<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>Oxalic acid
(CAS No: 144-62-7)
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/106, The Hague, March 30, 2004
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<pre>Preferred citation:
Health Council of the Netherlands: Committee on Updating of Occupational
Exposure Limits. Oxalic acid; Health-based Reassessment of Administrative
Occupational Exposure Limits. The Hague: Health Council of the Netherlands,
2004; 2000/15OSH/106.
all rights reserved
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<pre>1     Introduction
      The present document contains the assessment of the health hazard of oxalic acid
      by the Committee on Updating of Occupational Exposure Limits, a committee of
      the Health Council of the Netherlands. The first draft of this document was
      prepared by AAE Wibowo, Ph.D. (Coronel Institute, Academic Medical Centre,
      Amsterdam, the Netherlands).
           In November 1998, literature was searched in the databases Medline,
      Embase, and Chemical Abstracts, starting from 1966, 1988, and 1970,
      respectively. CD-ROM databases HSELINE, CISDOC, MHIDAS, and
      NIOSHTIC, covering the period from 1985/1987 up to and including 1998, and
      POLTOX (Toxline, Cambridge Scient. Abstr., FSTA), covering the period 1990
      up to and including 1994, were consulted as well. The following key words were
      used: oxalic acid and 144-62-7. Review papers from Baselt and Cravey (Bas89),
      Von Burg (Bur94), Hodgkinson and Zarembski (Hod68), Katz and Guest
      (Kat94), and Lundberg (Lun88) have been used. Where relevant, the original
      publications were reviewed and evaluated as will be indicated in the text. The
      final literature search was carried out in Toxline and Medline in September 2003.
           In October 2003, the President of the Health Council released a draft of the
      document for public review. No comments were received.
2     Identity
      name                     :   oxalic acid
      synonyms                 :   ethanedioic acid; dicarboxilic acid
      molecular formula        :   C2H2O4
      structural formula       :
      CAS number               :   144-62 –7
      Data from ACG99.
106-3 Oxalic acid
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<pre>3     Physical and chemical properties
      molecular weight             :     90.04
      boiling point                :     not available
      melting point                :     189.5oC; decomposes
      flash point                  :     not available
      vapour pressure              :     <0.1Pa
      solubility in water          :     soluble (at 20oC: 14 g/100mL )
      log Poctanol/water           :     -1.74 (estimated)
      conversion factors           :     not applicable
      Data from ACG99, NLM01, http://esc.syrres.com.
      Anhydrous oxalic acid is an odourless, white powder. Upon heating, it
      decomposes into carbon dioxide, carbon monoxide, formic acid, and water. The
      dihydrate is an odourless, colourless crystalline substance (ACG99, NLM01).
4     Uses
      The major uses of oxalic acid are in textile finishing, stripping and cleaning,
      calico printing and dyeing, paint, varnish, and rust removal, metal and equipment
      cleaning, wood cleaning, dye manufacture, chemical synthesis, and in paper,
      ceramics, photographic, and rubber industries (Kat94). In the US, EPA has
      published a Reregistration Eligibility Document for the use of oxalic acid as a
      disinfectant to control bacteria and germs, and as a sanitiser in toilet bowls,
      urinals, and bathroom premises (EPA92). According to the database of the Dutch
      Pesticide Authorisation Board (CTB), oxalic acid is not permitted for such uses
      in the Netherlands*.
            Oxalate is present in certain dietary plants, such as spinach, rhubarb, and tea
      (Bur94).
5     Biotransformation and kinetics
      The committee did not find information on the kinetics of oxalic acid following
      inhalation or dermal exposure.
            Following oral exposure, absorption through the gastrointestinal tract of
      normal healthy human is estimated to be 2.4% of the total oxalate load in food.
*      at: http://www.ctb-wageningen.nl.
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<pre>      Most of the absorption occurs within 1 to 8 hours after ingestion (Pre84). Berg
      (Ber90) and Williams (Wil79) reported an absorption by the gastrointestinal tract
      of 5 to 10%. In rats orally (gavage) dosed with 14C-labelled oxalate, ca. 25 and
      73% of the radiolabel were recovered in the urine and faeces, respectively,
      within 7 days (Ban79). In a normally fed dog, 80% of a single oral dose of 1000
      mg of oxalate was excreted in the urine within 9 days, while in a fasting dog, a
      dose of 1338 mg caused anuria for several days followed by urinary excretion of
      75% of the dose over the next 9 days. In pigs, 45-50% of an oral dose was
      urinary excreted (Bur94).
           There is little or no binding of oxalic acid by plasma proteins at physiological
      pH, and whole blood oxalate concentrations are only slightly higher (average 1.7
      mg/L) than plasma concentrations (Bas89). An average serum oxalate
      concentration of 1.4 mg/L with an upper limit of 2.4 mg/L was found in 20
      normal subjects (Bas89, Hod68).
