<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>N-Isopropylaniline
(CAS No: 768-52-5)
Health-based Reassessment of Administrative Occupational Exposure Limits
Committee on Updating of Occupational Exposure Limits,
a committee of the Health Council of the Netherlands
No. 2000/15OSH/083, The Hague, 22 October 2003
</pre>

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

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

<pre>Preferred citation:
Health Council of the Netherlands: Committee on Updating of Occupational
Exposure Limits. N-Isopropylaniline; Health-based Reassessment of
Administrative Occupational Exposure Limits. The Hague: Health Council of the
Netherlands, 2003; 2000/15OSH/083.
all rights reserved
</pre>

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

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

<pre>1     Introduction
      The present document contains the assessment of the health hazard of
      N-isopropylaniline by the Committee on Updating of Occupational Exposure
      Limits, a committee of the Health Council of the Netherlands. The first draft of
      this document was prepared by MA Maclaine Pont, M.Sc. (Wageningen
      University and Research Centre, Wageningen, the Netherlands).
           In May 2000, literature was searched in the databases Toxline, Medline, and
      Chemical Abstracts, starting from 1981, 1966, and 1937, respectively, and using
      the following key words: N-isopropylaniline; benzenamine, N-(1-methylethyl)-;
      and 768-52-5. The final search was carried out in Toxline and Medline in January
      2003.
           In April 2003, the President of the Health Council released a draft of the
      document for public review. The committee received no comments.
2     Identity
      name                    :    N-isopropylaniline
      synonyms                :    benzenamine, N-(1-methylethyl)-; N-phenylisopropylamine
      molecular formula       :    C9H13N
      structural formula      :
      CAS number              :    768-52-5
      Data from ACG99, NLM01.
083-3 N-Isopropylaniline
</pre>

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

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

<pre>3     Physical and chemical properties
      molecular weight       :    135.21
      boiling point          :    203oC; 206-208oC
      melting point          :    approximately -50oC
      flash point            :    100oC (open cup)
      vapour pressure        :    at 25oC: 4 Pa
      solubility in water    :    insoluble
      log Poctanol/water     :    2.53 (estimated)
      conversion factors     :    at 20oC, 101.3 kPa: 1 mg/m3 = 0.18 ppm
                                                       1 ppm = 6.5 mg/m3
      Data from: ACG99, Lew00, Lid99, http://esc.syrres.com.
      N-Isopropylaniline is a clear, straw-coloured liquid with a sweet, aromatic odour
      (ACG99).
           When heated to decomposition, the compound emits toxic fumes of NOx.
4     Uses
      N-isopropylaniline is employed in the dyeing of acrylic fibres and as a chemical
      intermediate (ACG99).
5     Biotransformation and kinetics
      After a single intraperitoneal injection of 14C-N-isopropylaniline in male rats
      (Sprague-Dawley; n=6) at 15 mg/kg bw, approximately 70% of the radioactivity
      was excreted via the urine in the first 24 hours. 4-Hydroxy-N-isopropylaniline,
      p-aminophenol, and N-phenyl-2-aminopropionic acid were the only metabolites
      detected accounting for 61, 8, and less than 1% of the radioactivity, respectively.
      After 96 hours, 80-90% of the radioactivity was excreted via the urine. The rest
      of the radioactivity was not accounted for (Ale69).
083-4 Health-based Reassessment of Administrative Occupational Exposure Limits
</pre>

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

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

<pre>6     Effects and mechanism of action
      Human data
      The committee did not find data on the toxic effects of N-isopropylaniline in
      humans.
      Animal data
      Irritation and sensitisation
      N-isopropylaniline was stated to be slightly irritating to the eyes of rabbits.
      Except for minor irritation, eyes were clear by the third day, while all animals
      were free of irritation within 7 days (no more data presented) (Mon85).
           N-isopropylaniline was stated to be slightly irritating to the skin of rabbits.
      All animals were free of irritation within 7 days (no more data presented)
      (Mon85).
           In a range-finding study preceding a dermal sensitisation test, covered 6-hour
      application of 0.3 mL of undiluted and diluted (10, 25, 50%) N-isopropylaniline
      to the clipped skin of guinea pigs (Hartley albino) did not cause irritation
      (observation times: 24 and 48 hours). In the sensitisation test, application of
      undiluted material, once a week for 3 weeks, produced slight to moderate
      irritation and necrosis after the first and second induction, respectively, while
      there was no irritation at a new site after the third induction. Challenging 14 days
      after the last induction exposure did not cause a significant dermal response, but
      some minor dermal effects were seen in irritation-control animals. The results
      from this study suggest some possible (cumulative) irritation, but no sensitisation
      (Aul86).
      Single exposure
      Exposure of rats (Sprague-Dawley; n=5/sex/group) to analytical vapour/aerosol
      concentrations of N-isopropylaniline of 1400, 1400, 1300, and 1000 mg/m3 *, for
      4 hours, caused mortality, mostly within 2 days, in 9/10 (5 males, 4 females),
      9/10 (5 males, 4 females), 5/10 (4 males, 1 female), and 1/10 (1 male) animals,
*     Particle-size analysis showed mass median aerodynamic diameters (± geometric standard deviation) of ca. 1.1 ±
      2.7, 1.7 ± 2.9, 1.2 ± 2.4, and 1.5 ± 2.3 µm, respectively.
083-5 N-Isopropylaniline
</pre>

