<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>Hydrogenated Terphenyl
Health-based recommendation on occupational exposure limits
To: the State Secretary of Social Affairs and Employment
No. 2020/09, The Hague, June 15, 2020
                                                            2 2
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<pre> Contents                                                                                    Hydrogenated Terphenyl | page 2 of 67
 contents
 01 Scope8                                                05 Kinetics and biomonitoring                                      18
      1.1  Background                                   9    5.1 Absorption, distribution, metabolism and excretion           19
      1.2  Committee and procedure                      9    5.2 Biomonitoring                                                19
      1.3  Data                                         9
      1.4  Quality assessment                           9 06 Effects20
                                                              6.1 Observations in humans                                       21
 02 Identity, properties and monitoring                11    6.2 Animal experiments                                           23
      2.1  Identity                                    12    6.3 Summary                                                      27
      2.2  Physical and chemical properties            12
      2.3  EU classification and labelling             12 07 Existing guidelines, standards and evaluation                   29
      2.4  Validated analytical methods                13    7.1 General population                                           30
                                                              7.2 Working population                                           30
 03 Sources14
      3.1  Natural sources                             15 08 Hazard assessment                                               32
      3.2  Man-made sources                            15    8.1 Hazard Identification                                        33
                                                              8.2 Quantitative hazard assessment                               33
 04 Exposure16                                               8.3 Classification                                               35
      4.1  General population                          17    8.4 Skin notation                                                36
      4.2  Working population                          17    8.5 Groups at extra risk                                         36
1       Health Council of the Netherlands | No. 2020/09                                          2                               3
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<pre> Contents                                                                      Hydrogenated Terphenyl | page 3 of 67
      References37
      Annexes44
      A    Criteria for testing reliability of animal and in vitro studies 45
      B    Reliability testing of epidemiological studies                  46
      C    Effects observed in animal studies                              48
      D    Benchmark dose analysis                                         62
2       Health Council of the Netherlands | No. 2020/09                           2                                4
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<pre> Samenvatting                                                                                                       Hydrogenated Terphenyl | page 4 of 67
 samenvatting
 Op verzoek van de minister van Sociale               geproduceerd. Gehydrogeneerd terfenyl is niet      wetenschappelijk onderzoek een gezondheids­
 Zaken en Werkgelegenheid (SZW) heeft de              of nauwelijks afbreekbaar in het mileu.            kundige advieswaarde is af te leiden op basis
 Gezondheidsraad een gezondheidskundige                                                                  van een veilige ondergrens. Met een veilige
 advieswaarde afgeleid voor de beroepsmatige          Nadelige gezondheidseffecten                       ondergrens wordt bedoeld: een blootstellings­
 blootstelling aan gehydrogeneerd terfenyl.           In de literatuur zijn meldingen van huidirritatie, niveau waarbij geen nadelige gezondheids­
 Dit advies is tot stand gekomen in de Commissie      hoofdpijn en keelpijn van mensen die op hun        effecten te verwachten zijn. Op basis van de
 Gezondheid en beroepsmatige blootstelling aan        werk per ongeluk met gehydrogeneerd terfenyl       gezondheidskundige advieswaarde van de
 stoffen (GBBS). Op www.gezondheidsraad.nl            in aanraking kwamen (accidentele blootstelling).   commissie kan de staatssecretaris een
 staat informatie over de taken van deze vaste        Verder is er weinig informatie beschikbaar over    grenswaarde voor beroepsmatige blootstelling
 commissie van de Gezondheidsraad.                    de relatie tussen blootstelling aan verschillende  vaststellen.
 De samenstelling van de commissie is te vinden       concentraties van deze stof en gezondheids­
 op de laatste pagina van dit advies.                 effecten bij mensen. Bij proefdieren kan           Geraadpleegde onderzoeken
                                                      langdurige blootstelling aan gehydrogeneerd        De commissie heeft de beschikbare onder­
 Gebruik van gehydrogeneerd terfenyl                  terfenyl leiden tot een toename in orgaan­         zoeken naar het optreden van schadelijke
 Gehydrogeneerd terfenyl heeft een toepassing         gewichten, waaronder de lever, en een afname       gezondheidseffecten door blootstelling aan
 als thermische vloeistof die voornamelijk in         van het lichaamsgewicht.                           gehydrogeneerd terfenyl beoordeeld.
 installaties gebruikt wordt om warmte of koeling                                                        Het dierexperimenteel onderzoek van Farr et al.
 over te dragen. De stof wordt ook gebruikt als       Gezondheidskundige advieswaarde                    (1989) geeft de meest duidelijke relatie weer
 drager voor textielkleurstof en als weekmaker.       Voor schadelijke stoffen waaraan mensen            tussen blootstelling aan gehydrogeneerd
 In de Europese Unie wordt jaarlijks meer dan         tijdens hun werk kunnen worden blootgesteld,       terfenyl en gezondheidseffecten. In twee
 1.000.000 kilogram gehydrogeneerd terfenyl           gaat de commissie GBBS na of er uit                verschillende onderzoeken zijn ratten her­-
3        Health Council of the Netherlands | No. 2020/09                                                               2                                5
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<pre> chapter 01 | Introduction                               Hydrogenated Terphenyl | page 5 of 67
 haaldelijk aan gehydrogeneerd terfenyl
 blootgesteld via twee verschillende toedienings­
 routes (oraal of via inhalatie). Nadelige gezond­
 heids­effecten die optraden bij toenemende
 blootstelling waren toename in orgaangewichten
 en afname in lichaamsgewicht.
 Histopathologisch onderzoek vertoonde geen
 afwijkingen. De toename in het relatieve
 levergewicht is door de commissie als
 uitgangspunt genomen voor het afleiden van
 de gezondheidskundige advieswaarde.
 Advies aan de staatssecretaris
 Voor de beroepsmatige blootstelling aan
 gehydrogeneerd terfenyl komt de commissie tot
 een gezondheidskundige advieswaarde van
 7,4 milligram (mg) per kubieke meter (m3) lucht,
 als een gemiddelde concentratie over een
 achturige werkdag.
4        Health Council of the Netherlands | No. 2020/09    2                                6
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<pre> Executive summary                                                                                               Hydrogenated Terphenyl | page 6 of 67
 executive summary
 At request of the Minister of Social Affairs and     Hydrogenated terphenyls are substances which    expected. This HBR-OEL is the base at which
 Employment, the Health Council recommends            are very persistent in the environment.         the State Secretary can set a legally-binding
 health based occupational exposure limits                                                            occupational exposure limit. When deriving an
 (HBR-OEL). This report contains an evaluation        Health effects                                  HBR-OEL limit, the principle is applied that an
 of the health hazard and recommendation for          The main effects reported in humans are skin    adverse health effect increases with an
 hydrogenated terphenyl. The evaluation is            irritation, headaches and sore throats after    increasing dose.
 performed by the Dutch Expert Committee on           accidental exposure. Limited human data are
 Occupational Safety (DECOS), a permanent             available on the association between exposure   Consulted research
 Committee of the Health Council. Additional          to hydrogenated terphenyl at different exposure The Committee has evaluated the studies on
 information on the task of the Committee can         levels and adverse health effects. Repeated     exposure to hydrogenated terphenyl, and
 be found at www.healthcouncil.nl. The members        exposure studies in animals revealed increase   observed adverse health effects that are suitable
 of the Committee are listed on the last page of      in organ weights (e.g., the liver), and body    for deriving an HBR-OEL. The most clear and
 the present advisory report.                         weight loss after exposure to hydrogenated      evident exposure-related adverse health effects
                                                      terphenyl.                                      of hydrogenated terphenyl were found in an
 Identified uses                                                                                      oral and an inhalation animal experiment.
 Hydrogenated terphenyl mixtures are used as          Health-based recommended occupational           The repeated exposure studies in rats revealed
 a heat transfer fluid (e.g., as a nuclear reactor-   exposure limit                                  an increase in organ weights, and body
 coolant), as textile dye carriers, and as            For hazardous substances to which people can    weight loss after inhalation and oral exposure
 plasticizers. The production rate in the European    be occupationally exposed, the Committee        to hydrogenated terphenyl. Histopathology
 Union is in excess of 1,000 tonnes per annum.        determines whether a concentration can be       showed no abnormalities. Relative liver weight
                                                      derived at which no adverse health effects are  changes were used to derive an HBR-OEL.
5        Health Council of the Netherlands | No. 2020/09                                                             2                                7
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<pre> Executive summary                                      Hydrogenated Terphenyl | page 7 of 67
 Recommendation to the State Secretary
 For occupational exposure to hydrogenated
 terphenyl, the Committee recommends a ­
 health-based occupational exposure limit for
 hydrogenated terphenyl of 7.4 mg per m3 air,
 which represents a mean concentration during
 an 8-hour working day.
6       Health Council of the Netherlands | No. 2020/09    2                                8
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<pre> chapter 01 | Scope                                    Hydrogenated Terphenyl | page 8 of 67
 01
 scope
7      Health Council of the Netherlands | No. 2020/09    2                                9
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<pre> chapter 01 | Scope                                                                                                 Hydrogenated Terphenyl | page 9 of 67
 1.1      Background                                                         In 2019, the president of the Health Council released a draft of the report
 At request of the minister of Social Affairs and Employment, the Dutch      for public review. The comments received have been taken into account
 expert Committee on Occupational Safety (DECOS), a committee of the         by the committee in deciding on the final recommendation of the advisory
 Health Council of the Netherlands, performs scientific evaluations on       report. The comments, and the replies by the Committee, can be found on
 the toxicity of substances that are used in the workplace. The purpose      the website of the Health Council.
 of the evaluations is to recommend health-based occupational exposure
 limits (HBR-OELs) for the concentration of the substance in the air,        1.3      Data
 provided the database allows the derivation of such a value.                The Committee’s recommendation is based on scientific data, which are
 These recommendations serve as a basis in setting legally binding           publicly available. The literature was retrieved from the online databases
 occupational exposure limit values by the minister.                         PubMed, Toxnet and Chemical Abstracts, using a search with the terms
                                                                             “terphenyl hydrogenated” and “CAS 61788-32-7”. Additional relevant
 In this advisory report such a recommendation is made for hydrogenated      literature was identified using the references of the retrieved literature and
 terphenyl. During use in a nuclear reactor, hydrogenated terphenyl          using the online data base from the European Chemicals Agency,
 becomes irradiated and conversion of the terphenyl to other hydrocarbons    regarding REACH legislation. The final search was carried out in
 and high polymers occurs to some extent.1-3 Because differences in          November 2019.
 toxicity have been observed for irradiated and nonirradiated hydrogenated
 terphenyl, and the composition of irradiated hydrogenated terphenyl         1.4      Quality assessment
 depends on the manner of operation of the nuclear reactor, this evaluation  To assess the quality of animal experiments and in vitro studies, the
 is restricted to the toxicity of nonirradiated hydrogenated terphenyl.1,4-7 Committee used the criteria set by Klimisch et al. 1997.8 The following
                                                                             categories of reliability were adopted: 1. Reliable without restriction;
 1.2      Committee and procedure                                            2. Reliable with restrictions; 3. Not reliable, and; 4. Not assignable
 The members of the Committee, and the consulted experts, are listed on      (Annex A). Studies which were assigned to reliability category 4 (not
 the last page this advisory report.                                         assignable), Industrial Bio-Test (IBT) studies (considered to be unreliable
8        Health Council of the Netherlands | No. 2020/09                                                                2                                 10
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<pre> chapter 01 | Scope                                                           Hydrogenated Terphenyl | page 10 of 67
 unless otherwise stated), and unspecified studies (according to the
 European Chemicals Agency) were not included in the evaluation.
 To assess the quality of human studies, the Committee used the criteria
 set by Money et al. 2013.9 The categories of reliability correspond to the
 data quality categories established by Klimisch et al. (1997): 1. Reliable
 without restriction; 2. Reliable with restrictions; 3. Not reliable, and;
 4. Not assignable (Annex B). In general, the Committee considers studies
 classified into categories 1 or 2 to be of sufficient quality for the
 identification of health effects and for the derivation of health-based
 advisory values. Studies classified into categories 3 or 4 are considered to
 be of insufficient quality to serve as evidence for deriving HBR-OELs.