           There is no evidence that oxalate is utilised or further metabolised by human
      tissues (Hod68). Following intravenous injection of radiolabelled oxalic acid,
      volunteers excreted 88-99% of the radiolabel in the urine within 36 hours
      (Bas89). The elimination half-life of oxalate was estimated to be about 90
      minutes (Ber90). Wahl and Kallee reported levels of 0.10 and 0.18 mmol/L
      oxalic acid in the saliva of healthy male and female subjects, respectively
      (Wah94). Urinary oxalic acid, which usually ranges from 8 to 40 mg/day, is
      derived largely from dietary ascorbic acid (35-44%), from the metabolism of
      glycine (40%), and the remainder from minor metabolic sources and from dietary
      oxalic acid. Calcium oxalate is a major constituent of urinary calculi and also
      often occurs as crystals in freshly voided urine. Normal tissue concentrations of
      oxalate, determined on single specimens, are 0.6, 2.3, and 4.0 mg/kg in the brain,
      the liver, and the kidney, respectively (Bas89).
6     Effects and mechanism of action
      The primary target organs for systemic oxalate toxicity appear to be the kidneys
      and the nervous system (Bur94). Systemic effects of oxalic acid toxicity are
      attributed largely to the calcium-complexing action of the acid, which depresses
      the level of calcium ions in body fluids. The resulting condition of
      hypocalcaemia produces severe disturbances in the activity of the heart and
      neural system (Kat94). The formation of calcium oxalate crystals, which is one
      of the factors in the pathogenesis of urinary stone disease, may also be attributed
      to exposure to oxalic acid.
106-5 Oxalic acid
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<pre>      Human data
      Exposure to airborne levels of oxalates is irritating to the eyes, nose, and throat;
      inhalation causes breathing difficulties and loss of consciousness (Bur94).
      Systemic oxalate poisoning in humans is characterised by local corrosive effects,
      renal damage, and a marked fall in plasma calcium levels, resulting in shock,
      collapse, and convulsions (Bas89).
      Oxalic acid may cause corrosion of the skin (Fit85). Skin lesions may be
      manifested by dermal cracking and slowly healing ulcers (Bur94). Gehring et al.
      reported that oxalic acid is a potent sensitising agent. Skin testing of oxalic acid
      in 26 patients with eczema on the dorsum of the foot from leather caused a
      positive reaction in 53.8% of these patients (Geh88).
          Laerum and Aarseth studied the cumulative prevalence of urolithiasis-
      induced colic episodes in 393 male workers of a Norwegian railroad depot using
      a questionnaire. A saturated oxalic acid solution had been used in repainting and
      cleaning of railroad cars for 28 years. Occupational exposure may have occurred
      by inhalation of oxalic-acid-containing steam or dust, and by skin contact with
      the solution. The levels of oxalic acid in workroom air were not measured. They
      workers were divided into 3 groups according to the magnitude of exposure:
      workers involved in the paint shop work with ‘high’ exposure, 3-4 hours/day
      (n=15); workers not involved in the paint shop work but occasionally using
      oxalic acid with ‘low-moderate’ exposure, 1-8 hours/week (n=25); and a group
      with no exposure to oxalic acid (n=353). A significant difference in the
      prevalence rate of urinary stone colic episodes was found between the groups
      with prevalence rates of 53.3, 32.0, and 11.9% for the ‘high’, ‘low-moderate’,
      and not exposed group, respectively, compared with a regional prevalence rate of
      2 cases per 1000 inhabitants per year. A selected group of 7 persons from the
      paint shop, who had had the most severe and long-lasting exposure to oxalic
      acid, reported a constant pharyngeal irritation and coughing when inhaling the
      steam containing oxalic acid, pollakiuria (an abnormal condition characterised
      by unduly frequent passage of urine), and slight dysuria, which regularly
      occurred during the first 20-30 minutes of exposure (Lae85)
          A comparative epidemiological study on renal lithiasis in gypsies in Spain
      showed that there was a relationship between family history of lithiasis and
      consumption of meat products, dairy products, and food rich in oxalic acid. The
      study included 11,871 gypsies and 4621 non-gypsies from the provinces of
      Granada and Almeria, and was based on personal interviews of a cultural,
      anthropological, and social nature (Tor84).
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<pre>           Ingestion of sorrel (Rumex crispus) with an estimated amount of 6 to 8 g of
      oxalic acid caused vomiting, diarrhoea, and impaired consciousness followed by
      hypocalcaemia, severe metabolic acidosis, kidney and liver failure, deep coma
      with respiratory depression, and death (from ventricular fibrillation) of a 53-year
      old man. Necropsy revealed hepatic centrilobular necrosis, swelling and
      retraction of glomeruli, and crystals of calcium oxalate in the renal cortex and
      vessels and capillaries of the liver, lung, and heart (Far89). In another case,
      accidental ingestion of about 15 g of oxalic acid had caused acute renal
      insufficiency. Renal biopsy showed acute tubular necrosis (Cec73).
      Animal data
      Irritation and sensitisation
      Like other strong acids, oxalic acid produces severe local burns of eyes, mucous
      membranes, and skin in animals. However, because its alkali salts are also
      corrosive, the acidity of oxalic acid is probably not primarily responsible for its
      effects on mucous membranes (Kat94).