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

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

<pre>             respectively (observation period: 14 days). Apart from death, the most common
             signs of toxicity during inhalation were hypoactivity and breathing difficulties.
             Post-exposure observations included hypoactivity and weight loss in all
             survivors except those exposed to 1000 mg/m3 that did not show signs of
             toxicity. No unusual gross necropsy findings were noted. From these data, a
             4-hour LC50 of 1223 mg/m3 was calculated (males: 1118 mg/m3; females: 1349
             mg/m3) (Dud86).
                  For rabbits, a dermal LD50 of 3550 mg/kg bw has been listed (Mon85).
                  For rats, an oral LD50 of 560 mg/kg bw has been presented (Mon85).
                  In a range-finding micronucleus test, intraperitoneal LD50 values of 389, 693,
             and 547 mg/kg bw were calculated for male mice, female mice, and both sexes
             combined, respectively (CD-1; n=2-3/sex/dose; dose range: 245-3500 mg/kg bw)
             (Flo90).
             Repeated exposure
             Groups of 15 male and 15 female Sprague-Dawley rats were exposed to N-
             isopropylaniline vapour concentrations of 0, 0.31, 2.8, or 31 mg/m3, 6 hours/day,
             5 days/week, for 2 weeks. All animals survived the exposures. There were no
             abnormalities noted during exposure. Twenty-four hours after the last exposure,
             changes in haematology parameters and differences in carboxyhaemoglobin
             (CO-Hb) and methaemoglobin (Met-Hb) levels were observed between exposed
             and control animals (see Table 1). There were no treatment-related changes in
             absolute or relative organ weights, gross or microscopic pathology (Dud90).
Table 1 Treatment-related effects in Sprague-Dawley rats after inhalation exposure to N-isopropylaniline vapours, 6 hours/day,
5 days/week, for 2 weeks (Dud90).
                                    males (n=15)                                           females (n=15)
                         3                 3            3            3            3
                   0 mg/m       0.31 mg/m      2.8 mg/m     31 mg/m        0 mg/m     0.31 mg/m3      2.8 mg/m3    31 mg/m3
     a
MCH (pg)           19.99        20.21          19.97        20.17          19.89      20.74           20.78        22.11**
MCHC(g/dL)         32.69        32.91          32.75        32.85          33.17      34.78           35.25         37.27**
% CO-Hb            1.7          2.0*           1.6          1.33**         1.7        2.0*            1.7          1.2**
% Met-Hb           0.5          0.5            0.7          1.4**          0.6        0.4             0.7          1.5**
a
    MCH = mean corpuscular haemoglobin; MCHC = mean corpuscular haemoglobin concentration; CO-Hb =
    carboxyhaemoglobin; Met-Hb = methaemoglobin.
    * p<0.05; ** p<0.01.
083-6        Health-based Reassessment of Administrative Occupational Exposure Limits
</pre>

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

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

<pre>      In concordance with the Dutch Expert Committee on Occupational Standards
      (DECOS), another committee of the Health Council of the Netherlands
      (DEC92), the committee considers CO-Hb levels <5% not to be toxicologically
      relevant, i.e., there will be only a small or negligible risk of effects on behaviour
      and mental capacities at these levels. Based on an increased Met-Hb level at 31
      mg/m3, the committee concludes that 2.8 mg/m3 is an NOAEL for male and
      female rats after 2-week, intermittent inhalation exposure to N-isopropylaniline.
          In rats (Sprague-Dawley; n=15/sex/group) exposed to analytical
      concentrations of N-isopropylamine of 0, 55, 160, or 490 mg/m3, 6 hours/day, 5
      days/week, for a total of 21 exposure days, clinical signs observed during the
      exposure periods included salivation, lachrymation, and hypoactivity in the high-
      concentration group, and dose-related increases in the frequency of nasal and
      oral discharge and encrustation, especially in the 2 higher concentration groups.
      Body weights of the animals exposed to 490 mg/m3 were statistically
      significantly lower than those of controls throughout the study. Analyses of
      blood samples collected from 10 animals/sex/group on study day 16 and from all
      animals just prior to termination (study days 29-31) showed statistically
      significantly elevated Met-Hb levels at all exposure concentrations at both time
      points. In the low- and mid-concentration groups, they amounted to ca. 2.7% and
      4.4%, respectively, at both time points, while levels in the high-concentration
      groups rose from 6.3% to 9.5%. Changes in other blood values indicated a mild
      haemolytic response in all exposure groups. Further, increases in total bilirubin
      and serum alanine aminotransferase (ALAT) levels were seen in the high-
      concentration animals. Organ weight changes included increases in relative
      spleen and kidney weights of males and females of the mid- and high-
      concentration groups, in absolute spleen weights of males and females of the
      high-concentration group and in males of the mid-concentration group, and in
      relative liver weights in high-concentration females. Upon macroscopic and
      microscopic examination, there were spleen (enlarged and/or purple-coloured
      primarily in high-concentration animals; congestion, increased haematopoiesis)
      and kidney (random cortical nephrosis with regeneration ranging to nephropathy
      in males; nephrosis with regeneration in the pars recta in females) lesions in
      nearly all animals exposed to 160 or 490 mg/m3. In the group exposed to 5
      mg/m3, 4 females showed increased haematopoiesis while renal lesions were
      observed in males. Based on reduced Hb and increased Met-Hb levels and
      increased splenic haematopoiesis, 55 mg/m3, the lowest level tested, was the
      LOAEL in this study (Rol85).
          Groups of 15 male and 15 female Sprague-Dawley rats were exposed to
      N-isopropylaniline concentrations of 0, 5, 20, or 100 mg/m3, 6 hours/day, 5 days/
083-7 N-Isopropylaniline
</pre>