9        Health Council of the Netherlands | No. 2020/09                          2                               11
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<pre> chapter 02 | Identity, properties and monitoring      Hydrogenated Terphenyl | page 11 of 67
 02
 identity, properties
 and monitoring
10     Health Council of the Netherlands | No. 2020/09     2                               12
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<pre> chapter 02 | Identity, properties and monitoring                                                                           Hydrogenated Terphenyl | page 12 of 67
 2.1     Identity                                                           Table 1. Physical and chemical properties of hydrogenated terphenyl
 Hydrogenated terphenyl is a complex mixture of various isomers of ­         CAS number        61788-32-7
                                                                             EC/EINECS         262-967-7
 ortho-, meta-, and para-terphenyls in various stages of hydrogenation.      number
                                                                             REACH Reg. Nr.    01-2119488183-33
 Five such stages exist for each of the three isomers.2 Commercial
                                                                             Synonyms          Hydrogenated diphenylbenzenes; hydrogenated phenylbiphenyls; hydrogenated
 available mixtures (Therminol® 66, HB-40®) are approximately 40%                              triphenyls
                                                                                               HB-40/00®; Therminol® 66
 hydrogenated mixtures of all three isomers.10,11,12 Hydrogenated terphenyl
                                                                             Use               Used as a plasticizer, and as a heat-transfer medium.
 is a substance that is very persistent and very bioaccumulative. It is,     Molecular weight  241 (average)
                                                                                               ≥ 236 - ≤ 248
 therefore, considered by the European Chemicals Agency as a substance
                                                                             Molecular formula (C6H7)3; C18Hn (18<n<36)
 of very high concern.  13
                                                                             Physical state    Clear oily pale yellow liquid with characteristic odour at 20°C and 1,013 hPa
                                                                             Solubility        61 µg/L at 20 °C in water
                                                                             Structure         A mixture of numerous compounds and isomers depending on the degree and
 2.2     Physical and chemical properties                                                      conditions of hydrogenation
 Physical and chemical properties of hydrogenated terphenyl are shown
 in table 1.14-17
                                                                             Relative density  Relative density of the vapour/air-mixture at 20 °C (air = 1), 1.00
                                                                             Vapour pressure   13 Pa at 25 °C; 0.002 - 1.781 Pa at 20 - 50 °C
                                                                             Log P octanol/    >6,5
                                                                             water
                                                                             Melting point     -32 °C (inchem), -24 °C (echa)
                                                                             Boiling point/    342 °C (1,013 hPa)
                                                                             range
                                                                             Flash point       170 °C (method: Pensky-Martens closed cup); 184 °C (method: Cleveland open
                                                                                               cup)
                                                                             Conversion factor 9.5 mg/m3 = 1 ppm (20 °C, 101 kPa)
                                                                            2.3         EU classification and labelling
                                                                            Hydrogenated terphenyl is not classified as a carcinogen.18
11       Health Council of the Netherlands | No. 2020/09                                                                           2                                         13
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<pre> chapter 02 | Identity, properties and monitoring                                                                                                     Hydrogenated Terphenyl | page 13 of 67
 2.4         Validated analytical methods                                                             Biological exposure monitoring
                                                                                                      Table 3 presents an analytical method for exposure monitoring in
 Environmental exposure monitoring                                                                    biological matrices.
 Validated European or international standards for exposure monitoring of
 hydrogenated terphenyl are not known. Table 2 shows the analytical                                   Table 3. Analytical methods.
 methods for the determination of hydrogenated terphenyl in air, which are                             Sample         Sample preparation          Analytical     Measuring range     Reference
                                                                                                       matrix                                     method
 published in the scientific literature.                                                               The lung,      Washed to remove any        Scintillation  Validated: unknown  Adamson and
                                                                                                       liver, kidney, coolant not located         counting       Results: 0 – 50,000 Furlong
                                                                                                       gut (mice)     intracellularly, dissolved                 Disintegrations Per (1974)12
 Table 2. Analytical methods for the determination of hydrogenated                                                    in a tissue solubilizer and                Minute
                                                                                                                      diluted with a luminophor
 terphenyl in air.                                                                                                    prior to scintillation
                                                                                                                      counting
  Air Sampling             Analytical                      Limit of detection or   Reference
  method                   Method (use)                    Measuring range in air
  Collection with 40%      Ultraviolet spectrophotometer   Limit of detection 0.87 Chai et al.
  alcohol solution         (workplace testing)             mg/m3                   (2004)19
  Adsorption by            Desorption by carbon disulfide, Abstract is not clear   Yu et al. (2010)20
  activated carbon         analysis by gas                 about matrix analysed
                           chromatography (workplace
                           testing)
  Trapping about 10 L      Gas chromatography utilizing a Range: 0-5,000 mg/m3     Bechtel (1985)21
  of air in an impinger    flame ionization detector and
  containing iso-octane    integration of the sum of all
                           chromatographic peaks
                           (inhalation study)
  Trapping air in glass    Gas chromatography using a      Range: 0-500 mg/m3      Farr (1986)22
  fibers containing filter flame ionization detector
  paper followed by        (inhalation study
  extraction with
  n-hexane
12          Health Council of the Netherlands | No. 2020/09                                                                                                    2                                14
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<pre> chapter 03 | Sources                                  Hydrogenated Terphenyl | page 14 of 67
 03
 sources
13     Health Council of the Netherlands | No. 2020/09     2                               15
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<pre> chapter 03 | Sources                                                          Hydrogenated Terphenyl | page 15 of 67
 3.1        Natural sources
 No data available.
 3.2        Man-made sources
 3.2.1      Production
 Terphenyls are produced commercially as ortho, meta, and para isomers.
 They are produced as the pure compounds. These terphenyls are blended
 and partially hydrogenated to form principal components.10 Commercial
 available hydrogenated terphenyls (Therminol® 66, HB-40®) are
 approximately 40% hydrogenated mixtures of ortho-, meta-, and para-
 terphenyls in various stages of hydrogenation, which are clear, yellow
 oils.10,1,12
 The partly hydrogenated terphenyl mixture HB-40® is produced
 commercially by the catalytic hydrogenation of Santowax® to about
 40% of maximum theoretical hydrogen uptake. Santowax® has the
 approximate composition: 7 wt% ortho-terphenyl, 50 wt% meta-terphenyl,
 23 wt% para-terphenyl, and 20 wt% triphenylene plus higher polyphenyls.1
 3.2.2      Use
 Hydrogenated terphenyl is used as a heat transfer fluid and as a nuclear
 reactor-coolant, as textile dye carriers, and as plasticizers. The production
 rate in the European Community is in excess of 1,000 tonnes per annum.3
14         Health Council of the Netherlands | No. 2020/09                         2                               16
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<pre> chapter 04 | Exposure                                 Hydrogenated Terphenyl | page 16 of 67
 04
 exposure
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<pre> chapter 04 | Exposure                                                         Hydrogenated Terphenyl | page 17 of 67
 4.1     General population
 No data available.
 4.2     Working population
 In the immediate vicinity of the reactor within the reactor building, a small
 concentration (0.1 mg/m3) of hydrogenated terphenyl was measured in the
 atmosphere.6
 At Chalk River Nuclear Laboratories (CRNL), organic coolant samples
 were taken over a five-day cycle in all the areas, which are normally
 accessible locations for workers. The investigation was done as a
 continuing program, and provided five-day average concentrations for
 each working area in turn. From such observations, the concentrations of
 hydrogenated terphenyl (HB-40®) in air have been found to range between
 0.89 mg/m3 (average, no data on minimum-maximum levels) in areas
 containing organic piping and equipment, and 0.094 mg/m3 (average,
 no data on minimum-maximum levels) in general working areas close by.23
 No other data on occupational exposure levels are available.
16       Health Council of the Netherlands | No. 2020/09                           2                               18
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<pre> chapter 05 | Kinetics and biomonitoring               Hydrogenated Terphenyl | page 18 of 67
 05
 kinetics and
 biomonitoring
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<pre> chapter 05 | Kinetics and biomonitoring                                                                            Hydrogenated Terphenyl | page 19 of 67
 5.1      Absorption, distribution, metabolism and excretion                   whole-body half-life was less than 1 day. Induction of drug-metabolizing
 Hydrogenated terphenyl is rapidly absorbed through the lungs and              enzymes was evident only at the highest doses, and the liver was more
 gastrointestinal tract.3 Although a limited number of studies indicate that   sensitive to the inducing effects of Therminol® 66 than was the kidney.
 hydrogenated terphenyl is absorbed via the skin, data on skin absorption      ECOD was more sensitive to Therminol® 66 than was AHH, and inhalation
 rates are missing.24                                                          produced a greater effect than did dietary exposure.11
 Adamson and Furlong (1974) studied clearance and tissue distribution          5.2     Biomonitoring
 of hydrogenated terphenyl in various organs of mice after inhalation          No data available.
 and ingestion of tritiated hydrogenated terphenyl (HB-40®) by using
 scintillation counting and autoradiography.12 Following inhalation, particles
 deposited in the lung were rapidly cleared. A large single oral dose of
 tritiated hydrogenated terphenyl was mostly cleared from the gut, the
 liver and the kidneys within a day, and only a low level of radioactivity
 (<800 desintegrations per minute) was retained up to one week.
 Brewster et al. (1992) studied the disposition of Therminol® 66 in rats after
 a single oral administration at doses of 0, 100, or 300 mg/kg bw, or after
 inhalation exposure at a concentration of 0 or 350 mg/m3, once for
 6 hours.11 They determined the effects on the hepatic and renal drug
 metabolizing enzymes ethoxycoumarin O-deethylase (ECOD), and aryl
 hydrocarbon hydroxylase (AHH). AHH is also known as CYP1A1. ECOD
 metabolizes 7-alkoxycoumarin to 7-hydroxycoumarin, and is cytochrome
 P-450-dependent. Approximately 30% of the oral dose was absorbed from
 the gastrointestinal tract. There was little accumulation in tissues, and the
18        Health Council of the Netherlands | No. 2020/09                                                               2                               20
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<pre> chapter 06 | Effects                                  Hydrogenated Terphenyl | page 20 of 67
 06
 effects
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<pre> chapter 06 | Effects                                                                                                                                Hydrogenated Terphenyl | page 21 of 67
 6.1       Observations in humans
 6.1.1     Health effects due to single or short-term exposure
 Limited data are available on the health effects of hydrogenated terphenyl
 in humans.
 Although there have been accidental releases of hot hydrogenated
 terphenyl from pressure in the vicinity of experimental equipment, the
 symptoms reported (headache and sore throat) subsided within 24 hours
 in every case.23 Table 4 presents the results of a skin sensitization study
 performed in humans with hydrogenated terphenyl.25 No evidence was
 reported that the test material acted as a sensitizer in any of the
 individuals included in the test.
 Table 4. Health effects due to short-term exposure.
  Reference      Substance           Study design and    Data on exposure and health assessment          Results                                         Remarks
                                     Population
  Shelanski and  Mixture of          Human voluntary     Method: Repeated Insult Patch Test              No instances of irritation or sensitization     No guideline followed, well-documented,
  Smith (1979)25 hydrogenated        experiment; skin    Dose: 0.2 ml neat test material as supplied                                                     available as unpublished report, minor
                 terphenyls (HB-40®) sensitization study Induction exposure: 15 induction doses during 5                                                 restrictions in reporting, but otherwise adequate
                                                         weeks, 24 hours per dose                                                                        for assessment
                 Impurities: 0.15%   51 subjects (M7/    Challenge exposure: 1 challenge dose,
                 phenyl              F44) per dose       exposure 24 hours                                                                               Reliability: 2
                 cyclohexane,                            Evaluation: 24, 48 and 72 hours after challenge
                 6.79% high boilers                      Interval between last induction dose and
                                                         challenge dose: 14 days
20        Health Council of the Netherlands | No. 2020/09                                                                                                2                                              22
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<pre> chapter 06 | Effects                                                                                                                                 Hydrogenated Terphenyl | page 22 of 67
 6.1.2     Health effects due to long-term exposure
 Table 5 presents the characteristics of a study on long-term exposure of
 workers to hydrogenated terphenyl.23
 Table 5. Cohort study on occupational exposure to hydrogenated
 terphenyl.
  Reference       Study design and                      Data on exposure and health assessment            Results                                         Remarks
                  population
  Weeks and       USA cohort study;                     Hydrogenated terphenyl, not specified.            No differences between regularly/frequently     Limitations include: no data on exposure
  Lentle (1970)23 n=47 male workers, regularly and                                                        exposed workers, and reference group            monitoring methods; no details on the
                  frequently exposed, matched with n=47 Average exposure levels measured in the                                                           substance the workers are exposed to (radiated
                  male workers, casual and infrequently working environment: 9.4x10-5 - 8.9x10-4 mg/l     Creatinin clearance in regularly/frequently     and/or irradiated hydrogenated terphenyl);
                  exposed to hydrogenated terphenyl     (corresponds with 0.094 - 0.89 mg/m3)             exposed workers was decreased after one year. limited information on smoking habits (group of
                                                                                                          However, a follow-up study showed no            casual and infrequently exposed workers
                  Location: workers exposed in working  Regularly and frequently exposed workers:         differences between regularly/frequently        contained more and heavier smokers than
                  areas of a nuclear reactor, and other consistent exposure (40 h/week, 5 days/week);     exposed workers and reference group after six regularly and frequently exposed workers);
                  research facilities                   reference group, casual and infrequent            years.26                                        limited number of cases
                                                        exposure
                  Mean age: 33 years                                                                                                                      Additional information:
                                                        Effect parameters: brief medical history on                                                       In cases of accidental exposure, symptoms
                                                        known renal and pulmonary disease, history on                                                     reported were headache and sore throat, which
                                                        skin disease; at t=0 and after one year: clinical                                                 subsided within 24 hours
                                                        and biochemical analysis (blood pressure,
                                                        pulmonary function, urinary and blood                                                             Reliability: 3
                                                        sampling)
 Overall, the Committee notes that there is a limited number of reliable
 data on exposure of humans.
21         Health Council of the Netherlands | No. 2020/09                                                                                                2                                            23
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<pre> chapter 06 | Effects                                                                                               Hydrogenated Terphenyl | page 23 of 67
 6.1.3   Carcinogenicity                                                     The acute oral toxicity of hydrogenated terphenyl is low, showing rat and
 No data available.                                                          mouse oral LD50 values in excess of 10 g/kg bw.5,27,28 After oral exposure
                                                                             to a single dose of hydrogenated terphenyl of 10 g/kg bw, observations on
 6.1.4   Reproductive and developmental effects                              rats included hypoactivity, diarrhea, faeces-stained and urine-stained fur.
