<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>2,6-Di-tert-butyl-p-cresol
(CAS No: 128-37-0)
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/101 The Hague, March 30, 2004
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<pre>Preferred citation:
Health Council of the Netherlands: Committee on Updating of Occupational
Exposure Limits. 2,6-Di-tert-butyl-p-cresol; Health-based Reassessment of
Administrative Occupational Exposure Limits. The Hague: Health Council of the
Netherlands, 2004; 2000/15OSH/101.
all rights reserved
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<pre>1     Introduction
      The present document contains the assessment of the health hazard of 2,6-di-tert-
      butyl-p-cresol (BHT) by the Committee on Updating of Occupatonal Exposure
      Limits, a committee of the Health Council of the Netherlands. The first draft of
      this document was prepared by MA Maclaine Pont, M.Sc. (Wageningen
      University and Research Centre, Wageningen, the Netherlands).
           The assessment of the toxicity of BHT was mainly based on the reviews by
      the Joint FAO/WHO Expert Committee on Food Additives (JECFA) (FAO96)
      and the American Conference of Industrial Hygienists (ACGIH) (ACG99).
      Where relevant, the original publications were reviewed and evaluated as will be
      indicated in the text. In addition, in May 2000, literature was searched in the
      databases Toxline, Medline, and Chemical Abstracts starting from 1990, 1990,
      and 1992, respectively, and using the following key words: BHT, butylated
      hydroxytoluene, and 128-37-0. The final literature search was carried out in
      Toxline and Medline in October 2003.
           In October 2003, the President of the Health Council released a draft of the
      document for public review. No comments were received.
2     Identity
      name                     :   2,6-di-tert-butyl-p-cresol
      synonyms                 :   2,6-di-tert-butyl-4-methylphenol; 2,6-bis(1,1-dimethylethyl)-4-
                                   methyl- phenol; butylated hydroxytoluene;
                                   butylhydroxytoluene; dibutylated hydroxytoluene
      molecular formula        :   C15 H24O
      structural formula       :
      CAS number               :   128-37-0
101-3 2,6-Di-tert-butyl-p-cresol
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<pre>3     Physical and chemical properties
      molecular weight     :  220.35
      boiling point        :  265oC
      melting point        :  71oC
      flash point          :  127oC (open cup)
      vapour pressure      :  at 20oC: 1.3 Pa
      solubility in water  :  insoluble (at 20oC: <1 mg/100 mL)
      log Poctanol/water   :  4.17, 5.1 (experimental); 5.03, 5.6, 6.2 (estimated)
      conversion factors   :  at 20oC, 101.3 kPa: 1 ppm = 9.2 mg/m3
                                                   1 mg/m3 = 0.11 ppm
      Data from ACG99, BUA94, IARC86, NLM03, http://esc.syrres.com.
      BHT is a white, crystalline, odourless solid. BHT is easily oxidisable and can act
      as a radical scavenger (ACG99, BUA94).
4     Uses
      BHT is widely used as a stabiliser and antioxidant for ground vehicle and
      aviation gasolines; lubricating, turbine, and insulating oils; and waxes, synthetic
      and natural rubbers, paints, plastics, and elastomers. Highly purified grades are
      suitable for use in foods to retard oxidation of animal fats, vegetable oils, and oil-
      soluble vitamins. It is also used in food packaging materials such as waxed
      papers, paperboard, and polyethylene. It is important in delaying the onset of
      rancidity of oils and fats in animal feeds and in preserving the essential nutrients
      and pigment-forming compounds of these foods (ACG99).
           In the Netherlands, BHT is allowed as antioxidant in fats and oils and in
      chewing gum at levels of 100-400 mg/kg (Ano99). In the US, regulations permit
      the use of BHT as a food additive in certain potato products, rice, margarine,
      breakfast cereals, chewing-gum, and certain meat products at specified levels
      ranging from 0.001-0.1% and in food packaging material in the USA (IARC86).
5     Biotransformation and kinetics
      Human data
      Male human volunteers (n=4), who were given a single oral dose of
      approximately 40 mg 14C-labelled BHT, excreted about 50% of the dose in the
101-4 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>      urine within 24 hours and 75% at the end of the observation period (11 days).
      BHT was biotransformed by oxidation of the 4-methyl group in the ring and of
      one of the tert-butyl methyl groups. Free and conjugated 3,5-di-tert-butyl-4-
      hydroxybenzoic acid (BHT-COOH) were minor urinary components (Dan68).
      However, in 2 other studies, in which human volunteers received single oral
      doses of 100 or 1000 mg of BHT, free and conjugated BHT-COOH were
      identified as major metabolites (Hol70). In a more recent study, a furan
      derivative, 5-carboxy-7-(1-carboxy-1-methylethyl)-3,3-dimethyl-2-hydroxy-2,3-
      dihydroxybenzofuran, was identified as a main human metabolite (Wie78) (see
      Figure1a, Annex I). In another study, 7 male volunteers were given an oral dose
      of BHT of 0.5 mg/kg bw. The peak BHT level in plasma was reached 90 minutes
      after dosing. Large variations were seen in BHT plasma concentrations (mean:
      0.09 mg/L). BHT-COOH (mainly conjugated) was excreted in amounts of 2.8%
      of the dose within 2 days (Ver89).
      Animal data
      After a single application of 5 mg 14C-labelled BHT in a lipophilic vehicle to the
      unoccluded skin of guinea pigs (n=5; application area: 1.66 mg/cm2), an average
      of 8.5% of the applied dose was excreted in the urine within 8 days. Most of he
      radioactivity (63%) was excreted within 24 hours after application. Washing of
      the skin, 24 hours after application, reduced the excretion to 5.4% of the applied
      dose. Courtheoux et al. conducted also a repeated dermal study, in which guinea
      pigs received daily doses of 5 mg BHT (1.66 mg/cm2) for 21 days. On days 1, 8,
      and 15 only, the animals were dosed with 5 mg 14C-BHT. The amounts of
      radioactivity excreted in urine were 4.4, 7.9, and 9.1% of the dose, within 7 days
      after each radiolabelled application. About 35% of the radioactivity was excreted
      within 24 hours after application. Washing of the skin, one hour before
      application of radiolabelled BHT, had no significant influence on the amount of
      absorption (Cou85).
           After a single oral dose of 14C-BHT of 1 mg to rats, 24 and 37% was excreted
      in the urine and 42 and 35% in the faeces in males and females, respectively,
      within 4 days (Dan65). In a later study, following single intragastic doses of
      14
         C-BHT of 20 or 500 mg/kg bw, 9-12 and 47-38% of the radioactivity were
      excreted in the urine and the faeces, respectively, 24 hours after administration,
      amounting to 16-69 and 70-64%, respectively, after 3 days (Mat84). BHT
      residues were found in the fat and the liver of rats, given approximately 250
      mg/kg bw/day BHT via the food for 35 days. The half-life of elimination of BHT
      from these tissues was 7 to 10 days (Dan65). In mice, approximately 75% of a
101-5 2,6-Di-tert-butyl-p-cresol
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<pre>      single oral dose was excreted in the urine during the first 24 hours. This was
      followed by a slower phase during which an additional 10% was excreted over
      the next 4 days. The total amount found in the faeces was less than 1% of the
      dose (Dau80). In another study in mice, 41-65% of the radioactivity was excreted
      in the faeces, 26-50% in the urine, and 6-9% in expired air within 24 hours after
      administration of single oral doses of 14C-BHT of 20 or 500 mg/kg bw. The half-
      life of elimination of radioactivity from the major tissues studied was 9-11 hours.
      However, when daily doses were given for 10 days, the half-life was 5-15 days
      (Mat84). Guinea pigs that were given a single oral dose of 5 mg 14C-BHT
      excreted 67% of the radioactivity in urine and 18% in the faeces within 7 days.
      Most of the urinary radioactivity (approximately 50% of the dose) was excreted
      in the first 24 hours urine. When given by the intravenous route, 60% of
      radioactivity was excreted in the urine and 15% in the faeces within 7 days
      (Cou85).
           Mice of the ddY strain responded to an intraperitoneal injection of BHT of
      400 mg/kg bw with a significant reduction in the glutathione content of lung
      tissue, but not of the liver or kidney tissue (Mas84). BHT binds to mouse lung
      tissue to a greater extent than to liver and kidney tissue, and more is bound in
      mouse than in rat tissues (Keh80).
      In rats, the predominant metabolic pathway involves oxidation of the 4-methyl
      group, yielding BHT-COOH (both free and glucuronidated) as a major
      metabolite, and 3,5-di-tert-butyl-4-hydroxybenzyl alcohol and benzaldehyde
      (BHT-OH and BHT-CHO) as minor metabolites. In addition, the mercapturic
      acid S-(3,5-di-tert-butyl-4-hydroxybenzyl)-N-acetylcysteine (BHT-mercapturic
      acid) was detected as a major metabolite (Dan68, Lad67). This mercapturic acid
      may be formed by reaction of BHT-quinone methide (2,6-di-tert-butyl-4-
      methylene-2,5-cyclohexadienone) with glutathione. This reactive BHT-quinone
      methide has been identified in the liver and bile of rats (Taj81, Tak79) and may
      be responsible for BHT-induced lung damage or hepatotoxicity in mice (Keh85,
      Miz87). Metabolites produced in mice are similar to those produced in rats,
      except that the major biotransformation in mice was by oxidation of the tert-
      methyl groups (Mat84). In rabbits, orally administered BHT was metabolised to
      BHT-OH, BHT-COOH, and BHT-dimer. The urinary metabolites of BHT
      comprised 38% as glucuronides, 17% as sulphates, and 7% as free phenols.
      Unchanged BHT was present only in the faeces (Aka62).
           The confirmed and tentative metabolic pathways are presented in Figures 1a
      and 1b (see Annex I).
101-6 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>6     Effects and mechanism of action
      Human data
      In a study on workers (‘not less than 15 individuals’) in the rubber and plastic
      industries, BHT was mildly irritating to the skin and a skin sensitiser in 29 and
      19% of the subjects, respectively (Mal52). In a study on eczema patients, 2 out of
      112 were positive in a patch test with 2% BHT (Roe76). In another study, 7
      patients with chronic asthma or chronic vasomotor rhinitis showed an
      exacerbation of respiratory symptoms following oral intake of 125 or 250 mg
      BHT plus butylated hydroxyanisole (BHA) (Fis73). Patch testing with BHT did
      not produce any positive reaction in 1336 eczema patients (Fly90). When 358
      patients from a dermatology clinic were patch tested with 2% BHT, none had an
      allergic reaction and 2 had an irritant reaction (Kan99). Double-blind, placebo-
      controlled challenge tests with a 1:1 mixture of BHT and BHA (50 mg) were
      carried out in 44 patients with chronic urticaria, in 91 with atopic dermatitis, and
      in 123 with contact dermatitis. No positive reactions were seen (Han86). In very
      rare cases, the intake of food containing BHT resulted in urticaria, a food-
      intolerance reaction (And97).
          Two cases of intoxication have been reported following incidental oral intake
      of high doses of BHT. In one case, a woman who ingested 4 g of BHT developed
      stomach cramp, general weakness, nausea and vomiting, followed by fatigue,
      mental disorientation, and short-term unconsciousness. A few days after the
      intake, the symptoms had disappeared (Shl86). In the other case, a woman who
      ingested 80 g BHT developed neurological symptoms within one hour, which
      were fully reversible (Gro86).
      Animal data
      Irritation and sensitisation
      BHT was slightly irritating to rabbit eyes (McO49, Bee76).
          When a dose of BHT of 420 mg/kg bw in ether was applied to the skin of
      rabbits, slight irritation was noted (McO49). This was confirmed in a later
      conducted patch test (Bee76). BHT had no skin-sensitising activity in guinea
      pigs following repeated application of the compound (Dei55). In a maximisation
      test with guinea pigs, animals sensitised to 2-methylol p-tert-butylphenol and
101-7 2,6-Di-tert-butyl-p-cresol
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<pre>      2,6-dimethylol p-tert-butylphenol did not show cross-reactions to a 13.3%
      solution of BHT (11/23 and 1/24 animals sensitised, respectively) (Zim98).
           With respect to the respiratory tract, the sensory irritation in the upper part
      was studied by determining the concentration associated with a 50% decrease in
      respiratory rate (RD50). After exposing male Swiss Webster mice (n=4/group) to
      vapour concentrations between 1.9 and 5.1 ppm (18-47 mg/m3) for 30 minutes,
      an RD50 for sensory irritation of 3.6 ppm (33 mg/m3) was calculated. None of the
      mice exhibited breathing patterns of pulmonary irritation (Sta97).
      Acute toxicity
      Results of acute lethal toxicity studies of BHT are summarised in Table 1.
      Table1 Summary of acute lethal toxicity studies of BHT in experimental animals.
      exposure              species (sex)                LD50 (mg/kg bw)     reference
      oral                  rat (male)                   1700                Dei55
                            rat (female)                 1970                Dei55
                            rat (male)                   1906                BUA94
                            rat (female)                 2255                BUA94
                            rat (male, female)           >10,000a            Spa78
                            rat (male, female)           2450                Kar59
                            rat                          2250                LSR73
                            rat                          5800                BUA94
                            mouse (male)                 1040                McO49
                            mouse                        1800                LSR73
                            mouse                        1350                BUA94
                            mouse                        2000                Kar59
                            rabbit                       2100-3200b          Dei55
                            rabbit                       3200                LSR73
                            guinea pig                   10,700b             Dei55
                            cat                          940-2100b           Dei55
      intravenous           mouse                        180                 NIO03
      intraperitoneal       rat                          8000                BUA94
                            mouse (male)                 138-3550c           Kaw81, Yam80
      a
           By gavage as 33% suspension in propylene glycol.
      b
           Approximate lethal dose.
      c
           Depending on mouse strain.
      The intraperitoneal LD50s for BHT showed considerable strain-dependent
      differences among (male) mice.
           At high doses, symptoms of poisoning were salivation, miosis, excitation,
      tremor, and signs of paralysis. Toxic signs before death included reduced body
101-8 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>      weight, breathing difficulties, coma, and enlarged lungs with pulmonary oedema
      and haemorrhages (BUA94).
          The effect of single oral dose of BHT on blood coagulation factors II
      (prothrombin), VII, IX, and X was studied in Sprague-Dawley rats, given 200,
      400, or 800 mg/kg bw. At 800 mg/kg bw, levels of coagulation factors II, VII,
      and X were reduced 48 hours after treatment (NOAEL: 400 mg/kg bw). Factor
      IX decreased in a dose-dependent fashion (Tak87). According to the committee,
      this indicates that the haemorrhages observed at high doses of BHT, leading to
      mortality, are due to inhibition of blood coagulation.
          In mice, a single intraperitoneal dose of BHT of 400 mg/kg bw caused
      pulmonary alveolar cells Type I necrosis and proliferation of alveolar cells Type
      II (Ada77). BHT-induced lung damage is associated with increased lung weight
      and biochemical changes, such as increases in DNA, RNA, and protein synthesis
      (Sah75), cyclic GMP levels (Kuo78), and protein phosphorylation (Mal79). Four
      strains of mice, with intraperitoneal LD50s ranging from 350-1700 mg/kg bw,
      developed similar levels of lung injury at equivalent doses, but no correlation
      could be made between lung injury and lethality (Keh90).
          Sprague-Dawley rats, given a single oral (gavage) dose of BHT of 500 mg/kg
      bw, did not show changes in serum levels of liver enzymes (ALAT, ASAT,
      alkaline phosphatase, or LDH) and of albumin. A slight reduction in the
      concentration of clotting factor IX was observed. There was no evidence of
      hepatocellular necrosis. However, mitotic activity of hepatocytes was increased,
      as well as hepatic epoxide hydrolase, ethoxyresorufin-O-deethylase (EROD),
      and ethoxycoumarin-O-deethylase (ECOD) enzyme activities, indicating hepatic
      enzyme induction (Pow91). When male F344 rats were given a single oral dose
      of 1000 mg BHT/kg bw, both renal injury (as demonstrated by proteinuria and
      enzymuria) and liver injury were observed. More marked effects were seen in
      rats pre-treated with phenobarbital (Nak88).
      Short-term toxicity
      In a dermal study, CD1 mice (n=10/sex/group) received 3 applications per week
      of 0.1% DMSO solutions containing 0, 5, 10, 20, 30 mg BHT, corresponding to
      BHT doses of 0, 140, 289, 678, or 867 mg/kg bw/day for males and 0, 208, 415,