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

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

<pre>              week, for approximately 14 weeks. The particle size was not analysed due to low
              aerosol concentrations of the exposure atmospheres. The treatment-related
              effects are summarised in Table 2. The authors concluded the following.
              Ophthalmologic examination of the control and high-level animals showed no
              ocular changes that could be attributed to test material exposure.
Table 2 Treatment-related effects in Sprague-Dawley rats after inhalation exposure to N-isopropylaniline, 6 hours/day, 5 days/
week, for approximately 14 weeks (Bec88).
                                             males (n=15)                                     females (n=15)
                                   0       5         20          100 mg/m3      0           5           20         100 mg/
      a                                                                b
HGB (g/dL)                         16.0    16.1      15.6        15.3*          16.0        16.1        15.9       15.0
MCV (femto-L)                      55.0    55.5      55.4        58.3**b        56.7        59.6        59.7       61.6**
MCHC (g/dL)                        35.4    35.4      35.6        35.5           35.4        34.9        33.9**     34.1*
relative spleen wt                 0.165   0.167     0.165       0.162*         0.177       0.180       0.192      0.199
relative kidney wt                 0.747   0.758     759         0.835*         0.674       0.717       0.725      0.773*
spleen:
  increased haematopoiesisc        2       1         4           2              0           2           4          6
  increased haemosiderinc          0       0         0           15**           0           1           0          15**
% O2-Hb                            24.8    17.4      18.8        18.5           21.7        21.8        22.3       20.1
% CO-Hb                            0.3     0.2       -0.1**      -0.8**         0.4         0.3         0.2        -0.5**
% Met-Hb                           0.9     1.4**     1.9**       4.0**          0.9         1.4**       1.9**      3.5**
a
      HGB = haemoglobin level; MCV = mean corpuscular volume; MCHC = mean corpuscular haemoglobin concentration;
      O2-Hb = oxyhaemoglobin; CO-Hb = carboxyhaemoglobin; Met-Hb = methaemoglobin.
b
      Within historical control range.
      * p<0.05, ** p<0.01.
c
      Expressed as number of animals.
              Methaemoglobinaemia, occurring in all exposure groups, was considered a
              treatment-related effect and displayed a definite dose response. The decreased
              haemoglobin values and increased MCV values appeared to be treatment-related
              but were within or very slightly above the historical control range, and, therefore,
              not considered to be relevant. The increase in both relative and absolute kidney
              weights in the high-level animals and the dark discolouration of the high-level
              male kidneys could be associated to test-material exposure. These changes were
              not accompanied by any obvious microscopic abnormalities and, therefore, their
              biological significance is unknown. Microscopically, increased haemosiderin in
              the spleens of all the high-level animals was considered a treatment-related effect
              and may have contributed to the slight increase in splenic weight for this group.
083-8         Health-based Reassessment of Administrative Occupational Exposure Limits
</pre>