           Oxalic acid, applied at an amount of 500 mg for 24 hours, was stated to be
      mildly irritating to the skin of rabbits (Kat94). When an ear of a rabbit was partly
      immersed in a saturated solution (stated to be 9.1% at 22oC) of anhydrous oxalic
      acid for 1 minute, no cutaneous reaction occurred while immersion for 5 minutes
      resulted in soon appearing redness that was still present with scaliness after 24
      hours. When a lintine disc saturated with a similar oxalic acid solution was
      applied to the shaved back skin of a rabbit for 24 hours, no skin reaction was
      seen (Kla55).
           Referring to separate reports, it was stated that instillation of 250 µg for 24
      hours or 100 mg for 4 seconds into the eyes of rabbits had caused severe
      irritation (Kat94).
      Acute toxicity
      The committee did not find data on the effects of oxalic acid following single
      exposure by inhalation.
           Dermal application of a dose of oxalic acid (as a 5% aqueous solution) of
      20,000 mg/kg bw did not induce mortality in rabbits. Following oral
      administration, LD50 values of 474 and 375 mg/kg bw were listed for male and
      female rats, respectively. When injected intraperitoneally, an LD50 of 270
      mg/kg bw in mice was mentioned (Kat94).
106-7 Oxalic acid
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<pre>          Kluwe et al. studied the effects of oxalic acid on the urogenital system of
      male F344 rats by giving the animals a single subcutaneous injection of 75
      mg/kg bw and subsequent evaluation after 24 hours and 3, 8, 25, and 75 days.
      Many of the dosed rats developed local lesions, like loss of hair and hard
      subcutaneous lumps. No behavioural changes or mortality were seen. The
      treatment produced glucosuria that persisted for at least 3 days. The serum
      calcium ion concentrations were unaffected, but serum sodium and potassium
      ion concentrations were transiently increased 24 hours and 3 days post-treatment.
      The serum creatinine concentrations were increased progressively 24 hours and 3
      days after treatment, but returned to normal by the eighth day. Similar effects
      occurred with blood urea nitrogen (BUN). Histological examinations showed
      birefringent crystals of calcium oxalate at the cortico-medullary junction and in
      the papilla of the kidneys, and were often associated with focal necrosis and
      mineralisation. There were no changes in weight and histology of the
      epididymides and testes. Other organ weights, including that of the brain, were
      unaffected by the treatment (Klu83).
      Repeated-dose toxicity
      The committee did not find studies on the toxicity of oxalic acid following
      repeated exposure by inhalation. In the available oral studies, no complete
      toxicological evaluation was made.
          Daily dietary administration of 0, 2.5% (females: 1980 mg/kg bw/day; males:
      1780 mg/kg bw/day), and 5% (females: 5300 mg/kg bw/day; males: 5200
      mg/kg bw/day), continuously for 70 days, to rats (Long-Evans; n=9-12/sex/
      group) caused mortality rates of 25% and less than 10% in the high- and low-
      dose group, respectively. In the high-dose group, clinical signs of toxicity
      (emaciation, stunted, gaunt with arched backs), increased food and water
      consumption, decreased body weights and growth rates, decreased absolute and
      increased relative organ weights (liver, kidney, spleen, adrenals, thyroid,
      reproductive organs), absence of body fat, minimal presence of adipose tissue
      normally adherent to visceral and endocrine tissues, and histological lesions in
      the kidneys and male and female reproductive tissues were observed. In the low-
      dose group, there were no overt signs of toxicity, and food and water
      consumption were comparable to that of controls. Body weight, growth rate,
      organ weight, and histological changes were similar but less consistent and
      pronounced than those found in the high-dose group (see also under
      ‘Reproduction toxicity’) (Gol77). In a subsequent study using the same protocol
      as described above, the effects of oxalic acid on the thyroid function were
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<pre>      investigated. Based on food intake, Goldman and Doering calculated that the
      daily intakes were 2100 and 1900 mg/kg bw for low-dose females and males,
      respectively, and 5300 mg/kg bw for both high-dose females and males. No data
      on mortality were presented, but otherwise results concerning overt signs of
      toxicity, body weight (gain), and liver, kidney, spleen, and endocrine tissue
      weights confirmed those of the previous study. Absolute thyroid weights were
      decreased in the high-dose, but not in the low-dose animals while relative thyroid
      weights were decreased in both dose groups. A marked reduction in the 24-hour
      radiolabelled iodine uptake was found in the high-dose, but not in the low-dose
      group. Furthermore, there were reductions in plasma 125I in both dose groups,
      dose-related increases - being statistically significant in the high-dose group - in
      plasma thyroid-stimulating hormone (TSH) levels, and increases in the thyroidal
      labelling of triiodothyronine (T3) content in the high-dose group, while labelling
      of tetraiodothyronine (T4) was unaffected. The authors concluded that dietary
      ingestion of doses of 5300 mg/kg bw oxalic acid can induce hypothyroidism or
      exacerbate conditions of latent hypothyroidism (Gol79).
