/group) were exposed to cyanamide aerosols at actual
       concentrations of 0, 148 (85-192), 263 (149-327), or 799 (408-1118) mg/m3, 6
       hours/day, 5 days/week. At the end of the treatment, animals in the high-
       concentration and control groups were observed for another 2 weeks, before
       macroscopic and microscopic examination was carried out. Particle sizes of the
       aerosol were smaller than 5 µm. No mortality or signs of intoxication were
       observed. In all treatment groups, male and female body weights were
       significantly reduced, and male and female relative heart and kidney weights
       significantly increased. Males showed increased absolute and relative gonad
       weights and increased relative brain weights and females increased relative liver
       and adrenal weights. In the high-concentration group, macroscopic and
       microscopic changes were found in the brain, liver, lungs, and heart. The
       LOAEL was 148 mg/m3, based on reduced body weight and changes in absolute
       and relative organ weights (SKW96a). The committee has doubts on the validity
       of this study, as apparently the actual aerosol concentration was only 5 to 8% of
       the nominal concentration. In addition, particle size and distribution were not
       given, and macroscopic and microscopic examination did not include the upper
       respiratory tract (Gre02).
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<pre>            In an unpublished dermal study, New Zealand white rabbits (n=3/sex/group)
       received aqueous cyanamide (50% active ingredient) on occluded skin at doses
       of 12.5, 25, or 37.5 mg active ingredient (a.i.)/kg bw/day, 6 hours/day, 5 days/
       week, for 3 weeks. No mortality was observed. At all dose levels, some animals
       showed weakness and lethargy. Skin reactions (erythema) were observed at the
       mid and high doses. At 12.5 mg/kg bw and above, absolute liver weight was
       significantly increased in males. Non-dose-related significant changes were
       noted for absolute or relative kidney, adrenal, or gonad weights, in particular at
       the high and low dose. At the high dose, microscopic examination revealed
       congestion in the kidneys, haemorrhages in the lungs, and microcavities in the
       brain. The LOAEL for systemic changes was 12.5 mg/kg bw/day (SKW96b).
            In an unpublished study, Sprague–Dawley rats (n=5/sex/group) were given
       doses of aqueous cyanamide (50% a.i.) of 5, 10, 20, or 40 mg a.i./kg bw/day by
       gavage, for 28 days. Reduced body weights were observed in male rats at 20 mg/
       kg bw/day and higher and in female rats at 40 mg/kg bw/day. Body weight gain
       was reduced in both sexes at 20 mg/kg bw and higher. At the high dose, a
       significant decrease in haemoglobin and haematocrit was observed in both males
       and females and in erythrocyte counts and mean corpuscular haemoglobin
       concentration in males. Monocyte counts were significantly increased in males.
       At 40 mg/kg bw/day, males showed significantly increased plasma bilirubin and
       uric acid levels, and at 10 mg/kg bw/day and above, significantly decreased total
       protein levels. At 40 mg/kg bw, relative liver and kidney weights were
       significantly increased in males and females and relative brain, thyroid, and
       parathyroid weights in males. At 20 mg/kg bw, relative liver and kidney weights
       were significantly increased in males only. Significant decreases in absolute
       testicular and epididymis weights were found at 20 mg/kg bw and above.
       Microscopic examination revealed a significantly increased incidence of small,
       colloid-poor thyroid follicles in males at 10 mg/kg bw and above, and in females
       at the high dose. High-dose females also showed follicular cellular hyperplasia.
       At the high dose, these changes were accompanied by increased serum
       thyreotropin and decreased T3 and T4 levels (not significant). At 10 mg/kg bw
       and above, a dose-relatedly increased incidence of bile duct hyperplasia was
       observed in male rats. The NOAEL was 5 mg/kg bw/day (SKW88c). In another
       unpublished study, Wistar rats (n=10/sex/group) were given cyanamide at
       dietary doses equivalent to 0, 0.5, 1.5, or 4.5 mg a.i./kg bw/day, for 90 days. No
       mortality or signs of toxicity were observed at any dose level. At the high dose,
       erythrocyte counts and relative liver weights were significantly increased in
       males and relative thymus weights decreased in females. Microscopic
       examination revealed an increased incidence of small thyroid follicles without
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<pre>       colloid and of proliferating epithelium and interfollicular cells at 1.5 mg/kg bw
       and above. The NOAEL was 0.5 mg/kg bw/day (SKW75).
           Groups of Sprague-Dawley rats (n=20/sex/group) received an aqueous
       cyanamide solution at doses of 0, 2, 7, or 25 mg a.i./kg bw daily by gavage, for 6
       months. At the end of the study, body weights were significantly decreased at 7
       mg/kg and above, compared with the control group. Of liver function tests,
       plasma alkaline phosphatase and bilirubin were significantly increased in males
       and ALAT activity in females at the high-dose. Plasma bilirubin levels in both
       sexes were significantly increased at 25 and 7 mg/kg bw/day. Microscopic
       examination, focussed on the presence of hepatocyte inclusion bodies, did not
       show treatment-related abnormalities in the liver, compared with control
       animals. The NOAEL was 2 mg/kg bw/day, based on changes in body weights
       and in liver function tests (Oba85).
           In another study on cyanamide-induced changes in the liver, 20 male Wistar
       rats were given an aqueous solution of cyanamide in Tween 80, at a dose level of
       16 mg a.i./kg bw/day by gavage, for 25 weeks. Control animals (n=5) received
       daily doses of 2 mL of Tween 80. During cyanamide treatment, 3 animals died.
       Treatment-related effects were significantly reduced body weights, increased
       plasma ALAT and ASAT levels, and inclusion bodies in the liver cells of all
       animals. No inclusion bodies were observed in the control animals or in groups
       of rats treated with calcium cyanamide or disulfiram (Val89).