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

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

<pre>              The increase in haemosiderin pigment in concert with some changes in
              haematology suggested that there might have been some alteration in red blood
              cell kinetics leading to accelerated red blood cell destruction. The mild increase
              in absolute spleen weight for mid-level females was not accompanied by any
              obvious microscopic abnormality and, therefore, was probably of no biological
              or toxicological significance. All other microscopic changes were considered
              non-exposure related (Bec88).
              With respect to this 14-week inhalation study, the committee concludes that 5
              mg/m3, the lowest concentration tested, was a LOAEL inducing
              methaemoglobinaemia in male and female rats.
              Groups of 10 male and 10 female Sprague-Dawley rats received dermal doses of
              N-isopropylaniline of 0, 25, 100, or 400 mg/kg bw, 6 hours/day, 5 days/week, for
              approximately one month (see Table3). The compound was applied undiluted
              and left unoccluded on the shaved skin. Approximately one-third of the test
              material apparently volatilised. Haematology and blood chemistry parameters
              were evaluated for all animals at sacrifice. All animals were given a complete
              gross necropsy. Brain, heart, kidneys, liver, spleen, and testes with epididymides
              weights were recorded at scheduled sacrifice. Approximately 30 tissues per
              animal were preserved. All tissues from the control and high-dose animals were
              examined microscopically. Tissues from the low- and mid-dose groups were also
              examined if treatment-related effects were noted at the high-dose level.
Table 3 Treatment-related effects after dermal dosing of N-isopropylaniline to Sprague-Dawley rats during one month (Nay87).
                                               males (n=10)                                  females (n=10)
                                 0          25        100       400 mg/kg        0         25        100        400 mg/kg
      a   6     3
RBC (10 /mm )                    7.00       7.96      7.83      7.15**           7.95      7.76      7.39**     7.04**
HGB (g/dL)                       16.0       15.2**    15.0**    14.2**           15.7      15.1      14.5**     14.7*
MCV (femto-L)                    67.3       50.2      57.7      61.0**           58.1      57.7      58.2       63.4**
MCH (pg)                         20.2       19.1*     19.2      19.9             19.7      19.5      19.7       20.9**
MCHC (g/dL)                      35.2       34.0      33.3**    32.6**           34.0      33.8      33.8       32.9**
reticulocytes (% of RBC)         1.00       1.30      2.10      3.16**           1.68      1.69      2.21       3.32**
relative spleen wt               0.190      0.196     0.200     0.256*            0.221    0.229     0.237      0.270*
spleen:
 increased haemosiderinb         0          0         0         10**             3         0         7          10**
 increased haematopoiesisb       0          1         4         10**             1         3         3          8**
083-9         N-Isopropylaniline
</pre>

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

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

<pre>% O2 -Hb                            28.03      23.09      25.55      26.87           29.64      33.34      32.88       33.99
         c
% CO-Hb                             0.56       0.54       -0.2       -1.27           0.49       0.69       0.32        0.05
% Met-Hb                            1.15BT     1.42       2.78**     5.91**          1.06BT     1.31       2.07**      3.43**
a
   RBC = total erythrocyte count; HGB = haemoglobin level; MCV = mean corpuscular volume; MCH = mean corpuscular
   haemoglobin; MCHC = mean corpuscular haemoglobin concentration; O2-Hb = oxyhaemoglobin; CO-Hb =
   carboxyhaemoglobin; Met-Hb = methaemoglobin.
b
   Expressed as number of animals.
c
   Elevated percentages of Met-Hb interfered with analysis of % CO-Hb in certain samples, causing apparent negative values
   to be reported; a statistical analysis was not performed and % desoxy-Hb could not be reliably determined.
   BT
      Bartlett's test indicates statistically significant difference (p<0.01) among variances of the different groups.
   * p<0.05, ** p<0.01.
            Skin abnormalities (dryness, abrasions, redness and/or scab formation) were
            noted at all dose levels, but were most common in 100- and 400-mg/kg females.
            Some of the lesions, particularly those noted at the lower dose levels, may have
            resulted from periodic shaving of the application sites before exposure. The
            percentage oxyhaemoglobin (O2-Hb), percentage carboxyhaemoglobin (CO-Hb),
            percentage methaemoglobin (Met-Hb), and percentage oxygen content of the
            blood were also determined. The deoxyhaemoglobin was also required by the
            protocol. However, due to interference in the measurement of CO-Hb in some
            animals with elevated Met-Hb levels, accurate results could not be reliably
            determined since the percentage deoxyhaemoglobin is determined from the total
            of % O2-Hb, % CO-Hb, and % Met-Hb. The effect of this deviation from the
            protocol on the results of the study could not be ascertained. Anyway, the authors
            concluded the following. Anaemia and methaemoglobinaemia, with associated
            splenic changes of increased weight and haemosiderin deposition and
            haemosiderosis, were present at the mid- and/or high-dose levels in both sexes.
            Epidermal thickening (acanthosis) was seen at all dose levels in males and at the
            2 highest doses in females. Based on the above results, N-isopropylaniline
            appeared to be absorbed through the intact skin of rats and produced a mild skin
            irritation and thickening as well as anaemia, methaemoglobinaemia, and
            associated splenic changes (Nay87). With respect to this 1-month dermal study,
            the committee concludes that 25 mg/kg bw, the lowest dose tested, is a LOAEL
            inducing an increase for the haemoglobin content of the blood of male rats, when
            administered dermally.
            The committee did not find data on toxic (including carcinogenic) effects
            following long-term exposure to N-isopropylaniline.
083-10      Health-based Reassessment of Administrative Occupational Exposure Limits
</pre>