      830, and 1245 mg/kg bw/day for females, for 4 weeks. Clinical signs were
      respiratory distress, lethargy, and weight loss, which started after the second
      application in male and female animals of the 20- and 30-mg groups and after the
      third application in most of the females of the 10-mg group and in one male and
      female of the remaining groups. A dose-related increased mortality occurred
101-9 2,6-Di-tert-butyl-p-cresol
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<pre>       mostly between the 4th and 8th day in 0/10, 1/10, 7/10, 8/10 males and 1/10,
       9/10, 10/10, and 10/10 females of the 5-, 10-, 20-, and 30-mg group, respectively.
       Macroscopic and microscopic examination showed congestion and enlargement
       of the lung and damage of alveolar type I-cells. The NOAEL for males was 140
       mg/kg bw/day and the LOAEL for females 208 mg/kg bw/day, the lowest dose
       tested. In a similar study in male and female rats and male hamsters, at dose
       levels of about 2000, 2300, and 3100 mg/kg bw/day, respectively, only slight
       growth retardation in male rats and hamsters was observed. At post-mortem
       gross and microscopic examinations, there were no remarkable treatment-related
       changes (Miy86).
       Groups of male Wistar rats were given oral (gavage) doses of BHT of 0, 25, 250,
       500 mg/kg bw/day (n=10/group) for 28 days. At the high dose, progressive
       periportal hepatocyte necrosis of the liver was observed and at 500 and 250
       mg/kg bw, a dose-related hepatomegaly. The NOAEL for liver injury was 25 mg/
       kg bw/day. Biochemical changes consisted of dose-related induction of epoxide
       hydrolase and reduction of glucose-6-phosphatase activity. BHT accumulated in
       fat in a dose-dependent fashion, but not in the liver (Pow86).
            In an old (1961) oral study, rats (n=3/sex/group) were given BHT via the diet,
       containing a 20% lard supplement, at doses equivalent to approximately 0, 50,
       100, 150, 200, or 250 mg/kg bw/day, for 6 weeks. At 150 mg/kg bw/day and
       above, a reduced growth rate was observed and at 100 mg/kg bw/day and above,
       the absolute and relative liver weights were increased in both sexes and the
       relative adrenal weight in males. Microscopic examination did not show
       abnormalities. A dose-related increase in cholesterol levels was observed at all
       dose levels. The NOAEL for increased liver weight was 50 mg/kg bw/day
       (FAO96).
            In a more recent study, groups of F344 rats (n=5/sex/group) were fed BHT
       via the diet at dose levels equivalent to approximately 310, 625, 1250, or 2500
       mg/kg bw/day, for 7 weeks. All animals in the high-dose group and one animal in
       the 1250 mg/kg bw group died. A dose-related decrease in body weight was
       observed, with animals in the 1250 mg/kg bw group weighing only 38 to 44% of
       control values. At this dose, a slight increase in haematopoiesis was also
       observed in both sexes. The LOAEL for reduced body weight was 310 mg/kg
       bw/day (NCI79).
            Groups of male ddY mice (n=10/group) were given BHT via the food at
       levels equivalent to 0, 1570, 1980, 2630, 3370, 4980, or 5470 mg/kg bw/day, for
       30 days. Body weights and absolute kidney weights were decreased and relative
       kidney weights increased in a dose-related fashion. Microscopic examination
101-10 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>       revealed a dose-related increase in toxic nephrosis, as indicated by tubular
       degeneration, necrosis dilatation, and cysts. No treatment-related changes were
       observed in the liver. The LOAEL for renal lesions and body weight reduction
       was 1570 mg/kg bw/day (Tak92).
            B6C3F1 mice (n=5/sex/group), given doses equivalent to approximately 465,
       930, 1875, 3750, or 7500 mg/kg bw/day for 7 weeks, showed dose-related
       mortality at the 2 high-dose levels and a dose-related decrease in body weight at
       all dose levels. Microscopic examination revealed vacuolisation of hepatocytes
       in animals at 3750 mg/kg bw/day. The NOAEL was 1875 mg/kg bw/day
       (NCI79).
            In another study, groups of B6C3F1 mice (n=10/sex/group) were given BHT
       at dietary doses equivalent to approximately 375, 750, 1500, 3000, or 6000
       mg/kg bw/day, for 10 weeks. In the high-dose group animals, body weight gain
       was significantly reduced. Microscopic examination revealed atrophy of the
       spleen, heart, and kidneys. No liver or lung damage was found. The NOAEL was
       3000 mg/kg bw/day (Ina88).
            Groups of C3H mice (n=26-46/sex/group) were given BHT via the diet at
       doses equivalent to 0, 39, or 390 mg/kg bw/day, for 10 months. Treatment-
       related decreases in body weights were seen at both levels. In males, a
       significantly increased incidence of hepatocellular adenomas was found in
       treated groups compared with controls, which was more pronounced at the low
       dose. No significant differences in lung tumours were found between treated and
       control groups (Lin86). A group of 18 male BALB/C mice, given BHT at a
       dietary level equivalent to 1125 mg/kg bw/day for 12 months, developed
       hyperplasia of the hepatic bile ducts with an associated subacute cholangitis
       (Cla73).
            Administration of 50 or 500 mg/kg bw BHT by gastric intubation to rhesus
       monkeys for 4 weeks produced no increase in liver weight or liver DNA, RNA,
       or protein content. The hepatocytes of monkeys given the high dose showed
       moderate proliferation of smooth endoplasmatic reticulum. Biochemically, an
       induction of the liver enzyme p-nitroanisole-O-demethylase was observed,
       which increased with time. No abnormalities were observed in clinical chemical
       liver function or electrolyte tests, in haematology, or in microscopic examination
       of other organs than the liver (All72).
            Feeding BHT to mice and rats also resulted in an increased activity of liver
       enzymes and increased liver weights. For example, giving BHT to female Wistar
       rats via the diet at doses equivalent to approximately 5, 50, 500, or 2500 mg/kg
       bw/day for 28 days, produced a dose-related increase in smooth endoplasmatic
       reticulum in hepatocytes and of liver aminopyrine demethylase activity, which
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<pre>       returned to normal within 10-20 days after discontinuation of BHT dosing. The
       NOAEL was 5 mg/kg bw/day (Bot70). Other studies showed increased activities
       in hepatic microsomal epoxide hydrolyse and glutathione-S-transferase in BHT-
       treated Swiss mice (Ham83) or in activities of hepatic microsomal biphenyl-4-
       hydroxylase (Cre66, Lak76), cytochrome P-450 (Bur72), ethyl morphine N-
       demethylase (Lak76), and glutathione-S-transferase (Par82) in BHT-treated rats.
       In a more recent study, Wistar rats given a dietary BHT level of approximately
       100 mg/kg bw/day, for 30 days, showed statistically significant increased liver
       weights, hepatic microsomal lipid peroxidase activity, hepatic phospholipids, and
       serum HDL cholesterol, compared to a control group (Yam95).
           Feeding of male ICR mice at approximately 75 or 750 mg/kg bw/day for 12
       months, resulted in statistically significant increased liver weights at the high
       dose, compared with a control group. Other organs were not affected. At both
       dose levels, enhanced activities were observed for intestinal glutathione
       S-transferase and hepatic glutathione peroxidase, while hepatic glutathione
       S-transferase was increased at the high dose only. No changes were observed in
       clinical chemical liver and kidney function tests and in serum cholesterol levels
       (Jan99).
       In several studies, the effects of BHT on blood clotting were investigated.
       Groups of male Sprague Dawley rats (n=10/group) were fed BHT at doses
       equivalent to approximately 450, 525, 600, 750, 900, or 1050 mg/kg bw/day for
       40 days. A dose-related effect on mortality was observed at levels of 525
       mg/kg bw/day or more during the period from 9 to 37 days. Spontaneous
       massive bleeding to the pleural and peritoneal cavities and external haemorrhage
       was observed in all dead animals. The prothrombin index (i.e., the ratio between
       the prothrombin times of control and BHT-treated animals) of surviving animals
       was decreased, dependent on BHT dose. At the lowest dose, the decrease was
       approximately 65% (Tak78a). In a follow-up study, the same strain of rats were
       given dietary levels of 7.5, 14.7, 34.1, 62.5, 129, 227, or 529 mg/kg bw/day of
       BHT for 1 week, or 6.7, 13.4, 29.9, 52.9, 96, 230, or 326 mg/kg bw/day for 4
       weeks. A significant decrease (14%) of the prothrombin index was already seen
       at 14.7 mg/kg bw/day, after one week of BHT administration (p <0.05).
       However, feeding for 4 weeks caused a significant decrease on the prothrombin
       index (21%) at the top dose only (Tak78b).
           Male albino rats given 3 consecutive daily doses of 380, 760, or 1520 mg
       BHT/kg bw/day did not show haemorrhages. However, a dose-related increase in
       prothrombin time (i.e., a decrease in prothrobin index) was observed at the 2
       high-dose levels (Kra84). Male Sprague-Dawley rats receiving approximately
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<pre>       190 mg BHT/kg bw/day for 2 weeks had decreased concentrations of vitamin K
       in the liver and inceased levels in the faeces. It was suggested that the vitamin K
       deficiency induced by BHT might be due to effects of BHT on absorption and
       excretion of vitamin K (Suz83). This was further investigated in a study, in
       which groups of Sprague-Dawley rats were given BHT at a dose of
       approximately 1000 mg/kg bw/day for 1 to 7 days. Vitamin K-dependent
       coagulation factors II (prothrombin), VII, VIII, IX, and X were significantly
       reduced in a time-dependent fashion when BHT was administered for 2 to 7
       days. Haemorrhages occurred in epididymis of rats given BHT for 4 to 7 days
       (Tak86).
            In another study, the effect of BHT on blood coagulation was investigated in
       rats, receiving BHT in vitamin K-sufficient and vitamin K-supplemented diets.
       Dosing of 3000 mg/kg bw/day for up to 21 days in a diet containing a minimum
       of 3 ppm vitamin K3 caused decreased levels of individual vitamin K-dependent
       clotting factors but had no effect on overall prothrombin time (involving factors
       II, V, VII, X, and fibrinogen). The effects on individual vitamin K-dependent
       clotting factors were prevented if rats were given BHT (3000 mg/kg bw/day) in
       diets supplemented with a further 250 ppm vitamin K3. In another 28-day
       experiment, the prothrombin time, measured with a more sensitive thrombotest,
       was prolonged in rats receiving 600 mg BHT/kg bw/day via the diet, containing
       3 ppm vitamin K3. No effect on prothrombin time was measured at BHT doses of
       12.5 or 125 mg/kg bw/day. The effect at 600 mg/kg bw/day was prevented by
       concurrent dietary supplementation with a further 3 ppm vitamin K3. The
       NOAEL for effects on vitamin K-dependent blood clotting factors, in rats given
       diets supplied with recommended amounts of vitamin K, was 125 mg/kg bw/day
       (Cot94).
            In a study to investigate the strain and species dependency of haemorrhages
       following BHT feeding, a number of strains of rats of both sexes (Sprague-
       Dawley, Wistar, Fischer), male mice (ICR, ddY, C3H/He, BALB/CaAn,
       C57BL/6), male New Zealand White rabbits, and male Beagle dogs were fed
       BHT at doses up to 1120 mg/kg bw/day for 3 weeks (rats), 1925 mg/kg bw/day
       for 1 week (mice), 390 mg/kg bw/day for 2 weeks (rabbits), and 760 mg/kg bw/
       day for 2 weeks (dogs). Male guinea pigs and male golden hamsters received
       intraperitoneal injections of up to 380 mg/kg bw/day and 760 mg/kg bw/day,
       respectively, for 3 days. Haemorrhagic deaths occurred among male rats of all
       strains and in female rats of the Fischer strain. Epididymal haemorrhages were
       observed in ddY mice and cerebral haemorrhages in some guinea pigs. No
       effects were noted in the other species. The prothrombin index was significantly
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<pre>             reduced in all strains of rats (both sexes) and mice (except ICR strain) but no
             significant changes were noted in the other species (Tak80).
                  In another study, haemorrhagic deaths were not observed in ddY male mice
             given BHT via the diet at levels ranging from 1570 to 5470 mg/kg bw/day for 30
             days or in guinea pigs fed 85 to 660 mg/kg bw/day for 14 to17 days. Prothrombin
             times were significantly increased in mice only, probably because of liver
             damage rather than by interference of BHT or a metabolite with vitamin K
             (Tak92).
             The results of the above short-term toxicity studies are summarised in Table 2.
Table 2 Summary of short-term toxicity studies of BHT.
exposure species (strain)         dose levels          exposure  critical effect        NOAEL          reference
route                             (mg/kg bw/day)       duration                         (mg/kg bw/day)
dermal mouse (CD1)                140-867 (males)      4 weeks   lung injury            140 (males)    Miy86
                                  208-1245 (females)                                    LOAEL: 208
                                                                                        (females)
         hamster                  2000 (males)         4 weeks   not identified         2000 (males)   Miy86
                                  2300 (females)                                        2300 (females)
oral     rat (Wistar)             0-500                4 weeks   liver injury           25             Pow86
         rat (Wistar)             0-2500               4 weeks   liver enzyme induction 5              Bot70
         rat (Wistar)             0-100                4 weeks   liver weight           LOAEL: 100     Yam95
         rat (not given)          0-150                6 weeks   liver weight           50             FAO96
         rat (F344)               0-2500               7 weeks   body weight            LOAEL: 310     NCI79
         rat (Sprague-Dawley)     0-1050               40 days   blood coagulation      LOAEL: 450     Tak78a
         rat (Sprague-Dawley)     7.5-529              7 days    blood coagulation      7.5            Tak78b
         rat (Sprague-Dawley)     6.7-326              4 weeks   blood coagulation      230            Tak78b
         rat (Sprague-Dawley)     0-600                4 weeks   blood coagulation      125            Cot94
         monkey (rhesus)          0-500                4 weeks   liver enzyme induction 50             All72
         mouse (ddY)              0-5470               4 weeks   renal injury           LOAEL: 1570    Tak92
         mouse (B6C3F1)           0-7500               7 weeks   liver injury           1875           NCI79
         mouse (B6C3F1)           375-6000             10 weeks  body weight            3000           Ina88
         mouse (C3H)              0-390                10 months body weight            LOAEL: 39      Lin86
         mouse (BALB/C)           1125                 12 months liver injury           LOAEL: 1125    Cla73
         mouse (ICR)              0-750                12 months liver enzyme induction LOAEL: 75      Jan99
         mouse (ddY)              0-5470               4 weeks   blood coagulation      LOAEL: 1570    Tak92
         dog (Beagle)             0-760                2 weeks   blood coagulation      760            Tak80
         guinea pig               0-2000               2 weeks   blood coagulation      660            Tak92
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<pre>       Long-term toxicity and carcinogenicity
       Groups of Fischer 344 rats (n=50/sex/group; controls: n=20/sex) were given
       BHT (purity: 99.9%) at dietary doses equivalent to 0, 150, or 300 mg/kg bw/day,
       for 105 weeks. There was no significant treatment-related effect of BHT on
       mortality, but body weights were decreased at both dose levels. Gross and
       microscopic examination of organs did not show statistical significant increases
       in the incidence of any tumour when compared to controls. In female rats, there
       was a dose-related statistically significant decrease in the incidence of adenomas
       of the pituitary. Apart from an increased incidence in focal alveolar hystiocytosis
       in the female animals of the low- and high-dose group (12/48 and 21/48,
       respectively, vs. 2/18 in controls), no (possibly) treatment-related non-neoplastic
       lesions were found in any of the groups. The LOAEL was 150 mg/kg bw, based
       on reduced body weight (NCI79).
           In another study, Wistar rats (n=57/sex/group) were given BHT (purity: not
       specifed) via the diet at doses equivalent to 0, 125, or 500 mg/kg bw/day, for 104
       weeks. At termination of the study, 65% of the control and >72% of treated rats
       were still alive. Treatment-related effects were a decrease in body weight gain at
       the high dose, increases in absolute and relative liver weights in animals of both
       groups, and increased GGT levels in males of both groups. Gross and
       microscopic examination showed a statistically significant increased incidence
       of pituitary adenomas in the low-dose, but not in high-dose female animals (6/46
       and 3/51, respectively, vs. 0/32 in controls). Since this effect was not dose-
       related, Hirose et al. concluded that the tumours observed did not seem to be