           In an unpublished study, male and female beagle dogs (n=4/sex/group)
       received orally (gavage) aqueous cyanamide solutions at doses of 0, 0.6, 2, or 6
       mg a.i./kg bw/day, continuously for 90 days. No mortality was observed during
       the treatment. At 6 mg/kg bw, a decreased body weight gain was observed in the
       high-dose animals. Clinical chemical tests showed decreased serum T3 and T4
       levels at 2 mg/kg bw and above. However, these changes were statistically
       significantly for T4 levels in males at 6 mg/kg bw/day only. At 6 and 2
       mg/kg bw, male dogs had significantly reduced serum ASAT activities and
       significantly increased serum ALAT activities. At 6 mg/kg bw/day, males had
       significant decreases in haemoglobin, haematocrit, and erythrocyte and
       reticulocyte counts, and at 2 mg/kg bw, platelet counts were significantly
       decreased. Monocyte counts were significantly increased in female dogs at 6 and
       2 mg/kg bw/day and in males at 2 mg/kg bw/day. Gross and microscopic
       examination revealed decreased (not statistically significant) absolute and
       relative testicular weights at 6 mg/kg bw/day. Atrophy of testicular tubuli,
       reduced spermatogenesis, or reduced spermatocyte counts in the epididymis
       were found in dogs at all dose levels, in a dose-related fashion. The LOAEL was
       0.6 mg/kg bw/day, based on testicular effects (SKW82c).
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<pre>            In another unpublished study, focussed on testicular effects, beagle dogs
       (n=4/group) received orally (gavage) aqueous cyanamide solution at doses of 0,
       0.6, and 6 mg a.i./kg bw/day, for 13 weeks. At the high dose, absolute and
       relative testicular weights were significantly decreased in 2 out of 4 animals.
       Macroscopic examination revealed enlarged cervical lymph nodes in 3 out of 4
       animals at 6 mg/kg bw/day, and 1 out of 4 animals at 0.6 mg/kg bw/day.
       Microscopic examination revealed atrophy and necrosis of germ epithelium cells
       and a reduced spermatocyte count in the epididymis. According to the authors,
       the NOAEL was 0.6 mg/kg bw/day (SKW86).
            In a next unpublished study, beagle dogs (n=4 /sex/dose group) received 50%
       aqueous cyanamide solutions by gavage at dose levels of 0, 0.1, 0.5, or 2.5 mg
       a.i./kg bw/day and of 0, 0.2, 1.0, and 5.0 mg a.i./kg bw/day, continuously for the
       first 2 weeks and the subsequent 50 weeks, respectively. No mortality was
       observed during the treatment. Effects in high-dose animals were tremor,
       salivation, and reduced body weight gain, compared with the controls. At week
       52, high-dose females showed decreased haemoglobin levels (not significant),
       and high-dose males significantly decreased leukocyte counts and significantly
       increased monocyte counts. However, leukocyte counts were significantly
       depressed in males at 1 mg/kg bw/day. Mean corpuscular haemoglobin
       concentration (MCHC) was significantly decreased at 5 and 1
       mg/kg bw/day in both males and females. At the high dose, serum T4 was
       significantly decreased in males, serum creatinine, uric acid, and calcium in
       females and serum albumin in both males and females. A statistically significant
       increase in relative, but not in absolute thyroid and parathyroid weights was
       found in females. Microscopic examination revealed extramedullary
       haemopoiesis in the spleen, thymus atrophy, chronic inflammation of the testes,
       hypo- and aspermatogenesis, hypospermia, and immature sperm in the
       epididymis in males, enlarged and pale spleens in females, and pigmentation of
       liver (Kupffer) cells and (little) stones in the gall bladder in both sexes at 5 mg/kg
       bw/day. At 1 mg/kg bw, there was only immature sperm observed in 1 out of 4
       dogs. The NOAEL was 0.2 mg/kg bw/day, based on effects on the male
       reproductive system (immature sperm) at 1.0 mg/kg bw (SKW89c).
            Groups of 40 male Wistar rats and 40 male Sprague-Dawley rats were given
       intraperitoneal injections of aqueous cyanamide solutions, at doses of 0, 8, or 16
       mg a.i./kg bw/day, for 1 year. A statistically significant dose-related decrease in
       body weight gain was observed in both strains. Also in both strains, increased
       plasma bilirubin levels and decreased plasma albumin levels and
       albumin/globulin ratios were found in rats treated with 16 mg/kg bw/day. No
       hepatocyte inclusion bodies were detected in any of the animals (Oba85).
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<pre>       Calcium cyanamide
       In 2 separate range-finding experiments for a carcinogenicity study (see ‘Chronic
       toxicity and carcinogenicity’), F344 rats (n=5/sex/dose level) were fed
       commercial calcium cyanamide (63% a.i.) at doses equivalent to 0, 13, 19, 25,
       28, 31, 38, 47, 94, 126, 252, 315, 504, and 945 mg a.i./kg bw/day, for 7 weeks.
       All rats given doses of 252 mg/kg bw and above died. No mortality was observed
       at lower doses. A treatment-related decrease in body weight was observed. At 13
       mg/kg bw/day, males and females showed mean body weight decreases of 11 and
       3% of mean body weight of controls, respectively. Microscopic examination
       revealed bile duct hyperplasia in the livers of male and female rats at doses of 47
       mg/kg bw/day and above. Thyroid hyperplasia was found in all treated groups,
       except at 13 mg/kg bw/day. The NOAEL for female rats was 13 mg/kg bw/day.
       For male rats, a LOAEL could not be established (NCI79).
            Male albino Sherman rats (n=24) received calcium cyanamide via the diet at
       doses equivalent to approximately 52 mg a.i./kg bw/day, for 4 weeks. Then,
       levels were increased to approximately 60 mg a.i./kg bw/day for 6 weeks,
       followed by an increase to approximately 102 mg/kg bw/day during the last 4
       weeks. A group of 30 control animals was also included. Groups of treated and
       control animals were killed immediately and 2, 4, and 16 weeks after the last
       treatment. One treated animal died during the last week of the study. Effects at
       the end of treatment were significant reductions of food intake and of body
       weight compared with the control group, which continued until 16 weeks of
       recovery. Haematology changes included a decreased red blood cell volume,
       accompanied with an increase of reticulocytes, and increased white blood cell
       counts. Macroscopic examination showed a marked increase in absolute and
       relative thyroid weights and increased relative weights of pituitary and adrenal
       glands, testis, liver, and spleen. Absolute and relative weights of seminal vesicles
       and absolute ventral prostate weights were significantly reduced compared with
       control animals. Major microscopic changes were decreased spermatogenesis in
       3 out of 5 animals and testicular atrophy. After 16 weeks of recovery, there was
       still a moderate general oedema, slight general anaemia, extreme epithelial
       proliferation in the thyroid gland, numerous thyroidectomy cells, marked
       dystrophy in the anterior pituitary gland, moderate atrophy of the adrenal cortex,
       moderate fibrosis in the liver, moderate siderosis in the spleen, slight
       osteoporosis in the femur, and moderate reduction of spermatogenesis in the
       testis (Ben65).