 No data available.                                                          No abnormalities were noted at gross necropsy.28
 6.2     Animal experiments                                                  In a dermal irritation study according to the method of Draize, the
 Studies performed in laboratory animals are summarized in Annex C.          researchers reported that hydrogenated terphenyl was found to be mild or
                                                                             not irritating to rabbit skin. The primary dermal irritation index (PDII) was
 6.2.1   Health effects due to single exposure                               2.0 on a scale of 8.0 (0.0 (no irritation) up to 8.0 (extreme irritation).27
 The summarized studies in Annex C (Table C1) comprise one inhalation        In another study, dermal exposure of rabbits to hydrogenated terphenyl
 study in rats, and five oral studies of which four were performed in rats   resulted in a PDII of 0.1 (minimal irritation) on a scale of 8.0. Effects were
 and one in mice. Furthermore, three rabbit studies using dermal             fully reversible.29 A study for acute dermal toxicity in rabbits showed that
 applications, and one rabbit study with ocular exposure were available.     no deaths resulted from a dermal (occlusive) dosage of 2 g/kg bw.30
                                                                             There were no abnormal clinical and behavioural observations, and no
 In an acute inhalation study performed by Bechtel (1985), six groups of     abnormalities were seen at gross necropsy.
 12 rats per group were exposed to hydrogenated terphenyl once for 4
 hours.21 Mean exposure concentrations ranged from 2.5 to 4.7 g/m3.          In an eye irritation study in rabbits, the Draize score was 0.3 (no irritation)
 Immediately after exposure, observations included: salivation, wet fur on   on a scale of 110 (very severe irritation) after a single exposure to 0.1 ml
 the ventral side (due to salivation), discharges and/or encrustations about undiluted hydrogenated terphenyl.31
 the nose and eyes, laboured breathing, procumbent posture, and fur
 coated with test material. No terminal necropsy findings were reported,     Based on the observed health effects due to single exposure in animals,
 which are considered to be related to the test material.21                  the Committee concludes that the acute toxicity of hydrogenated terphenyl
                                                                             in animals is low after oral, inhalation and dermal exposure. In addition,
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<pre> chapter 06 | Effects                                                                                             Hydrogenated Terphenyl | page 24 of 67
 hydrogenated terphenyl is considered to be not irritating to rabbit skin or ppm. In this study, the no-observed-adverse-effect-level (NOAEL) was
 eyes.                                                                       1,000 ppm in the diet, corresponding with 60 mg/kg bw/day.32
 6.2.2   Health effects due to short-term exposure                           A dermal repeated dose administration study was performed in rats.24
 Three animal studies on short-term exposure to hydrogenated terphenyl       Hydrogenated terphenyl was admininistrated by dermal application to
 were identified. Two studies were rated with a high reliability score, and  5 males and 5 females per dose and control (abraded skin and unabraded
 are briefly described below. More details on the three studies are given    skin), at dose levels of 0, 125, 500 and 2,000 mg/kg bw, 5 days per week
 in Annex C, Table C2.                                                       for 3 consequitive weeks. At macroscopic examination, commonly
                                                                             observed findings were thickening and crust formation of the skin, which
 An oral dose range finding study was performed in rats, which were          were observed at all applied doses in both sexes. Gross and microscopic
 exposed to dose levels of 0, 1,000, 5,000, 10,000, or 20,000 ppm            changes on the skin application sites were observed at the dosage levels
 (corresponding with concentrations of 0, 60, 300, 600, or 1,200 mg/kg       of 125, 500 and 2,000 mg/kg bw/day. There were no other clinical effects
 bw/day) for two weeks.32 After two weeks of exposure mean body weights      observed. The authors considered the findings to be related to the dermal
 were reduced in the males and females at the 10,000 ppm (reduction of       application of hydrogenated terphenyl. The distribution and severity of the
 10% and 8%, respectively), and 20,000 ppm dose levels (reduction of         skin changes were generally more pronounced among male and female
 27% and 17% respectively). The female rats at 5,000 ppm also exhibited      rabbits at the 2,000 mg/kg bw.33
 an 8% reduction in mean body weight. Mean kidney weights were reduced
 in males and females at the 20,000 ppm dose level (approximately 22%        Overall, the Committee notes that there is a limited number of reliable
 and 20%, respectively). Dose-related increases were observed in the         animal data on the association between exposure to hydrogenated
 mean absolute liver weights, and relative liver to body weights of the      terphenyl at different dose levels and adverse effects after short-term
 treated males and females. Increases noted in mean liver weights ranged     exposure of animals. The available data show that limited changes were
 from 10% in the low-dose females to 144% in the high-dose females.          seen after exposure to hydrogenated terphenyl. The Committee considers
 Similar increases were observed in the treated males. Liver gross           the increase in (relative) liver weights in animals to be related to the
 changes were seen in animals at dose level 5,000, 10,000, and 20,000        systemic effects of hydrogenated terphenyl.
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<pre> chapter 06 | Effects                                                                                               Hydrogenated Terphenyl | page 25 of 67
 6.2.3    Health effects due to subchronic exposure                            were decreased for the group IV females (500 mg/m3) compared to the
 Annex C (Table C3) gives an overview of four animal expirements on            control females, and the mean total protein, albumin and calcium levels
 subchronic exposure to hydrogenated terphenyl and health effects.             were increased for group III and IV females (100 and 500 mg/m3,
 Two studies with a high reliability score are described below.                respectively) compared to control females. However, the researchers
                                                                               concluded that the majority of values were within historical control ranges,
 In a thirteen week inhalation toxicity study performed by Farr et al.         and were considered toxicologically not significant. The mean blood urea
 (1986, 1989), 15 rats per sex per group were exposed to hydrogenated          nitrogen level was increased for group IV males at test week 14 compared
 terphenyl at concentrations of 0 (group I), 10 (group II), 100 (group III)    to control males. However, values were within historical ranges and no
 and 500 mg/m3 (group IV) for 6 hours per day, 5 days per week.10,22           renal pathology was seen. Therefore, the researchers considered this
                                                                               difference not to be toxicologically significant.10,22 The NOAEL was
 Predominant clinical signs included lacrimation and rough coat in treated     reported to be 100 mg/m3.
 males, and dried brown material about the face in treated females. Liver
 weight changes were observed in animals at different exposure levels.         In an oral study performed by Farr et al. (1984, 1989), groups of 12 male
 The mean absolute and relative liver weights were increased for all groups    and 12 female rats were given diets containing 0, 50, 200 or 2,000 ppm
 of treated males compared to control males. The differences between           hydrogenated terphenyl for 14 weeks.10,34 Combined male and female
 treated and control males were statistically significant for all comparisons, nominal dietary doses of hydrogenated terphenyl was 0, 3, 12 and
 except for the absolute liver weights of group II and III males (10 and 100   120 mg/kg bw/day, respectively.
 mg/m3, respectively). Mean absolute and relative liver weights were not
 statistically significant changed in the exposed females compared to          At the highest dose, body weight loss and increases in liver, kidney and
 control females. There were no other exposure-related findings in the         adrenal weights were observed, but no other effects. There was an
 organ weight data of the males or females. There were no effects on gross     increased incidence of renal tubular lesions (foci of tubular epithelial cell
 pathological findings, and no effects on non-neoplastic histopathological     hypertrophy, and basophilia, a non-neoplastic histopathological finding) in
 findings. No hematological changes were noted by the researchers.             high dosed males when compared to control males. The researchers
 The mean serum glutamic oxaloacetic transaminase and glucose levels           considered the finding to represent regeneration. Effects were observed
24       Health Council of the Netherlands | No. 2020/09                                                                  2                                  26
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<pre> chapter 06 | Effects                                                                                              Hydrogenated Terphenyl | page 26 of 67
 on haematological findings (decrease in haemoglobin concentration,           Annex C (Table C4) presents dermal carcinogenicity studies on
 haematocrit and erythrocyte counts, slight increase in mean platelet count,  hydrogenated terphenyl, performed by Henderson and Weeks (1973).7
 statistically significant in high dosed males), and clinical biochemistry    The results of these studies indicate that the possibility of cancer
 (mean cholesterol increased in high dosed males, mean glucose                occurring in the skin of mice exposed to hydrogenated terphenyl is
 decreased in high dose dfemales, and mean calcium levels increased in        negligible. However, the Committee is of the opinion that dermal
 mid- and high dosed females). The NOAEL identified by the researchers        carcinogenicity studies were too limited for a conclusion.
 was 12 mg/kg bw/day (200 ppm).
                                                                              6.2.6   Genotoxicity
 Overall, the Committee notes that there is a limited number of reliable      Three in vitro studies were identified, presenting the results of bacterial
 animal data on subchronic exposure to hydrogenated terphenyl. The            and mammalian cell mutation assays.27,35,36 The studies showed that
 Committee concludes that hydrogenated terphenyl may cause an increase        hydrogenated terphenyl is not genotoxic in vitro. More details are given in
 in (relative) organ weights in animals (i.e., the liver, the kidneys and the Annex C, Table C5.
 adrenal glands), which is considered to be related to the systemic adverse
 health effects of hydrogenated terphenyl.                                    The mutagenic potential of hydrogenated terphenyl was also determined
                                                                              by a rat bone marrow cytogenetics assay.37 Rats were exposed to
 6.2.4    Non-carcinogenic adverse health effects due                         hydrogenated terphenyl at doses of 0, 250, 1,250 and 2,500 mg/kg bw.
          to long-term exposure                                               Cells from exposed animals and controls, were evaluated microscopically
 No data available.                                                           for mitotic index, and chromosomal abnormalities. No chromosomal
                                                                              damage was noted. Details are presented in Annex C, Table C6.
 6.2.5    Carcinogenicity
 Data on the potential carcinogenicity of hydrogenated terphenyl is very      The Committee notes that the bacterial and mammalian cell mutation
 limited. No carcinogenicity data are available after inhalation or oral      assays, and the in vivo chromosome aberration assay were negative.
 exposure.                                                                    Therefore, the Committee concludes that there are no indications of
                                                                              genotoxicity.
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<pre> chapter 06 | Effects                                                                                            Hydrogenated Terphenyl | page 27 of 67
 6.2.7     Reproductive and developmental effects                           An oral dose range finding study was performed in a teratology study with
                                                                            hydrogenated terphenyl in rats from days 6 to15 of pregnancy.39 The
 Fertility                                                                  maternal NOAEL was 250 mg/kg bw/day. The developmental NOAEL was
 An oral two-generation reproductive toxicity study in male and female rats 1,000 mg/kg bw/day.39
 was performed with hydrogenated terphenyl. Details are given in Annex C,
 Table C7.38 There were no adverse reproductive effects in any of the       The Committee noted that developmental toxicity could be related to
 measured parameters/indices in adult rats or their offspring. On the basis maternal toxicity, because in both studies maternal toxicity is observed at
 of these findings, the Committee noted that no reproductive effects were   lower exposure levels than developmental toxicity. Therefore, the
 seen in rats at the highest intake levels of 1,000 ppm (62.0 mg/kg bw/day  Committee is not able to conclude whether hydrogenated terphenyl could
 for males and 81.2 mg/kg bw/day for females).                              induce direct adverse effects on the developing embryo.
 Development                                                                Lactation
 Two developmental toxicity studies with hydrogenated terphenyl in          No data available.
 animals were identified and are summarized below.39,40 Details are shown
 in Annex C, Table C8.                                                      6.3      Summary
                                                                            A number of studies are available on the potential toxicity of hydrogenated
 Developmental toxicity was tested by oral administration of hydrogenated   terphenyl. The majority of these studies are animal experiments or in vitro
 terphenyl in rats from day 6 to 15 of gestation at 125, 500 and 1,500 mg/  assays.
 kg bw/day.40 Maternal toxicity was observed from 500 mg/kg bw/day,
 leading to foetotoxicity and malformations at 1,500 mg/kg bw/day. The      Observations in humans
 NOAEL for maternal toxicity was 125 mg/kg bw/day, the NOAEL for            Data on humans are limited to one skin sensitization study, and one study
 foetotoxicity was 500 mg/kg bw/day.                                        on long-term exposure of workers in a nuclear reactor. The results of the
                                                                            skin sensitation study were negative. The study on long-term exposure is
                                                                            of limited quality, one of the reasons being inadequate quantification of the
26        Health Council of the Netherlands | No. 2020/09                                                             2                                 28
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<pre> chapter 06 | Effects                                                                                                Hydrogenated Terphenyl | page 28 of 67
 exposure levels to which the participants were exposed. After accidental      effects after inhalation or oral intake of hydrogenated terphenyl up to 14
 exposure, the main adverse health effects reported by workers were skin       weeks.
 irritation, headaches and sore throats. Therefore, the Committee is of the
 opinion that human studies on the toxicity of hydrogenated terphenyl were     Carcinogenicity and genotoxicity
 too limited to allow derivation of a HBR-OEL.                                 The results of the animal studies on dermal carcinogenicity indicate that
                                                                               skin cancer risk in mice, exposed to hydrogenated terphenyl, is negligible.
 Animal experiments                                                            No other animal carcinogenicity experiments have been performed. The
 A number of animal acute toxicity studies have been performed that report     Committee notes that the bacterial and mammalian cell mutation assays
 LD50 values, ranging from more than 10 to 25 g/kg bw (oral                    and an in vivo chromosome aberration assay in rats were negative. The
 administration, rats). The Committee concludes that the acute toxicity of     Committee concludes that there are no indications of genotoxicity.
 hydrogenated terphenyl in animals is low after oral, inhalation and dermal
 exposure. In addition, hydrogenated terphenyl is considered to be not         Reproductive and developmental effects
 irritating to rabbit skin or eyes.                                            The Committee concluded that there is insufficient data available to
                                                                               classify hydrogenated terphenyl as a reproductive toxicant.
 The Committee noted that there is a limited number of reliable animal data    The Committee noted that developmental toxicity could be related to
 on short-term exposure. Increase in (relative) liver weights in animals after maternal toxicity, because in both animal studies maternal toxicity is
 oral intake of hydrogenated terphenyl (15 days, 7 days/week), is              observed at lower exposure levels than developmental toxicity. Therefore,
 considered to be related to the systemic effects of hydrogenated              the Committee is not able to conclude whether hydrogenated terphenyl
 terphenyl.                                                                    could induce direct adverse effects on the developing embryo.
