Acute Inhalation Toxicity Testing

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Acute Inhalation Toxicity Testing

• Trigger for inhalation testing exposure-related
• Maximum technically attainable concen-tration
  procedures not clearly defined (EU)
• Definition of appropriate particle-size
  procedures not clearly defined (EU)
• Conversely Strictly-defined definition of
  particle-size in US-Guidelines (OPPTS, EPA-SEP)

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Inhalation ToxicityTriggers for Testing
Other regulations
Vp gt 10 mPa 50 ?m gt PM gt 1
Work-place/ use pattern
Acute inhalation (LC50,RD50,OPPTS 870.1350)
Acute/ repeated exposure studies
Acute/ repeated exposure studies
Repeated exposure (4 / 13 wks)

• AOEL

Classification
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Inhalation Toxicity Testing Interpretation
powders solid smelts, waxes dust-free granulates
liquids low/high viscosity low volatility
Liquids of high volatility or gases
LC50 a property of product?
Acute Inhalation Testing

• mode of action
• biological significance
• relevance for human health

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Particle-size Acute Lethal Potency of Pulmonary
Irritant Aerosols
(4 x 314 mg/m³)
(4 x 541 mg/m³)
) 1 x 4-h, ) 1 x 1-h
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Dust (Agrochemical)Particle-size Inhalation
Toxicity
) According to Directive 91/414 EU no testing
required ) Classification Directive 67/548 -
Annex VI
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Inhalation Toxicity - Dust
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Respirable Fraction - What does this mean?
Marketed Products
Tested Product

• no exposure potential
• moderate inhalability
• low respirability

• high exposure potential
• high inhalability
• high respirability

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Agrochemical Dust - Product Tested vs. Reality
Active ingred., technical
Marketed formulation
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Summary of Critical Issues

• Trigger for inhalation testing risk-related
• no testing by inhalation required
• Work-place exposure or specific down-stream uses
  of formulations containing the substance under
  consideration may require work-place limits
  (AOELs)
• Acute subchronic inhalation studies
• Mechanistic / specialized studies
• Acceptable occupational exposure levels
• Use of data for classification of marketed
  product

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Testing and Interpretation of Inhalation Toxicity
Data

• Harmonization of required particle-size for acute
  inhalation studies
• Standardization of particle-size analyses
• Comparison of product in test and that marketed
• An LC50 cannot be regarded to be intrinsic

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Particle-size Analysis
Aspiration efficiencies have to be taken into
account, i.e., all methodologies used showed
measure the same atmosphere
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Optimization of Respirability
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Deposition/Action of irritant Particles within
the Respiratory Tract
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Particle-size of Marketed Product
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Interpretation of Findings
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EU-Preparation Directive
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Recommendations

• Particle-size used in bioassay and real-world
  needs to be compared
• Adjustments need to be made in order to classify
  substances according to the specified marketed
  product
• The likelihood of acute effects to occur, i.e.,
  the intensity and duration of exposure needs to
  be considered
• Real-life inhalation hazards may be more
  appropriately addressed by AOELs rather than
  classification (local vs. systemic effects)