            In a study on calcium cyanamide-induced changes in the liver, 20 male
       Wistar rats were given a solution of calcium cyanamide in Tween 80, at a dose
       level of 30 mg a.i./kg bw/day by gavage, for 25 weeks. During treatment, 9
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<pre>            animals died. Control animals (n=5) received daily doses of 2 mL of Tween 80.
            Treatment-related effects were significantly reduced body weights and
            significantly increased plasma ALAT and ASAT levels. No inclusion bodies
            were observed in liver cells of the treated or control animals (Val89).
                  In a range-finding experiment for a carcinogenicity study (see ‘Chronic
            toxicity and carcinogenicity’), B6C3F1 mice (n=5/sex/group) were given calcium
            cyanamide (63% a.i.) via the diet at doses equivalent to 0, 100, 200, 270, 540,
            675, 1080, and 2025 mg a.i./kg bw/day, for 7 weeks. In the high-dose group, all
            mice died. No mortality occurred in the other groups. A treatment-related
            decrease in body weight was observed; at 100 mg/kg bw/day, males and females
            showed mean body weight decreases of 8% and 13%, respectively, compared
            with mean body weight of controls. At 1080 mg/kg bw, males and females
            showed trace amounts of bile duct hyperplasia. Periportal hepatocytes with pale-
            staining vacuolated cytoplasm were seen in the males. Focal hepatic necrosis
            occurred in 4 females. At 675 mg/kg bw/day, the livers of all animals were
            essentially normal. The LOAEL was 100 mg/kg bw/day, based on reduced body
            weights (NCI79).
                  A summary of short-term toxicity studies with cyanamide or calcium
            cyanamide is given in Table 2.
Table 2 Summary of short-term toxicity studies with cyanamide or calcium cyanamide in experimental animals.
substance;     species (strain, number,    dose level; exposure      critical effect            NOAELa        reference
exposure route sex)                        duration
cyanamide
inhalation     rat (Wistar; n=5-8/sex/      0, 148, 263, 799 mg/m3; body weight decrease;       LOAEL:        SKW96a
               group)                       6 h/d, 5 d/wk, 2 wks     changes in absolute and    148 mg/m3
                                                                     relative organ weights
dermal         rabbit (New Zealand;        0, 12.5, 25, 37.5 mg/kg organ weight changes         LOAEL:        SKW96b
               n=3/sex/group)              bw;3 wks                                             12.5 mg/kg bw
oral           rat (Sprague-Dawley;        0, 5, 10, 20, 40 mg/kg    thyroid changes; bile duct 5 mg/kg bw    SKW88c
                n=5/sex/group)             bw; 4 wks                 hyperplasia
               rat (Wistar; n=10/sex/      0, 0.5, 1.5, 4.5 mg/kg    thyroid changes            0.5 mg/kg bw  SKW75
               group)                      bw; 13 wks
               rat (Sprague-Dawley;        0, 2, 7, 25 mg/kg bw;     body weight decrease;      2 mg/kg bw    Oba85
                n=20/sex/group)            25 wks                    liver function changes
               rat (Wistar; n=20 males;    0, 16 mg/kg bw; 25 wks body weight decrease;         LOAEL:        Val89
               controls: n=5)                                        liver function changes,    16 mg/kg bw
                                                                     incl. inclusion bodies
               dog (beagle; n=4/sex/       0, 0.6, 2, 6 mg/kg bw;    male reproduction system LOAEL:          SKW82c
               group)                      13 wks                                               0.6 mg/kg bw
               dog (beagle; n=4 males/     0, 0.6, 6 mg/kg bw; 13 male reproduction system 0.6 mg/kg bw       SKW86a
               group)                      wks
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<pre>                dog (beagle; n=4/sex/      0, 0.1, 0.5, 2.5 mg/kg  male reproduction system 0.2 mg/kg bw SKW89c
                group)                     bw, 2 wks, then 0, 0.2,
                                           1.0, 5.0 mg/kg bw, 52
                                           wks
intraperitoneal rat (Wistar, Sprague-      0, 8, 16 mg/kg bw; 52   body weight decrease     LOAEL:       Oba85
                Dawley; n=40 males/strain/ wks                                              8 mg/kg bw
                group)
calcium cyanamide
oral            rat (F344; n=5/sex/dose)   0, 13-945 mg/kg bw; 7   body weight decreases;   LOAEL:       NCI79
                                           wks                     thyroid changes          13 mg/kg bw
                rat (Sherman; n=24 males; 0, 52 mg/kg bw, 4 wks,   body weight decrease;    LOAEL:       Ben65
                controls: n=30)            then 60 mg/kg bw, 6     anaemia; testicular,     52-102 mg/kg
                                           wks, then 102, 4 wks    thyroid, liver changes   bw
                rat (Wistar; n=20 males;   0, 30; 25 wks           mortality; body weight   LOAEL:       Val89
                controls: n=5)                                     decrease; liver injury   30 mg/kg bw
                mouse (B6C3F1; n=5/sex/    0, 100-2025 mg/kg bw;   body weight decrease     LOAEL:       NCI79
                group)                     7 wks                                            100 mg/kg bw
             Chronic toxicity and carcinogenicity
             Cyanamide
             Male and female Sprague-Dawley Crl:CD BR rats (n=20/sex/group) received
             aqueous cyanamide solutions by gavage at dose levels of 0, 2.5, 7.5, or 30 mg/kg
             bw/day for 16 weeks, followed by doses of 0, 1.0, 2.5, or 7.5 mg/kg bw/day for
             the subsequent 75 weeks. During the first 16 weeks, signs of toxicity (weakness,
             tremor) were observed in the high-dose animals and decreased body weights and
             body weight gains in the mid-dose group. In addition, changes in haematological
             parameters (decrease in erythrocyte counts, haemoglobin and haematocrit
             values; decrease in platelet counts; increase in leukocyte counts), as well as in
             clinical chemistry parameters (decrease in serum albumin, total protein, glucose,
             ALAT, and T3 levels) were found. From week 17 onwards, signs of toxicity
             disappeared. However, at 7.5 mg/kg bw, body weights and feed intake were
             significantly decreased in both males and females. Leukocyte and lymphocyte
             counts were significantly increased at 1 and 7.5 mg/kg bw in female rats, but not
             at 2.5 mg/kg bw/day. These changes were, therefore, considered to be unrelated
             to exposure. Serum T3 values were decreased in males, dose relatedly, at 1
             mg/kg bw/day and above, and in females at 7.5 mg/kg bw/day. This decrease was
             statistically significant at 7.5 mg/kg bw/day for both males and females. Serum
             T4 levels were significantly decreased in high-dose males only. Microscopic
             examination revealed a dose-related, statistically significantly increased
             incidence of small, colloid-poor thyroid follicles at 2.5 mg/kg bw/day for males
             and at 7.5 mg/kg bw/day for females. High-dose females showed an increased
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<pre>       incidence of adrenal haematocysts, breast fibroadenomas, and ovarian cysts. In
       females, uterus dilatation was found at 1 mg/kg bw/day and above, and polyps of
       the endometrium at 2.5 mg/kg bw/day. No data were reported on the incidences
       of neoplastic lesions in organs and tissues. The NOAEL was set at 1.0 mg
       cyanamide/kg bw/day (SKW91b).