                                                                               The Committee noted that there is no data available on the effects of
 Based on the results of animal studies on subchronic exposure to              hydrogenated terphenyl on or via lactation.
 hydrogenated terphenyl, the Committee concludes that, although
 histopathology showed no abnormalities, body weight loss and increase in
 (relative) organ weights (e.g., the liver) are the most relevant observed
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<pre> chapter 07 | Existing guidelines, standards and evaluation Hydrogenated Terphenyl | page 29 of 67
 07
 existing guidelines,
 standards and
 evaluation
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<pre> chapter 07 | Existing guidelines, standards and evaluation                                                               Hydrogenated Terphenyl | page 30 of 67
 7.1     General population                                              Table 6. Occupational exposure limits (as 8-hour time-weighted
 Guidelines or standards for exposure limits for hydrogenated terphenyl  averages and 15 minutes time weighted averages) for hydrogenated
 for the general population are not known.                               terphenyl in various countries.
                                                                          Country                           TWA, 8 hours                    TWA, 15 minutes    Reference
                                                                          - organisation
 7.2     Working population                                               The Netherlands (2019)            19 mg/m3                        48 mg/m3           43
 Principal effects of exposure to hydrogenated terphenyl listed bij OSHA  (adopted from European Union)
                                                                          European Union (2017)             19 mg/m3                        48 mg/m3           44
 are: HE3 (Chronic (Cumulative) Toxicity-Long-term organ toxicity other   - SCOEL (1994)                    2 ppm (19 mg/m3)                5 ppm (48 mg/m3)   3
                                                                          Germany
 than nervous, respiratory, hematologic or reproductive) and HE10         - AGS (2017)                      19 mg/m3 (inhalable fraction)                      45
 (Respiratory Effects Other Than Irritation-Cumulative lung damage).41    Norway (2009)                     0.4 ppm; 4.4 mg/m3              -                  46
                                                                          Denmark (2011)                    0.4 ppm; 4.4 mg/m3              -                  47
 The European Chemicals Agency agreed that terphenyl hydrogenated         USA
 meets the criteria set out in Article 57 of REACH for identification as  - ACGIH (2001)                    0.5 ppm; 5 mg/m3                                   2
                                                                          - OSHA PEL                        0.5 ppm; 5 mg/m3                                   41
 substance of very high concern, and included terphenyl hydrogenated in   - NIOSH                           0.5 ppm; 5 mg/m3                                   41
                                                                          ACGIH, American Conference of Governmental Industrial Hygienists; AGS, Ausschuss für
 the Candidate List for eventual inclusion in Annex XIV.14,42             Gefahrstoffe; NIOSH, National Institute for Occupational Safety and Health; OSHA, Occupational
                                                                          Safety and Health Admninistration; PEL, Permissable Exposure Limit; SCOEL, Scienific Committee
                                                                          on Occupational Exposure Limits; TWA, time weighed average contration.
 7.2.1   Occupational Exposure Limits
 Occupational exposure limits for hydrogenated terphenyl in some         In the evaluation by the SCOEL (1994) the quantitative hazard
 European countries and the USA, are presented in Table 6.               assessment is based on animal data as it is concluded that there are no
                                                                         available human data relating to exposure levels in excess of 0.1 ppm
                                                                         (0.95 mg/m3).3 Based on the inhalation study of Farr et al. (1989), the
                                                                         SCOEL used a NOAEL of 10 ppm (95 mg/m3) as a starting point.
                                                                         To allow for the extrapolation from animals to humans, an uncertainty
                                                                         factor of 5 was considered appropriate. The recommended 8-hour time
                                                                         weighted average (TWA) by the SCOEL is 2 ppm (19 mg/m3).
                                                                         Because of the reports of irritation in workers exposed to unspecified
29       Health Council of the Netherlands | No. 2020/09                                                                        2                                        31
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<pre> chapter 07 | Existing guidelines, standards and evaluation              Hydrogenated Terphenyl | page 31 of 67
 concentrations of hydrogenated terphenyl, a STEL (15 minutes) of 5 ppm
 (48 mg/m3) was proposed by the SCOEL to limit peaks in exposure,
 which could result in irritation.
 7.2.2   Classification on the carcinogenic properties
 So far known, hydrogenated terphenyl is not classified as a carcinogen.
 7.2.3   Classification on the reproduction toxic properties
 So far known, hydrogenated terphenyl is not classified as toxic to
 reproduction and development.
 7.2.4   Biological limit values
 No biological limit values have been set.
 7.2.5   Skin and sensitization notation
 In various countries, a skin notation was considered not to be
 necessary.3,43,44
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<pre> chapter 08 | Hazard assessment                        Hydrogenated Terphenyl | page 32 of 67
 08
 hazard
 assessment
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<pre> chapter 08 | Hazard assessment                                                                                     Hydrogenated Terphenyl | page 33 of 67
 8.1     Hazard Identification                                                 liver weight changes the most relevant observed adverse health effect for
 The main adverse health effects observed in humans were skin irritation,      hydrogenated terphenyl-induced toxicity.
 headaches, and sore throats after accidental exposure. These effects
 were reported, presumably following accidental spillages, and exposure        8.2     Quantitative hazard assessment
 to unspecified concentrations of hydrogenated terphenyl. The Committee        8.2.1   Critical study
 notes that there is a limited number of reliable data on exposure to          In deriving an HBR-OEL, the committee prefers using data from
 humans.                                                                       epidemiological studies rather than animal experiments, because
                                                                               epidemiological data do not involve the uncertainties associated with the
 Animal experiments on health effects due to single exposure indicate that     biological differences between animals and humans. Furthermore, the
 the acute toxicity of hydrogenated terphenyl in animals is low after oral,    exposure conditions in epidemiological studies reflect real life exposure
 inhalation, and dermal exposure. In addition, hydrogenated terphenyl is       circumstances in an occupational setting. Data from animal experiments
 considered to be not irritating to rabbit skin or eyes. Repeated dose         are considered only if epidemiological data are of insufficient quality or too
 studies in animals revealed body weight loss, and increase in (relative)      limited. In the case of hydrogenated terphenyl epidemiological data are
 organ weights after inhalation or oral exposure to hydrogenated terphenyl.    limited and insufficient, and, therefore, the committee used data from
 Because body weight loss was observed not only in the oral study, but         animal experiments.
 also in highly exposed male rats in an inhalation study, the Committee
 considers body weight loss to be an adverse health effect, which is not       The most clear and evident exposure-related effects of hydrogenated
 related to palatability problems. In addition, taking also into account the   terphenyl on organ weights are found in an inhalation and oral study in
 effects on liver weight, the Committee is of the opinion that the increase in rats, which was prublished by Farr et al. (1989).10 Increased absolute liver
 relative liver weight is an adverse health effect, although histopathological weights, and liver/body weight ratios, were seen at the high-exposure
 findings are negative. While the absolute liver weight was statistically      level in both sexes from the oral study, and in high-exposed males from
 significantly increased only at the high exposure level in male rats from     the inhalation study. Absolute kidney weights and kidney/body weight
 the inhalation study, relative liver weights were statistically significantly ratios were increased only in the high-dose animals of both sexes in the
 increased at all exposure levels. Overall, the Committee considers relative   oral study. Haematology and clinical chemistry showed no abnormalities;
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<pre> chapter 08 | Hazard assessment                                                                                      Hydrogenated Terphenyl | page 34 of 67
 changes observed were within the historical control ranges. Gross and        a defined critical effect size (CES). Literature shows that there is no
 histopathological examinations revealed no lesions to hydrogenated           consensus on critical effect sizes of organ weights.48 Small increase in
 terphenyl administration in either study. Although the significance of organ liver weight without significant histological findings, or marked changes in
 weight changes in absence of pathological observations is uncertain, the     clinical chemistry, is interpreted as an adaptive and not as an adverse
 committee is of the opinion that exposure to hydrogenated terphenyl is       health effect. In addition, it is important to consider that the liver weight
 harmful to the liver and the kidneys, which is supported by observations     may vary in healthy animals to up to 20%.49 The Committee notes that in
 in other studies.5,12                                                        the inhalation study and in the oral study by Farr et al. (1989), increase in
                                                                              liver to body weight ratio was more than 20% at the highest exposure
 Inhalation studies are most relevant for the occupational situation, but the level. Also, a decrease of body weight gain was evident at high exposure
 Committee also considers systemic health effects observed in oral            in male rats in the inhalation study. The Committee is of the opinion that a
 studies, which it considers relevant when these effects are also expected    CES of 20% is appropriate for changes in liver to body weight ratios in
 to occur after inhalation exposure. Therefore, the Committee has retrieved   rats.49
 and examined the results of the inhalation study, as well as the oral study
 published by Farr et al. (1989).10,22,34 Because no significant increase in  For the establishment of an HBR-OEL several aspects have to be
 the liver weight, and the liver to body weight ratio, were noted in female   considered:
 rats from the inhalation study, the Committee decided to use the data from   1. Interspecies differences. The Committee noted that in this case the
 male rats only. This means that the Committee considers male rats to be         effects were systemic, and, therefore a default uncertainty factor of
 more vulnerable to hydrogenated terphenyl than female rats.                     three should be applied.
                                                                              2. Intraspecies differences. Due to possible differences among workers,
 8.2.2   Derivation and recommendation of an HBR-OEL (8-hour TWA)                the Committee is of the opinion that another uncertainty factor of three
 In deriving an HBR-OEL, the Committee performed a benchmark dose-               is required.50
 analysis (BMD-analysis). Details on the analyses are shown in Annex D.       3. Differences beween experimental conditions and exposure pattern of
 The lowest BMDL is used as a starting point in deriving an HBR-OEL.The          the worker. Data were derived from an animal experiment, in which rats
 BMDL is the 95% lower confidence limit of the BMD that corresponds with         were exposed to hydrogenated terphenyl for a period of approximately
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<pre> chapter 08 | Hazard assessment                                                                                                       Hydrogenated Terphenyl | page 35 of 67
     14 weeks. The Committee is of the opinion that an adjustment factor of                     8.2.3   Short term exposure limit (STEL; 15-minutes TWA)
     2 is required to extrapolate from subchronic to chronic exposure for                       Based on the available literature indicating that the acute toxicity of
     which an HBR-OEL is derived.51,52                                                          hydrogenated terphenyls is low, the Committee concludes that a STEL
                                                                                                is not applicable.
 The Committee estimated the following HBR-OELs (8-hour TWA, Table 7):
                                                                                                8.2.4   Ceiling value
 Table 7 Health-based recommended occupational exposure                                         Not applicable.
 limit (8-hour TWA).
  Exposure in    Critical       BMDL                              Uncertainty         HBR-OEL   8.3     Classification
  rats           effect size                                      factors
  Inhalation     Relative liver 134 mg/m3                         3 (interspecies)    7.4 mg/m3 8.3.1   Classification as a carcinogenic substance
  (mg/m3)        weight                                           3 (intraspecies)
                 0.20                                             2 (subchr-chronic)
                                                                                                No human or animal carcinogenicity data are available on inhalation or
  Oral           Relative liver 19.1 mg/kg/day (corresponds       3 (interspecies)    7.4 mg/m3 oral exposure. The results of the study on dermal carcinogenitity in mice
  (mg/kg/day)    weight         with 133.7 mg/m3, based on        3 (intraspecies)
                 0.20           100% absorption, 70 kg body       2 (subchr-chronic)            indicate that the possibility of cancer occurring in the skin exposed to
                                weight, and a respiratory volume
                                of 10 m3/working day)#
                                                                                                hydrogenated terphenyl is negligible. Overall, the Committee concludes
                                                                                                that data are too limited to classify hydrogenated terphenyl as a
 # The Committee used default values for absorption, body weight and respiratory volume,
 because true values are unknown.                                                               carcinogen.
 Overall, the Committee recommends a health-based occupational                                  8.3.2   Classification as reproduction toxic substance
 exposure limit for hydrogenated terphenyl of 7.4 mg/m3, as an 8-hour                           No studies in humans are available. In two well-performed animal studies,
 TWA.                                                                                           maternal toxicity occured before adverse health effects on development
                                                                                                were noted. Since maternal toxicity by itself may induce developmental
                                                                                                effects, it is unclear to the DECOS whether hydrogenated terphenyl is
                                                                                                able to induce developmental effects. No data are available on effects on
                                                                                                lactation. Overall, the DECOS is of the opinion that, because of maternal
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<pre> chapter 08 | Hazard assessment                                               Hydrogenated Terphenyl | page 36 of 67
 toxicity, there are insufficient data for classifying hydrogenated terphenyl
 as a reproduction toxic substance.
 8.4      Skin notation
 The purpose of a skin notation is to indicate the need to prevent skin
 contamination when systemic effects may result from percutaneous
 absorption of a substance as a gas, a solid, or a liquid. To determine
 whether a skin notation needs to be applied, the Committee uses the
 document “Strategy for assigning a skin notation” by the European Centre
 for Ecotoxicology and Toxicology of Chemicals (Strategy for assigning a
 “skin notation”, ECETOC Document No. 31 (Revised 1993). According to
 the guidance, a skin notation is warranted when human experience
 indicates the importance of skin penetration. A skin notation should be
 applied when exposure of 2,000 cm2 of skin (both hands and forearms) to
 hydrogenated terphenyl during one hour could result in an absorbed
 amount exceeding 10% of the amount that can be absorbed via the lungs
 on exposure for eight hours to the HBR-OEL. Although a limited number of
 studies indicate that hydrogenated terphenyl is absorbed via the skin, data
 on skin absorption rates are missing. Therefore, the DECOS is not able to
 conclude whether a skin notation is recommendable.
 8.5      Groups at extra risk
 No data available.