          In the first, dose range-finding part of a reproduction toxicity according to the
      NTP Reproductive Assessment by Continuous Breeding (RACB) protocol (see
      below under ‘reproduction toxicity’), CD-1 mice (n=8/sex/group) were given
      daily oral (drinking water) doses of oxalic acid dihydrate of 0.25 to 5.0%
      (estimated to be ca. 350 to 3500 mg/kg bw/day), for 14 consecutive days.
      Clinical signs of toxicity (rough hair coat; hunched back) were observed in
      almost all animals of the 2 highest dose groups (i.e., 2.5 and 5%, ca. 1600 and
      3500 mg/kg bw/day) starting at day 6 while one male animal of the 1%-dose
      group (ca. 1000 mg/kg bw/day) had rough hair coat. Body weight losses (by
      about 35-45%) and very high mortality (75-88%) were seen in the 2 highest dose
      groups. There were no deaths (apart from one male of the 0.25%-dose group) or
      effects on body weight gain (apart from a 3% increase in males of the 1%-dose
      group vs. 11% in male controls) in any of the other groups.
          In the second part, parental animals (n=20/sex/group; controls: n=40/sex)
      were given daily oral (drinking water) doses of 0, 0.05, 0.10, and 0.2%
      (estimated to be 0, 89, 162, and 275 mg/kg bw/day, respectively), for 18 weeks.
      All but 10 animals per sex representative of the control and high-dose group
      were sacrificed during week 19-21. Of the selected animals necropsied at week
      23, body, liver, kidney (including adrenal glands), prostate, testis, cauda,
      epididymis, and seminal vesicle (with coagulating glands) weights and blood
      serum calcium levels were determined and sperm morphology and vaginal
      cytology evaluated (see below under ‘reproduction toxicity’). It was, however,
      not clear to the committee whether these high-dose animals were treated during
106-9 Oxalic acid
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<pre>       week 18-23. No symptoms of toxicity or compound-related mortality were
       observed during treatment. In the 2 highest dose groups, there was a dose-related
       decrease in water consumption. No effect on body weight (gain) was noticed in
       any of the treated groups at any of the measurement points. Apart from a
       statistically significant increase in kidney weights adjusted for body weight at
       necropsy* in females, no effect was seen on body weight, absolute and adjusted
       liver and kidney weight, and blood serum calcium levels in the high-dose mice
       selected for necropsy. In males, there was a decrease in absolute and adjusted
       prostate weight while the other reproductive organ weights did not differ from
       those of controls (Gul85).
            When solutions of oxalic acid of 0, 30, 50, or 60 mg/animal (i.e., 0, 136, 227,
       272 mg/kg bw) were orally (gavage) administered to female rats (Wistar;
       n=5/group) mated 10 days previously, all animals of the 2 higher dose groups
       died within 7 days showing anorexia, depression, rapid breathing, and body
       weight loss before death. At necropsy, macro- and microscopic findings included
       severe haemorrhagic gastritis, ballooned, most empty small intestine, small
       amounts of blood in the small intestine, and oxalate crystals in the gastric
       mucosa and the renal tubules, accompanied by tubulonephrosis. In the animals of
       the low-dose group, no compound-related effects were seen during exposure and
       upon post-mortem evaluation. In the subsequent study in which mated female
       animals (n=10/group) were given 0, 35, or 45 mg/animal (i.e., 0, 175, 225
       mg/kg bw), mortality (low dose: 1/10, high dose: 1/10), haemorraghic gastritis
       with oxalate crystals in gastric mucosa (in 1/10 and 3/10, respectively), and
       marked renal oxalosis (in 5/10 and 7/10, respectively) were observed (She80).
        Mutagenicity and genotoxicity
       In vitro, (anhydrous) oxalic acid was negative when tested in the absence and the
       presence of metabolic activation systems obtained from induced rat and hamster
       livers in S. typhimurium strains TA98, TA100, TA1535, and TA1537 (Haw83).
       In separate studies, oxalic acid was reported to be negative in S. typhimurium
       strains TA92, TA94, TA98, TA100, TA1535, TA1537 (tested with and without
       induced rat liver S9) (Ish84) or TA97, TA98, TA100, TA102, TA104 (tested
       with and without induced rat liver S9) (Say87). Oxalic acid was found positive
       when tested without metabolic activation in the Microscreen assay using E. coli
*      It was not clear how these adjusted organ weights were determined or calculated. They were not relative weights
       expressed as g organ weight/100 g bw.
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<pre>       strain WP2s(λ) with lambda prophage induction (indicative of DNA damage) as
       an endpoint (not tested with S9) (Ros91).
           Tested in mammalian cell systems, oxalic acid was found negative in a test
       for polyploidy and chromosomal aberrations in Chinese hamster lung fibroblasts
       (tested without metabolic activation only) (Ish84).
           The committee did not find data on the (potential) in vivo genotoxicity of
       oxalic acid.
