SECTION 11: Toxicological Information

Overview

This section provides comprehensive information about the toxicological health effects and data used to identify those effects, ensuring consistency with classification and labelling requirements under the CLP Regulation. The information should align with hazard classifications from Section 3 and exposure controls from Section 8.

Key Toxicological Data Requirements

Parameter Required Information CLP Reference
Acute toxicity LD₅₀/LC₅₀ values by route (oral, dermal, inhalation) Annex I, 3.1
Skin corrosion/irritation Test results and classification rationale Annex I, 3.2
Serious eye damage/irritation In vivo/vitro test outcomes Annex I, 3.3
Respiratory/skin sensitization Guinea pig maximization test (GPMT) or LLNA results Annex I, 3.4
Mutagenicity Ames test, in vitro cytogenetics data Annex I, 3.5
Carcinogenicity IARC classifications or equivalent studies Annex I, 3.6
Reproductive toxicity Teratogenicity, fertility impacts Annex I, 3.7
STOT Target organ effects (single/repeated exposure) Annex I, 3.8-3.9
Aspiration hazard Viscosity data, hydrocarbon content Annex I, 3.10

1. Acute Toxicity

  • Routes of exposure: oral, dermal, inhalation
  • Acute Toxicity Estimates (ATE) or LD50/LC50 values where available
  • Species-specific data and test methods used
  • Human experience data if available
  • Dose levels and exposure durations

Classification Criteria:

  • Category 1: LD₅₀ ≤ 5 mg/kg (oral)
  • Category 2: 5 < LD₅₀ ≤ 50 mg/kg (oral)
  • Category 3: 50 < LD₅₀ ≤ 300 mg/kg (oral)
  • Category 4: 300 < LD₅₀ ≤ 2000 mg/kg (oral)

Similar tiered criteria exist for dermal and inhalation routes.

2. Skin Effects

  • Corrosion/irritation test results
  • pH values and extremes
  • Human experience data
  • Reversibility of effects
  • Test methods used (in vitro/in vivo)

Testing Methods:

  • OECD TG 404: Acute Dermal Irritation/Corrosion
  • OECD TG 431: In Vitro Skin Corrosion
  • OECD TG 439: In Vitro Skin Irritation

3. Eye Effects

  • Serious eye damage/irritation data
  • Severity and reversibility of effects
  • pH considerations
  • Test methods and observations
  • Human experience reports

Testing Methods:

  • OECD TG 405: Acute Eye Irritation/Corrosion
  • OECD TG 437: Bovine Corneal Opacity and Permeability Test
  • OECD TG 492: Reconstructed Human Cornea-like Epithelium

4. Sensitization

  • Respiratory and skin sensitization data
  • Evidence from human exposure
  • Animal test results (e.g., LLNA, GPMT)
  • Mechanisms of action
  • Concentration thresholds

Classification Thresholds:

For skin sensitizers, Category 1 is assigned when:

  • ≥ 30% positive response in GPMT at ≤ 0.1% intradermal induction dose, or
  • ≥ 60% positive response in GPMT at > 0.1% to ≤ 1% intradermal induction dose, or
  • ≥ 15% positive response in LLNA

5. Genetic Effects

  • Mutagenicity/genotoxicity data
  • In vitro and in vivo test results
  • Mode of action information
  • Structure-activity relationships

Common Tests:

  • Ames test (bacterial reverse mutation)
  • Chromosomal aberration test
  • Micronucleus test
  • Comet assay

6. Carcinogenicity

  • Human epidemiological studies
  • Animal carcinogenicity data
  • Exposure duration and dose relationships
  • Target organs affected
  • Mechanistic information

Classification Systems:

  • IARC: Group 1 (carcinogenic), 2A (probably carcinogenic), 2B (possibly carcinogenic), 3 (not classifiable), 4 (probably not carcinogenic)
  • CLP: Category 1A (known human carcinogen), 1B (presumed human carcinogen), 2 (suspected human carcinogen)