            Crl:CD-1 mice (n=60/sex/group) were given cyanamide via the drinking
       water at doses equivalent to on average 0, 11, 30, or 76 mg/kg bw/day for males
       and on average 0, 14, 35, or 101 mg/kg bw/day for females. Terminal sacrifices
       were scheduled at 100 and 104 weeks for males and females, respectively.
       Mortality was increased in high-dose females, compared to the control group.
       Treatment-related decreases in body weight gain were found at all dose levels for
       males and at the mid- and high-dose level for females. Relative brain weight was
       significantly increased at the top dose in males only. Microscopic examination
       revealed a dose-related increase of chronic cystitis, characterised by urothelial
       hyperplasia, fibrosis, and leukocyte infiltration in males and females at the mid
       and high dose. In the kidneys, focal nephropathy, vacuolar degeneration, and
       atrophic tubuli were found in high-dose females and in mid- and high-dose
       males. Other, non-neoplastic changes were treatment-related lung oedema in
       high-dose males and in females treated with 14 mg/kg bw and above.
       Hypertrophy and ventricular dilatation of the heart were observed in males at all
       dose levels and in females at the low dose only. A statistically significant
       proliferation of biliar liver cells was observed in the high-dose males. In high-
       dose females, a statistically significantly increased incidence of ovarian
       granulosa-theca cell tumours was found (controls: 2/60, low-dose: 1/60, mid-
       dose: 6/60, high-dose: 8/58). The diagnosis of granulosa-theca cell tumour in a
       third control animal was equivocal because of the occurrence of necrotic lesions.
       If included, the incidence of this tumour in the control group would have been
       3/60. Comparison of this incidence with that of the high-dose group (8/58) did
       not give a statistically significant difference. In none of the other organs or
       tissues, an increased incidence of tumours was found at any dose level, compared
       to the controls. The LOAEL was 11 mg/kg bw/day for males, and 14 mg/kg
       bw/day for females (SKW90a).
       Calcium cyanamide
       In a carcinogenicity study, F344 rats (n=50/sex/group) were given a commercial
       formulation of calcium cyanamide (63% a.i.) via the diet at doses equivalent to
       3.2 or 6.4 mg a.i./kg bw/day for males and to 3.2 or 12.6 mg a.i./kg bw for
       females, for 107 weeks. The control group comprised 20 animals of each sex.
       Survival was 70% or greater in all dosed and control groups of each sex at the
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<pre>       end of the study, and sufficient numbers of animals were at risk in all groups for
       the potential development of late-appearing tumours. Mean body weights of the
       dosed rats were presented in a figure only reporting quantitative data and
       statistical analyses. Those of the high-dose males and females were stated to be
       slightly lower when compared to the corresponding controls and those of the
       low-dose animals slightly and inconsistently lower. No statistically significant
       differences in neoplasms in any organ or tissue occurred between the treated rats
       of either sex compared with the controls. No treatment-related non-neoplastic
       lesions were observed in any organ or tissue although there was a dose-related,
       not statistically significant increase in the incidence of pheochromocytomas in
       females when compared with control animals. The authors concluded that under
       the conditions of the study, the test formulation of calcium cyanamide was not
       carcinogenic to F344 rats of either sex (NCI79).
           B6C3F1 mice (n=50/sex/dose level) were given the same commercial
       formulation of calcium cyanamide (63% a.i.) as in the above rat study, via the
       diet at doses equivalent to 31.5 or 126 mg a.i./kg bw/day for 107 weeks. The
       control group comprised 20 animals per sex. A dose-related increased mortality
       occurred in male mice, but survival was 76% or greater in the dosed and control
       groups, and sufficient numbers of animals were at risk in all groups for the
       potential development of late-appearing tumours. Mean body weights of the
       treated animals, which as for the rats (see above) were presented in a figure only,
       were stated to be slightly decreased compared with the controls, except for the
       low-dose female mice, whose mean body weights were unaffected by the test
       chemical. Except for haemangiosarcomas in males and malignant lymphomas or
       leukaemias in females, microscopic examination did not reveal differences in
       tumour incidences between treated and control groups. Analyses of the
       incidences of haemangiosarcomas (controls 1/20 (5%); low dose 2/50 (4%); high
       dose 10/50 (20%)) showed a dose-related linear trend (p=0.006; Cochran-
       Armitage test) and no statistically significant difference (Fisher exact test) when
       comparing incidences in the individual dose groups with those in the control
       group. The incidence of these tumours in historical control male B6C3F1 mice
       was 4%, and the highest incidence observed was 10%. Similar analyses of the
       incidences of malignant lymphomas or leukaemias (controls: 1/20 (5%), low
       dose: 11/46 (24%); high dose: 18/50 (36%)) showed a dose-related linear trend
       (p=0.009; Cochran-Armitage test) and a statistically significantly increased
       incidence in the high-dose group (p=0.006; Fisher exact test) when compared to
       the control group. However, the incidence of the lymphomas or leukaemias in
       historical control female B6C3F1 mice was 21%, suggesting that the incidence of
       these tumours in the matched control group of the present study may have been
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<pre>       abnormally low, according to the authors. Thus, neither the incidences of
       haemangiosarcomas in the male mice nor of lymphomas or leukaemias in the
       female mice can clearly be related to administration of the test chemical. The
       authors concluded that under the conditions of the study, the test formulation of
       calcium cyanamide was not carcinogenic for B6C3F1 mice of either sex. No
       treatment-related non-neoplastic lesions were observed (NCI79). The committee
       concludes that under the conditions of these NCI studies, calcium cyanamide is
       not carcinogenic to rats and mice and does not induce non-neoplastic lesions at
       the highest doses tested, i.e., 6.4 and 12.6 mg/kg bw/day in male and female rats,
       respectively, and 126 mg/kg bw in male and female mice. Therefore, the animals
       might have been able to tolerate higher doses for the duration of the study (107
       weeks), and a higher top-dose level should have been used in this study. Since
       quantitative data and statistical analyses with respect to body weights were
       lacking and haematology and clinical chemistry end points were not investigated,
       the committee cannot establish NOAELs.