       Reproduction toxicity
       Daily dietary administration of oxalic acid of 5300 mg/kg bw, for 70 days, to
       female rats (Long-Evans; n=10) caused decreased absolute and relative ovary
       and uterus weights and prolonged dioestrus. Upon histological examination, the
       ovarian tissue was dense and compact, with small cells, absence of adipose
       tissue, depressed follicular development, and dense, compact interstitial tissue.
       Luteal cells contained dark, condensed, and shrunken nuclei. In male rats (n=9)
       given 5200 mg/kg bw, absolute weights of the testes and absolute and relative
       weights of prostate and seminal vesicles were decreased while relative testes
       weights were increased. Histological examination showed compact testis tissue
       with seminiferous tubules of small diameter containing immature Sertoli cells
       and spermatogonia with absence of mitosis, as well as decreased interstitial
       tissue. Similar but less intense effects were seen in male and female rats given
       daily doses of 1780 and 1980 mg/kg bw, respectively. It should be noted that
       these doses caused rather severe systemic toxicity (see also under ‘Repeated dose
       toxicity’) (Gol77).
           The (potential) effects of oxalic acid (dihydrate) on fertility and reproduction
       were assessed according to the NTP RACB protocol. CD-1 mice (n=20/sex/
       group; controls: n=40/sex) were given daily oral (drinking water) doses of 0,
       0.05, 0.10, and 0.2% (estimated to be 0, 89, 162, and 275 mg/kg bw/day,
       respectively), for a 1-week pre-mating period, a 14-week cohabitation period
       (during which animals were pairwisely housed), and an additional 6-week period
       during which the dams were allowed to deliver and wean a final litter.
       Thereafter, animals of the last litter of the high-dose group (n=10/sex; F1
       generation) were treated with the same dose and allowed to mate and deliver one
       F2 litter. Of the high-dose F0 and F1 generation, 10 animals per sex per group
       were selected for sperm morphology (motility, density, abnormality) and vaginal
       cytology (relative frequency of oestrus stages, oestrus cycle length) evaluation.
       At the 2 lower doses, there were no effects on maternal, fertility, and
       reproduction toxicity parameters, apart from a decrease in water consumption in
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<pre>       the mid-dose group. In the high-dose group, the only effects seen in the parental
       F0 mice were decreased water consumption in both sexes and increased
       adjusted* kidney weights in females. With respect to fertility and reproductive
       organs, decreases in absolute and adjusted prostate weights (p<0.05) and
       increases in the incidence of abnormal sperm (7.20 vs. 5.33; not stat. sign.), in
       the average oestrus cycle length (5.3 days vs. 4.8 days), and in the relative
       frequency of the oestrus stage (21% vs. 11%) were observed. Further, there were
       decreases in the number of litters per fertile pairs (4.7 vs. 4.92 in controls;
       p<0.05) and in average pup weight (adjusted for litter size; 1.53 vs. 1.56 in
       controls; p<0.01). Evaluation of the final litter produced by the F0 animals
       showed that treatment did not affect pup survival or pup body weight gain for up
       to 14 days after delivery. With respect to the F1 animals, there was no effect on
       water consumption. At necropsy, statistically significant increases in absolute
       (males) or adjusted (females) kidney weights were found. As to fertility and
       reproductive organs, prostate weights were not affected, the incidence of
       abnormal sperm was increased (4.01 vs. 2.22 in controls; p<0.05), the average
       oestrus cycle length was similar among groups (4.9 days vs. 4.8 days) while the
       relative frequency of oestrus was increased (37% vs. 31%). Further, statistically
       significant decreases in the total number of live fetuses and in the number of live
       female pups were observed (Gul85).
            When pregnant female rats (Wistar; n=5/group) were orally (gavage) given
       daily doses of 30 mg/animal (i.e., 136 mg/kg bw/day, starting day 10 after
       mating until parturition, tubulonephrosis (marked vacuolation of proximal
       tubular cells, pycnotic and karyorrhectic nuclei) but no oxalosis was observed in
       the kidneys of all newborn. In the maternal animals, no compound-related effects
       were seen during exposure and upon post-mortem evaluation. In the follow-up
       study at doses of 35 and 45 mg/animal (i.e., 175, 225 mg/kg bw), inducing
       mortality and gastric and renal effects in the maternal animals, no abortions,
       gross malformations, or renal effects were seen in the offspring. However, there
       was a dose-related reduction in litter sizes (8.8 and 7.2, respectively, vs. 12.2 in
       controls) (see also under ‘repeated dose toxicity’) (She80).
       In vitro experiments
       Using blood samples from human volunteers, oxalic acid significantly inhibited
       human thrombocyte aggregation. Oxalic acid was suggested to bind platelet
*      It was not clear how these adjusted organ weights were determined or calculated. They were not relative weights
       expressed as g organ weight/100 g bw.
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<pre>       cytosolic calcium and to inhibit cAMP function after transmembrane diffusion
       (Cam86).
