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3.8.2.: Classification criteria for substances
3.8.2.1.
Substances of Category 1 and Category 2
3.8.2.1.1.
Substances are classified for immediate or delayed effects separately, by the use of expert judgement (see 1.1.1) on the basis of the weight of all evidence available, including the use of recommended guidance values (see 3.8.2.1.9). Substances are then placed in Category 1 or 2, depending upon the nature and severity of the effect(s) observed (Table 3.8.1).
3.8.2.1.2.
The relevant route or routes of exposure by which the classified substance produces damage shall be identified (see 3.8.1.5).
3.8.2.1.3.
Classification is determined by expert judgement (see section 1.1.1), on the basis of the weight of all evidence available including the guidance presented below.
3.8.2.1.4.
Weight of evidence of all data (see section 1.1.1), including human incidents, epidemiology, and studies conducted in experimental animals, is used to substantiate specific target organ toxic effects that merit classification.
3.8.2.1.5.
The information required to evaluate specific target organ toxicity comes either from single exposure in humans, such as: exposure at home, in the workplace or environmentally, or from studies conducted in experimental animals. The standard animal studies in rats or mice that provide this information are acute toxicity studies which can include clinical observations and detailed macroscopic and microscopic examination to enable the toxic effects on target tissues/organs to be identified. Results of acute toxicity studies conducted in other species may also provide relevant information.
3.8.2.1.6.
In exceptional cases, based on expert judgement, it is appropriate to place certain substances with human evidence of target organ toxicity in Category 2:
(a)
when the weight of human evidence is not sufficiently convincing to warrant Category 1 classification, and/or
(b)
based on the nature and severity of effects.
Dose/concentration levels in humans shall not be considered in the classification and any available evidence from animal studies shall be consistent with the Category 2 classification. In other words, if there are also animal data available on the substance that warrant Category 1 classification, the substance shall be classified as Category 1.
3.8.2.1.7.
Effects considered to support classification for Category 1 and 2
3.8.2.1.7.1.
Classification is supported by evidence associating single exposure to the substance with a consistent and identifiable toxic effect.
3.8.2.1.7.2.
Evidence from human experience/incidents is usually restricted to reports of adverse health consequence, often with uncertainty about exposure conditions, and may not provide the scientific detail that can be obtained from well-conducted studies in experimental animals.
3.8.2.1.7.3.
Evidence from appropriate studies in experimental animals can furnish much more detail, in the form of clinical observations, and macroscopic and microscopic pathological examination, and this can often reveal hazards that may not be life-threatening but could indicate functional impairment. Consequently all available evidence, and relevance to human health, must be taken into consideration in the classification process, including but not limited to the following effects in humans and/or animals:
(a)
morbidity resulting from single exposure;
(b)
significant functional changes, more than transient in nature, in the respiratory system, central or peripheral nervous systems, other organs or other organ systems, including signs of central nervous system depression and effects on special senses (such as sight, hearing and sense of smell);
(c)
any consistent and significant adverse change in clinical biochemistry, haematology, or urinalysis parameters;
(d)
significant organ damage noted at necropsy and/or subsequently seen or confirmed at microscopic examination;
(e)
multi-focal or diffuse necrosis, fibrosis or granuloma formation in vital organs with regenerative capacity;
(f)
morphological changes that are potentially reversible but provide clear evidence of marked organ dysfunction;
(g)
evidence of appreciable cell death (including cell degeneration and reduced cell number) in vital organs incapable of regeneration.
3.8.2.1.8.
Effects considered not to support classification for Category 1 and 2
It is recognised that effects may be seen that does not justify classification. Such effects in humans and/or animals include, but are not limited to:
(a)
clinical observations or small changes in bodyweight gain, food consumption or water intake that may have some toxicological importance but that do not, by themselves, indicate ‘significant’ toxicity;
(b)
small changes in clinical biochemistry, haematology or urinalysis parameters and/or transient effects, when such changes or effects are of doubtful or minimal toxicological importance;
(c)
changes in organ weights with no evidence of organ dysfunction;
(d)
adaptive responses that are not considered toxicologically relevant;
(e)
substance-induced species-specific mechanisms of toxicity, i.e. demonstrated with reasonable certainty to be not relevant for human health, shall not justify classification.
