NMP EU CLASSIFICATION DEVELOPMENTAL EFFECTS

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NMP - EU CLASSIFICATION DEVELOPMENTAL EFFECTS
ECBI/47/02 Add.5

• Consideration of
• normal handling and use
• and kinetic data

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NMP - EU classification on developmental
effectsconsidering normal handling and use

• Exposure information
• 15 minute exposure to an aqueous NMP (15 one
  hand) is equivalent to inhalation of 10 mg/m3 NMP
  over 8 h with respect to absorption and
  elimination profileh) equivalent to 80
  mg/personk) or 1.3 mg/kg bw
• large scale use human exposure as solvent in
  agrochemicals was assessed using POEMi). This
  determistic model allows assessment of inhalation
  and dermal exposure. For the daily usage of about
  10kg NMP the model predicts a safety factor of at
  least 180 - assuming no protective personal
  equipment - with respect to combined
  dermal/inhalative exposure this factor is based
  on a dermal NOAEL of 237 mg/kg bwj).
• Workplace measurement via biomonitoring in the
  shoe industry is ongoing

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NMP - EU classification on developmental
effectsconsidering normal handling and use

• Although NMP has been tested via the oral, dermal
  and inhalative routesa) in rats and rabbits,
  severe developmental effects were limited to oral
  application (rat and rabbit)
• and in one species (rat) to high dose levels via
  the dermal route a, j).
• No such findings were seen in rabbits after
  dermal application at a limit dose of 1,000 mg/kg
  body weighta).
• No such findings were noted in rats and rabbits
  via inhalation although concentrations tested
  were at vapor saturation (rat) and above
  (rabbit)a).

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NMP - EU classification on developmental
effectsconsidering normal handling and use
In vivo results dermal resorption b,c, d) NMP
will be absorbed through the skin of rats and the
absorption rate is modified by various
factors water progressively decreases NMP
absorption while organic co-solvents like
d-limonene initially increase absorption differenc
es also are observed depending on occluded,
semi-occluded or open exposure In vitro results
dermal resorption rat skin is about 2-fold more
permeable than human skin (see table below) d) a
recent study extended human skin data towards
lower concentrations e)
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NMP - EU classification on developmental
effectsconsidering normal handling and use

• Dermal absorption/effects in the rat
  developmental toxicity study
• findings observed in the rat study are of
  borderline significance with respect to severity
  if one compares the effects to the oral studies
• if one would correct the dose for the absorption
  situation in humans the effect dose would be
  clearly above 1,000 mg/kg body weight
• comparison of 14C-NMP plasma concentration after
  oral and dermal exposure in rats indicates that
  oral dose has a much higher bioavailability (see
  table)
• experience in humans indicates the possibility
  that prolongated release from the skin tissue
  might avoid a peak effect (this is subjected to
  further PbPK work initiated by industry)
• skin contact with aqueous NMP in humans would
  result in painful edema probably due to influx of
  water into the skin f)

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NMP - EU classification on developmental
effectsconsidering normal handling and use
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NMP - EU classification on developmental
effectsconsidering normal handling and use

• Summary
• severe developmental effects of NMP are seen
  after oral exposure to rats and rabbits (not a
  route of exposure during normal handling and use)
• after dermal exposure effects were only seen in
  rats at high dose levels and their severity was
  much less pronounced as compared to oral studies
• if a two fold lower resorption in humans is taken
  into account based on existing data with NMP the
  effect dose is clearly above 1,000 mg/kg body
  weight
• only marginal developmental toxicity was noted
  via inhalation in rats (vapor saturation) and
  rabbits (aerosol/vapor mixture) taking into
  account that most of the exposure would be via
  vapor and aerosols these high concentrations are
  only formed under drastic conditions and are
  irritant to humans
• available exposure models and experiments taking
  practical use conditions into account indicate
  sufficient safety factors

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NMP - EU classification on developmental
effectsconsidering normal handling and use

• Conclusion
• with respect to normal handling and use and the
  provision of the criteria that animal tests
  should reflect the risks to man in an appropriate
  way, the existing extensive data on developmental
  toxicity of NMP do not warrant a category 2
  classification but rather a category 3 is
  appropriate
• Referencesa) ECBI/47/02 Rev. 1
• b) 14C-N-methylpyrrolidone topical
  application dermal absorption study in the rat
  Huntingdon Life Sciences/UK 4 December 1998)
• c) Inveresk Laboratories/UK 2003 (in vivo
  percutaneous absorption of 14C-N-Methylpyrrolido
  ne in the rat - report not yet available)
• d) Safepharm Laboratories/UK 2003 (in vitro
  absorption of 14C-N-Methylpyrrolidone in human
  skin - study report not yet available)
• e) 14C-N-Methylpyrrolidone in vitro dermal
  penetration study using human and rat skin
  Huntingdon Life Sciences/UK 13 June 2002)
• f) Leira H.L. et al. 1992 (as cited in
  ECBI/47/02) Rev. 1
• g) E. I. duPont de Nemours and Company, Haskell
  Lanboratory for Toxicology and Industrial
  Medicine Delaware/USA Report
• No. 19714-0050 (1995)
• h) Akrill P. et al. Toxicology Letters 134,
  265-269 (2002)
• i) EU Directive 91/414/EEC - Predictive
  Operation Exposure Model
• j) Becci P.J. et al.1982 (as cited in
  ECBI/47/02)
• k) Documenta Geigy, Wissenschaftliche Tabellen,
  Georg Thieme Verlag, 1975 Ventilation volume
  of 16.4 l/min for slight working women.