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Examples of GHS Specific Target Organ Toxicant Classification

Little Pro on 2019-07-13 Views:  Update:2019-07-25

In our previous article we have covered GHS Classification Criteria for Specific Target Organ Toxicant upon repeated exposure (STOT Re). Now we would like to give you a few classification examples.

Refresh of GHS Classification Criteria for STOT Re

There are 2 categories for specific target organ toxicity (repeated exposure) under GHS. GHS uses guidance value C as cut-off value to determine the hazard category of STOT Re and it is defined as test dose/concentration at which there is evidence of significant health effects. Guidance value C is usually much higher than NOAEL or higher than/equal to LOAEL. 

The guidance value C below is for a standard 90d repeated dose toxicity study. They shall be extrapolated for toxicity studies of greater or lesser duration using dose/exposure time extrapolation similar to Haber’s rule. For example, if only a 28-day study is available, 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
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

For the classification of untested mixtures, most of countries have adopted the following concentration limits.

  • STOT Re Category 1: When a mixture contains an ingredient with category 1 STOT >=10%
  • STOT Re Category 2: When a mixture contains an ingredient with category 1 STOT between 1% and 10% or contains an ingredient with category 2  STOT>=10%

Example 1: STOT Re Classification Based on 90d Study

Let's assume that we have obtained reliable 90d oral repeated dose toxicity data for substance A. Its result is listed as follows. Then substance A will be classified as STOT Re Category 2 because adverse effects on blood have already been observed at 40mg/kg bw/day on both male and female rats. We can reasonably expect more significant health effects on blood at higher dose (guidance C value >=40mg/kg). This will justify a STOT Re Category 2 classification. 

Type of Study - Effects NOAEL in ppm (mg/kg bw/d) LOAEL in ppm (mg/kg bw/d)

Rat, oral 13 weeks

Dose: 0, 50, 500, 1000 ppm (M: 0, 3.8, 40, 67 mg/kg bw/d, F: 0, 4, 40, 80 mg/kg bw/d)

Hematological changes in F: ( decrease in RBC count, Hb, Ht)

 50 (M: 3.8, F: 4)  500 (M: 40, F: 40)

Resulted hazard communication element is listed as follows:

  • Signal word: Warning
  • Hazard statement: H373 May cause damage to the blood through prolonged or repeated exposure

Example 2: STOT Re Classification Based on 28d Study

Let's assume that we have only obtained reliable 28d oral and inhalation repeated dose toxicity data for substance B. Its result is listed as follows. 

Type of Study - Effects NOAEL in ppm (mg/kg bw/d) LOAEL in ppm (mg/kg bw/d)

Rat, oral 28 days (gavage)

Dose:  0; 1; 10; 50 mg/kg bw/d

10 mg/kg bw/d: Increased liver weight (not statistically significant) and  decrease in RBC count by 10%

50 mg/kg bw/d: mortality (1/8 males; 2/8 females); hepato- and nephrotoxicity responsible for mortality - severe effects

 1 10

Rat, inhalation 28 days

Dose:  0.5; 5; and 25 mg/m3 /6h/d

Effects: Some local effects such as respiratory tract and focal squamous metaplasia and inflammation in the larynx are observed

NOAEC for local effects: 5 mg/m3 /6h/d

NOAEC for systemic effects: 25 mg/m3 /6h/d

 -

For oral route, 30 mg/kg bw is the guidance value for Category 1 STOT Re classification based on a 4 week study according to Haber’s rule: (10 mg/kg bw x 3 ). Since only insignificant effects are observed in the 28d oral study at 10mg/kg bw/d and severe effects are observed at 50mg/kg bw/day, we can reasonably estimate that we will get moderate effects up to 30mg/kg bw/day but these effects are not "significant" enough. Thust STOT Re cateogry 2 classification is proposed for oral route based on significant effects expected at >=30mg/kg bw/day. 

For inhalation route, classification is not warranted since there are no systemic effects observed at the highest test concentration and the local effects observed have been covered by other GHS hazard categories (i.e, irritation).

Example 3: STOT Re Classification for Mixture

Attention should be paid to example 4. This is because STOT category 1 and category 2 are not additive hazards.

Examples Compostion Classification

1

  • Ingredient 1 (STOT Re Category 1): 12%
  • Other ingredients: No classification

STOT Re Category 1

Justification:

Contains >=10% STOT Re Category 1 ingredient

2

  • Ingredient 1 (STOT Re Category 1): 5%
  • Ingredient 2 (STOT Re Category 2): 2%
  • Other ingredients: No classification

STOT Re Category 2

Justification:
Contains 1~10% STOT Re Category 1 ingredient

3
  • Ingredient 1 (STOT Re Category 2): 20%
  • Other ingredients: No classification

STOT Re Category 2

Justification:

Contains >10% STOT Re Category 2 ingredient

4
  • Ingredient 1 (STOT Re Category 2): 5%
  • Ingredient 2 (STOT Re Category 2): 7%
  • Other ingredients: No classification

Not classified

Justification:

Does not contain any STOT Re Category 2 ingredient > 10% even though the sum exceeds 10%

References

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