       induced by BHT treatment. The LOAEL was 125 mg/kg bw/day (Hir81).
           Groups of male F344 rats (n=21/group; controls: n=36) were fed BHT
       (purity: not specified) at doses equivalent to 0, 7.7, 23, 75, 225, or 450
       mg/kg bw/day for 76 weeks. In a second experiment, 27 animals received 900
       mg/kg bw/day for 110 weeks. At 225 mg/kg bw/day and above, body weights
       were decreased and at 450 mg/kg bw/day, absolute and relative liver weights
       were increased compared with controls. Gross and microscopic examination
       revealed a decreased incidence of pre-neoplastic liver foci in rats receiving 900
       mg/kg bw/day. Hepatocellular adenomas were found in all groups, with no
       treatment-related trend in incidence. No statistically signicant differences were
       found in the incidence of grossly observable tumours in specific organs. The
       NOAEL was 75 mg/kg bw/day (Wil90b).
           In a 2-generation long-term toxicity study, groups of Wistar SPF rats (n=40-
       60/sex/group) were given BHT (purity:>99.5%) via the diet at doses equivalent
       to 0, 25, 100, or 500 mg/kg bw/day for 13 weeks, after which time the males and
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<pre>       females within each group were mated. Females were maintained on treatment
       throughout pregnancy and the lactation period (see Section ‘Reproduction
       toxicity’). Groups of offspring (F1) of each sex (n=80-100/sex/group) were
       continued on the same treatment, except that the high-dose level was reduced to
       250 mg/kg bw/day, due to renal toxicity in the parents. The dosing was
       terminated when the progenies were 141-144 weeks of age. There was dose-
       related increase in survival in all treated groups. At 2 years of age, survival rates
       in the high-dose group were 86% in both male and female rats vs. 70 and 69% in
       male and female controls, respectively; at study termination, these figures were
       44 and 39% for high-dose males and females, respectively, vs. 16 and 17% in the
       corresponding control groups. Body weights were reduced in all treated groups
       in a dose-related fashion. No changes were observed in haematological
       parameters. Microscopic examination revealed increased incidences of liver
       adenomas (males: 1/80, 5/80, and 18/99 in low-, mid-, and high-dose group,
       controls: 1/100; females: 3/79, 6/80, and 12/99, respectively, vs. 2/100) and
       carcinomas (males: 0/80, 1/80, and 8/80, respectively, vs. 1/100; females: 0/79,
       0/80, and 2/99, respectively, vs. 0/100). The first adenoma and carcinoma in
       treated animals were seen in high-dose males at week 115 and week 132,
       respectively, while all carcinomas and most of the adenomas were found at
       termination. In the high-dose males, there was also one
       haemangioendotheliosarcoma. Non-neoplastic lesions included a dose-related
       increased incidence of bile duct proliferation and cysts in males and focal
       cellular enlargement in females. The LOAEL was 25 mg/kg bw/day, based on
       body weight loss. The NOAEL for liver carcinomas was 100 mg/kg bw/day
       (Ols86). The committee is of the opinion that, due to the large differences in
       survival time between treatment and control groups, it is difficult to draw
       conclusions about the significance of the observed tumour incidences of the liver
       in the treated groups.
           Groups of BALB/c mice (n=100 males, 50 females) were given dietary doses
       of BHT equivalent to 0 or 1125 mg/kg bw/day, for 18 months. Mortality was low
       in both groups (>90% survived the end of the study). No difference was observed
       in the incidence of lung tumours or reticulum cell sarcomas between treated and
       control mice. No liver tumour, thymic lymphoma, myeloid leukaemia, or tumour
       of the forestomach was seen in BHT-treated mice (Cla78).
           In another study, groups of B6C3F1 mice (n=50/sex/group; controls:
       n=20/sex) received BHT (purity: 99.9%) via the diet at doses equivalent to 450
       or 900 mg/kg bw/day, for 107 or 108 weeks. Dose-related decreases in mortality
       and body weight were observed. Statistically significant increases in the
       incidence of alveolar/bronchiolar adenomas or carcinomas were found in
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<pre>       females of the low-dose, but not of the high-dose group (16/46 and 7/50,
       respectively, vs. 1/20 in controls). No differences in the incidence of any other
       tumour were seen between treated and control groups. Significant non-neoplastic
       effects comprised dose-related increases in hepatocytomegaly, peliosis, cellular
       degeneration, and cytoplasmic vacuolation of the liver in male rats (NCI79).
           Groups of B6C3F1 mice (n=50-52/sex/group) were given BHT (purity: not
       specified) via the diet at dose levels equivalent to 0, 30, 150, or 750
       mg/kg bw/day, for 96 weeks, and were maintained on basal diet for a further 8
       weeks. Survival at termination of the study was >60% in all groups. Body
       weights of females in the mid- and high-dose groups and of males in the
       high-dose group were lower than controls. At the high dose, serum ALAT and
       ASAT were increased, but no other compound-related effects were observed in
       the haematological and biochemical analysis in serum and urine or in gross or
       microscopic examination of organs. There were no statistically significant
       differences in the incidence of neoplasmas between BHT-treated and control
       groups (Shi82).
           BHT (purity: not given) was administered to B6C3F1 mice (n=50/sex/group)
       via the diet, at concentrations 0, 1640, or 3480 mg/kg bw/day (males) or 0, 1750,
       or 4130 mg/kg bw/day (females), for 104 weeks, and were maintained on basal
       diet for a further 16 weeks prior to pathological examination. A dose-related
       decrease in body weight was observed in both sexes. Survival at the end of the
       study was increased with dose. In male mice, there was a statistically significant
       dose-related increase in hepatocellular adenomas and in foci of altered
       hepatocytes. The incidence of hepatocellular carcinomas was not statistically
       significantly different between treated and control groups (Ina88).
       The results of the above long-term toxicity studies are summarised in Table 3.
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<pre>Table 3 Summary of long-term oral toxicity studies of BHT.
species (strain)          dose levels            exposure duration     critical effect NOAEL          reference
                          (mg/kg bw/day)                                               (mg/kg bw/day)
rat (F344)                0-300                  105 weeks             body weight     LOAEL: 150     NCI79
rat (Wistar)              0-500                  104 weeks             liver weight    LOAEL: 125     Hir81
rat (F344)                0-900                  110 weeks             body weight     75             Wil90b
rat (Wistar)a             0-250                  144 weeks             body weight     LOAEL: 25      Ols86
mouse (BALB/c)            0, 1125                18 months             tumours         1125           Cla78
mouse (B6C3F1)            0-900                  107 weeks             liver injury    LOAEL: 450     NCI79
mouse (B6C3F1)            0-750                  96 weeksb             body weight     30             Shi82
mouse (B6C3F1)            0-3480 (males)         104 weeksc            liver injury    LOAEL: 1640    Ina88
                          0-4130 (females)
a
     Second generation of a 2-genereation reproduction toxicity study.
b
     Followed by an 8-week exposure-free period.
c
     Followed by a 16-week exposure-free period.
              BHT was studied in mice and rats for its ability to modify the carcinogenicity of
              selected chemical agents. When administered with known carcinogens, BHT
              enhanced, inhibited, or had no effect on carcinogenicity (IARC86). In a range of
              studies, it was demonstrated that BHT administration before or simultaneously
              with the carcinogen evidently had a protective influence, whereas a subsequent
              BHT administration had a promoting effect (IARC86, BUA94, FAO96).
              Mutagenicity and genotoxicity
              Mutagenicity assays comprised tests for the detection of gene mutations in
              bacteria (in vitro and host-mediated assays), mammalian cells, and Drosophila
              (in vitro) and for cytogenicity in mammalian cells (in vitro and in vivo), e.g.,
              sister chromatid exchanges (SCE), structural chromosomal effects (chromosome
              aberrations and micronucleus formation), numerical chromosome effects
              (polyploidy), and dominant lethal mutations (in vivo), and other genotoxicity
              assays, e.g., tests for DNA damage/repair (in vitro) and DNA binding (in vivo).
              •   In vitro tests:
                  • Gene mutation assays. Tests for reverse mutations in several strains of S.
                      typhimurium (TA97, TA98, TA100, TA102, TA104, TA1535, TA1537,
                      TA1538), and E. coli were negative when tested at concentrations up to 10
                      mg/plate, in the absence or presence of a rat liver S9 metabolic activation
                      system (Bru75, Det93, Hag88, Kin81, Wil90a, Yos90).
                      BHT was negative in a host-mediated assay in mice, given BHT as single
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<pre>              oral doses of 30, 900, or 1400 mg/kg bw or as repeated doses of 30, 250,
              or 500 mg/kg bw/day, for 5 days, using S. typhimurium G46 and TA1530
              as markers (Bom02, BUA94, FAO96).
              BHT did not induce gene mutations in the HPRT forward mutation assay
              in cultured rat liver epithelial cell lines at 60-90 µg/mL, in the absence of
              a metabolic activation system (Wil90a). However, positive results were
              obtained in the HPRT assay in cultured V79 Chinese hamster cells and in
              the TK+/- assay in cultured L5178Y mouse lymphoma cells but only after
              metabolic activation at (slightly) cytotoxic concentrations (Pas84,
              McG88).
              BHT did not induce sex-linked recessive lethal mutations in D.
              melanogaster (Pra74, Maz83, San83).
           • Cytogenicity assays. BHT did not induce SCEs or chromosome
              aberrations in several studies using various cultured Chinese hamster cell
              lines (ovary, lung, DON, V79) (Bom92, BUA94). However, in the
              absence of metabolic activation, a dose-related increase in the frequency
              of chromosome aberrations was observed in cultured human WI-38
              embryonic lung cells at concentrations ranging from 2.5 to 250 µg/mL
              (Bom02, FAO96) and induction of polyploidy in CHO cells at BHT
              concentrations 5 and 10 µg/mL (Pat87).
           • Other assays. BHT gave a positive result in one, modified, B. subtilus
              rec+/- assay while negative results were obtained in 5 other rec-assays
              performed using standard conditions (Bom02). BHT was negative in the
              umu test in S. typhimurium strain TA1535/pSK1002 at concentrations up
              to 1320 µg/mL (Hei96) and in the SOS chromotest in E. coli strain PQ37
              (Bom02, BUA94).
              BHT did not affect the mitotic recombination frequency in S. cerevisiae
              strain D4 or in a host-mediated assay in ICR Swiss mice using S.
              cerevisiae strain D3 at single oral doses of 30, 900, or 1400 mg/kg bw or 5
              daily doses of 30, 250, or 500 mg/kg bw (Bom02, BUA94, FAO96).
              In cultured rat hepatocytes, BHT did not induce DNA repair synthesis at
              concentrations ranging from 0.01 and 10 µg/mL (Wil90a). BHT caused
              inhibition of replicative DNA synthesis in cultured human HeLa S3 cells,
              when tested at concentrations ranging from 333 to 1320 µg/mL (Hei96).
       •   In vivo tests:
           Dominant lethal mutations were not induced when male ICR Swiss mice
           were given a single intraperitoneal injection of 250-2000 mg BHT/kg bw and
           mated for 8 successive weeks (Eps72). Negative results were also found in
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<pre>           mice treated with BHT via the food for 8 weeks, at a level equivalent to 1500
           mg/kg bw/day (She86). In Sprague-Dawley rats, BHT did not induce
           dominant lethal mutations following single doses of 30, 900, or 1400
           mg/kg bw by gavage, but positive results were obtained following repeated
           doses of 30 or 500, but not 250 mg/kg bw/day, for 5 days (Bru75). Similar
           positive results were obtained in another study, in which male Sprague-
           Dawley rats were given 50, 150, or 500 mg/kg bw/day via the diet for 10
           weeks, before mating (She86). The outcome of these studies was considered
           to be positive based on an increased number of dead implants. However,
           according to current guidelines, results should be evaluated based on
           comparison of the number of live implants in treated and control animals
           (and not of death implants). Since no differences in the number of live
           implants were noted between exposed and control groups, the committee
           considers these studies to be negative.
           BHT did not induce an increased incidence in micronuclei in bone marrow of
           male and in female mice after a single intraperitoneal injection of 75 mg/kg
           bw (Pas86) or in female mice, following repeated intraperitoneal doses of 50-
           1000 mg/kg bw/day, for 5 days (Bru79). In rats, given BHT at single doses of
           30, 900, or 1400 mg/kg bw or repeated (5 days) oral doses of 30, 250, or 500
           mg/kg bw, no increased incidence of micronuclei in bone marrow cells was
           observed (Bom02, FAO96). No clastogenic effects were noted in bone
           marrow of mice (ICR) or rats (Wistar, Sprague-Dawley), given BHT in the
           diet at doses equivalent to 2000 and 750 mg/kg bw/day, respectively, for 9
           months (Bom02).
           Changes in migration patterns of DNA in the alkaline comet assay, indicative
           of DNA damage, were demonstrated in the glandular stomach (at 500 and
           1000 mg/kg bw), the colon (at 100, 500, 1000 mg/kg bw), the bladder (at
           500, 1000 mg/kg bw), and the brain (at 1000 mg/kg bw) obtained from male
           ddY mice (n=4/group) 3 hours after single oral doses of 0, 10, 100, 500, or
           1000 mg/kg bw. In samples obtained 24 hours after dosing, a ‘positive’ effect
           was seen in only in the stomach of mice given 1000 mg/kg bw. There were no
           effects in the lungs, liver, kidneys, and bone marrow (Sas02). Following oral
           (gavage) administration of 5 mg 14C-BHT to male Wistar rats, relatively
           small amounts of radioactivity were bound to liver DNA but adduct
           formation/identification was not addressed (Nak80).
       In summary, the majority of tests showed no evidence for BHT to induce gene
       mutations or other genotoxic effects.
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<pre>       Reproduction toxicity
       Following repeated intraperitoneal doses of 50-1000 mg/kg bw/day, for 5 days,
       sperm abnormalities were observed in mice, 40 days after the last injection of
       doses of 250 mg/kg bw/day and above (Bru79).
       In a 2-generation reproduction study, groups of Wistar albino rats (n=16 females
       and 2 males/group) were given BHT (purity: >99.5%) via the diet at doses
       equivalent to 0, 500, 750, or 1000 mg/kg bw/day for 5 weeks, after which time
       the males and females within each group were mated. Females were maintained
       on treatment throughout pregnancy and the lactation period. At weaning (21 days
       after birth), 14 pups from each dose group received control diet for 4 weeks. At
       the end of the lactation period, body weights of dams were significantly reduced
       at the 2 higher doses. Absolute and relative liver weights were significantly
       increased at all dose levels. Livers of dams treated with BHT at 750 and 1000
       mg/kg bw/day showed hypertrophy, proliferation of the smooth endoplasmatic
       reticulum, and proliferation of the bile duct. No microscopic changes were yet
       seen in livers at day 19 or 20 of gestation. In F1 offspring, there were no
       differences in the litter or pup weight, number of pups per litter born, or number
       of pups born dead or dying within 4 days between treated and control rats. No
       developmental abnormalities were observed in any of the pups. At weaning, pups
       showed significant, dose-related body and absolute liver weights at all dose
       levels, which persisted until the end of the experiment, 4 weeks after weaning.
       The LOAEL for both maternal and reproduction toxicity was 500 mg/kg bw/day
       (McF97).
            In a second experiment, the same authors studied the development of liver
       changes in the parental (F0) and F1generation of rats, treated under a regimen
       identical to that producing tumours in the study of Olsen et al. (see ‘Long-term
       toxicity and carcinogenicity’). Groups of Wistar albino rats (n=50 females and 7
       males/group) were given BHT (purity: >99.5%) via the diet at doses equivalent
       to 0, 25, 100, or 500 mg/kg bw/day for 5 weeks, after which time the males and
       females within each group were mated. Females were maintained on treatment
       throughout pregnancy and lactation. In addition, 5 non-pregnant female animals