       Mutagenicity and genotoxicity
       Cyanamide
       In vitro tests:
       • Gene mutation assays. Cyanamide was negative when tested with and
           without rat liver metabolic activation in several strains of S. typhimurium
           (TA98, TA100, TA1535, TA1537 and TA1538) at doses of 10-5000 µg/mL
           (Cad84) or of 0.02-2.54 mg/plate (SKW87a). Tests in E. coli strains GY4015
           and GY5027, with and without induced-rat liver metabolic activation at
           doses up to 50-5000 µg/ml, were negative as well (Cad84).
       • Other genotoxicity assays. Cyanamide did not induce DNA single strand
           breaks in rat hepatocytes at doses of 1.3, 13, or 126 mg/L (Sin83). In a DNA
           repair assay with primary rat hepatocytes, cyanamide did not induce
           unscheduled DNA synthesis (UDS) at doses between 5.95 and 143 mg/L
           (SKW87b).
       In vivo tests:
       • Cytogenicity assays. Swiss mice (n=6/sex/group) received oral doses of
           cyanamide of 0, 10, 49, or 247 mg/kg bw/day, for 2 consecutive days. At 24
           hours after the last dose, no increase was observed in the frequency of
           micronuclei in normochromic and polychromic bone marrow cells, compared
           with control animals (Men84). In ICR mice (n=5/sex/group), oral (gavage) of
           single doses of cyanamide of 0, 32, 157, or 330 mg/kg bw did not result in
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<pre>           changes in the incidence of micronuclei in polychromatic erythrocytes of
           bone marrow cells at any dose level, compared with control animals. At the
           high dose, mortality was observed in 2 out of 5 male animals (SKW87c).
       Calcium cyanamide
       In vitro tests:
       • Gene mutation assays. Tests for reverse mutations in several strains of S.
           typhimurium (TA98, TA100, TA1537) were negative both with and without
           rat and hamster liver metabolic activation. In strain TA1535, it was weakly
           positive with but negative without metabolic activation systems (Haw83,
           Ten86).
           The chemical did not induce sex-linked recessive lethality in D.
           melanogaster following feeding or injection of doses of 2000 or 1000 ppm,
           respectively (Yoo85).
       • Other genotoxicity assays. The compound did not induce gene conversion,
           chromosomal non-disjunction, or chromosomal crossing-over in A. nidulans
           with mouse liver metabolic activation (Val83).
       In vivo tests:
       Calcium cyanamide did not induce hepatic DNA damage, by an alkaline elution
       assay, in female Sprague-Dawley rats, when 2 oral doses of 96 mg/kg bw were
       given 21 and 4 hours before sacrifice (Kit93).
       The committee concluded that cyanamide or calcium cyanamide has no
       mutagenic or genotoxic potential.
       Reproduction toxicity
       Cyanamide
       In a 2-generation study, 8-week-old male (n=20/group) and female (n=40/group)
       Sprague-Dawley rats received oral (gavage) doses of aqueous cyanamide of 0, 2,
       7, or 25 mg a.i./kg bw/day, for 70 days and 15 days, respectively, until mating. In
       females, treatment continued throughout pregnancy and lactation. Twenty dams
       per group were sacrificed on day 13 of gestation. F1 male and female offspring
       from dams that delivered normally (day 21 of gestation) were selected at random
       to be mated, and treated with 0, 2, 7, or 25 mg cyanamide/kg bw/day, from their
       weaning to the weaning of the F2 generation. In F0 animals, a significant
       decrease in fertility index was observed at the high dose, compared with the
       controls. No effects were shown on mating percentages in any of the treated
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<pre>       groups. In a separate experiment, a significant decreased fertility index was
       observed when untreated females were mated with males dosed with 25 mg/kg
       bw cyanamide. However, no statistical difference in fertility index was found
       when females were treated with 25 mg/kg bw cyanamide and mated with
       untreated males. The mating percentages were not affected. This result suggests
       that the decrease in fertility index in F0 animals is related to cyanamide treatment
       of males. In rats sacrificed on day 13 of gestation, significantly decreased body
       weight gains, number of corpora lutea, and number of implantations were
       obtained at 25 mg/kg bw/day, compared with the controls. No abnormalities
       were noted in number of resorptions, living or dead embryos, or mean embryo
       weight in any of the groups. In F0 animals that delivered normally, the number of
       live pups born and litter weights were significantly increased at 2 mg/kg
       bw/day, as well as the number of implantations, and live born pups at 7 mg/kg
       bw/day group. However, at 25 mg/kg bw/day, the number of implantations and
       live born pups, as well as maternal body weight gain were significantly reduced.
       Mean individual birth weights were significantly increased. In the F1 generation,
       no treatment-related effects were observed with respect to mean pup weights
       during the lactation period and in the development of pups. At delivery of the F2
       generation, no differences were observed between treated and control groups in
       mean body weight gain, number of implantations, resorptions, live born or dead
       pups, mean living birth weight, or mean litter weight. Mean pup weights of the
       F2 generation during lactation were not different in treated groups, compared
       with controls. The authors suggest that the F1 generation could have become
       adapted to cyanamide. Gross examination of organs and tissues revealed that no
       abnormalities occurred in female rats of both F0 and F1 generations. In F0 males,
       treated with 25 mg/kg bw/day, ‘relative’* epididymis and prostate weights, and
       at 7 mg/kg bw, ‘relative’ prostate weights were significantly reduced, compared
       with controls. ‘Relative’ testes weights remained unaffected. No abnormalities in
       reproductive organ weights were seen in F1 animals. Microscopic examination
       showed testicular atrophy in 4 out of 20 F0 males in the high-dose group. This
       effect was observed at a low incidence in the F1 generation: 1 out of 6 males in
       the high-dose group and 1 out of 18 in the control group. The parental NOAEL
       was 7 mg/kg bw/day, based on reduced body weights at 25 mg/kg bw/day. The
       reproductive NOAEL was also 7 mg/kg bw/day, based on effects on the
       reproductive system, reduced fertility index, and reduced number of
       implantations and live born pups in F0 animals at 25 mg/kg bw/day (Val87).