            Using LLC-PK1 cell cultures, exposure to high levels of oxalate produced
       damage of renal epithelial cells as evidenced by morphological alterations,
       increased uptake of vital dyes, and decline in cell numbers (Sch95).
7      Existing guidelines
       The current administrative occupational exposure limit (MAC) for oxalic acid in
       the Netherlands is 1 mg/m3, 8-hour TWA.
            Existing occupational exposure limits for oxalic acid in some European
       countries and in the USA are summarised in the annex.
8      Assessment of health hazard
       Occupational exposure to oxalic acid may occur by inhalation of its aerosols
       (from steam of hot water solution) or dusts, and possibly also from direct skin
       contact with an oxalic-acid-containing solution. Being a strong acid, the
       compound may cause severe local effects. Systemic effects of oxalic acid
       toxicity are attributed largely to the calcium-complexing action of the acid,
       which depresses the level of calcium ions in body fluids. The resulting condition
       of hypocalcaemia produces severe disturbances in the activity of the heart and
       neural system. The formation of calcium oxalate crystals, which is one of the
       factors in the pathogenesis of urinary stone disease, may also be attributed to
       exposure to oxalic acid.
            The committee did not find data on the kinetics of oxalic acid following
       inhalation or dermal exposure. Following oral ingestion, humans absorb about 2
       to 10% of oxalate in the food through the gastrointestinal tract while in rats, ca.
       25 and 73% of radiolabelled oxalate were excreted in the urine and faeces,
       respectively. There is no evidence that oxalate is utilised or metabolised by
       human tissues. Human serum, urine, and tissues can contain oxalate originating
       from dietary and metabolic (glycine) sources.
            Skin testing of oxalic acid in patients with eczema on the dorsum of the foot
       from leather caused a positive sensitising reaction in half of these patients.
       Respiratory tract irritation as well as urination problems were reported by
       railroad shopmen occupationally exposed to steam containing unknown levels of
       oxalic acid. In these workers, a causal relationship between occupational
       exposure to oxalic acid and increased prevalence of urolithiasis-induced colic
       episodes was found.
106-13 Oxalic acid
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<pre>           In rabbits, oxalic acid was mildly and severely irritating to the skin and eyes,
       respectively. The committee did not find experimental animal data on local and
       systemic effects following single or repeated exposure by inhalation. No
       mortality was observed in rabbits dermally exposed to single doses of 20,000
       mg/kg bw. In rats, oral LD50 values of 375 and 474 mg/kg bw were found for
       females and males, respectively.
           In a 70-day repeated oral (diet) rat study (Gol79), doses of 1780 (males) or
       1980 (females) mg/kg bw induced mortality, changes in body weight (gain), in
       weights of several organs including male and female reproductive organs, and in
       oestrus cycle, and histological lesions in kidneys and in male and female
       reproductive organs. Lower doses were not tested in this study. In a fertility and
       reproduction toxicity study (Gul85) in which parental mice were orally (drinking
       water) given daily doses up to 275 mg/kg bw, for 18 weeks, no toxic symptoms,
       treatment-related mortality, or effects on body weight were observed. Apart from
       a statistically significant increase in kidney weights adjusted for body weight at
       necropsy in females and a decrease in absolute and adjusted prostate weight in
       males, no effects were seen on absolute and adjusted liver, kidney, and
       reproductive organ weights, and blood serum calcium levels. The committee did
       not find data from lifetime toxicity studies.
           Oxalic acid was not mutagenic in S. typhimurium but caused DNA damage in
       E. coli (tested without metabolic activation). It was not clastogenic in Chinese
       hamster fibroblasts. The committee did not find data from other in vitro or in
       vivo mutagenicity and genotoxicity studies.
           In a 2-generation reproduction toxicity study using mice (Gul85), no effects
       were seen on parental toxicity and reproductive (including fertility) toxicity at
       doses up to 162 mg/kg bw. At 275 mg/kg bw, the highest dose tested, parental
       effects as described above and reproductive effects including increases in the
       percentage of abnormal sperm, in the average oestrus cycle length, and in the
       relative frequency of the oestrus stage, as well as modest decreases (4-5%) in the
       number of litters per pair and in pup weights, adjusted for litter size, were found
       in the F0 generation while in the F1 generation, increased female kidney weights
       (adjusted for body weight at necropsy), increased abnormal sperm, increased
       relative frequency of oestrus length, and decreased number of live pups per litter
       were seen.
       The committee considers irritation of the upper respiratory tract, eyes, and skin
       to be the critical effects in occupational exposure to oxalic acid. However, the
       committee did not find data on thresholds of these effects.
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<pre>       The committee considers the toxicological database on oxalic acid too poor to
       justify recommendation of a health-based occupational exposure limit.
       From the NOAEL of 162 mg/kg bw/day found in a 2-generation reproduction
       toxicity study in mice, the committee concludes that the current MAC value of 1
       mg/m3 offers sufficient protection from systemic effects from inhalation
       exposure to oxalic acid. However, because of lack of information, the committee
       cannot conclude whether the current MAC value offers sufficient protection
       from irritation.