35       Health Council of the Netherlands | No. 2020/09                          2                               37
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<pre> References                                            Hydrogenated Terphenyl | page 37 of 67
        references
36     Health Council of the Netherlands | No. 2020/09     2                               38
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<pre> References                                                                                                       Hydrogenated Terphenyl | page 38 of 67
 1
   Tomlinson M, Smee JL, Winters EB, Arneson MC. Atomic Energy of          7
                                                                              Henderson JS, Weeks JL. A study of the carcinogenicity for skin of a
   Canada Limited, Whiteshell Nuclear Research Establishment, Pinawa,         polyphenyl coolant. IMS Ind Med Surg 1973; 42(2): 10-21 (Summary
   Manitoba, Canada. Reactor Organic Coolants: I. Characteristics of          available at https://echa.europa.eu/registration-dossier/-/registered-
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                                                                              Klimisch HJ, Andreae M, Tillmann U. A systematic approach for
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   Values: Hydrogenated Terphenyls (nonirradiated). 2001.                     data. Regul Toxicol Pharmacol 1997; 25(1): 1-5.
 3
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 6
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                                                                               Farr CH. Monsanto Company, St. Louis, Missouri 63166, USA.
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    isomerenmengsel. SDU Geraadpleegd: 27 July 2018.                           Toxicological Information; Repeated dose toxicity: Inhalation 001 Key
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                                                                               Johnson D. Monsanto Company, St. Louis, Missouri 63166, USA.
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    Acute Toxicity of Therminol ® 66 Administered by Inhalation to Sprague-    Amber Liquid. Available for consultation at The Health Council of The
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    Summary publically available at https://echa.europa.eu/registration-
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    001 Key study.                                                              Key study.
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    Hawkins RJ, Weeks JL. Whiteshell Nuclear Research Establishment.         30
                                                                                Chow CP, Besserman M. Monsanto Company, St. Louis, Missouri
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    registration-dossier/-/registered-dossier/15941 Toxicological               Primary Eye Irritation of HB-40 ® Plasticizer to Rabbits. Available for
    Information; Acute Toxicity Oral 002 Supporting study; Irritation/          consultation at The Health Council of The Netherlands: Unpublished
    corrosion Skin 002 Supporting study; Genetic toxicity: in vitro 004         report, 1980; R 80-36. Summary publically available at https://echa.
    Supporting study).                                                          europa.eu/registration-dossier/-/registered-dossier/15941 Toxicological
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                                                                                Farr CH. Monsanto Company, St. Louis, Missouri 63166, USA. A
    Available for consultation at The Health Council of The Netherlands:        Two-week Dietary Range-Finding Toxicity Study of Therminol ® 66 in
    Unpublished report, 1980; 7R 80-39. Summary publically available at         Rats. Available for consultation at The Health Council of The
    https://echa.europa.eu/registration-dossier/-/registered-dossier/15941      Netherlands: Unpublished report, 1985; BD-84-258. Summary
    Toxicological Information, Acute Toxicity: Oral 001 Key study.              publically available at https://echa.europa.eu/registration-dossier/-/
 29
    Branch DK, Maylor MW, Mace GM. Monsanto Company, St. Louis,                 registered-dossier/15941 Toxicological Information; Repeated dose
    Missouri 63166, USA. Primary Skin Irritation of HB-40 ® Plasticizer to      toxicity: Oral 002 Supporting study
    Rabbits. Available for consultation at The Health Council of The         33
                                                                                European Chemicals Agency (ECHA). Information from Registration
    Netherlands: Unpublished Report, 1980; R 80-38. Summary publically          Dossiers: Terphenyl, hydrogenated https://echa.europa.eu/registration-
    available at https://echa.europa.eu/registration-dossier/-/registered-      dossier/-/registered-dossier/15941/1.
39       Health Council of the Netherlands | No. 2020/09                                                               2                                41
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<pre> References                                                                                                        Hydrogenated Terphenyl | page 41 of 67
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    Nair R. Monsanto Company, St. Louis, Missouri 63166, USA. A Three           https://echa.europa.eu/registration-dossier/-/registered-dossier/15941
    Month Oral Toxicity Feeding Study in Rats with Terminol-66. Available       Toxicological Information; Genetic toxicity: in vivo Key study.
    for consultation at The Health Council of The Netherlands: Unpublished   38
                                                                                Naylor MW, Ruecker FA. Monsanto Company, St. Louis, Missouri
    report, 1984; BD-84-360. Summary publically available at https://echa.      63166, USA. Two Generation Reporoduction Study of Therminol ®66
    europa.eu/registration-dossier/-/registered-dossier/15941 Toxicological     Heat Transfer Fluid in the Diet of Albino Rats. Available for consultation
    Information; Repeated dose toxicity: Oral 001 Key study.                    at The Health Council of The Netherlands: Unpublished report, 1991;
 35
    Godek EG, Naismith RW, Matthews RJ. Monsanto Company, St. Louis,            MSL-11457. Summary publically available at https://echa.europa.eu/
    Missouri 63166, USA. CHO/HGPRT Mammalian Cell Forward Gene                  registration-dossier/-/registered-dossier/15941 Toxicological
    Mutation Assay. Available for consultation at The Health Council of The     Information; Toxicity to reproduction: Key study.
    Netherlands: Unpublished report, 1985; PK-84-150. Summary                39
                                                                                Nair R. Monsanto Company, St. Louis, Missouri 63166, USA. A Range-
    publically available at https://echa.europa.eu/registration-dossier/-/      finding Study to Evaluate the Toxicity of Therminol ® 66 in the Pregnant
    registered-dossier/15941 Toxicological Information; Genetic toxicity: in    Rat. Available for consultation at The Health Council of The
    vitro 002 Key study.                                                        Netherlands: Unpublished report, 1985; BD-84-067. Summary
 36
    Kulik FA, Ross WD. Monsanto Company, St. Louis, Missouri 63166,             publically available at https://echa.europa.eu/registration-dossier/-/
    USA. Salmonella Mutagenicity Assay of HB-40 ®, DA-78-184.                   registered-dossier/15941 Toxicological Information; Developmental
    Unpublished report. Available for consultation at The Health Council of     toxicity/teratogenicity 002 Supporting study.
    The Netherlands (Title page only): Summary publically available at       40
                                                                                Farr CH. Monsanto Company, St. Louis, Missouri 63166, USA. A
    https://echa.europa.eu/registration-dossier/-/registered-dossier/15941      Teratology Study in Rats with Therminol ®66. Available for consultation
    Toxicological Information; Genetic toxicity: in vitro 001 Key study.        at The Health Council of The Netherlands: Unpublished report, 1986.
 37
    Blazak WF. Monsanto Company, St. Louis, Missouri 63166, USA. An             Summary publically available at https://echa.europa.eu/registration-
    Assessment of the Mutagenic Potential of Therminol ®66 Utilizing the        dossier/-/registered-dossier/15941 Toxicological Information: Toxicity to
    Acute IN VIVO Rat Bone Marrow Cytogenetics Assay (SR-84-415).               reproduction, Developmental toxicity/teratogenicity 001 Key study.
    Available for consultation at The Health Council of The Netherlands:
    Upublished report, 1986; SR-84-415. Summary publically available at
40       Health Council of the Netherlands | No. 2020/09                                                               2                                 42
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    Terphenyls. https://www.osha.gov/chemicaldata/chemResult.                  Januar 2006
    html?recNo=444. Geraadpleegd: 14 June 2018.                             46
                                                                               Arbeidstilsynet V, best.nr. 361. Veiledning om Administrative normer for
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    Rijksinstituut voor Volksgezondheid en Milieu (RIVM). Totale lijst van     forurensning i arbeidsatmosfære. 2009:
    Zeer zorgwekkende stoffen. website “Risico’s van stoffen”: www.rivm.nl/ 47
                                                                               NIOSH. Terphenyls, hydrogenated. The National Institute for
    rvs https://rvszoeksysteem.rivm.nl/ZZSlijst/TotaleLijst. Geraadpleegd:     Occupational Safety and Health: Registry of Toxic Effects of Chemical
    30 July 2018.                                                              Substances (RTECS), 2017. https://www.cdc.gov/niosh-rtecs/
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    Wettenbank. Lijst van wettelijke grenswaarden op grond van de              wz63b758.html. Geraadpleegd: 14 June 2018
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    Arbeidsomstandighedenbesluit. Overheid.nl,                                 Assessment, TNO Nutrition and Food Research, P.O. Box 360,
    Arbeidsomstandighedenregeling, Bijlage XIII. behorend bij artikel 4.19,    NL-3700 AJ Zeist, The Netherlands. Critical effect sizes in toxicological
    eerste lid: https://wetten.overheid.nl/BWBR0008587/2019-01-                risk assessment: a comprehensive and critical evaluation.
    01#BijlageXIII.                                                            Environmental Toxicology and Pharmacology 2001; 10: 33-52.
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    grenswaarden voor beroepsmatige blootstelling uit hoofde van Richtlijn     Sons Ltd: 2019.
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    2000/39/EG en 2009/161/EU van de Commissie. Publicatieblad van de          and food Research Institute. Methods for the establishment of Health-
    Europese Unie L27/115: https://eur-lex.europa.eu/legal-content/NL/         Based Recommended Occupational Exposure Limits for existing
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    toxicological data. Ann Occup Hyg 2002; 46(2): 175-85.
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    Adamson IY, Bowden DH, Wyatt JP. The acute toxicity of reactor
    polyphenyls on the lung. Arch Environ Health 1969; 19(4): 499-504
    (Summary available at https://echa.europa.eu/registration-dossier/-/
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42       Health Council of the Netherlands | No. 2020/09                      2                               44
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<pre> Annexes                                              Hydrogenated Terphenyl | page 44 of 67
        annexes
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<pre> Annexes                                                                                                             Hydrogenated Terphenyl | page 45 of 67
 A          criteria for testing reliability of                                   Reliability 4 (not assignable)
            animal and in vitro studies                                           For example, only short abstract available; only secondary literature
                                                                                  (review, tables, books, etc.).
 To assess the reliability of animal and in vitro studies, the Committee uses
 the criteria set by Klimisch et al. 1997.8 A summary of the criteria of the
 reliability scores is given below. Only studies with a reliability score of 1 or
 2 are considered in assessing genotoxicity and carcinogenicity.
 Reliability 1 (reliable without restriction)
 For example, guideline study (OECD, etc.); comparable to guideline study;
 test procedure according to national standards (DIN, etc.).
 Reliability 2 (reliable with restrictions)
 For example, acceptable, well-documented publication/study report which
 meets basic scientific principles; basic data given: comparable to
 guidelines/standards; comparable to guideline study with acceptable
 restrictions.
 Reliability 3 (not reliable)
 For example, method not validated; documentation insufficient for
 assessment; does not meet important criteria of today standard methods;
 relevant methodological deficiencies; unsuitable test system.
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<pre> Annexes                                                                                                            Hydrogenated Terphenyl | page 46 of 67
 B          reliability testing of                                           5. The sample/exposure range was sufficient to study the question under
            epidemiological studies                                             investigation, so that effects estimates are not constrained by high
                                                                                imprecision.
                                                                             6. The data were analysed using appropriate statistical techniques to
 To assess the reliability of epidemiological studies, the Committee uses       address the research questions and model assumptions.
 the criteria set by Money et al.(2013).9 A summary of the reliability       7. The methodology and results were comprehensively and transparently
 categories set by Money et al. (2013) is given below. Only studies with a      reported according to relevant guidelines (e.g., the STROBE guidelines
 reliability score of 1 or 2 are considered in assessing genotoxicity and       for observational data, Von Elm et al. 2007).
 carcinogenicity.
                                                                             Acute or specific outcomes
 Reliability 1 (reliable without restriction)                                The same principles should be applied as for chronic, non-specific
 Chronic, non-specific outcomes                                              outcomes. The focus lies more with how well exposure has been
 Appropriate study design to research question.                              characterised, and the disease outcome is defined.
 1. Selected subjects or persons at risk represent appropriate exposure
    distributions. Adequate procedures of follow-up and reduction of loss to Reliability 2 (reliable with restrictions)
    follow up were performed.                                                Chronic, non-specific outcomes
 2. Exposure assessment was made independent of outcome with                 Applies to studies which possess most of the qualities of studies with
    validated methods, preferentially with individual exposure data.         reliability 1. The overall quality is comprised due to minor, but obvious,
 3. Effect data were collected independently from exposure status, using     methodological limitations. Examples include well-designed and
    standardized data collection procedures/registries.                      conducted studies, but with limited measurement data, possibility of some
 4. The possibility of serious bias has been reduced by design, controlled   residual confounding, some imprecision due to small sample size or low
    through statistical adjustment, and/or quantified through sensitivity    exposure range.
    analyses.
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<pre> Annexes                                                                  Hydrogenated Terphenyl | page 47 of 67
 Acute or specific outcomes
 The same principles should be applied as for chronic, non-specific
 outcomes. Examples of shortcomings may include a lack of individual
 exposure data, and effects derived from self-reported outcomes.
 Note: some studies with serious methodological limitations may provide
 reliable information for an acute or specific outcome.
 Reliability 3 (not reliable)
 The studies fail to meet one or more of the most basic standards
 necessary to interpret epidemiologic research, such as appropriate study
 design to the research question. Shortcomings may include using census
 job titles as a surrogate for exposure.
 Reliability 4 (not assignable)
 This includes studies or data which do not give sufficient details about
 methodology used, or which are short listed in abstracts or secondary
 literature.
