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GHS: Factors to Consider When Classifying A Substance as A Specific Target Organ Toxicant

By Little Pro on 2017-05-26 Views:  Update:2017-06-20

A substance will be classified as a Specific Target Organ Toxicant (STOT) if it produces specific target organ toxicity/systemic effects that are not specifically addressed elsewhere in the GHS. All significant health effects that can impair function, both reversible and irreversible, following single exposure or repeated exposure, are included. Other specific toxic effects, such as acute lethality/toxicity, eye and skin corrosivity/irritation, skin and respiratory sensitisation, carcinogenicity, mutagenicity and reproductive toxicity are not considered since they are assessed separately in the GHS. In this article, we will try to summarize the main factors to consider (i.e., the choice of guidance value) when classifying a substance as a specific target organ toxicant. 

Overview

Since human data is often not available, we reply on animal studies to predict the type and severity of the health hazards of a substance. Since toxicity depends on doses, GHS provides guidance value C from animal studies to help us determine the hazard category of specific target organ toxicity. Guidance value C is defined as test dose/concentration at which there is evidence of significant health effects.

To determine whether a substance is a specific target organ toxicant, one must know: 

  • How to choose correct guidance value C and use it for classification purpose.
  • How to differentiate significant health effects from insignificant ones.

In the following part of this article, we will answer above 2 questions for STOT - single exposure and STOT - repeated exposure

Specific Target Organ Toxicity - Single Exposure

The below below summarizes GHS classification criteria for specific target organ toxicity following single exposure based on animal studies (i.e, rat).  It should be noted that the guidance value C here is not LD50 or LC50. It is usually lower than LD50 or LC50. For example, oral LD50 (rat)=1000mg/kg means that 50% of rats can die at 1000mg/kg. If actual test concentration is much lower than 1000mg/kg (i.e, 100mg/kg), siginificat health effects might still be observed even though no rats would die. 

GHS STOT Single Exposure

Specific Target Organ Toxicity - Repeated Exposure

The table summarizes GHS classification criteria for STOT repeated exposure. Standard 90d repeated dose toxicity study in rat serves as the most important study to determine the hazard category of the specific target organ toxicity of a chemical substance following repeated exposure. The guidance value C is not NOAEL since there is no toxic effect observed at NOAEL. The guidance value C is usually bigger than NOAEL and more like LOAEL.

The guidance value C in the table below can be used as a basis to extrapolate equivalent guidance values for toxicity studies of greater or lesser duration, using dose/exposure time extrapolation similar to Haber’s rule for inhalation. For example, for a 28-day study the guidance values below would be increased by a factor of 3

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:

  • Guidance value C (oral, rat) ≤ 10 mg/kg bw/d
  • Guidance value C (dermal, rat or rabbit) ≤20 mg/kg bw/d
  • Guidance value C (inhalation, rat, gas) ≤ 50ppm/6h/d
  • Guidance value C (inhalation, rat, vapour) ≤ 0.2 mg/l/6h/d
  • Guidance value C (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<Guidance value C (oral, rat) ≤ 100 mg/kg bw/d
  • 20<Guidance value C (dermal, rat or rabbit) ≤200 mg/kg bw/d
  • 50<Guidance value C (inhalation, rat, gas) ≤ 250ppm/6h/d
  • 0.2<Guidance value C (inhalation, rat, vapour) ≤ 1 mg/l/6h/d
  • 0.02<Guidance value C (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%.

Significant Health Effects vs Insignificant Effects

Singificant health effects that support STOT classification include:

  • Morbidity resulting from single exposure, mobidity or death from repeated exposure
  • Significant functional changes in the central or peripheral nervous systems or other organ systems, including signs of central nervous system depression and effects on special senses (e.g., sight, hearing and sense of smell).
  • Any consistent and significant adverse change in clinical biochemistry, haematology, or urinalysis parameters.
  • Significant organ damage that may be noted at necropsy and/or subsequently seen or confirmed at microscopic examination.
  • Multifocal or diffuse necrosis, fibrosis or granuloma formation in vital organs with regenerative capacity.
  • Morphological changes that are potentially reversible but provide clear evidence of marked organ dysfunction.
  • Evidence of appreciable cell death (including cell degeneration and reduced cell number) in vital organs incapable of regeneration.

Insignificant effects that do not justify STOT classification include:

  • Clinical observations or small changes in bodyweight gain, food consumption or water intake
  • Small changes in clinical biochemistry, haematology or urinalysis parameters and/or transient effects
  • Changes in organ weights with no evidence or organ dysfunction.
  • Adaptive responses that are not considered toxicologically relevant.
  • Substance-induced species-specific mechanisms of toxicity, i.e. demonstrated with reasonable certainty to be not relevant for human health, should not justify classification.
  • Where there are only local effects, at the site of administration for the routes tested, and especially when adequate testing by other principal routes show lack of specific target organ/systemic toxicity.

Reference

UN GHS Classification Criteria Part 3 - Health Hazards

 

 Tags: Topics - GHSToxicology and Health Risk Assessment

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