       References
ACG99  American Conference of Governmental Industrial Hygienists (ACGIH). Oxalic acid. In: TLVs® and
       other occupational exposure values -1999. [CD-ROM]. Cincinnati OH, USA: ACGIH®, Inc, 1999.
ACG03a American Conference of Governmental Industrial Hygienists (ACGIH). Guide to occupational
       exposure values - 2003. Cincinnati OH, USA: ACGIH®, Inc, 2003: 101.
ACG03b American Conference of Governmental Industrial Hygienists (ACGIH). 2003 TLVs® and BEIs®
       based on the documentaion of the Threshold Limit Values for chemical substances and physical
       agents & Biological Exposure Indices. Cincinnati OH, USA: ACGIH®, Inc, 2003: 45.
Arb02  Arbejdstilsynet. Grænseværdier for stoffer og materialer. Copenhagen, Denmark: Arbejdstilsynet,
       2002: 33 (At-vejledning C.0.1).
Ban79  Bannwart C, Hagmaier V, Rutishauser G, et al. Absorption of oxalic acid in rats by means of a 14C
       method. Eur Urol 1979; 5: 276-7.
Bas89  Baselt RC, Cravey RH, eds. In: Disposition of toxic drugs and chemicals in man. Chicago IL, USA:
       Year Book Medical Publ, Inc, 1989.
Ber90  Berg W. Stoffwechsel und Pathophysiologie der Oxalsäure. Z Urol Nephrol 1990; 83: 481-8.
Bur94  Von Burg R. Oxalic acid and sodium oxalate. J Appl Toxicol 1994; 14: 233-7.
Cam86  Camici M, Evangelisti L, Raspolli-Galetti M. The effect of oxalic acid on the aggregability of human
       platelet rich plasma. Prostaglandins Leukot Med 1986; 21: 107-10.
Cec73  Ceci CF, Jorge MA, Basaluzzo JM, et al. Insuficiencia renal aguda por ingestion de acido oxalico.
       Soc Arg Invest Clin 1973; 33: 550-3.
DFG03  Deutsche Forschungsgemeinschaft (DFG): Commission for the Investigation of Health Hazards of
       Chemical Compounds in the Work Area. List of MAK and BAT values 2003. Maximum
       concentrations and Biological Tolerance Values at the workplace Weinheim, FRG: Wiley-VCH
       Verlag GmbH & Co. KGaA, 2003; rep no 39.
EC04   European Commission: Directorate General of Employment and Social Affairs. OELs already
       included in Commission Directives. http://europe.eu.int/comm/employment_social/h&s/areas/
       oels4_en.htm.
106-15 Oxalic acid
</pre>

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

<pre>EPA92  US Environmental Protection Agency (EPA). EPA R.E.D. Facts. Oxalic acid. Washignton DC, USA:
       US EPA, Office of Prevention, Pesticides, and Toxic Substances, 1992; EPA rep no EPA-738-F-92-
       014.
Far89  Farré M, Xirgu J, Salgado A, et al. Fatal oxalic acid poisoning from sorrel soup. Lancet 1989; 2:
       1524.
Fit85  Fitzpatrick KT, Moylan JA. Emergency care of chemical burns. Postgrad Med 1985; 78: 189-94.
Geh88  Gehring W, Gloor M, Gehse M. Fußrückenekzeme infolge von Ledersensibilisierung. Fortschr Med
       1988; 106: 51-2.
Gol77  Goldman M, Doering GJ, Nelson RG. Effect of dietary ingestion of oxalic acid on growth and
       reproduction in male and female Long-Evans rats. Res Commun Chem Pathol Pharmacol 1977; 18:
       369-72.
Gol79  Goldman M, Doering GJ. The effect of dietary ingestion of oxalic acid on thyroid function in male
       and female Long-Evans rats. Toxicol Appl Pharmacol 1979; 48: 409-14.
Gul85  Gulati DK, Barnes LH, Welch M, et al. Oxalic acid: reproduction and fertility assesment in CD-1
       mice when administered in drinking water. Lexington KY, USA: Environ Health Research and
       Testing, 1985
Haw83  Haworth S, Lawlor T, Mortelmans K, et al. Salmonella mutagenicity test results for 250 chemicals.
       Environ Mutagen 1983; 5 (suppl 1): 3-142.
Hod68  Hodgkinson A, Zarembski PM . Oxalic acid metabolism in man: a review. Calcif Tissue Res 1968; 2:
       115-32.
HSE02  Health and Safety Executive (HSE). EH40/2002. Occupational Exposure Limits 2002. Sudbury
       (Suffolk), England: HSE Books, 2002: 23.
Ish84  Ishidate M Jr, Sofuni T, Yoshikawa K, et al. Primary mutagenicity screening of food additives
       currently used in Japan. Food Chem Toxicol 1984; 22: 623-36.
Kat94  Katz GV, Guest D. In: Clayton GD, Clayton FE, eds. Toxicology. 4th ed. New York, USA: John
       Wiley & Sons, Inc: 3573-7 (Patty's industrial hygiene and toxicology; Vol II, Pt E).