       were treated with 0 or 500 mg/kg bw/day, in parallel with lactating dams. Groups
       of F1 offspring were continued on the same treatment at weaning, except that the
       high-dose level was reduced to 250 mg/kg bw/day. The study was terminated at
       week 22 post-weaning (25 weeks after birth). Maternal body weights during
       pregnancy and lactation were not significantly different in BHT-treated animals
       compared with untreated controls. No changes were observed in fertility index,
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<pre>       resorption sites per dam, number of fetuses per dam, number of pups per litter
       born, and pup weight between treated and control rats. Dams sacrificed on days
       19 or 20 of gestation did not show significant increased absolute or relative liver
       weights. At day 21 of lactation, dams and non-lactating rats, treated with 500
       mg BHT/kg bw, had significant increased absolute and relative liver weights
       compared to controls. Microscopic examination of livers of dams revealed
       centrilobular liver enlargement in rats receiving 100 and 500 mg/kg bw/day and
       proliferation of smooth endoplasmatic reticulum at 500 mg/kg bw/day. At 100
       mg/kg bw/day and above, there was evidence of hyperactivity of the thyroids in
       some of the animals. Biochemical analyses were conducted on livers of lactating
       and non-lactating rats treated with 500 mg BHT/kg bw/day and of corresponding
       controls. BHT-treated rats showed decreased glucose-6-phosphatase (G-6-PP)
       activity (p<0.05 in lactating animals), decreased glutathione (GSH) levels
       (lactating animals only; p<0.05), and increased glutathione-S- transferase (GST)
       activity (p<0.05). Of the liver enzymes involved in the metabolism of
       xenobiotics, the activities of cytochrome P450 (CYP450) (p<0.05 in non-
       lactating animals) and pentoxyresorufin-O-depentylase (PROD) (p<0.001) were
       increased, but the activity of ethoxyresorufin-O-deethylase (EROD) was
       decreased (p<0.05 in lactating animals). In F1 offspring of BHT-treated rats, no
       differences were observed in number of pups dying within 4 days after birth,
       compared with controls. Dose-related decreased body weights were observed at
       weaning (p<0.05 at 250 mg/kg bw/day), 4 weeks after weaning (p<0.05 at 100
       and 250 mg/kg bw/day), and 22 weeks after weaning (p<0.05, at 250
       mg/kg bw/day). At all time points, absolute liver weights remained unchanged in
       BHT-treated animals compared with controls. Biochemical analyses were
       conducted on livers from fetuses (delivered on day 19 or 20 of gestation) and
       from pups at weaning and at 4 and 22 weeks after weaning. A dose-related
       decrease in G-6-PP activity was observed at all 4 time points, which coincided
       with the decreases in body weight in BHT-treated animals. GSH concentrations
       were significantly reduced in pups treated with 250 mg/kg bw/day, 4 and 22
       weeks after weaning. GST activities were increased in a dose-related fashion at
       weaning and 4 and 22 weeks after weaning. Of xenobiotic metabolising
       enzymes, CYP450 activity was increased (p<0.05) at 22 weeks after weaning in
       pups treated with 250 mg
       BHT/kg bw/day. EROD activity was significantly increased at weaning and at 22
       post-weaning (at 100 and 200 mg/kg bw/day), and at 4 weeks post-weaning (at
       25, 100, and 250 mg/kg bw/day). Benzphetamine N-demethylase activity was
       significantly increased at weaning only and epoxide hydrolase at weaning and at
       4 and 22 weeks after weaning, at the high-dose level only. Microscopic
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<pre>       examination showed proliferation of the smooth endoplasmatic reticulum of
       livers of pups treated with 250 mg/kg bw/day. No other significant changes of the
       liver were observed. Of the other tissues, mild hyperactivity of the thyroid was
       observed at doses of 100 and 250 mg/kg bw. The NOAEL for both maternal and
       reproduction toxicity was 25 mg/kg bw. The maternal NOAEL was based on
       microscopic changes of the liver and the reproductive NOAEL on decreased
       body weights, changes in enzyme activities of the liver, and microscopic changes
       of the thyroid. McFarlane et al. concluded that the only major difference between
       exposure to BHT of a single generation or over 2 generations is that pups born to
       dams receiving high doses of BHT (100 mg/kg bw and above) fail to gain weight
       and develop at the same rate as those born to untreated dams. The most likely
       explanation is malnutrition of the pups. According to McFarlane et al., this could
       predispose animals to an increase in incidence of tumours in later life (McF97).
           The committee concluded that at 25 mg/kg bw no effects have been observed
       in rats when exposed in utero and post-natally up to 22 weeks of age.
       Several other studies have been performed, which are summarised in IARC86
       and FAO96. The more recent studies are presented hereunder.
           Groups of Wistar (n=40-60/sex/group) received BHT (purity: >99.5%) via
       the diet at doses equivalent to 0, 25, 100, or 500 mg/kg bw/day, beginning at 13
       weeks before mating. Females were maintained on treatment throughout
       pregnancy and lactation. At 500 mg/kg bw/day, body weights were decreased in
       male and female rats. There were no differences in gestation index, viability
       index at birth, and viability index at the end of lactation between BHT-treated
       and control rats. The litter size, the number of males per litter, and the average
       birth weight of the pups were significantly lower at 100 and 500 mg/kg bw
       compared with the controls. During lactation, pup body weights were
       significantly reduced at all dose levels in a dose-related fashion. The NOAEL for
       maternal toxicity was 100 mg/kg bw, but a NOAEL for reproduction toxicity
       could not be established (Ols86).
           In another study, groups of male and female Wistar SPF rats (n=46/sex/
       group) received 0 or 500 mg/kg bw/day of BHT (purity: not given) via the food
       for 13 weeks before mating and throughout gestation and lactation. Effects of
       treatment were a decrease in body weight and weight gain before and during
       gestation. Length of gestation, number of offspring, and birth weight were
       similar in treated and control animals. Offspring nursed by BHT-treated dams
       had significantly reduced average body weight and weight gain. Pups exposed to
       BHT in utero showed a relatively slower development than control pups, when
       fostered with non-treated mothers. Pups exposed to BHT in utero or during
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<pre>       lactation showed alterations in auditory and visual function and in locomotive
       coordination tests, compared with non-BHT-treated pups. Microscopic
       examination of brain tissue revealed a higher incidence in average number of
       dead cells (Mey80).
           In an earlier experiment, male and female Sprague-Dawley rats were given
       BHT (purity: not given) via the diet at doses equivalent to 625, 1250, or 2500
       mg/kg bw/day, beginning from the week before mating and continuing in
       females through lactation and weaning. Mortality of pups from dams treated with
       1250 or 2500 mg/kg bw/day was significantly higher than controls. Pre-weaning
       pups from high-dose mothers weighed significantly less than controls at ages 7,
       14, and 21 days. Neurobehavioural effects were found in pre-weaning rats at the
       high-dose level only. Post-weaning males in the 1250 mg/kg bw/day dose group
       showed an effect on passive avoidance. No effects on basic motor coordination
       were found in BHT-treated animals. The NOAEL for reproductive and
       behavioural effects was 625 mg/kg bw/day (Bru78).
           In a 3-generation study in mice, groups of Crj:CD-1 mice (n=10/sex/group)
       received BHT via the diet at levels equivalent to 0, 20, 70, 200, or 615
       mg/kg bw/day, starting at 5 weeks of age. At 9 weeks of age, the mice were
       mated for 5 days. The F1 offspring was weaned at 4 weeks of age, and 10
       mice/sex/group were selected for mating at 9 weeks of age. In F1 high-dose pups,
       a decreased body weight was observed during lactation (day 7 to day 21), but no
       body weight differences were noted in the BHT-treated F2 pups compared with
       the controls. No significant effects were noted in reproductive parameters. In the
       F2 males, one of the neurobehavioural tests (180° turn in the open field trial) was
       affected during lactation but this effect was not seen in F1 animals or males and
       not considered of toxicological significance. The NOAELs for reproductive and
       neurobehavioural effects were 200 and 615 mg/kg bw/day, respectively (Tan93).
7      Existing Guidelines
       The current administrative occupational exposure limit (MAC) for BHT in the
       Netherlands is 10 mg/m3, 8-hour TWA.
           Existing occupational exposure limits for BHT in some European countries
       and in the USA are summarised in Annex II.
8      Assessment of health hazard
       Workers can be exposed to BHT through inhalation of dust or aerosol or by
       direct skin contact when handling the compound. No data is available on the
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<pre>       percentage uptake of the compound through the lungs. The dermal absorption of
       BHT in a lipophilic vehicle in guinea pigs was maximally 3% of the applied dose
       within 24 hours after application. Following oral intake, absorption was at least
       75% of the dose in humans, 80-90% in rats, 85% in guinea pigs, and close to
       100% in mice. Following repeated application, BHT will accumulate in the fat
       and, to a lesser extent, in the liver. The half-life of elimination from these tissues
       was 5-15 days in the rat. Metabolism of BHT occurs via 3 main pathways, i.e.,
       oxidation of the 4-methyl group, oxidation of one or both t-butyl moieties, and
       ring oxidation, resulting in a range of breakdown products. The latter pathway
       involves formation of the reactive metabolite butylhydroxytoluene quinone
       methide, which may bind covalently to biomacromolecules in tissues. This
       pathway was demonstrated in rats, but not in humans, where only products of
       oxidation and conjugation of alkyl substituents were identified as urinary
       components. Following a single oral dose, most of the metabolites are excreted
       in the urine and the faeces within 24 hours after application. The committee
       concludes that repeated doses of BHT lead to accumulation in fatty tissues,
       which are cleared within 1-2 weeks without BHT exposure.
           Case studies in humans showed that BHT is mildly irritating to the skin and
       in some cases a skin sensitiser. Incidental oral intake of estimated doses of 4 and
       80 g of BHT did not cause fatalities.
           In experimental animals, BHT was slightly irritating to the skin and the eyes
       of rabbits, but no skin sensitisation was demonstrated in guinea pigs. However,
       BHT vapour was irritating to the lungs of mice, at airborne levels between 17
       and 47 mg/m3 (1.9 and 5.1 ppm). The estimated RD50 for sensory irritation was
       33 mg/m3 (3.6 ppm). No acute lethal inhalation or dermal toxicity studies with
       BHT have been reported. Based on the results of acute oral toxicity studies in
       rats and mice, the committee considers the compound not to present an acute
       health hazard following oral intake. In rats, symptoms of poisoning following
       acute high oral doses were haemorrhages, which are possibly due to inhibition of
       vitamin K-dependent blood coagulation factors II, VII, IX, and X by the
       metabolite BHT-quinone methide. Considerable differences were noted in
       sensitivity between different strains of mice to the acute effects of BHT
       following intraperitoneal injection. According to the committee, this difference
       in sensitivity is due to genetic differences in BHT metabolism.
           Short-term dermal exposure to BHT caused lung damage in mice at levels
       >200 mg/kg bw/day. At oral doses >25 mg/kg bw/day, decreased body weights
       and effects on the liver have been reported in rats and mice as well as renal injury
       in mice. In monkeys, rats, and mice, induction of hepatic enzymes involved in
       the metabolism of xenobiotics was measured, accompanied in rats and mice by
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<pre>       proliferation of the smooth endoplasmatic reticulum and liver enlargement,
       leading to increased liver weights. Oral administration of doses of BHT of 125
       mg/kg bw/day for 28 days to Sprague-Dawley rats, supplied with recommended
       dietary amounts of vitamin K, did not cause effects on blood coagulation.
       Experiments in male and female rats of 3 different strains, male mice of 5
       different strains, male rabbits, and male dogs suggested that these effects were
       species and strain dependent.
           Non-neoplastic effects of long-term exposure to BHT in rats, at doses >75
       mg/kg bw/day, were reduced body weight and increased absolute and relative
       liver weights. In mice, effects were decreased body weights and liver injury at
       doses of 450 mg/kg bw and above.
           In some genotoxicity tests, positive results were obtained, amongst others at
       (slightly) cytotoxic concentrations in the presence of a metabolic activating
       system in mutation assays with cultured mammalian cells. However, since BHT
       was negative in most in vitro and in vivo genotoxicity assays, the committee
       considers BHT not to be a mutagenic/genotoxic compound.
           With regard to carcinogenicity, BHT showed an increased incidence of
       pulmonary tumours in female mice at the lower (450 mg/kg bw/day), but not at
       the higher (900 mg/kg bw/day) dose level. In 3 other studies, there was no
       difference in tumour incidence among treated and control groups. In one study in
       rats, an increased incidence in pituitary adenomas was seen in low-dose (125
       mg/kg bw/day), but not in high-dose (500 mg/kg bw/day) animals. In another rat
       study, hepatocarcinomas were observed following lifetime exposure to 250 mg
       BHT/kg bw/day of a group of rats from dams treated with BHT before mating
       and throughout pregnancy and lactation. The committee is of the opinion that it
       is difficult to draw conclusions about the observed incidence of liver carcinomas
       in the treated group, because of the large differences in survival between
       treatment and control groups. Two other carcinogenicity studies in rats did not
       show differences in tumour incidence among treated and control groups. In view
       of the lack of evidence for mutagenicity or genotoxicity of BHT, the committee
       considers that the carcinogenicity in mice and rats, observed in some of the
       above long-term experiments, is not through genotoxic mechanisms. The
       committee agrees with the conclusion of IARC, that ‘the carcinogenicity of BHT
       to humans could not be evaluated’.
           In reproductive toxicity studies in rats, the most sensitive treatment-related
       effects in offspring were a decrease in body weight and induction of xenobiotic-
       metabolising hepatic enzymes at doses of 100 mg/kg bw/day and above,
       beginning at the lactation period and continuing for at least 22 weeks post-
       weaning. Treatment-related decreased body weights generally occurred at a
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<pre>       lower level in offspring than in dams. Fetotoxicity was observed in one study
       only, at 1250 mg/kg bw and above.
       Based on the above data, the committee concludes that decreases in body weight
       in BHT-treated offspring and hepatic enzyme induction are the most sensitive
       toxic effects in animal studies. These effects have not been demonstrated in
       short- and long-term studies at oral doses of 25 mg/kg bw/day and below, and in
       the key 2-generation reproductive study of Mc Farlane et al. (McF97). The
       committee takes the NOAEL of 25 mg/kg bw/day from this study as a starting
       point in establishing a health-based recommended occupational exposure limit
       (HBROEL). 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 35 mg/kg bw. For the
       extrapolation to a HBROEL, a factor of 4 for allometric scaling from rats to
       humans, based on caloric demand, and an overall factor of 18, covering inter-
       and intraspecies variation and the differences between experimental conditions
       and the exposure pattern of the workers, are applied, resulting in a NAEL for
       humans of 0.5 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 5 mg/m3 is recommended for BHT.
       The committee recommends a health-based occupational exposure limit of 5
       mg/m3 for 2,6-di-tert-butyl-p-cresol, as inhalable dust, as an 8-hour time-
       weighted average (TWA).
       References
ACG99  American Conference of Governmental Industrial Hygienists (ACGIH). 2,6-Di-tert-butyl-p-cresol.
       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: 18.
ACG03b American Conference of Governmental Industrial Hygienists (ACGIH). 2003 TLVs® and BEIs®
       based on the documentation of the Threshold Limit Values for chemical substances and physical
       agents & Biological Exposure Indices. Cincinnati OH, USA: ACGIH®, Inc, 2003: 18.
Ada77  Adamson IYR, Bowden DH, Cote MG, et al. Lung injury induced by butylated hydroxytoluene.
       Cytodynamic and biochemical studies in mice. Lab Invest 1977; 36: 26-32.
101-27 2,6-Di-tert-butyl-p-cresol
</pre>

