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Repeated Dose Toxicity

By Little Pro on 2016-04-25 Views:  Update:2017-01-18

The primary goal of repeated dose toxicity studies is to characterize the adverse toxicological effects occurring as a result of repeated daily dosing with, or exposure, to a substance for a specified period up to the expected lifespan of the test species (usually from 3 weeks up to 2 years in animal studies). Effects include changes in morphology, physiology, growth or life span, clinical chemistry and behaviour.

The repeated dose toxicity studies are essential for the quantitative risk assessment of chemical substances. The studies yield information on general characteristics of the toxicity, the toxicity to specific target organs, the dose–response relationship, responses to toxic metabolites formed in the organism, delayed responses, cumulative effects, and information on reversibility/irreversibility of the effect.

Dose Descriptor for Repeated Dose Toxicity

Typically, a NOAEL or LOAEL can be obtained from repeated dose toxicity studies.

  • No Observed Adverse Effect Level (NOAEL): The highest exposure level at which there are no biologically significant increases in the frequency or severity of adverse effect between the exposed population and its appropriate control; some effects may be produced at this level, but they are not considered adverse effects. 
  • Lowest Observed Adverse Effect Level (LOAEL): The lowest exposure level at which there are biologically significant increases in frequency or severity of adverse effects between the exposed population and its appropriate control group. 
  • The units of NOAEL or LOAEL: mg/kg/bw/day or ppm. For inthalation route, the unit can be mg/L/6h/day.

NOAEL is not only used for determining the hazard classification of the specific target organ systematic toxicity of a chemical substance, but also used to derive threshold safety exposure dose to humans such as derived no effect level (DNEL), occupational exposure limit (OEL) and acceptable daily intake (ADI).

GHS Classification Criteria for Specific Target Organ Toxicity Repeated Exposure

GHS has set classification criteria for classifying substances and mixtures that produce specific target organ toxicity arising from repeated exposure. All significant health effects that impair function, both reversible or irreversible, immediate and/or delayed are included.

NOAEL from standard 90d repeated dose toxicity study serves as the most important guidance value to determine the classification  of the specific target organ toxicity of a chemical substance. NOAEL from repeated dose toxicity studies of greater or lesser duration can be used to derive equivalent guidance value by extrapolation. 

Category Classification Criteria and Guidance Value
Category 1

Reliable evidence on the substance or mixture (including bridging) of an adverse effect on specific organ/systems or systemic toxicity in humans or animals. May be named for specific organ/system.

For tested substances and mixtures:

  • NOAEL (oral, rat) ≤ 10 mg/kg bw/d
  • NOAEL (dermal, rat or rabbit) ≤20 mg/kg bw/d
  • NOAEL (inhalation, rat, gas) ≤ 50ppm/6h/d
  • NOAEL (inhalation, rat, vapour) ≤ 0.2 mg/l/6h/d
  • NOAEL (inhalation, rat, dust/mist/fume) ≤ 0.02mg/l/6h/d

Mixture that lacks sufficient data, but contains Category 1 ingredient: ≥ 1 to ≤ 10% for some authorities; and ≥ 10% for all authorities.

Category 2

Evidence on the substance or mixture (including bridging) of an adverse effect on specific organ/systems or systemic toxicity from animal studies or humans. May be named for specific organ/system.

For substances and tested mixtures:

  • 10<NOAEL (oral, rat) ≤ 100 mg/kg bw/d
  • 20<NOAEL (dermal, rat or rabbit) ≤200 mg/kg bw/d
  • 50<NOAEL (inhalation, rat, gas) ≤ 250ppm/6h/d
  • 0.2<NOAEL (inhalation, rat, vapour) ≤ 1 mg/l/6h/d
  • 0.02<NOAEL (inhalation, rat, dust/mist/fume) ≤ 0.2mg/l/6h/d

Mixture that lacks sufficient data, but contains Category 1 ingredient: ≥ 1.0 but ≤ 10% for some authorities and/or contains Category 2 ingredient: ≥ 1.0 or ≥ 10%.

Repeated Dose Toxicity Testing Guidelines

In repeated dose toxicity studies, usually 3 dose levels are given. The highest of three dose levels should be chosen with the aim to induce toxicity but not death. A descending sequence of dose levels should be selected to demonstrate any dose-related response and a no-observed-adverse-effect level (NOAEL) at the lowest dose level.

The guidelines for subacute, subchronic and chronic repeated dose toxicity studies are listed as follows:

Type Guidelines Endpoints
Sub-acute
  • 28-day Oral Toxicity Study in Rodents (OECD TG 407)
  • Dermal Toxicity: 21/28-day Study (rat, rabbit or guinea pig) (OECD TG 410)
  • Inhalation Toxicity: 28-Day Study in Rodents (OECD TG 412)
  • Often used as dose-range finding study for subchronic studies. 
NOAEL or LOAEL
Subchornic
  • 90-Day Oral Toxicity Study in Rodents (OECD TG 408)
  • 90-Day Oral Toxicity Study in Non-Rodents (OECD TG 409) * 
  • Dermal Toxicity: 90-day Study (rat, rabbit or guinea pig) (OECD TG 411)
  • Inhalation Toxicity: 90-day Study in Rodents (OECD TG 413)
  • Usually two species are used in 90d study.
  • Critical for GHS classification and chemical risk assessment.
NOAEL or LOAEL
Chronic
  • Chronic Toxicity Studies in Rodents (OECD TG 452)
  • Combined Chronic Toxicity/Carcinogenicity Studies (OECD TG 453)
NOAEL or LOAEL

Congratulations!

You have learned the definition of repeated dose toxicity, different types of repeated dose toxicity studies (sub-acute, sub-chronic, chronic), dose descriptor for repeated toxicity (NOAEL and LOAEL), GHS classification criteria for specific target organ toxicity and  testing guidelines.

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 Tags: Topics - CRAToxicology and Health Risk Assessment

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