Kla55  Klauder JV, Shelanski L, Gabriel K. Industrial uses of compounds of fluorine and oxalic acid. AMA
       Arch Ind Health 1955; 12: 412-9.
Klu83  Kluwe WM, Gupta BN, Lamb JC IV. The comparative effects of 1,2-dibromo-3-chloropropane
       (DBCP) and its metabolites, 3-chloro-1,2-propaneoxide (Epichlorhydrin), 3-chloro-1,2-propanediol
       (Alphachlorohydrin), and oxalic acid, on the urogenital system of male rats. Toxicol Appl Pharmacol
       1983; 70: 67-86.
Lae85  Laerum E, Aarseth S. Urolithiasis in railroad shopmen in relation to oxalic acid exposure at work.
       Scand J Work Environ Health 1985; 11: 97-100.
Lun88  Lundberg P. Consensus report for oxalic acid. In: Scientific basis for Swedish occupational
       standards IX. Arbete och Hälsa 1988; (32): 102-5.
NLM01  US National Library of Medicine (NLM). Oxalic acid. In: Hazardous Substances Data Bank (HSDB)
       (last review date oxalic acid file: 28 February 1992); http://toxnet.nlm.nih.gov.
106-16 Health-based Reassessment of Administrative Occupational Exposure Limits
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<br><br>====================================================================== Pagina 17 ======================================================================

<pre>Pre84  Prenen JA, Boer P, Dorhout Mees EJ. Absorption kinetics of oxalate from oxalate-rich food in man.
       Am J Clin Nutr 1984; 40: 1007-10.
Ros91  Rossmann TG, Molina M, Meyer L, et al. Performance of 133 compounds in the lambda prophage
       indcution endpoint of the Microscreen assay and a comparison with S. typhimurium mutagenicity
       and rodent carcinogenicity assays. Mutat Res 1991; 260: 349-67.
Say87  Sayato Y, Nakamuro K, Ueno H. Mutagenicity of products formed by ozonation of
       naphthoresorcinol in aqueous solutions. Mutat Res 1987; 189: 217-22.
Sch95  Scheid CR, Koul HK, Kennington L, et al. Oxalate-induced damage to renal tubular cells. Scanning
       Microsc 1995; 9: 1097-107.
She80  Sheik-Omar AR, Schiefer HB. Effects of feeding oxalic acid to pregnant rats. Pertanika 1980; 3: 25-
       31.
Swe00  Swedish National Board of Occupational Safety and Health. Occupational exposure limit values and
       measures against air contaminants. Solna, Sweden: National Board of Occupational Safety and
       Health, 2000: 64 (Ordinance AFS 2000:3).
SZW03  Ministerie van Sociale Zaken en Werkgelegenheid (SZW). Nationale MAC-lijst 2003. The
       Hague, The Netherlands: Sdu, Servicecentrum Uitgevers, 2003: 37.
Tor84  Torres Ramirez C, Fernandez Morales E, Zuluaga Gomez A, et al. An epidemiological study of renal
       lithiasis in gypsies and others in Spain. J Urol 1984; 131: 853-6.
TRG00  TRGS 900. Grenzwerte in der Luft am Arbeitsplatz; Technische Regeln für Gefahrstoffe. BArbBl
       2001; 2.
Wah94  Wahl R, Kallee E. Oxalic acid in saliva, teeth and tooth tartar. Eur J Clin Chem Clin Biochem 1994;
       32: 821-5.
Wil79  Williams HE. The absorption, excretion and metabolism of oxalic acid. In: Idiopathic urinary bladder
       stone disease. London, England: Castlehouse Publ, 1979: 287-96.
106-17 Oxalic acid
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<pre>              Annex
Occupational exposure limits for oxalic acid 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        -         1             8h                      administrative               SZW03
Employment
Germany
- AGS                                   -         1c            8h                                                   TRG00
- DFG MAK-Kommission                    -         -                                                                  DFG03
Great Britain
- HSE                                   -         1             8h                      OES                          HSE02
                                        -         2             15 min
Sweden                                  -         1             8h                                                   Swe00
                                        -         2             15 min
Denmark                                 -         1             8h                                                   Arb02
USA
- ACGIH                                 -         1             8h                      TLV                          ACG03b
                                        -         2             15 min                  STEL
- OSHA                                  -         1             8h                      PEL                          ACG03a
- NIOSH                                 -         1             10 h                    REL                          ACG03a
                                        -         2             15 min                  STEL
European Union
- SCOEL                                 -         1             8h                      ILVd                         EC04
a
     S = skin notation; which mean that skin absorption may contribute considerably to body burden; sens = substance can cause
     sensitisation.
b
     Reference to the most recent official publication of occupational exposure limits.
c
     Measured as the inhalable fraction of the aerosol.
d
     Listed among compounds for which OELs are already included in Commission Directives.
106-18        Health-based Reassessment of Administrative Occupational Exposure Limits
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