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

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

<pre>       Mutagenicity and genotoxicity
       In vitro, N-isopropylaniline was negative in a gene mutation assay using S.
       typhimurium strains TA100, TA1535, and TA1537 with and without metabolic
       activating systems containing 10% induced rat or hamster liver S9. In strain
       TA98, results were negative when tested without (2 separate experiments) and
       with metabolic activation containing 5% or 30% induced hamster liver (one
       experiment each) or 10% rat liver S9 (2 separate experiments); in the presence of
       a 10% hamster liver S9-containing metabolic activation mix, a weakly positive
       (with 1.6-, 2,2-, and 2.2-fold increases in number of mutants over controls), a
       questionable positive (1.3-, 1.4-, and 1.7-fold increases), and a negative result
       were obtained (Zei87). N-isopropylaniline (purity: 97.4%) did not induce
       unscheduled DNA synthesis in primary rat hepatocyte cultures when tested in 2
       separate experiments at adequate dose ranges (Bak86).
           In vivo, a single intraperitoneal dose of 200 mg/kg bw did not cause a
       statistically significant increase in the number of micronucleated polychromatic
       erythrocytes (PCE) obtained from bone marrow of male and female mice
       (n=5/sex/group) sacrificed 24 or 48 hours after injection. This dose, selected
       from a rang-finding study (see section ‘single exposure’), caused a statistically
       significant decrease in the PCE/total erythrocyte ratio in treated male mice
       sacrificed at 48 h, but not in any of the other N-isopropylaniline-treated or
       control groups. In the treated males sacrificed at 48 hours (but not in the other
       groups), mean body weights were statistically significantly decreased as well
       (Flo90).
       Reproduction toxicity
       Groups of 20 male Sprague-Dawley rats were exposed to (analytical)
       concentrations of N-isopropylaniline of 0, 5, 20, or 100 mg/m3, 6 hours/day, 5
       days/week, for approximately 11 weeks. Exposures continued on a 5-day-per-
       week schedule during a 2-week mating period, during which each male was co-
       housed with one untreated female for 5 nights, and 3 days later with a second
       untreated female for another 5 nights, and for 2 weeks thereafter. Males were
       then discarded without necropsy (except in case of unscheduled death). Females
       were sacrificed on gestational days 14 or 15, and uteri and ovaries were
       examined to assess pregnancy status, number and state of nidations and corpora
       lutea. No effects on body weight or clinical signs of toxicity were noted during
       the exposure period in any of the treated male groups. Treatment did not affect
       male fertility. In females, no effects were seen on copulation rates, pregnancy
083-11 N-Isopropylaniline
</pre>

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

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

<pre>       rates, pre-coital times, or on the incidence of pre- and post-implantation losses
       and the number of dead fetuses (Rey88). From this study, the committee
       concluded that the NOAEL for male rat fertility following inhalation exposure is
       ≥100 mg/m3.
            Groups of 25 female Sprague-Dawley rats were exposed to (analytical)
       concentrations of 0, 5, 20, or 100 mg/m3, 6 hours/day, 5 days/week, for
       approximately 11 weeks. Exposures continued on a 5-day-per-week schedule
       during the mating period during which each female was co-housed with one
       untreated male for 5 days or, in case of no mating/copulatory evidence, 3 days
       later with another untreated male for another 5 days. Once copulation was
       confirmed, females were exposed on a 7-day-per-week basis during gestational
       days 0 through 20. They were allowed to deliver their pups. On lactation day 4,
       litters were culled randomly to 8 pups, 4 of each sex, when possible. All adult
       females with litters were necropsied after weaning, all weanling pups on
       approximately lactation day 21. No clinical signs of toxicity of compound-
       related changes in survival, body weight (gain), and gross pathology were seen in
       any of the maternal animal groups; haematology, organ weight determination,
       and microscopic examination were (obviously) not performed in the maternal
       animals. In the high-exposure group, there were fewer confirmed copulations
       (20 vs. 24). In this group, pregnancy rate was decreased: pregnant females
       included 48% of the paired females and 60% of females with confirmed
       copulation (compared to 72 and 75%, respectively, among controls). The cause
       of the decrease in pregnancy rate was not determined. Pre-coital and gestational
       time lengths were not affected. With respect to the offspring, there were no
       changes in litter size, pup viability, pup weights, gross lesions, or microscopic
       observations (examined only in high concentration group) in any of the treated
       weanling groups (Rey88). From this study, the committee concluded that the
       NOAELs for maternal, female fertility, and developmental toxicity in rats
       following inhalation exposure are ≥100, 20, and ≥100 mg/m3, respectively.
            In a range-finding oral (gavage) study, female Charles River COBS CD rats
       (n=5/group) received daily doses of N-isopropylaniline of 0, 5, 25, 75, 150, or
       300 mg/kg bw on gestational days 6 through 15, and were sacrificed at
       gestational day 20. Maternal toxicity observed included decreased mean body
       weight gains during treatment and throughout the entire gestation period in the
       300-mg/kg bw group and enlarged, discoloured spleens in the 150- and
       300-mg/kg bw groups. Developmental toxicity was found in the 300-mg/kg bw
       group only and consisted of decreases in the mean number of viable fetuses and
       in the mean total implantations and an increase in the mean post-implantation
       loss (Sku84). In the subsequent study, mated female rats (n=25/group) received
083-12 Health-based Reassessment of Administrative Occupational Exposure Limits
</pre>