*      According to an accompanying table, organ weights were relative to brain weights and not to body weights, and
       are therefore in fact absolute weights (see Fer73).
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<pre>           In another 2-generation study, 7-week-old Crl:CD rats (n=26/sex/group)
       received aqueous cyanamide by gavage, initially at dose levels of 0, 2.5, 7.5, or
       30 mg a.i./kg bw/day. Because of decreases in body weight at 30 mg/kg bw/day
       and in food consumption and body weight gain at 7.5 mg/kg bw/day and above,
       doses were reduced after 12 weeks, shortly before mating, to levels 0, 1.25, 3.75,
       or 15 mg/kg bw/day. F1 animals were also treated with these doses. The fertility
       indices were low at all dose levels (including controls). In F0 animals treated
       with 0, 1.25, 3.75, or 15 mg/kg bw day, indices were 77, 91, 83, or 65%,
       respectively, and in F1 animals 96, 88, 88, or 83%, respectively. The gestation
       index in the high-dose F1 rats was decreased compared to the low- and mid-dose
       groups, or the controls. The survival rates of F1 pups after 4 days were 92
       (controls), 83, 88, or 84, respectively, and in F2 pups, 93 (controls), 87, 82, or 81,
       respectively. Based on data from a historical control group (10% mortality) and
       on the lack of any developmental effects in pups, the authors did not consider the
       reduced survival rates in F2 pups as treatment-related effects. However, based on
       control data from other sources (5% mortality), the committee considers the
       reduced survival rates in F1 and F2 pups as dose-related effects. Mean litter sizes
       in the low- and mid-dose rats were increased compared to the controls, both for
       F1 and F2 progenies. Body weights of F1 progeny were decreased at 3.75 mg/kg
       bw/day and above for both sexes compared to the control group. No treatment-
       related changes were observed in body weights of F2 pups. According to the
       authors, the NOAEL for maternal and reproductive toxicity was 1.25 mg/kg
       bw/day (SKW90b). However, according to the committee, methodological flaws
       do not allow the setting a NOAEL/LOAEL for maternal or reproductive toxicity
       in this study.
           In a developmental toxicity study, pregnant rats (n=25/group) were given oral
       (gavage) doses of aqueous cyanamide of 0, 5, 15, or 45 mg a.i./kg bw/day, during
       days 6 to 15 of gestation. Animals were sacrificed on gestation day 20. Effects on
       dams were a decrease in body weight gain at 5 mg/kg bw/day and in feed
       consumption and body weight at the high and mid dose, compared to controls. A
       decrease in uterus weight of pregnant rats was observed at the top dose. Fetuses
       of dams treated with 45 mg/kg bw/day showed a decreased body weight and an
       increased incidence of hernia of the diaphragm. Gross and microscopic
       examination showed visceral abnormalities in fetuses at the high dose. No further
       details were provided. The LOAEL for maternal toxicity was 5 mg/kg bw/day.
       For developmental toxicity, the NOAEL was 15 mg/kg bw/day (SKW89d).
           In another developmental toxicity study, pregnant New Zealand White
       rabbits received aqueous cyanamide by gavage at doses 0, 2, 5.9, or 17.6
       mg a.i./kg bw/day, during days 6 to 19 of gestation. Animals in the high-dose
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<pre>       group showed slightly decreased body weights, not statistically significant
       increases in early resorptions, dead fetuses, or post-implantation loss, and a
       statistically significant decrease in live fetuses. Fetuses of dams treated with 17.6
       mg cyanamide/kg bw/day had not significantly decreased body weights.
       Microscopic examination revealed a significantly increased incidence of
       anomalies of the eyes in fetuses at the mid and high dose. Focal disintegration of
       liver structure was demonstrated in fetuses at the high dose. The NOAELs for
       maternal and developmental toxicity were 5.9 and 2 mg/kg bw/day, respectively
       (SKW89e).
7      Existing guidelines
       The current administrative occupational exposure limits in the Netherlands
       (MAC) for cyanamide and calcium cyanamide are 2 mg/m3 and 0.5 mg/m3,
       8-hour TWA, respectively.
           Existing occupational exposure limits in some European countries and in the
       USA are summarised in Annex I (cyanamide) and Annex II (calcium
       cyanamide).
8      Assessment of health hazard
       The health hazard assessment of (calcium) cyanamide is based to a large extent
       on unpublished studies presented and discussed in a toxicology review by the
       German MAK committee (Gre02).
           Occupational exposure to cyanamide or calcium cyanamide may occur by
       inhalation of vapour or dust or by skin contact during the manufacture and use of
       the substances. Following skin contact or oral ingestion, calcium cyanamide is
       readily converted into cyanamide. No quantitative data is available of the
       percentage of pulmonary absorption of the compounds or on the conversion of
       inhaled calcium cyanamide into cyanamide. In a human volunteer study, the
       dermal absorption was approximately 10%, when 20 mg cyanamide, as an
       aqueous solution, was administered on the occluded skin for 6 hours. In rats, the
       dermal absorption varied from 2 to 11%, when cyanamide was applied on the
       skin for 24 hours at doses of 0.1-10 mg/animal. Following administration of
       single oral doses of 0.3-1.5 mg cyanamide/kg bw, the extent of absorption in
       human volunteers varied from 53 to 70%, depending on the dose level. In rats,
       99-105% of a single oral dose of cyanamide was absorbed and in dogs at least
       67-83%. No accumulation of cyanamide residues was found in tissues of rats, 7
       days after administration of single or repeated oral doses. Following absorption,
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<pre>       a large proportion of cyanamide is acetylated into N-acetylcyanamide (ca. 40%
       in humans, ca. 45% in rats, and ca. 87% in dogs), and most of the metabolite is
       excreted in the urine within 24 hours. The committee concludes that following
       exposure, the compound is readily absorbed, metabolised, and eliminated from
       the body.