====================================================================== Einde pagina 27 =================================================================

<br><br>====================================================================== Pagina 28 ======================================================================

<pre>Aka62  Akagi M, Aoki I. Studies on food additives. VI. Metabolism of 2,6-di-tert-butyl-p-cresol (BHT) in a
       rabbit. (1) Determination and paper chromatography of a metabolite. Chem Pharm Bull 1962; 10:
       101-5.
All72  Allen JR, Engblom JF. Ultrastructural and biochemical changes in the liver of monkeys given
       butylated hydroxytoluene and butylated hydroxyanisole. Food Cosmet Toxicol 1972; 10: 769-79.
And97  Anderson JA. Food allergy and intolerance. In: Lieberman P, Anderson JA, ed. Allergic diseases;
       diagnosis and treatment. Totowa, NJ, USA: Humana Press, 1997: 255-74 (Chapter 15).
Ano99  Anonymous. Dutch law on consumer goods.Warenwet. Koninklijke Vermande BV, Lelystad, the
       Netherlands 1999. Levensmiddelen (A-10.1). Warenwetregeling Gebruik van additieven met
       uitzondering van kleurstoffen en zoetstoffen in levensmiddelen. Bijlage III. Additieven die slechts in
       bepaalde eet- en drinkwaren zijn toegelaten. Deel II. antixoydanten.
Arb02  Arbejdstilsynet. Grænseværdier for stoffer og materialer. Copenhagen, Denmark: Arbejdstilsynet,
       2002: 22 (At-vejledning C.0.1).
Bee76  Van Beek L. Primary skin and eye irritation tests with the compound WRT 15 in albino rabbits. Zeist,
       the Netherlands: TNO Nutrition and Food Research, 1976; unpublished study, cited in BUA94.
Bom02  Bomhard EM, Bremmer JN, Herbold BA. Review of the mutagenicity/genotoxicity of butylated
       hydroxytoluene. Mutat Res 2002; 277: 187-200.
Bot70  Botham CM, Conning DM, Hayes J, et al. Effects of butylated hydroxytoluene on the enzyme
       activity and ultrastructure of rat hepatocytes. Food Cosmet Toxicol 1970; 8:1-8.
Bru75  Brusick D. Mutagenic evaluation of compound FDA 71-25: butylated hydroxytoluene (IONOL).
       Kensington MD, USA: Litton Bionetics, Inc, 1975; unpublished report, cited in FAO96.
Bru78  Brunner R, Vorhees C, Butcher K. Psychotoxicity of selected food additives and related compounds.
       1978; unpublished report, cited in FAO96
Bru79  Bruce WR, Heddle JA. The mutagenic activity of 61 agents as determined by the micronucleus,
       Salmonella, and sperm abnormality assays. Can J Genet Cytol 1979; 21: 319-33.
BUA94  GDCh-Advisory Committee on Existing Chemical of Environmental Relevance (Beratergremium für
       umweltrelevante Altstoffe) (BUA)). Butylated hydroxytoluene (2,6-bis(1,1-dimethylethyl)-4-
       methylphenol). Stuttgart, FRG: S. Hirzel-Wissenschaftliche Verlagsgesellschaft, 1994; BUA report
       58.
Bur72  Burrows CM, Cumming DM, Gartland CJ, et al. Topanol 354 (BHT and BHA): Comparison of
       biochemical and ultrastructural effects on rat hepatocytes. Alderley Park (Cheshire), England, 1972;
       unpublished report, cited in FAO96.
Cla73  Clapp NK, Tyndall RL, Cumming RB. Hyperplasia of hepatic bile ducts in mice following long-term
       administration of butylated hydroxytoluene. Food Cosmetic Toxicol 1973: 11: 847-9.
Cla78  Clapp NK, Tyndall RL, Satterfield LC, et al. Selective sex-related modification of
       diethylnitrosamine-induced carcinogenesis in BALB/c mice by concomitant administration of
       butylated hydroxytoluene J Natl Cancer Inst 1978; 61:177-82.
101-28 Health-based Reassessment of Administrative Occupational Exposure Limits
</pre>