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

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

<pre>       daily doses of 0, 30, 100, or 350 mg/kg bw on gestational days 6 through 15. The
       study was terminated by scheduled sacrifice of the dams on gestational day 20,
       which was immediately followed by Caesarean sections to examine uteri and
       ovaries and to remove fetuses for evaluation. In the high-dose group, 2 dams
       died. Further, maternal toxicity was observed in the form of excessive salivation,
       hair loss, decreased activity and/or brown urine, and decreased body weight gain.
       A dose-related increase in the occurrence of a dark and/or enlarged spleen was
       observed in dams of the mid- and high-dose groups. Increased extramedullary
       haematopoiesis was noted at microscopic examination of a random sample of 4
       high-dose dams. Similar gross findings suggested the presence of this
       microscopic finding in the mid- and high-dose dams not microscopically
       examined. There were no biologically meaningful differences in maternal
       survival, appearance, behaviour, or body weight gain between the low- and mid-
       dose group dams and the controls. In the high-dose group, statistically significant
       increases in post-implantation loss and the number of dead fetuses, a statistically
       significant decrease in fetal weight, a statistically significant increase in the
       number of litters with malformed fetuses (primarily bent ribs, bent scapulae, and
       bent limb bones; brachymelia, brachydactyly, anasarca, and bent clavicle were
       seen as well), and an increase in the incidence of number of fetuses with skeletal
       variations. In the low- and mid-dose groups, Caesarean section observations, or
       fetal morphological findings were comparable to those in the control group
       (Lau84). From this study, the committee concludes that the NOAELs for
       maternal and developmental toxicity in rats following oral exposure are 30 and
       100 mg/kg bw/day, respectively.
7      Existing guidelines
       The current occupational exposure limit (MAC) for N-isopropylaniline in the
       Netherlands is 10 mg/m3 (2 ppm), 8-hour TWA, with a skin notation.
           Existing occupational exposure limits for N-isopropylaniline in some
       European countries and in the USA are summarised in the annex.
8      Assessment of health hazard
       The committee did not find data on the toxicokinetics and toxicodynamics of
       N-isopropylaniline in humans.
           Following a single intraperitoneal injection into rats, 70 and 80-90% of the
       radioactivity administered were excreted in the urine after 24 and 96 hours,
083-13 N-Isopropylaniline
</pre>

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

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

<pre>       respectively, 4-hydroxy-N-isopropylaniline being the main metabolite, while no
       parent compound was detected.
            N-isopropylaniline was stated to be slightly irritating to the eyes and skin of
       rabbits. In guinea pigs, there were indications of some slight (cumulative)
       irritation but not of a sensitising potential.
            Acute lethal toxicity data included a 4-hour LC50 of 1223 mg/m3 in rats and a
       dermal LD50 of 3550 mg/kg bw in rabbits.
            From 2- and 14-week inhalation and 4-week dermal toxicity studies, the
       committee concludes that methaemoglobinaemia is the main effect following
       repeated exposure to N-isopropylaniline in rats. In the 14-week study (Bec88), a
       statistically significant, dose-dependent increase in the percentage of Met-Hb
       was found in rats, ranging from 1.4 to 3.5-4% at 5 and 100 mg/m3, the lowest and
       highest concentrations tested, respectively. At the latter level, effects on kidneys
       (increased weights; dark discolouration in males) and spleens (increased
       weights; increased haemosiderin pigment) were observed as well.
            The fertility of male rats was not affected when exposed to 100 mg/m3 for 11
       weeks before mating with untreated females. In females exposed to 100 mg/m3
       for 11 weeks before mating with untreated males, pregnancy rate was decreased,
       but there were no effects on pregnancy outcome. Female fertility was not
       affected at exposure to 20 mg/m3. When female rats were orally treated during
       gestational days 6 to 15, no developmental effects and slight maternal toxicity
       (dark and/or enlarged spleens) were seen at doses of 100 mg/kg bw. Doses of 350
       mg/kg bw induced developmental effects (increased post-implantation losses,
       increased number of dead fetusus, decreased fetal weights, increased number of
       litters with malformed fetuses, increased number of fetuses with skeletal
       malformations) as well as maternal toxicity (mortality, excessive salivation, hair
       loss, decreased activity, brown urine, decreased body weight gain, enlarged/dark
       spleen, increased extramedullary haematopoiesis).
            N-isopropylaniline was not mutagenic in S. typhimurium. It did not cause
       DNA damage (UDS) in cultured rat hepatocytes. In vivo, it did not induce
       increases in the frequency of micronuclei in bone marrow of intraperitoneal
       injected mice. The committee did not find data on the potential carcinogenicity
       of N-isopropylaniline.
            The committee considers methaemoglobinaemia to be the critical effect, and
       the 14-week inhalation study with rats (Bec88) as the key study. At the lowest
       concentration tested, 5 mg/m3, the percentage of Met-Hb was increased.
       However, this was only a marginal increase, also when taken into account that a
       similar percentage of Met-Hb (viz., 1.4%) was found after exposure to 31 mg/m3
       for 2 weeks (Table 1). Both figures were statistically significantly increased
083-14 Health-based Reassessment of Administrative Occupational Exposure Limits
</pre>