            Case studies in humans show that cyanamide induced skin sensitisation,
       mostly related to its medicinal use. Fatalities have been reported in humans
       consuming alcohol after exposure to calcium cyanamide. In a number of
       occupational health studies, conducted between 1981 and 1993, no health
       impairments related to calcium cyanamide exposure have been reported. Patch
       tests did not reveal cases of skin sensitisation. Exposures to calcium cyanamide,
       measured with static air monitoring, varied from 0.23 to 8.3 mg/m3. In a special
       study in workers engaged in calcium cyanamide processes, a mean daily
       absorption of approximately 0.1 mg cyanamide/kg bw or 0.2 mg calcium
       cyanamide/kg bw, via all routes of exposure, did not induce effects on the thyroid
       or the gonadal function.
            The main effect of calcium cyanamide exposure were vasomotoric
       disturbances after drinking alcohol, leading to flushing, i.e., redness of the head,
       the neck, and the upper part of the body, often combined with tachycardia and
       dyspnoea. A connection between this so-called antabuse effect of workers and
       potential exposure to calcium cyanamide air levels could not be demonstrated.
       Based on several human volunteer studies, it was suggested that the antabuse
       effect started with a daily intake of more than 25 mg calcium cyanamide
       (equivalent to 13.1 mg cyanamide). When cyanamide is given to alcoholics to
       induce the antabuse effect, the dose is generally 50-70 mg per day.
            In experimental animals, both cyanamide and calcium cyanamide were
       irritating to the eyes and the skin. Cyanamide also was a skin sensitiser.
       Inhalation of the compound caused irritation of the mucous membranes. Based
       on the results of acute lethal toxicity studies, the committee considers the
       substances to be of low toxicity by inhalation, but toxic after dermal and oral
       exposure. The committee did not find data from valid inhalation studies.
       Subacute and subchronic oral toxicity studies, varying from 2 to 52 weeks,
       showed that the male reproductive system, the thyroid, and the liver are the most
       sensitive target organs following exposure to cyanamide. The NOAEL in the dog
       was 0.2 mg/kg bw/day, based on effects on the male reproductive system (52-
       week study), and in the rat, 0.5 mg/kg bw/day, based on thyroid changes (13-
       week study). In a 3-week dermal study in rabbits, the LOAEL was 12.5 mg/kg
       bw/day, based on relative and absolute organ weight changes. In a 7-week oral
       study with calcium cyanamide, a NOAEL for thyroid changes in male and
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<pre>       female rats of 13 mg/kg bw/day was observed (equivalent to 6.8 mg/kg bw/day
       cyanamide).
            Unpublished chronic oral toxicity studies with cyanamide in rats and mice
       showed a NOAEL of 1.0 mg/kg bw/day for the rat, based on thyroid changes, a
       LOAEL of 14 mg/kg bw for female mice, based on treatment-related lung
       oedema, and a LOAEL of 11 mg/kg bw for male mice, based on effects on the
       heart and decreased body weights. Female mice showed a dose-related increased
       incidence of ovarian granulosa-theca cell tumours, which was statistically
       significant at the high dose. The committee considers the statistical significance
       at the high dose as equivocal, because of uncertainty on the incidence of this
       tumour in control animals (either 3/60 or 2/60). No carcinogenicity data were
       reported in the rat study. In NTP carcinogenicity studies with calcium
       cyanamide, no treatment-related neoplasms were observed in rats. In male mice,
       an increased incidence of haemangiosarcomas of the circulatory system was
       found at the high dose (126 mg/kg bw/day), which was not statistically
       significantly different from concurrent and the historical control groups. In
       female mice, at the high dose, the incidence of lymphomas and leukaemias was
       significantly increased compared with the concurrent control group, but not with
       the historical control group. The committee concluded that under the conditions
       of these studies, the test formulation of calcium cyanamide was not carcinogenic
       to rats or mice. However, since no non-neoplastic lesions were observed at the
       highest dose levels tested, the animals might have been able to tolerate higher
       doses for the duration of the study (107 weeks), and, therefore, a higher top-dose
       level should have been used in this study.
            Neither cyanamide nor calcium cyanamide induced gene mutations or
       cytogenetic effects in in vitro and in vivo studies, which supports the non-
       carcinogenicity of these substances.
            In a reproductive toxicity study, cyanamide induced a decreased fertility rate
       and testicular atrophy in rats at 25 mg/kg bw/day. No effects on fertility,
       embryotoxic, and reproductive parameters were observed at 7 mg/kg bw/day.
       Unpublished developmental toxicity studies reported a NOAEL for
       developmental abnormalities of 15 mg/kg bw/day for the rat and of 2 mg/kg
       bw/day for the rabbit.
            The committee considers the effects on the reproductive system of the male
       dog as the critical effect of exposure to cyanamide. These effects described in 3
       studies with dosing regimens ranging from 0.2 to 6.0 mg/kg bw/day for 13 weeks
       and from 0.2 to 5.0 mg/kg bw/day for 52 weeks included chronic inflammation
       of the testes, atrophy of testicular tubuli, atrophy and necrosis of germ epithelium
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<pre>       cells, hypo- and aspermatogenesis, and reduced spermatocyte counts and
       immature sperm in the epididymides.
            The committee takes the (unpublished) 52-week dog study with cyanamide
       as a starting point in deriving a health-based recommended occupational
       exposure limit (HBROEL). In this study, 0.2 mg/kg bw was the NOAEL, based
       on immature sperm seen at the next higher dose level of 1.0 mg/kg bw. Since
       workers are exposed for 5 days a week, this NOAEL from a continuous study
       (i.e., 7 days a week) is adjusted by multiplying with a factor of 7/5 resulting in a
       no-adverse-effect level (NAEL) of 0.28 mg/kg bw. For the extrapolation to a
       HBROEL, a factor of 1.4 for allometric scaling from dogs to humans, based on
       caloric demand, and an overall factor of 9, covering inter-and intraspecies
       variation, are applied, resulting in a NAEL for humans of 0.022 mg/kg bw/day.
       Assuming a 70-kg worker inhales 10 m3 of air during an 8-hour working day and
       a retention of 100%, and applying the preferred value approach, a HBROEL of
       0.2 mg/m3 is recommended for cyanamide.
       The committee recommends a health-based occupational exposure limit for
       cyanamide and calcium cyanamide together of 0.2 mg/m3, expressed as
       cyanamide, as the inhalable fraction, as an 8-hour time weighted average. Since
       calcium cyanamide is readily converted into cyanamide into the body, this
       occupational exposure limit applies for cyanamide and calcium cyanamide
       together.