46        Health Council of the Netherlands | No. 2020/09                     2                               48
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<pre> Annexes                                                                                                                                            Hydrogenated Terphenyl | page 48 of 67
 C effects observed in animal studies
 Table C1. Health effects due to single exposure
 Inhalation exposure
  Reference        Substance       Study design and    Data on exposure and effect endpoints          Results                                            Remarks
                                   animal species
  Bechtel (1985)21 Mixture of      Acute toxicity test Concentrations: 0, 2.5, 3.6, 4.4, and 4.7 g/m3 LC50 > 4.7 g/m3                                    Test Guideline equivalent or similar to OECD
                   hydrogenated                        (aerosol)                                                                                         Guideline 403 (Acute Inhalation Toxicity);
                   terphenyls      Sprague-Dawley                                                     Clinical signs immediately after exposure:         GLP-compliant study; unpublished report; no
                   (Therminol® 66) rats,               Single exposure: 4 hours                       salivation, wet fur on the ventral side, discharge restrictions, adequate for assessment; reliability
                                   Males and females; Observation period: 14 days, animals held in    and/or encrustation about the nose and eyes;       1
                                   N=6/sex/group       ambient and elevated temperatures              labored breathing; prostrate condition (not
                                                                                                      specified) and fur coated with test material
                                                       Endpoint: LC50
47         Health Council of the Netherlands | No. 2020/09                                                                                               2                                                49
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<pre> Annexes                                                                                                                                               Hydrogenated Terphenyl | page 49 of 67
 Oral exposure
 Reference       Substance           Study design and     Data on exposure and effect endpoints         Results                                            Remarks
                                     animal species
 Clark et al     Therminol® 66.      Acute toxicity test  Dosages spaced at about 0.1 log increments.   LD50 > 24 g/kg bw                                  GLP compliance not specified; reliability 1
 (1979)27                                                 Maximum dose applied: 24 g/kg bw (by gavage)
                 General             Female Fischer                                                     No clinical signs of toxicity other than diarrhea
                 composition:        344 Rats; N=5/       Test period: 14 days                          during the first 24 hours (dose not specified)
                 modified            group;
                 terphenyls, no      control animals not  Endpoint: LD50
                 details             mentioned
 Branch          Mixture of          Acute toxicity test  Single dose by gavage, 10 g/kg bw             LD50 > 10 g/kg bw                                  Test Guideline equivalent or similar to the
 (1980)28        hydrogenated                                                                                                                              deleted OECD Guideline 401 (Acute Oral
                 terphenyls (HB-40®) Male and female      Observation period: 15 days                   Observations (n observed/dosed):                   Toxicity); Guideline 401 was deleted in 2002;
                                     Sprague-Dawley                                                     - hypoactivity (10/10)                             GLP compliance; reliability 1
                 Impurities: 0.15%   rats; N=5/sex/       Endpoint: LD50                                - diarrhea (8/10)
                 phenyl              group, no control                                                  - feces-stained fur (10/10)
                 cyclohexane,        animals                                                            - urine-stained fur (10/10)
                 6.79% high boilers
 Adamson and     hydrogenated        Acute Toxicity test. Various doses by gavage, between 1 and        LD50 approximately 17.5 g/kg bw                    GLP compliance not specified; no data on
 Weeks (1973)5   terphenyl (HB-40®)                       50 g/kg bw.                                                                                      clinical observations and gross pathology;
                 or mineral oil      Hooded male rats;                                                                                                     reliability 2
                                     N=6/group            Endpoint: LD50
 Adamson and     hydrogenated        Acute Toxicity test  Exposure: various doses by gavage, between 1  LD50 approximately                                 GPL compliance not specified; no data on
 Weeks (1973)5   terphenyl (HB-40®)                       and 50 g/kg bw                                12.5 g/kg bw                                       clinical observations and gross pathology;
                 or mineral oil      Male mouse                                                                                                            reliability 2
                                     JAX® Black Mice      Endpoint: LD50
                                     (strain not
                                     specified);
                                     N=6/group
 Hasegawa et al. Hydrogenated        Acute toxicity test. 6 increasing dose levels, not specified       Acute toxic symptom: sedation                      Documentation insufficient for assessment;
 198953          terphenyl                                                                                                                                 reliability 3
                                     Male and female      Observation period: 14 days                   Changes in tissue: congestion of viscera
                                     Wistar rats; N=10/
                                     group                Endpoints: clinical signs, changes in tissue, LD50 male: 25 g/kg bw.
                                                          organ toxicity, and LD50                      LD50 female: 24 g/kg bw
48        Health Council of the Netherlands | No. 2020/09                                                                                                  2                                             50
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<pre> Annexes                                                                                                                                                   Hydrogenated Terphenyl | page 50 of 67
 Dermal exposure
 Reference       Substance           Study design and     Data on exposure and effect endpoints              Results                                           Remarks
                                     animal species
 Chow and        Mixture of          Acute dermal         Occlusive, shaved dorsal surface                   No exposure-related effects                       Test Guideline equivalent or similar to OECD
 Besserman       hydrogenated        toxicity test                                                                                                             Guideline 402 (Acute Dermal Toxicity); reliability
 (1980)30        terphenyls (HB-40®)                      Dose: 2 g/kg bw                                                                                      1
                                     Male and female
                 Impurities: 0.15    New Zealand White    Exposure: 24 hours continuous
                 phenyl              rabbits; N=5/sex     Observation period: 14 days
                 cyclohexane,
                 6.79% high boilers
 Branch et al.   Mixture of          Irritation/corrosion Draize test: occlusive, dorsal surface, intact and Primary dermal irritation index (PDII): 0.1 on a  Reliability 1
 (1980)29,33     hydrogenated        study                abraded skin                                       scale of 8.0 (fully reversible); erythema score
                 terphenyls (HB-40 )
                                   ®
                                                                                                             0.1 on a scale of 4 (fully reversible); edema
                                     Male and female      Amount applied: 0.5 mL neat substance to each score: 0 on a scale of 4 (fully reversible)
                 Impurities: 0.15    New Zealand White    application site
                 phenyl              rabbits; N=3/sex
                 cyclohexane,                             Exposure: 24 hours
                 6.79% high boilers                       Observation period: 14 days
                                                          Reading times primary dermal irritation index
                                                          (PDII): 24, 72 hrs
 Clark et al.    Therminol® 66       Irritation/corrosion Draize test: skin abraded and unabraded            Primary dermal irritation index (PDII): 2 on a    Reliability 2
 (1979)27                            study                                                                   scale of 8.0. Impossible to calculate mean
                 General                                  Reading times: 24 and 72 hours after               erythema score and mean edema score from
                 composition:        Male and female      application                                        data
                 modified            New Zealand White
                 terphenyls, no      rabbits; N=3/sex
                 details
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<pre> Annexes                                                                                                                                                  Hydrogenated Terphenyl | page 51 of 67
 Ocular exposure
  Reference       Substance           Study design and     Data on exposure and effect endpoints            Results                                           Remarks
                                      animal species
  Chow            Mixture of          Eye irritation study Draize test: ocular contact, right eye           Conjunctivae score: 0 on a scale of 3;            Reliability: 2
  (1980)31,33     hydrogenated                                                                              Chemosis score: 0 on a scale of 4; Cornea
                  terphenyls (HB-40®) Male and female      Dose: 0.1 mL of undiluted Terphenyl              opacity score: 0.06 on a scale of 4 (fully
                                      New Zealand White    hydrogenated                                     reversible within 48h);
                  Impurities: 0.15    rabbits; N=3/sex                                                      Iris score: 0 on a scale of 2; Draize score: 0.3
                  phenyl                                   Reading times Draize score: 24, 48 and 72        on a scale of 110 (fully reversibel within 48h)
                  cyclohexane,                             hours
                  6.79% high boilers
 Table C2. Health effects due to short-term exposure
 Inhalation exposure
  Reference       Substance           Study design and     Data on exposure and effect endpoints            Results                                           Remarks
                                      animal species
  Adamson et al   Compressed air      Mouse strain not     Exposure: 0.5 g/m3 (aerosol), 7 hours/day for 2, Weight loss after exposure during 7 hours/day     Documentation infsufficient for assessment: no
  (1969)54        containing a        specified; sex not   4, 6 or 8 days or 4 hours/day for 2 or 4 days    compared to controls. After exposure during       statistical analysis, no data on exact exposure
                  mixture of ortho-,  specified; N=16/                                                      4hours/day weight gain was similar compared       concentration, no data on percentage of higher
                  para-, and meta-    group                Endpoints: animal weight, food consumption,      to controls                                       polymers in oil; reliability 3
                  terphenyls, with a                       hematocrit levels and hematologic counts,
                  small concentration                      alveolar cell counts, abnormalities in paraffin  Histopathology of the lungs showed change of
                  of higher polymers                       sections from the lung, liver, kidney, bladder,  mitochondria in alveolar type 2 cells, however
                                                           adrenal, spleen, heart, brain, and bone marrow   this change was reversible 42 days after final
                                                                                                            exposure
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<pre> Annexes                                                                                                                                        Hydrogenated Terphenyl | page 52 of 67
 Oral exposure
 Reference      Substance         Study design and Data on exposure and effect endpoints          Results                                           Remarks
                                  animal species
 Farr (1985)32  Mixture of        Male and female  Dose (by feed): 0 (c, control) 1,000; 5,000;   NOAEL: 60 mg/kg bw/day                            GLP-compliant study; statistical evaluations
                hydrogenated      Sprague-Dawley   10,000; 20,000 ppm, corresponding with 60;     LOAEL: 300 mg/kg bw/day.                          were not done because of small numbers of
                terphenyls.       rats;            300; 600; 1,200 mg/kg bw/day                                                                     animals on test in this range-finding study;
                (Therminol® 66®)  N=5/sex/group                                                   Data in mean%±SD, increasing dose                 reliability 1
                Assume 100%                        Exposure: 15 days, 7 days/week
                active ingredient                                                                 Males
                                                   Endpoints: physical observations, body weight, Kidneys to terminal bw ratio:
                                                   food consumption, gross postmortem             0.85±0.03 (c), 0.86±0.05, 0.88±0.08,
                                                   examinations; no histopathological             0.91±0.03, 0.93±0.05
                                                   examinations                                   Liver to terminal bw ratio:
                                                                                                  3.33±0.18 (c), 3.88±0.21, 6.68±0.15,
                                                                                                  8.71±0.45, 10.15±0.26
                                                                                                  Females
                                                                                                  Kidneys to terminal bw ratio:
                                                                                                  0.86±0.08 (c), 0.93±0.09, 0.89±0.09,
                                                                                                  0.87±0.03, 0.85±0.04
                                                                                                  Liver to terminal bw ratio:
                                                                                                  3.13±0.16 (c), 3.66±0.15, 5.03±0.39,
                                                                                                  6.80±0.51, 9.55±0.81
                                                                                                  Food consumption increased at 10,000 ppm
                                                                                                  and 20,000 ppm (males only)
                                                                                                  Liver gross pathological changes: enlargement,
                                                                                                  surface irregularities (raised tan foci) and
                                                                                                  discolorations (primarily mottled tan) at 5,000,
                                                                                                  10,000 and/or 20,000 ppm
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<pre> Annexes                                                                                                                                             Hydrogenated Terphenyl | page 53 of 67
 Dermal exposure
 Reference       Substance            Study design and  Data on exposure and effect endpoints           Results                                          Remarks
                                      animal species
 Johnson         High Boiling Liquid, Male and female   Dermal: occlusive, abraded skin and unabraded   Dermal irritation (very slight to moderate       GLP compliant, well-documented study;
 (1981)24        Hydrocarbon          New Zealand White skin                                            erythema, edema, atonia, skin pealing,           reliability 1
                 (HB-40®)             Rabbits; N=5/sex/                                                 coriaceous and very slight to marked skin
                                      group             Dose (nominal): 0, 125, 500, and 2,000 mg/kg    fissures were observed for some rabbits in all
                                                        bw/day                                          test groups)
                                                        Exposure: 6 hours/day, 5 days/week for 21 days Macroscopy: thickening and crust formation at
                                                                                                        125, 500 and 2,000 mg/kg bw among male and
                                                        Endpoints: mortality, clinical effects, body    females.