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

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

<pre>       compared with the control groups; however, the biological significance of this
       increase is questionable. Furthermore, the ACGIH has a Biological Exposure
       Index of 1.5% MetHb. Therefore, the committee considers 5 mg/m3 as a NOAEL
       that can be taken as a starting point in deriving a health-based recommended
       occupational exposure limit (HBROEL). For extrapolation to a HBROEL, an
       overall assessment factor of 9 is established. This factor covers the following
       aspects: inter- and intraspecies variation. Thus, applying this factor of 9 and the
       preferred-value approach, a health-based occupational exposure limit of 0.5
       mg/m3 is recommended for N-isopropylaniline.
       The committee recommends a health-based occupational exposure limit for
       N-isopropylaniline of 0.5 mg/m3, as an 8-hour time-weighted average (TWA).
       Because of lack of quantitative data on skin absorption, the committee cannot
       advise with respect to a skin notation.
       References
ACG99  American Conference of Governmental Industrial Hygienists (ACGIH). N-isopropylaniline. In:
       TLVs® and other occupational exposure values - 1999. [CD-ROM]. Cincinnati OH, USA: ACGIH®,
       Inc, 1999.
ACG03a American Conference of Governmental Industrial Hygienists (ACGIH). Guide to occupational
       exposure values - 2003. Cincinnati OH, USA: ACGIH®, Inc, 2003: 75.
ACG03b American Conference of Governmental Industrial Hygienists (ACGIH). 2003 TLVs® and BEIs®
       based on the documentation of the Threshold Limit Values for chemical substances and physical
       agents & Biological Exposure Indices. Cincinnati OH, USA: ACGIH®, Inc, 2003: 36.
Ale69  Alexander WE, Sitar DS. Metabolism of N-isopropylaniline-14C in the rat. Can J Pharm Sci 1969; 4:
       32-4.
Arb02  Arbejdstilsynet. Grænseværdier for stoffer og materialer. Copenhagen, Denmark: Arbejdstilsynet,
       2002: 29 (At-vejledning C.0.1).
Aul86  Auletta CS, Trimmer JE, Webb M. A closed-patch repeated insult dermal sensitization study in
       guinea pigs (Buehler method) with N-isopropylaniline. East Millstone NJ, USA: Bio/dynamics, Inc,
       1986 (available from National Technical Information Service, Springfield VA, USA; order no: NTIS/
       OTS0572514).
Bak86  Bakke JP, Mirsalis JC. Evaluation of the potential of N-isopropylaniline to induce unscheduled DNA
       synthesis in primary rat hepatocyte cultures. Menlo Park CA, USA: SRI International, 1986; SRI proj
       no LSC-1689 (available from National Technical Information Service, Springfield VA, USA; order
       no: NTIS/OTS0572516).
083-15 N-Isopropylaniline
</pre>

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

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

<pre>Bec88  Bechtel CL, Ruecker FA. Three-month study of N-isopropylaniline administered to male and female
       Sprague-Dawley rats by inhalation. St Louis MO, USA: Monsanto Company, Environmental Health
       Laboratory, 1988; study no EHL 86100 (available from National Technical Information Service,
       Springfield VA, USA; order no: NTIS/OTS0513418-1).
DEC92  Dutch Expert Committee on Occupational Standards (DECOS). Health-based recommended
       occupational exposure limit for carbon monoxide. The Hague, the Netherlands: SDU,
       Servicecentrum Uitgevers, 1992; (rep no RA 7/92).
DFG02  Deutsche Forschungsgemeinschaft (DFG): Commission for the Investigation of Health Hazards of
       Chemical Compounds in the Work Area. List of MAK and BAT values 2002. Maximum
       concentrations and biological tolerance values at the workplace. Weinheim, FRG: Wiley-VCH, 2002;
       rep no 38.
Dud86  Dudek BR, Roloff MV. Acute toxicity of N-isopropylaniline administered by inhalation to Sprague-
       Dawley male and female rats. St Louis MO, USA: Monsanto Company, Environmental Health
       Laboratory, 1986; study no EHL 86003 (available from National Technical Information Service,
       Springfield VA, USA; order no: NTIS/OTS0572512).
Dud90  Dudek BR, Raju NR, Folk RM. Two week study of N-isopropylaniline administered to male and
       female Sprague-Dawley rats by inhalation. St Louis MO, USA: Monsanto Company, Environmental
       Health Laboratory, 1990; study no EHL 89030 (available from National Technical Information
       Service, Springfield VA, USA; order no: NTIS/OTS0572515).
EC03   European Commission: Directorate General of Employment and Social Affairs. Occupational
       exposure limits (OELs). http://europe.eu.int/comm/employment_social/h&s/areas/oels_en.htm.
Flo90  Flowers LJ, Li AP. Screening assay report: micronucleus screening assay of N-isopropylaniline. St
       Louis MO, USA: Monsanto Company, Environmental Health Laboratory, 1990; study no EHL 88240
       (available from National Technical Information Service, Springfield VA, USA; order no: NTIS/
       OTS0572513).
HSE02  Health and Safety Executive (HSE). EH40/2002. Occupational Exposure Limits 2002. Sudbury
       (Suffolk), England: HSE Books, 2002.
Lau84  Laughlin KA, Schardein JL, Blair M. N-isopropylaniline. Teratology study in rats (IR-83-295).
       Mattawan MI, USA: International Research and Development Corporation, 1984 (available from
       National Technical Information Service, Springfield VA, USA; order no: NTIS/OTS0522377).
Lew00  Lewis sr. RJ, ed. Sax's dangerous properties of industrial materials. 10th ed. New York, USA: Van
       Nostrand Reinhold, 2000: 2155.
Lid99  Lide DR, ed. CRC Handbook of chemistry and physics. 80th ed. Boca Raton, USA: CRC Press,
       1999; 3-24.
Mon85  Monsanto Company. Monsanto material safety data: N-Isopropylamine. St Louis MO, USA:
       Monsanto Company, 1985; MSDS no: 000768525 (available from National Technical Information
       Service, Springfield VA, USA; order no: NTIS/OTS0513418-1).
Nay87  Naylor MW, Ruecker FA. One month dermal study of N-isopropylaniline in Sprague-Dawley rats. St
       Louis MO, USA: Monsanto Company, Environmental Health Laboratory, 1987; study no EHL 86069
083-16 Health-based Reassessment of Administrative Occupational Exposure Limits
</pre>