       The committee considers a skin notation warranted if the amount taken up via the
       skin of hands and forearms (i.e., 2000 cm2) for 1 hour is more than 10% of the
       amount taken up by inhalation at a HBROEL based on systemic toxicity for 8
       hours. Using a penetration rate of 12 µg/cm2/h determined in human volunteers,
       the amount calculated to be taken up by the worker via the skin under the
       aforementioned premises amounts to 24 mg, which is considerable compared
       with the amount of 2 mg that could be taken up following an 8-hour exposure to
       the HBROEL of 0.2 mg/m3. Therefore, the committee recommends a skin
       notation.
       References
Aba99  Abajo P, Feal C, Sanz ST, et al. Eczematous erythroderma induced by cyanamide. Contact Dermatitis
       1999; 40: 160-1.
ACG99a American Conference of Governmental Industrial Hygienists (ACGIH). Cyanamide. In: TLVs® and
       other occupational exposure values - 1999. [CD-ROM]. Cincinnati OH, USA: ACGIH®, 1999.
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<pre>ACG99b American Conference of Governmental Industrial Hygienists (ACGIH). Calcium cyanamide. In:
       TLVs® and other occupational exposure values - 1999. [CD-ROM]. Cincinnati OH, USA: ACGIH®,
       1999.
ACG04a American Conference of Governmental Industrial Hygienists (ACGIH). Guide to occupational
       exposure values - 2004. Cincinnati OH, USA: ACGIH®, 2004: 22, 39.
ACG04b American Conference of Governmental Industrial Hygienists (ACGIH). 2004 TLVs® and BEIs®
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       agents & Biological Exposure Indices. Cincinnati OH, USA: ACGIH®, 2004: 16, 21.
Arb02  Arbejdstilsynet. Grænseværdier for stoffer og materialer. Copenhagen, Denmark: Arbejdstilsynet,
       2002: 19, 21 (At-vejledning C.0.1).
Ben65  Benitz KF, Kramer AW, Dambach G. Comparative studies on the morphologic effects of calcium
       carbimide, propylthiouracil, and disufliram in male rats. Toxicol Appl Pharmacol 1965; 7: 128-62.
Bla75  Black H. Contact dermatitis from lead cyanamide. Contact Dermatitis 1975; 6:389
Bri80  Brien JF, Peachey JE, Loomis CW. Intraindividual variability in the calcium carbimide-ethanol
       interaction. Eur J Clin Pharmacol 1980; 18: 199-205.
Bri83  Brien JF, Loomis CW. Disposition and pharmacokinetics of disulfiram and calcium carbimide
       (calcium cyanamide). Drug Metab Rev 1983; 14: 113-26.
Bru86  Bruguera M, Lamar C, Bernet M, et al. Hepatic disease associated with ground-glass inclusions in
       hepatocytes after cyanamide therapy. Arch Pathol Lab Med 1986; 110: 906-10.
Bud96  Budavari S, O'Neill MJ, Smith A, et al, eds. The Merck index. An encyclopedia of chemicals, drugs,
       and biologicals. 12th ed. Whitehouse Station, NJ, USA: Merck & Co, 1996: 272, 451-2.
Cad84  Cadena A, Arso J, Vallès JM, et al. Evaluacion de la posible mutagenicidad de la cianimida mediante
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<pre>              Annex I
Occupational exposure limits for cyanamide in various countries.
country                              occupational            time-weighted         type of             notea     referenceb
- organisation                       exposure limit          average               exposure limit
                                     ppm        mg/m3
the Netherlands
- Ministry of Social Affairs and     -          2            8h                    administrative                SZW04
Employment
Germany
- AGS                                0.58       1c           8h                                        S         TRG04
                                     2.32       4            15 min
- DFG MAK-Kommission                 0.58       2            8h                                        S, sens,e DFG04
                                     1.19                    15 mind
Great Britain
- HSE                                -          2            8h                    OES                           HSE02
Sweden                               -          2            8h                                        S         Swe00
                                     -          4            15 min
Denmark                              -          2            8h                                                  Arb02
USA
- ACGIH                              -          2            8h                    TLV                           ACG04b
- OSHA                               -          -                                                                AGG04a
- NIOSH                              -          2            10 h                  REL                           ACG04a
European Union
- SCOEL                              -          2            8h                    ILVf                          EC04
a
     S = skin notation; which means that skin absorption may contribute considerably to the body burden; sens = substance can
     cause sensitisation.
b
     Reference to the most recent official publication of occupational exposure limits.
c
     Measured as inhalable fraction of the aerosol.
d
     Maximum number per shift: 4, with a minimum interval between peaks of 1 hour.
e
     Listed among substances for which there is no reason to fear a risk of damage to the embryo or fetus when MAK and BAT
     values are observed.
f
     Listed among compounds for which OELs are already included in Commission Directives.
133-39        Cyanamide and calcium cyanamide
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<pre>              Annex II
Occupational exposure limits for calcium cyanamide in various countries.
country                            occupational               time-weighted         type of                 notea      referenceb
- organisation                     exposure limit             average               exposure limit
                                   ppm         mg/m3
the Netherlands
- Ministry of Social Affairs and -             0.5            8h                    administrative                     SZW04
Employment
Germany
- AGS                              -           1c             8h                                           S           TRG04
                                   -           4              15 min
- DFG MAK-Kommission               -           1c             8h                                           S           DFG04
                                   -           2              15 mind
Great Britain
- HSE                              -           0.5            8h                    OES                                HSE02
                                   -           1              15 min
Sweden                             -           -                                                                       Swe00
Denmark                             -          0.5            8h                                                       Arb02
USA
- ACGIH                            -           0.5            8h                    TLV                    A4e         ACG04b
- OSHA                             -           -                                                                       ACG04a
- NIOSH                            -           0.5            10 h                  REL                                ACG04a
European Union
- SCOEL                            -           -                                                                       EC04
a
     S = skin notation; which means that skin absorption may contribute considerably to the body burden; sens = substance can
     cause sensitisation.
b
     Reference to the most recent official publication of occupational exposure limits.
c
     Measured as inhalable fraction of the aerosol.
d
     Maximum number per shift: 4, with a minimum interval between peaks of 1 hour.
e
     Classified in carcinogen 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 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.
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