====================================================================== Einde pagina 28 =================================================================

<br><br>====================================================================== Pagina 29 ======================================================================

<pre>Cot94  Cottrell S, Andrews CM, Clayton D, et al. The dose-dependent effect of BHT (butylated
       hydroxytoluene) on itamn K-dependent blood coagulation in rats. Food Chem Toxicol 1994; 32: 589-
       94.
Cou85  Courtheoux SI, Wepierre JL, Marty JP. Topical pharmacokinetics of [14C] butylated hydroxytoluene
       in the guinea pig. Dermatology 1985; 9: 153-64.
Cre66  Creaven PJ, Davies WH, Williams RT. The effect of butylated hydroxytoluene, butylated
       hydroxyanisole, and octyl gallate upon liver weight and biphenyl 4-hydroxylate activity in the rat. J
       Pharm Pharmacol 1966; 18: 485-9.
Dan65  Daniel JW, Gage JC. The absorption and excretion of butylated hydroxytoluene (BHT) in the rat.
       Food Cosmet Toxicol 1965; 3: 405-15.
Dan68  Daniel JW, Gage IC, Jones DI. The metabolism of 3,5-tert-butyl-4-hydroxytoluene in the rat and in
       man. Biochem J 1968; 106: 783-90.
Dau80  Daugherty JP, Beach L, Franks H, et al. Tissue distribution and excretion of radioactivity in male and
       female mice after a single administration of 14C-butylated hydroxytoluene. Res Commun Subst
       Abuse 1980; 1: 99-110.
Dei55  Deichmann WB, Clemmer JJ, Rakoczy R, et al. Toxicity of ditertiarybutylmethylphenol. Arch Ind
       Health 1955; 11: 93-101.
Det93  Detringer SD, Torous DK, Tometsko AM. In vitro system for detecting non-genotoxic carcinogens.
       Environ Mol Mutagen 1993; 21: 332-8.
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: 48 (rep no 39).
EC04   European Commission: Directorate General of Employment and Social Affairs. Occupational
       exposure limits (OELs). http://europe.eu.int/comm/employment_social/h&s/areas/oels_en.htm.
Eps72  Epstein SS, Arnold E, Andrea J, et al. Detection of chemical mutagens by the dominant lethal assay
       in the mouse. Toxicol Appl Pharmacol 1972; 23: 288-325.
FAO96  Food and Agricultural Organization/World Health Organization (FAO/WHO): Joint FAO/WHO
       Expert Committee on Food Additives (JECFA). Butylated hydroxytoluene (BHT). In: Toxicological
       evaluation of certain food additives and contaminants in food. Geneva, Switzerland: World Health
       Organization, 1996: 1-86; WHO Food Additives Series 35.
Fis73  Fisherman EW, Cohen G. Chemical intolerance to butylated hydroxyanisole (BHA) and butylated
       hydroxytoluene (BHT) and vascular response as an indicator and monitor of drug intolerance. Ann
       Allergy 1973; 31:126-33.
Fly90  Flyvholm MA, Menné T. Sensitizing risk of butylated hydroxytoluene based on exposure and effect
       data. Contact Dermatitis 1990; 23: 341-5.
Gro86  Grogan WA. Toxicity from BHT ingestion. West J Med 1986; 145: 245-6.
101-29 2,6-Di-tert-butyl-p-cresol
</pre>