                                                        weights, dermal irritation, clinical chemistry, Microscopy: acanthosis, hyperkeratosis,
                                                        organ weights, macroscopy and microscopy of     inflammatory cell infiltrates. Microabscesses at
                                                        selected tissues                                2,000 mg/kg bw. The distribution and relative
                                                                                                        severity of the skin changes were generally
                                                                                                        more pronounced among male and female
                                                                                                        rabbits at the 2,000 mg/kg bw dosage level
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<pre> Annexes                                                                                                                                          Hydrogenated Terphenyl | page 54 of 67
 Table C3. Health effects due to subchronic exposure
 Inhalation exposure
  Reference       Substance       Study design and Data on exposure and effect endpoints             Results                                          Remarks
                                  animal species
  Farr (1986)22   Mixture         Male and female  Concentration (aerosol):                          NOAEL was 100 mg/m³                              OECD Guideline 413 (subchronic inhalation
  Farr et al.     (Therminol® 66) Sprague-Dawley   - Group I: 0 mg/m³ air (control);                                                                  toxicity: 90-Day Study), GLP compliant;
  (1989)10                        rats; N= 15/sex/ - Group II: 10 mg/m³ air corresponding to 11.4   Clinical effects observed (increased incidences  reliability 1
                                  group              mg/m³ (males) and 11.3 mg/m³ (females);         of excess lacrimation and rough coat exhibited
                                                   - Group III: 100 mg/m³ air corresponding to 98.7 by all groups of treated males compared to
                                                     mg/m³ (males) and 98.4 mg/m³ (females);         control males; dried brown material about the
                                                   - Group IV: 500 mg/m³ air corresponding to 480   face exhibited by females, primarily in the
                                                     mg/m³ (males) and 479 mg/m³ (females)           mid- and high-dose animals)
                                                   Exposure: 6 hours/day, 5 days/week for 13         Effects on body weight and weight changes:
                                                   weeks                                             - terminal mean body weight males, mean
                                                                                                       (g)±SD: 586±33, 570±41, 594±54, 543±15*
                                                   Endpoints: clinical signs, body weights, major
                                                   organ weights haematology and clinical            Effects on organ weights
                                                   chemistry, gross postmortem examination,          - absolute liver weight males, mean (g)±SD:
                                                   histopathology.                                     18.62±1.42, 19.76±2.29, 20.74±2.77,
                                                                                                       21.60±3.40*
                                                                                                     - liver/total body weight males (x100) mean
                                                                                                       (g)±SD: 3.15±0.16, 3.46±0.25**, 3.49±0.24**,
                                                                                                       3.97±0.37**
                                                                                                     Statistically significant: *p≤0.05, **p≤0.01
                                                                                                     Mortality observed (N=1 in group I female); no
                                                                                                     other exposure-related effects observed
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<pre> Annexes                                                                                                                                        Hydrogenated Terphenyl | page 55 of 67
 Oral exposure
 Reference       Substance       Study design and Data on exposure and effect endpoints            Results                                                                Remarks
                                 animal species
 Farr et al      Therminol® 66   Male and female  Dose: 0 (c; control), 50, 200, or 2,000 ppm      NOAEL 12 mg/kg bw/day (200 ppm)                                        Reliability 1
 (1989)10                        Sprague-Dawley   (corresponding to 0, 3, 12 and 120 mg/kg
 Nair (1984)34                   (CD) rats; N=12/ bw/day)                                          Data, mean±SD, increasing dose
                                 sex/group
                                                  Exposure for approximately 14 weeks              Males
                                                                                                   Terminal body weight (g):
                                                  Endpoints: observations for clinical signs, body 476±49 (c), 503±41, 486±57, 464±54
                                                  weights,ophthalmoscopy, haematology and          Liver weight (g) mean±SD:
                                                  clinical chemistry, major organ weights, gross   13,17±1.46 (c), 13.82±1.42, 14.35±2.38, 19.32±2.49**
                                                  and histopathology                               Liver to body weight ratio (g/100g):
                                                                                                   2.77±0.09 (c), 2.75±0.15, 2.94±0.21, 4.18±0.42**
                                                                                                   Kidney weight (g):
                                                                                                   3.13±0.40 (c), 3.23±0.35, 3.15±0.32, 3.36±0.38
                                                                                                   Kidney to body weight ratio (g/kg):
                                                                                                   6.61±0.81 (c), 6.42±0.58, 6.52±0.58, 7.27±0.59*
                                                                                                   Adrenal to body weight ratio (mg/g):
                                                                                                   1.13±0.21 (c), 1.07±0.22, 1.11±0.17, 1.18±0.18
                                                                                                   Females
                                                                                                   Terminal body weight (g):
                                                                                                   280±26 (c), 280±36, 287±30, 262±17
                                                                                                   Liver weight (g):
                                                                                                   7.52±1.5 (c), 7.52±1.05, 7.82±0.84, 9.07±1.16**
                                                                                                   Liver to body weight ratio (g/100g):
                                                                                                   2.68±0.25 (c), 2.69±0.21, 2.69±0.18, 3.45±0.29**
                                                                                                   Kidney weight (g):
                                                                                                   1.81±0.16 (c), 1.91±0.28, 1.98±0.27, 2.02±0.23
                                                                                                   Kidney to body weight ratio (g/kg):
                                                                                                   6.63±0.58 (c), 6.84±0.60, 6.90±0.93, 7.70±0.52*
                                                                                                   Adrenal to body weight ratio (mg/g):
                                                                                                   2.34±0.31 (c), 2.43±0.40, 2.28±0.43, 2.73±0.34*
                                                                                                   Statistically significant, *p≤0.05, **p≤0.01
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<pre> Annexes                                                                                                                                              Hydrogenated Terphenyl | page 56 of 67
 Reference       Substance          Study design and    Data on exposure and effect endpoints          Results                                                                        Remarks
                                    animal species
                                                                                                       Effects on haematological findings (decrease in haemoglobin concentration,
                                                                                                       haematocrit and erythrocyte counts, slight increase in mean platelet count,
                                                                                                       statistically significant in high-dose males) and clinical biochemistry (mean
                                                                                                       cholesterol increased in high dose males, mean glucose decreased in high
                                                                                                       dose females, mean calcium levels increased in mid- and high dose females)
 Adamson and     hydrogenated       Male JAX® mouse     Dose (by gavage): 20, 250, 600, 1,200, 2,000   NOAEL was 600 mg/kg body weight/day                                            Documentation
 Weeks (1973)5   terphenyl (HB-40®) (strain not         mg/kg bw/day                                                                                                                  infsufficient for
                 or mineral oil     specified); N=10/                                                  Mitochondrial changes in epithelial cells of proximal tubulus. At high doses   assessment;
                                    group               Exposure: 112 days; 1 or 2 doses/week.         these cells became necrotic as interstitial nephritis and scarring developed.  reliability 3
                                                                                                       The nephritis was irreversible and followed 16 weeks of 1,200 mg/kg bw/day.
                                                        Endpoints:histopathology and total protein in  Hepatic changes were observed only at the ultrastructural level where abundant
                                                        liver (µg/mg tissue)                           smooth endoplasmic was seen
 Percutaneous exposure
 Reference       Substance          Study design and    Data on exposure and effect endpoints          Results                                               Remarks
                                    animal species
 Verkkala and    A terphenyl        Male Wistar rats;   Percutaneous, tail, 1.5 cm distal to the anus, No systemic toxicity (The total absorbed              Reliability 3
 Havolainen      mixture, 40%       number of animals   12 cm2                                         terphenyl dose exceeded the acute LD50
 (1983)55        aromatic bonds     (test and controls)                                                reported by the producer as 10 g/kg body wt).
                 hydrogenated       unknown             Absorbed dose: 0.23±0.05 g/12 cm2 skin in 3h;  Dark discolorisation of the skin without
                                                        cumulative total dose: 39 g/kg bw/8 weeks;     appearance of papillomas.
                                                        exposure: 3 hours/day, 4-8 weeks.              No effect on motor conduction time (no
                                                                                                       demyelination), polyphasia and progressively
                                                        Endpoint: Motor conduction time/muscle         decreasing muscle responses (signs of axonal
                                                        responses                                      damage)
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<pre> Annexes                                                                                                                                            Hydrogenated Terphenyl | page 57 of 67
 Table C4. Carcinogenicity studies in animals
  Reference     Substance           Study design and Data on exposure and effect endpoints             Results                                          Remarks
                                    animal species
  Henderson and hydrogenated        Skin exposure    Dermal, dose: 50 mg HB-40® or 270 mg tar          After 37 weeks, no skin tumour had appeared      Reliability 2
  Weeks         terphenyl (HB-40®), study            (control) applied at regular intervals (weekly)   on skin painted with terphenyl, hydrogenated;
  19737         Landsteiner tar                      Exposure: 37 weeks with terphenyl,                proportion of autopsied positive controls with
                (positive control)  Male and female  hydrogenated and then 22 weeks with croton oil    skin cancer: 20/23
                                    Balb/c Mouse;    (solvent)
                                    N=10/sex                                                           Proportion of autopsied mice with skin cancer
                                                     Endpoints:all skin tumours, skin cancers,         after 59 weeks: HB-40®: 0/24
                                                     mammary tumours, long tumours, leukemia,
                                                     pancreatic adeno cancers, ovarian tumours
  Henderson and hydrogenated        Skin exposure    Dermal dose: 50 mg/week                           No skin tumours observed                         Reliability 2
  Weeks         terphenyl (HB-40®), study
  19737         Landsteiner tar                      Exposure: 14 weeks with terphenyl,
                (positive control)  Male and female  hydrogenated (5, 4, 3, 2 or 1 times/week),
                                    Balb/c mouse;    therafter 13 weeks, twice weekly with croton oil)
                                    N=10/sex
                                                     Endpoint: skin carcinogenicity
  Henderson and hydrogenated        Skin exposure    Dermal dose: 50 mg/week                           No skin carcinogenicity, the tumours found fell  Reliability 2
  Weeks         terphenyl (HB-40®), study                                                              within normal histological range
  19737         Landsteiner tar                      Exposure: 37 weeks, once/week.
                (positive control)  Male/female PLA
                                    mouse; N=10/sex  Endpoint: skin carcinogenicity
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<pre> Annexes                                                                                                                                               Hydrogenated Terphenyl | page 58 of 67
 Table C5. Bacterial and mammalian cell mutation assays
  Reference       Substance        Cell system          Data on exposure                                 Results                                            Remarks
  Clark et al.    Therminol 66
                            ®
                                   Bacterial reverse    Test concentrations: up to 10,000 µg/plate       Mutagenicity: no effect (no details)               Reliability 1
  (1979)27                         mutation assay: S.
                  General          typhimurium TA                                                        Cytotoxicity not observed up to 10,000 µg/plate
                  composition:     1535, TA 1537, TA
                  modified terphe- 98 and TA 100; with
                  nyls, no details and without
                                   metabolic activation
  Kulik (1978)36  40% hydrogenated Bacterial reverse    Test concentrations: 0.01, 0.04, 0.2, 1.0, 3.0,  Mutagenicity: no effect                            Comparable to guideline study; reliability 2
                  terphenyls       mutation assay: S.   10.0 µL/plate
                                   typhimurium TA                                                        No cytotoxicity but tested up to limit
                                   1535, TA 1537, TA    3 positive controls (with or without S-9 mix), 3 concentrations
                                   98 and TA 100; with  replications.
                                   and without
                                   metabolic activation
  Godek et al.    Mixture          Mammalian cell       Test concentrations: 0, 25, 50, 75, 100 and 300  Mutagenicity: no effect                            GLP compliant, unpublished report, adequate
  (1985)35        Therminol® 66    gene mutation        µg/mL                                                                                               assessment; reliability 1
                                   assay; Chinese                                                        Cytotoxicity not bserved up to 1,000 µg/mL
                                   hamster ovary        Test included positive control                   (precipitation of the test article was apparent at
                                   (CHO), cell line                                                      all doses above 100 µg/mL)
                                   CHO-K1-BH4; with
                                   and without
                                   metabolic activation
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<pre> Annexes                                                                                                                                         Hydrogenated Terphenyl | page 59 of 67
 Table C6. Rat bone marrow clastogenicity
  Reference       Substance       Study design and Data on exposure and effect endpoints              Results                                        Remarks
                                  animal species
  Blazak          Complex mixture Mammalian Bone   Single intraperitoneal injection of 0, 250, 1,250, Genotoxicity: no effect                        OECD Guideline 475; reliability 1
  (1986)37        Therminol® 66   Marrow           and 2,500 mg/kg bw
                                  Chromosome                                                          Results 24h (negative control, 2,500 mg/kg bw
                                  Aberration Test  Sampling time 6, 12, 24 hours after dosing         and positive control respectively):
                                  Male/female      Negative control: corn oil                         Mitotic Index (mean % ± SEM):
                                  Fischer 344      Positive controle: 0.2 mg/kg bw                    F: 5.05±0.44, 6.36±1.07, 3.31±0.34
                                  Rat; N=18/sex/   triethyenemelamine (TEM)                           M: 5.82±0.31, 7.22±0.98, 4.79±0.65.
                                  dose/ sampling
                                  time             Endpoints: microscopically evaluation for mitotic Number of aberrant cells: total number of cells
                                                   index (percent metaphase cells) and                with aberrant chromosomes including
                                                   chromosomal abnormalities                          aneuploidy and polypoloidy (mean % ± SEM)
                                                                                                      F: 0, 0.83±0.83, 28.33±5.75
                                                                                                      M: 0.33±0.33, 0.33±0.33, 24.33±3.71
                                                                                                      Overall frequency of aberrations (mean % ±
                                                                                                      SEM):
                                                                                                      F: 0, 0.01, 1.10±0.27
                                                                                                      M: 0.003±0.003, 0.003±0.003, 0.86±0.11.