7. Reproductive Toxicity

  • Fertility effects
  • Developmental toxicity
  • Maternal toxicity
  • Human evidence
  • Dose-response relationships

Testing Methods:

  • OECD TG 414: Prenatal Developmental Toxicity Study
  • OECD TG 416: Two-Generation Reproduction Toxicity
  • OECD TG 421/422: Reproduction/Developmental Toxicity Screening Test

8. Specific Target Organ Toxicity

Single Exposure (STOT-SE):

  • Target organs affected
  • Route of exposure
  • Concentration/dose relationship
  • Reversibility

Repeated Exposure (STOT-RE):

  • Cumulative effects
  • Target organs
  • Recovery potential
  • Exposure duration

Classification Guidance:

STOT-SE Category 1: Significant toxicity in humans or animal studies at ≤ 300 mg/kg body weight

STOT-RE Category 1: Significant toxicity in humans or animal studies at ≤ 10 mg/kg body weight/day (90-day study)

9. Aspiration Hazard

  • Physical properties (viscosity)
  • Human experience
  • Animal studies

Classification Criteria:

Category 1 aspiration hazard if:

  • Kinematic viscosity ≤ 20.5 mm²/s (measured at 40°C) for hydrocarbons, or
  • Based on reliable and good quality human evidence

10. Toxicokinetics

  • Metabolism and distribution data
  • Excretion pathways
  • Half-life information
  • Species-specific considerations

Example: Ethanol Toxicokinetics

  • Absorption: Complete GI absorption within 2-6 hours
  • Metabolism: 90% hepatic oxidation via ADH/CYP2E1
  • Excretion: 5-10% unchanged in urine/breath

11. Other Information

  • Phototoxicity and photoallergy data
  • Endocrine disruption potential
  • Neurotoxicity effects
  • Immunotoxicity data
  • Other relevant toxicological endpoints

Endocrine disrupting properties must be indicated in accordance with the 2020/878 amendment to REACH Annex II.

Example: Benzene Toxicity Profile

Acute Effects

  • LC₅₀ (inh): 10,000 ppm/7h (rat)
  • LD₅₀ (oral): 930 mg/kg (mouse)

Chronic Effects

  • IARC Group 1 carcinogen (leukemia)
  • STOT-RE: Hematopoietic system damage
  • Reproductive: Ovarian atrophy in chronic exposure

Biomonitoring

  • Urinary S-phenylmercapturic acid >50 μg/g creatinine indicates exposure

Acute Effects Overview

Exposure Route Symptoms First Aid Measures
Inhalation Cough, dizziness, respiratory irritation Remove to fresh air
Skin Contact Erythema, chemical burns Wash with water 15+ minutes
Eye Contact Corneal damage, conjunctivitis Immediate irrigation 30 minutes
Ingestion GI irritation, CNS depression Do NOT induce vomiting

Testing Standards Reference

Test OECD Guideline CLP Relevance
Acute Oral Toxicity TG 423 Cat 1-4 Classification
Skin Sensitization TG 406 (GPMT) Cat 1 Determination
Prenatal Toxicity TG 414 Developmental Effects
In Vitro Genotoxicity TG 487 Mutagenicity Assessment

Data Quality and Reporting

  • Scientific accuracy and justification
  • Test methodology references
  • Species/sex/number of test subjects
  • Exposure routes considered
  • Positive and negative findings
  • Data gaps and uncertainties
  • Human data prioritization
  • QSARs where applicable

Quality Assurance Checklist

  • Verify consistency between toxicological data and hazard classification
  • Ensure all mandatory endpoints are addressed
  • Validate that test methods comply with OECD guidelines
  • Check that data is species-specific and includes exposure routes
  • Confirm that human data is prioritized when available
  • Verify that data gaps are acknowledged and justified

Critical Requirements

New Requirements (2023)