====================================================================== Einde pagina 29 =================================================================

<br><br>====================================================================== Pagina 30 ======================================================================

<pre>Hag88  Hageman GJ, Verhagen H, Kleinjans JC. Butylated hydroxyanisole, butylated hydroxytoluene, and
       tert-butylhydroxyquinone are not mutagenic in the Salmonella microsome assay using new tester
       strains. Mutat Res 1988; 208: 207-11.
Ham83  Hammock BD, Ota K. Differential induction of cytosolic epoxide hydrolase, microsomal epoxide
       hydrolase and glutathione-S-transferase activities. Toxicol Appl Pharmacol 1983; 71: 254-65.
Han86  Hannuksela M, Lahti A. Peroral challenge tests with food additives in urticaria and atopic dermatitis.
       Int J Dermatol 1986; 25: 178-80.
Hei96  Heil J, Reifferscheid G, Waldmann P, et al. Genotoxicity of dental materials. Mutat Res 1996; 368:
       181-94.
Hir81  Hirose M, Shibata M, Hagiwara A, et al. Chronic toxicity of butylated hydroxytoluene in Wistar rats.
       Food Comet Toxicol 1981; 19: 147-51.
Hol70  Holder GM, Ryan AJ, Watson TR, et al. The metabolism of butylated hydroxytoluene in man. J
       Pharm Pharmacol 1970; 22: 375-6.
HSE02  Health and Safety Executive (HSE). EH40/2002. Occupational exposure limits 2002. Sudbury
       (Suffolk), England: HSE Books, 2002: 17.
IARC86 International Agency for Research on Cancer (IARC). Butylated hydroxytoluene (BHT). In: Some
       naturally occurring and synthetic food components, furocoumarins and ultraviolet radiation. Lyon,
       France : International Agency for Research on Cancer, 1986: 161-206 (IARC monographs on the
       evaluation of the carcinogenic risk of chemicals to humans; Vol 40).
Ina88  Inai K, Kobuke T, Nambu S, et al. Hepatocellular tumorigenicity of buylated hydroxytoluene
       administered orally to B6C3F1 mice. Jpn J Cancer Res 1988; 79: 49-58.
Ish80  Ishidate M, Yoshkawa K, Sofuni T. A primary screen for mutagenicity of food additives in Japan.
       Mutagens Toxicol 1980; 3: 82-90.
Jan99  Jang IS, Chae KR, Kong TS, et al. Effects of long-term vitamin E and butylated hydroxytoluene
       supplemented diets on murine intestinal and hepatic antioxidant enzyme activities. Asian-Aus J Anim
       Sci 1999; 12: 932-8.
Kan99  Kanerva L, Jolanki R, Alanko K, et al. Patch-test reactions to plastic and glue allergens. Acta
       Dermatol Venereol 1999; 79: 296-300.
Kar59  Karplyuk IA. [A toxicological characteristics of phenolic antioxidants of alimentary fats]. in Russian.
       Vopr Pitan1959; 18:24-9; cited in BUA94.
Kaw81  Kawano S, Nakao T, Hiraga K, et al. Strain differences in butylated hydroxytoluene induced deaths in
       male mice Toxicol Appl Pharmacol 1981; 61: 475-9.
Keh80  Kehrer JP, Witschi H. Effects of drug metabolism inhibitors on butylated hydroxytoluene-induced
       pulmonary toxicity in mice. Toxicol Appl Pharmacol 1980; 53: 333-42.
Keh85  Kehrer JP, Kacew S. Systematically applied chemicals that damage lung tissue. Toxicology 1985;
       35: 251-93.
Keh90  Kehrer JP, DiGiovanni J. Comparison of lung injury induced in 4 strains of mice by butylated
       hydroxytoluene. Toxicol Lett 1990; 52: 55-61.
101-30 Health-based Reassessment of Administrative Occupational Exposure Limits
</pre>

====================================================================== Einde pagina 30 =================================================================

<br><br>====================================================================== Pagina 31 ======================================================================

<pre>Kin81  Kinae N, Hashizume T, Makita T, et al. Studies on the toxicity of pulp and paper mill effleunts - I.
       Mutagenicity of the sediment samples derived from kraft paper mills. Water Res 1981; 15:17-24.
Kra84  Krasavage WJ. The lack of effect of tertiary butylhydroquinone on prothrombin time in male rats.
       Drug Chem Toxicol 1984; 7: 329-34.
Kuo78  Kuo JF, Brackett NL, Stubbs JW, et al. Involvements of cyclic nucleotide systems in enlarged mice
       lungs produced by butylated hydroxytoluene. Biochem Pharmacol 1978; 27:1671-5.
Lad67  Ladomery LG, Ryan AJ, Wright SE. The biliary metabolites of butylated hydroxytoluene in the rat. J
       Pharm Pharmacol 1967;19: 388-94.
Lak76  Lake BG, Longland RC, Gangolli SD, et al. The influence of some foreign componds on hepatic
       xenobiotic metabolism and the urinary excretion of D-glucuronic acid metabolites in the rat. Toxicol
       Appl Pharmacol 1976; 35: 113-22.
Lin86  Lindenschmidt RC, Tryka AF , Goad ME, et al. The effects of dietary butylated hydroxytoluene on
       liver and colon tumor development in mice. Toxicology 1986; 38:151-60.
LSR73  Life Sciences Research Office (LSRO)/Federation of American Societies for Experimental Biology.
       Evaluation of the health aspects of butylated hydroxytoluene as a food ingredient. Bethesda MD,
       USA: Life Sciences Research Office, 1973; cited in BUA94 (report available from the National
       Technical Information Service, Springfield VA, USA; order no PB259917).
Mal52  Mallette FS, von Haam E. Studies on the toxicity and skin effects of compounds used in the rubber
       and plastic industries. I. Accelerators, activators, and antioxidants. Arch Ind Hyg Occup Med 1952;
       5: 311-7.
Mal79  Malkinson AM. Altered phosphorylation of lung proteins following administration of butylated
       hydroxytoluene to mice. Life Sci 1979; 24: 465-71.
Mas84  Masuda Y, Nakayama N. Prevention of butylated hydroxytoluene-induced lung damage by
       diethyldithiocarbamate and carbon disulfide in mice. Toxicol Appl Pharmacol 1984; 75: 81-90.
Mat84  Matsuo M, Mihara K, Okuna M, et al. Comparative metabolism of 3,5-di-tert-butyl-4 hydroxytoluene
       (BHT) in mice and rats. Food Chem Toxicol 1984; 22: 345-54.
Maz83  Mazar Barnett B, Munoz ER. Recessive lethals induced by ethyl methanesulfonate and diethyl sulfate
       in Drosophila melanogaster post-meiotic male cells pre-treated with butylated hydroxytoluene. Mutat
       Res 1983; 110: 49-57.
McF97  McFarlane M, Price SC, Cottrell S, et al. Hepatic and associated response of rat to pregnancy,
       lactation and simultaneous treatment with butylated hydroxytoluene. Food Chem Toxicol 1997; 35:
       753-67.
McG88  McGregor DB, Brown A, Cattanach P, et al. Responses of the L5178Y tk+ /tk- mouse lymphoma cell
       forward mutation assay. II. 18 coded chemicals. Environ Mol Mutagen 1988; 11: 91-118.
McO49  McOmie WA, Anderson HH, Estess FM. Comparative toxicity of certain t-butyl substituted cresols
       and xylenols. J Am Pharm Assoc Sci Ed 1949; 38: 366-9.
Mey80  Meyer O, Hansen E. Behaviuoral anddevelopmental effects of butylated hydroxytoluene dosed to rats
       in utero and in the lactation period. Toxicology 1980; 16: 247-58.
101-31 2,6-Di-tert-butyl-p-cresol
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<br><br>====================================================================== Pagina 32 ======================================================================

<pre>Miy86  Miyakawa Y, Takahashi M, Furukawa F. et al. Pneumotoxicity of butylated hydroxytoluene applied
       dermally to CD-1 mice. Toxicol Lett 1986; 34: 99-105.
Miz87  Mizutani T, Nomura H, Yamamoto K, et al. Hepatotoxicity of butylated hydroxytoluene and its
       analogs in mice Toxicol Appl Pharmacol 1987; 87:166-76.
Nak80  Nakagawa Y, Hiraga K, Suga T. Biological fate of butylated hydroxytoluene (BHT)- binding of BHT
       to nucleic acid in vivo. Biochem Pharmacol 1980; 29: 1304-6.
Nak88  Nakagawa Y, Tayama K. Nephrotoxicity of butylated hydroxytoluene in phenobarbital-pretreated
       male rats. Arch Toxicol 1988; 1: 359-65.
NCI79  US National Cancer Institute. Bioassay of butylated hydroxytoluene (BHT) for possible
       carcinogenicity. Bethesda MD, USA: National Cancer Institute, 1979; NCI Carcinogenesis Technical
       Report Series No 150; DHEW Report No NIH 79-1706 (available from the National Technical
       Information Service, Springfield VA, USA; order no PB298539).
NIO03  US National Institute for Occupational Safety and Health (NIOSH), ed. p-Cresol, 2,6-di-t-butyl-. In:
       Registry of Toxic Effects of Chemical Substances (RTECS) (last update: October 2002); http://
       www.cdc.gov/niosh/rtecs/go7829b8.html.
NLM03  US National Library of Medicine (NLM), ed. 2,6-Di-t-butyl-p-cresol. In: Hazardous Substances Data
       Bank (HSDB) (last revision date BHT file: 6 August 2002; last review date: 9 September 1993);
       http://www.toxnet.nlm.nih.gov.
Ols86  Olsen P, Meyer O, Bille N, et al. Carcinogenicity study on butylated hydroxytoluene (BHT) in Wistar
       rats exposed in utero. Food Chem Toxicol 1986; 24: 1-12.
Par82  Partridge CA, Dao DD, Awasthi YC. Induction of glutathione-linked detoxification system by dietary
       antioxidants. Fed Proc 1982; 41: 2152.
Pas84  Paschin YV, Bahitova LM. Inhibition of the mutagenicity of benzo(a)pyene in the V79/HGPRT
       system by bioantioxidants. Mutat Res 1984; 137: 57-9.
Pas86  Paschin YV, Bakhitova LM, Benthen TI. Increased antimutagenic activity of simple substituted
       phenols mixed with the hindered phenolic antioxidant dibunol. Food Chem Toxicol 1986; 24: 881-3.
Pat87  Patterson RM, Keith LA, Stewart J. Increase in chromosomal abnormalities in Chinese hamster ovary
       cells treated with butylated hydroxytoluene in vitro. Toxicol in Vitro 1987; 1: 55-7.
Pow86  Powell CJ, Connelly JC, Jones SM, et al. Hepatic responses to the administration of high doses of
       BHT to the rat. Food Chem Toxicol 1986; 24:1131-43.
Pow91  Powell CJ, Connelly JC. The site specificity and sensitivity of the rat lver to butylated
       hydroxytoluene-induced damage. Toxicol Appl Pharmcol 1991, 108: 67-77.
Pra74  Prasad O, Kamra OP. Radiosensitisation of Drosophila sperm by commonly used food additives-
       butylated hydroxyanisole and butylated hydroxytoluene. Int J Radiat Biol 1974; 25: 67-72.
Roe76  Roed-Petersen J, Hjorth N. Contact dermatitis from antioxidants. Hidden sensitizers in topical
       medications and food. Brit J Derm 1976; 94: 233.
Sah75  Saheb W, Witschi H. Lung growth in mice after a single dose of butylated hydroxytoluene. Toxicol
       Appl Pharmacol 1975; 33:309-319
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</pre>