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

<br><br>====================================================================== Pagina 17 ======================================================================

<pre>       (available from National Technical Information Service, Springfield VA, USA; order no: NTIS/
       OTS0513419).
NLM01  US National Library of Medicine (NLM), ed. N-Isopropylaniline. In: Hazardous Substances Data
       Bank (HSDB) (last review date N-isopropylaniline file: 29 January 2000); http://toxnet.nlm.nih.gov.
Rey88  Reyna MS, Ruecker FA. Reproduction and fertility studies with N-isopropylaniline (N-IPA) by
       inhalation in Sprague-Dawley rats. St Louis MO, USA: Monsanto Company, Environmental Health
       Laboratory, 1988; study no EHL 86097, 86098, 86099 (available from National Technical
       Information Service, Springfield VA, USA; order no: NTIS/OTS0522377).
Rol85  Roloff MV. One-month study of N-isopropylaniline administered to male and female Sprague-
       Dawley rats by inhalation. St Louis MO, USA: Monsanto Company, Environmental Health
       Laboratory, 1985; study no EHL 820157 (available from National Technical Information Service,
       Springfield VA, USA; order no: NTIS/OTS0543181).
Sku84  Skutt VA. N-Isopropylaniline. Range-finding teratology study in rats (IR-83-294). Mattawan MI,
       USA: International Research and Development Corporation, 1984 (available from National
       Technical Information Service, Springfield VA, USA; order no: NTIS/OTS0522377).
Swe00  Swedish National Board of Occupational Safety and Health. Occupational exposure limit values and
       measures against air contaminants. Solna, Sweden: National Board of Occupational Safety and
       Health, 2000; Ordinance AFS 2000:3.
SZW03  Ministerie van Sociale Zaken en Werkgelegenheid (SZW). Nationale MAC-lijst 2003. The Hague,
       the Netherlands: Sdu, Servicecentrum Uitgevers, 2003: 31.
TRG00  TRGS 900. Grenzwerte in der Luft am Arbeitsplatz; Technische Regeln für Gefahrstoffe. BArbBl
       2000; 2.
Zei87  Zeiger E, Anderson B, Haworth S, et al. Salmonella mutagenicity tests: III. Results from the testing
       of 255 chemicals. Environ Mutagen 1987; 9 (Suppl 9): 1-109.
083-17 N-Isopropylaniline
</pre>

====================================================================== Einde pagina 17 =================================================================

<br><br>====================================================================== Pagina 18 ======================================================================

<pre>              Annex
Occupational exposure limits for N-isopropylaniline in various countries.
country                                occupational           time-weighted       type of             notea     referenceb
- organisation                         exposure limit         average             exposure limit
                                       ppm       mg/m3
the Netherlands
- Ministry of Social Affairs and       2         10           8h                  administrative      S         SZW03
Employment
Germany
- AGS                                  -         10           8h                                      S         TRG00
- DFG MAK-Kommission                   -         -                                                              DFG02
Great Britain
- HSE                                  -         -                                                              HSE02
Sweden                                 -         -                                                              Swe00
Denmark                                2         10           8h                                      S         Arb02
USA
- ACGIH                                2         -            8h                  TLV                 S         ACG03b
- OSHA                                 -         -                                                              ACG03a
- NIOSH                                2         10           10 h                REL                 S         ACG03a
European Union
- SCOEL                                -         -                                                              EC03
a
     S = skin notation, which means that skin absorption may contribute considerably to body burden; sens = substance can
     cause sensitisation.
b
     Reference to the most recent official publication of occupational exposure limits.
083-18        Health-based Reassessment of Administrative Occupational Exposure Limits
</pre>

====================================================================== Einde pagina 18 =================================================================

<br><br>