                                                                                                      Toxicity: no effects
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<pre> Annexes                                                                                                                                              Hydrogenated Terphenyl | page 60 of 67
 Table C7. Reproductive oral toxicity study in animals
  Reference       Substance          Study design and   Data on exposure and effect endpoints            Results                                            Remarks
                                     animal species
  Naylor and      Complex mixture of Two-Generation     Exposure route: oral by feed                     PO (First parental animals): effects on body       OECD Guideline 416, GLP compliant;
  Ruecker         terphenyl and      Reproduction                                                        weight or weight gain (during the last three       unpublished report, no restrictions, adequate for
  (1991)38        quaterphenyl       Toxicity Study     F0 Adults: 0, 30, 100, 300 and 1,000 ppm (1.8, weeks in 1,000 ppm dietary level males of the        assessment; reliability 1
                  isomers                               6.1, 18.5 and 62.0 mg/kg bw/day for males, and F0 generation and in 1,000 ppm dietary level
                  (Therminol® 66)    Male and female    2.5, 8.3,24.4 and 81.2 mg/kg bw/day for          F1a dams during gestation), effects on food
                                     Sprague-Dawley     females); 7 days/week                            consumption and compound intake (decrease
                                     rats; N=30 adults/                                                  in part of the females and increase in part of the
                                     sex/group          F1a Adults: 0, 30, 100, 300 and 1,000 ppm (1.9, males), other effects not specified or negative
                                                        6.1, 18.2 and 63.1 mg/kg bw/day for males, and
                                                        2.4, 8.1,24.3 and 80.6 mg/kg bw/day for          F1 generation: no effect
                                                        females); 7 days/week
                                                        Endpoints: Two-generation reproductive toxicity,
                                                        body weights, food consumption, survival,
                                                        clinical observations, gross and microscopic
                                                        examinations
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<pre> Annexes                                                                                                                                             Hydrogenated Terphenyl | page 61 of 67
 Table C8. Developmental oral toxicity study in animals
  Reference      Substance         Study design and  Data on exposure and effect endpoints            Results                                             Remarks
                                   animal species
  Nair (1985)39  Purity: 100%      Female Sprague-   Exposure route: oral by gavage                   Embryotoxic/ teratogenic effects:                   Reliability 1
                 (assumed for      Dawly rats; N=5/                                                   - At 500 mg/kg bw/day: a slight decrease in
                 preparation of    group             Exposure: 0 (control), 125, 250, 500, 1,000 and    mean maternal food consumption,
                 dosing solutions)                   2,000 mg/kg bw/day; days 6-15 of gestation       - At 1,000 mg/kg bw/day: indication of maternal
                 (Therminol® 66)                                                                        toxicity (reduction in mean weight gain and
                                                     Endpoints:                                         reduction in food consumption
                                                     Females: weight, physical evaluation, food       - At 2,000 mg/kg bw/day: maternal toxicity
                                                     consumption, post mortem evaluation (day 20        (reduced weight gain and food consumption),
                                                     of gestation), recording of uterine implantation   embryotoxic/fetotoxic effects (increase in
                                                     data                                               resorption data, decrease in mean fetal
                                                     Fetuses: weight, sex, external malformation        weight)
  Farr (1986)40  Mixture,          Prenatal          Exposure route: oral by gavage                   - At 500 mg/kg bw/day: slight maternal toxicity    According to OECD Guideline 414; reliability 1
                 concentration     Developmental                                                        (reduced food consumption)
                 Presumed to be    Toxicity Study    Exposure: 0 (control), 125, 500 and 1,500 mg/    - At 1,500 mg/kg bw/day: severe maternal
                 100% for purposes                   kg bw/day; gestation days: from day 6-15 of        toxicity (mortality 12.5%, reduced mean weight
                 of formulating    Female Sprague-   pregnancy; once per day.                           data and reduced weight gain during the
                 dosing solutions  Dawly rats; N=24/                                                    treatment period, reduced food consumption,
                 (Therminol® 66)   group             Endpoints:                                         and physical findings) as well as fetotoxicity
                                                     Females: body weights, food consumption,           (reduced fetal weights, increased incidence of
                                                     physical evaluation, gross postmortem              fetuses with certain ossification variations);
                                                     evaluation, corpora lutea/uterine implantation     however, no clear embryotoxicity, a statistically
                                                     data registration                                  significant increase in the incidence of fetuses
                                                     Fetus: weight, sex, gross examination/             with skeletal malformations (cleft palate,
                                                     malformations, visceral evaluation/                rostral area of nose elevated) with a unique
                                                     microdissection procedure or evaluation for        syndrome of observations (related to the
                                                     skeletal malformations/ ossification variations    severe maternal toxicity?)
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<pre> Annexes                                                                                                                           Hydrogenated Terphenyl | page 62 of 67
 D benchmark dose analysis                                                    Table D1. Effects of hydrogenated terphenyl in rats following inhalation
                                                                              exposure for 13 weeks10,22
 Data                                                                         Male rats
 The most clear and evident dose related effects of hydrogenated               Exposure level                 0 mg/m3        10 mg/m3     100 mg/m3   500 mg/m3   Number of
                                                                                                                                                                  animals
 terphenyl are found in a inhalation and oral study in rats published by Farr  Terminal body weight           586±33         570±41       594±54      543±53*     n=14;15;14;15
                                                                               (g), mean±SD                                                                       respectively
 et al (1989).10,22,34 Tables D1 and D2 show data on the liver and liver to
                                                                               Liver weight (g),              18.62±1.42     19.76±2.29   20.74±2.77  21.60±3.40* n=15, all groups
 body weight ratio changes, from which a BMDL could be calculated.             mean±SD
                                                                               Liver to body weight           3.15±0.16      3.46±0.25**  3.49±0.24** 3.97±0.37** n=14;15;14;15
                                                                               ratio (g/100g), mean                                                               respectively
                                                                               ±SD
                                                                              Female rats
                                                                               Exposure level                 0 mg/m3        10 mg/m3     100 mg/m3   500 mg/m3   Number of
                                                                                                                                                                  animals
                                                                               Terminal body weight           299±25         305±19       308±33      298±26      n=14;12;15;14
                                                                               (g), mean±SD                                                                       respectively
                                                                               Liver weight (g),              10.77±1.30     10.41±1.02   10.35±1.20  11.04±1.34  n=14;12;15;14
                                                                               mean±SD                                                                            respectively.
                                                                               Liver to body weight           3.61±.034      3.41±0.23    3.37±0.35   3.72±0.33   n=14;12;15;14
                                                                               ratio (g/100g), mean                                                               respectively
                                                                               ±SD
                                                                              */** Statistically significant at p≤0.005* or p≤0.01**.
61       Health Council of the Netherlands | No. 2020/09                                                                                 2                                       63
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<pre> Annexes                                                                                                                                     Hydrogenated Terphenyl | page 63 of 67
 Table D2. Effects of hydrogenated terphenyl in rats following oral                                      BMD-analysis
 exposure for 13 weeks10,34                                                                              The Committee used the BMD-modelling method and software provided
                                                                                                         by the European Food Safety Authority (EFSA) and the National Institute
 Male rats                                                                                               for Public Health and the Environment (RIVM, Netherlands).56 Results of
  Target exposure level, (ppm)                 0              50             200            2,000        the BMD-analyses are presented in Table D3.
  Target exposure level, (mg/kg/day)           0              3              12             120
  Estimated dietary test article               0              3.90±0.25      15.9±0.91      156±10.08
  consumption (mg/kg/day)
                                                                                                         Table D3. Benchmark Dose modelling.
  Terminal body weight (g), mean±SD            476±49         503±41         486±57         464±54
                                                                                                          Exposure     Sex   Weights for     Value for       BMD        Final BMD Values
  Liver weight (g), mean±SD                    13.17±1.46     13.82±1.42     14.34±2.34     19.32±2.49**
                                                                                                                             Model Averaging critical effect confidence (BMDL-BMDU)
  Liver to body weight ratio (g/100g),         2.77±0.09      2.75±0.15      2.94±0.21      4.18±0.42**
                                                                                                                                             size (CES)      intervals
  mean±SD
                                                                                                          Inhalation   Males 0.3259 EXP      relative liver  0.9        134 - 590
                                                                                                          (mg/m3)            0.3259 HILL     weight
 Female rats                                                                                                                 0.0788 INVEXP   CES 0.20
                                                                                                                             0.2695 LOGN
  Target exposure level, (ppm)                 0              50             200            2,000
                                                                                                          Oral (mg/kg/ Males 0.2274 EXP      relative liver  0.9        19.1 – 72.4
  Target exposure level, (mg/kg/day)           0              3              12             120           day)               0.2274 HILL     weight
  Estimated dietary test article               0              3.90±0.25      15.9±0.91      156±10.08                        0.2862 INVEXP   CES 0.20
  consumption (mg/kg/day)                                                                                                    0.259 LOGN
  Terminal body weight (g)                     280±26         280±36         287±30         262±17
  mean±SD
  Liver weight (g), mean±SD                    7.52±1.5       7.52±1.05      7.82±0.84      9.07±1.16**
  Liver to body weight ratio (g/100g),         2.68±0.25      2.69±0.21      2.69±0.18      3.45±0.29**
  mean±SD
 ** Statistically significant at p≤0.01. N=12 animals per group, except female rats exposed to 200 ppm
 (n=11 for terminal body weight and liver to body weight ratio).
62          Health Council of the Netherlands | No. 2020/09                                                                                         2                                  64
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<pre> Annexes                                                                                     Hydrogenated Terphenyl | page 64 of 67
 Fitted Models Inhalation data                               Fitted Models Oral data
 model               converged      loglik  npar    AIC      model              converged loglik   npar    AIC
 full model          yes            71.47   5        -132.94 full model         yes       62.17    5        -114.34
 null model          yes            46.92   2         -89.84 null model         yes       13.31    2         -22.62
 Expon. m3-          yes            68.98   4        -129.96 Expon. m3-         yes       61.58    4        -115.16
 Expon. m5-          no             68.98   5        -127.96 Expon. m5-         yes       62.12    5        -114.24
 Hill m3-            yes            68.98   4        -129.96 Hill m3-           ®
                                                                                 yes      61.58    4        -115.16
 Hill m5-            yes            65.84   5        -121.68 Hill m5-           ®
                                                                                 yes      62.12    5        -114.24
 Inv.Expon. m3-      yes            63.67   4        -119.34 Inv.Expon. m3-     ®
                                                                                 yes      61.81    4        -115.62
 Inv.Expon. m5-      yes            68.56   5        -127.12 Inv.Expon. m5-     ®
                                                                                 yes      62.12    5        -114.24
 LN m3-              yes            68.79   4        -129.58 LN m3-             ®
                                                                                 yes      61.71    4        -115.42
 LN m5-              yes            65.83   5        -121.66 LN m5-             ®
                                                                                 yes      62.12    5        -114.24
63        Health Council of the Netherlands | No. 2020/09                                        2                               65
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<pre>                                                                                                                                                         Hydrogenated Terphenyl | page 65 of 67
 The Committee
 The members of the Dutch Expert Committee on Occupational Safety for the toxicologic                  •  L.A. Smit, Epidemiologist, Institute for Risk Assessment Sciences, University Utrecht
 evaluation and recommendation of a health-based occupational exposure limit for hydrogenated          •  R.C.H. Vermeulen, Epidemiologist, Institute for Risk Assessment Sciences, University Utrecht
 terphenyl
 •   F.G.M. Russel, Professor of Pharmacology and Toxicology, Radboud University Medical Center,       Consulted experts
     Nijmegen, chairman                                                                                •  A.H. Piersma, Professor of Reproductive and Developmental Toxicology, Utrecht University,
 •   P.J. Boogaard, Professor of Environmental Health and Human Biomonitoring, Wageningen                 and National Institute for Public Health and the Environment, Bilthoven, structurally consulted expert
     University and Research Centre, and Toxicologist, Shell International BV, The Hague                  (until December 31, 2019)
     (until December 31, 2019)
 •   H. Bouwmeester, associate professor of toxicology, Wageningen University and Research Centre,     Observers
     Wageningen (from January 1, 2020)                                                                 •  H. Stigter, Occupational Physician, Inspectorate SZW, Ministry of Social Affairs
 •   R. Houba, Occupational Hygienist, Netherlands Expertise Centre for Occupational Respiratory          and Employment, The Hague
     Disorders, Utrecht                                                                                •  D. Theodori, Social and Economic Council, The Hague
 •   I. Kreis, professor in Epidemiology, Royal College of Surgeons, London, the UK
     (from January 1, 2020)                                                                            Scientific secretary
 •   E.D. Kroese, Toxicologist, TNO, Zeist                                                             •  B.E. Smink, Health Council of the Netherlands, The Hague
 •   C.F. Kuper, Toxicologic pathologist, Utrecht
 •   H. van Loveren, Emeritus Professor of Immunotoxicology, Maastricht University                     Members of Health Council Committees are appointed in a personal capacity because of their special
 •   I.M.C.M. Rietjens, Professor of Toxicology, Wageningen University and Research Centre             expertise in the matters to be addressed. Nonetheless, it is precisely because of this expertise that they
     (until December 31, 2019)                                                                         may also have interests. This in itself does not necessarily present an obstacle for membership of a
 •   M. Rooseboom, toxicologist, Shell International BV, The Hague (from January 1, 2020)              Health Council Committee. Transparency regarding possible conflicts of interest is nonetheless
 •   G.B.G.J. van Rooy, Occupational physician/toxicologist, Arbo Unie Expert Centre for Chemical Risk important, both for the chairperson and members of a Committee and for the President of the Health
     Management, and Radboud UMC Outpatient Clinic for Occupational Clinical Toxicology, Nijmegen      Council. On being invited to join a Committee, members are asked to submit a form detailing the
64          Health Council of the Netherlands | No. 2020/09                                                                                                    2                                                66
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<pre>                                                                                                          Hydrogenated Terphenyl | page 66 of 67
 functions they hold and any other material and immaterial interests which could be relevant for the
 Committee’s work. For each substance to be evaluated, the members are asked about their potential
 conflicts of interest. An expert with a personal financial interest cannot be a member of the Committee.
 In case of other, less clearly marked interests, experts can be consulted as non-members when their
 expertise is considered essential for the advisory report. By law, an expert working at an organization
 that is part of a Ministry cannot be a member of a Health Council Committee. Such an expert can be
 consulted as a non-member when there are no conflicting interests involved. It is the responsibility of
 the President of the Health Council, after consulting the chairman of the Committee, to assess the
 interests indicated and decides on the consequences for a possible membership.
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<pre> The Health Council of the Netherlands, established in 1902, is an independent scientific advisory body. Its remit is “to advise the government and
 Parliament on the current level of knowledge with respect to public health issues and health (services) research...” (Section 22, Health Act).
 The Health Council receives most requests for advice from the Ministers of Health, Welfare and Sport, Infrastructure and Water Management, Social
 Affairs and Employment, and Agriculture, Nature and Food Quality. The Council can publish advisory reports on its own initiative. It usually does this in
 order to ask attention for developments or trends that are thought to be relevant to government policy.
 Most Health Council reports are prepared by multidisciplinary committees of Dutch or, sometimes, foreign experts, appointed in a personal capacity.
 The reports are available to the public.
 This publication can be downloaded from www.healthcouncil.nl.
 Preferred citation:
 Health Council of the Netherlands. Hydrogenated Terphenyl.
 The Hague: Health Council of the Netherlands, 2020; publication no. 2020/09.
 All rights reserved
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