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<br><br>====================================================================== Pagina 33 ======================================================================

<pre>San83  Sankaranarayanan K. The effect of butylated hydroxytoluene o radiation and chemically-induced
       genetic damagein Drosophila melanogaster. Mutat Res 1983; 108: 203-23.
Sas02  Sasaki YF, Kawaguchi S, Kamaya A, et al. The comet assay with 8 mouse organs: results with 39
       currently used food additives. Mutat Res 2002; 519: 103-19.
She86  Sheu CW, Cain KT, Rushbrook CJ, et al. Tests for mutagenic effects of ammoniated glycyrrhizin,
       butylated hydroxytoluene, and gum Arabic in rodent germ cells. Environ Mutagen 1986; 8: 357-67.
Shi82  Shirai T, Hagiwara A, Kurata Y, et al. Lack of carcinogenicity of butylated hydroxytoluene on long-
       term administration to B6C3F1 mice. Food Chem Toxicology 1982; 20: 861-5.
Shl86  Shlian DM, Gldstone J. Toxicity of butylated hydroxytoluene (letter to the editor). N Engl J Med
       1986; 314: 648-9.
Spa78  Spanjers MT, Til HP. Determination of the acute oral toxicity of Vulkanox KB in rats. Zeist, the
       Netherlands: TNO Nutrtion and Food Research, 1978; unpublished study, cited in BUA94.
Sta97  Stadler JC, Lavoie DA. Sensory irritation in mice with carpet emission chemicals (abstract, with
       overhead sheets). Toxicologist 1997; 36: 326.
Suz83  Suzuki H, Nakao T, Hiraga K. Vitamin K content of liver and faeces from vitamin K-deficient and
       butylated hydroxytoluene (BHT)-treated male rats. Toxicol Appl Pharmacol 1983; 67:152-5.
Swe00  Swedish National Board of Occupational Safety and Health. Occupational exposure limit values and
       measures against air contaminants. Solna, Sweden: National Board of Occupational Safety and
       Health, 2000; Ordinance AFS 2000:3.
SZW03  Ministerie van Sociale Zaken en Werkgelegenheid (SZW). Nationale MAC-lijst 2003. The Hague,
       the Netherlands: Sdu, Servicecentrum Uitgevers, 2003: 25.
Taj81  Tajama K, Yamamoto K, Mizutani T. Biotransformation of butylated hydroxytoluene (BHT) to BHT-
       quinone methide in rats. Chem Pharm Bull 1981; 29: 3738-41.
Tak78a Takahashi O, Hiraga K. Dose-response study of haemorrhagic death by dietary butylated
       hydroxytoluene (BHT) in male rats. Toxicol Appl Pharmacol 1978; 43: 399-406.
Tak78b Takahashi O, Hiraga K. Effects of low levels of butylated hydroxytoluene on the prothrombin index
       of male rats. Food Cosmet Toxicol 1978; 16: 475-7.
Tak79  Takahashi O, Hiraga O. 2,6-di-tert-butyl-4-methylene-2,5-cyclohexadienone: a hepatic metabolite of
       butylated hydroxytoluene in rats. Food Cosmet Toxicol 1979;17: 451-4.
Tak80  Takahashi O, Hayashida S, Hiraga K. Species differences in the haemorrhagic response of butylated
       hydroxytoluene. Food Cosmet Toxicol 1980; 18: 229-35.
Tak86  Takahashi O. Feeding of butylated hydroxytoluene to rats caused a apid decrease in blood
       coagulation factors II (prothrombin), VII, IX, and X. Arch Toxicol 1986; 58: 177-81.
Tak87  Takahashi O. Decrease in blood coagulation factors II (prothrombin), VII, IX and X in the rat after a
       single dose of butylated hydroxytoluene Food Chem Toxicol 1987; 25:219-24.
Tak92  Takahashi O. Haemorrhages due to defective blood coagulation do not occur in mice and guinea pigs
       fed butylated hydroxytoluene, but nephrotoxicity is found in mice. Food Chem Toxicol 1992; 30: 89-
       97.
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<br><br>====================================================================== Pagina 34 ======================================================================

<pre>Tan93  Tanaka T, Oishi S, Takahashi O. Three generation toxicity study of butylated hydroxytoluene
       administered to mice. Toxicol Lett 1993; 66: 295-304.
TRG00  TRGS 900. Grenzwerte in der Luft am Arbeitsplatz; Technische Regeln für Gefahrstoffe. BArbBl
       2000; 2.
Ver89  Verhagen H, Becker HHG, Comuth PAWV, et al. Disposition of single oral doses of butylated
       hydroxytoluene in man and in rat. Food Chem Toxicol 1989, 27: 765-72.
Wie78  Wiebe LI, Mercer JR, Ryan AJ. Urinary metabolites of 3,5-di-(1-(13C)methyl-1-methylethyl)-4-
       hydroxytoluene (BHT-13C) in man. Drug Metab Dispos 1978; 6: 296-302.
Wil90a Williams GM, McQueen CA, Tong C. Toxicity studies of butylated hydroxyanisole and butylated
       hydroxytoluene. I. Genetic and cellular effects. Food Chem Toxicol 1990; 28: 793-8.
Wil90b Williams GM, Wang CX, Iatropoulos MJ. Toxicity studies of butylated hydroxyanisole and butylated
       hydroxytoluene. II. Chronic feeding studies. Food Chem Toxicol 1990; 28:799-806.
Wit89  Witschi H, Malkinson AM, Thompson JA. Metabolism and pulmonary toxicity of butylated
       hydroxytoluene (BHT). Pharmacol Ther 1989; 1989: 89-113.
Yam80  Yamamoto K, Tajima K, Mizutani T. The acute toxicity of butylated hydroxytoluene induced deaths
       in male mice. Toxicol Lett 1980; 6: 173-5.
Yam95  Yamamoto K, Fukuda N, Shiroi S, et al. Effect of dietary antioxidants on the susceptibility to hepatic
       microsomal lipid peroxidation in the rat. Ann Nutr Metab 1995; 39: 99-106.
Yos90  Yoshida Y. Study on mutagenicity and antimutagenicity of BHT and is derivatives in a bacterial assay
       Mutat Res 1990; 242: 209-17.
Zim98  Zimerson E, Bruze M. Contact allergy to the monomers of p-tert-butylphenol-formaldehyde resin in
       the guinea pig. Contact Dermatitis 1998; 39: 222-6.
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<pre>       Annex I
         I     3,5-di-tert-butyl-4-hydroxytoluene (BHT)
         II    4-carboxy-2-(1-carboxy-1-methylethyl)-6-(1-formyl-1-methylethyl)phenol
         III   5-arboxy-7-(1-carboxy-1-methylethyl)-3,3-dimethyl-2-hydroxy-2,3-dihydroxybenzofuran
         IV    glucuronide of III
         V     2,6-di-tert-butyl-4-hydroxymethylphenol (BHT-OH, BHT-alcohol)
         VI    3,5-di-tert-butyl-4-hydroxybenzaldehyde (BHT-CHO, BHT-aldehyde)
         VII   3,5-di-tert-butyl-4-hydroxybenzoic acid (BHT-COOH, BHT-acid)
         VIII  3,5-di-tert-butyl-4-hydroxymethylphenol-glycin conjugate
         IX    α-hydroxy-2,6-di-tert-butyl-p-cresol (α-hydroxy-BHT)
         X     α-hydroxy-2,6-di-tert-butyl-4-hydroxymethylphenol glucuronide
         XI    3,5-di-tert-butyl-4-hydroxybenzoic acid ester-glucuronide
         XII   α-hydroxy-2,6-di-tert-butyl-4-hydroxymethylphenol
         XIII   α-hydroxy-2,6-di-tert-butyl-4-hydroxybenzaldehyde
       Figure 1a Metabolic pathways of BHT: oxidation and conjugation of alkyl substituents (from
       BUA94; see also Wit89).
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<pre>        I     3,5-di-tert-butyl-4-hydroxytoluene (BHT)
        II    phenoxy radical
        III   2,6-di-tert-butyl-4-hydroperoxy-4-methylcyclohexa-2,5-diene-1-one
              (BHT-OOH, hydroxyperoxy-BHT)
        IV 2,6-di-tert-butyl-4-hydroxy-4-methylcyclohexa-2,5-diene-1-one
        V     α-hydroxy-2,6-di-tert-butyl-4-hydroxy-4-methylcyclohexa-2,5-diene-1-one
        VI S-(3,5-di-tert-butyl-4-hydroxybenzyl)glutathione (BHT-glutathione)
        VII 2,6-di-tert-butyl-4-methylene-cyclohexa-2,5-diene-1-one (BHT-quinone methide)
        VIII quinoxy radical
        IX rearrangment products
        X     2,6-di-tert-butyl-p-benzoquinone
        XI S-(3,5-di-tert-butyl-4-hydroxybenzyl)-N-acetylcysteine (BHT mercapturic acid)
        XII 2,6-di-tert-butyl-4-(methylthio)methylphenol
        XIII 2,6-di-tert-butylhydroquinone
        Figure 1b Metabolic pathways of BHT: ring oxidation (from BUA94; see also Wit89).
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<pre>              Annex II
Occupational exposure limits for butylated hydroxytoluene 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 -              10                                                                  SZW03
Employment
Germany
- AGS                             -             10c               8h                 administrative                 TRG00
- DFG MAK-Kommission              -             -d                                                                  DFG03
Great Britain
- HSE                             -             10                8h                 OES                            HSE02
Sweden                            -             -                                                                   Swe00
Denmark                           -             10                8h                                                Arb02
USA
- ACGIH                           -             2c                8h                 TLV                 A4e        ACG03b
- OSHA                            -             -                 -                                                 ACG03a
- NIOSH                           -             10                10 h               REL                            ACG03a
European Union
- SCOEL                           -             -                                                                   EC04
a
     S = skin notation, which means that skin absorption may contribute considerably to body burden; sens = substance can
     cause sensitisation.
b
     Reference to the most recent official publication of occupational exposure limits.
c
     Inhalable fraction of vapour plus aerosol.
d
     Listed among compounds for which studies of the effects in man or experimental animals have yielded insufficient
     information for the establishment of MAK values.
e
     Classified in carcinogenicity category A4, i.e., not classifiable as a human carcinogen: agents which cause concern that
     they could be carcinogenic for humans but which cannot be assessed conclusively because of a lack of data. In vitro or
     animal studies do not provide indications of carcinogenicity which are sufficient to classify the agent into one of the other
     categories.
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<pre>101-38 Health-based Reassessment of Administrative Occupational Exposure Limits</pre>

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