3.8.2.1.9.
Guidance values to assist with classification based on the results obtained from studies conducted in experimental animals for Category 1 and 2
3.8.2.1.9.1.
In order to help reach a decision about whether a substance shall be classified or not, and to what degree it shall be classified (Category 1 or Category 2), dose/concentration ‘guidance values’ are provided for consideration of the dose/concentration which has been shown to produce significant health effects. The principal argument for proposing such guidance values is that all substances are potentially toxic and there has to be a reasonable dose/concentration above which a degree of toxic effect is acknowledged.
3.8.2.1.9.2.
Thus, in animal studies, when significant toxic effects are observed that indicate classification, consideration of the dose/concentration at which these effects were seen, in relation to the suggested guidance values, provides useful information to help assess the need to classify (since the toxic effects are a consequence of the hazardous property(ies) and also the dose/concentration).
3.8.2.1.9.3.
The guidance value (C) ranges for single-dose exposure which has produced a significant non-lethal toxic effect are those applicable to acute toxicity testing, as indicated in Table 3.8.2.
Table 3.8.2
Guidance value ranges for single-dose exposures a
|
|
Guidance value ranges for: |
|||
|
Route of exposure |
Units |
Category 1 |
Category 2 |
Category 3 |
|
Oral (rat) |
mg/kg body weight |
C ≤ 300 |
2 000 ≥ C > 300 |
Guidance values do not apply b |
|
Dermal (rat or rabbit) |
mg/kg body weight |
C ≤ 1 000 |
2 000 ≥ C > 1 000 |
|
|
Inhalation (rat) gas |
ppmV/4h |
C ≤ 2 500 |
20 000 ≥ C > 2 500 |
|
|
Inhalation (rat) vapour |
mg/l/4h |
C ≤ 10 |
20 ≥ C > 10 |
|
|
mg/l/4h |
C ≤ 1,0 |
5,0 ≥ C > 1,0 |
||
Note
(a)
The guidance values and ranges mentioned in Table 3.8.2 are intended only for guidance purposes, i.e. to be used as part of the weight of evidence approach, and to assist with decision about classification. They are not intended as strict demarcation values.
(b)
Guidance values are not provided for Category 3 substances since this classification is primarily based on human data. Animal data, if available, shall be included in the weight of evidence evaluation.
3.8.2.1.10.
Other considerations
3.8.2.1.10.1.
When a substance is characterised only by use of animal data (typical of new substances, but also true for many existing substances), the classification process includes reference to dose/concentration guidance values as one of the elements that contribute to the weight of evidence approach.
3.8.2.1.10.2.
When well-substantiated human data are available showing a specific target organ toxic effect that can be reliably attributed to single exposure to a substance, the substance shall normally be classified. Positive human data, regardless of probable dose, predominates over animal data. Thus, if a substance is unclassified because specific target organ toxicity observed was considered not relevant or significant to humans, if subsequent human incident data become available showing a specific target organ toxic effect, the substance shall be classified.
3.8.2.1.10.3.
A substance that has not been tested for specific target organ toxicity may, where appropriate, be classified on the basis of data from a validated structure activity relationship and expert judgement-based extrapolation from a structural analogue that has previously been classified together with substantial support from consideration of other important factors such as formation of common significant metabolites.
3.8.2.1.10.4.
Saturated vapour concentration shall be considered, where appropriate, as an additional element to provide for specific health and safety protection
3.8.2.2.
Substances of Category 3: Transient target organ effects
3.8.2.2.1.
Criteria for respiratory tract irritation
The criteria for classifying substances as Category 3 for respiratory tract irritation are:
(a)
respiratory irritant effects (characterised by localised redness, oedema, pruritis and/or pain) that impair function with symptoms such as cough, pain, choking, and breathing difficulties are included. This evaluation will be based primarily on human data;
(b)
subjective human observations could be supported by objective measurements of clear respiratory tract irritation (RTI) (such as electrophysiological responses, biomarkers of inflammation in nasal or bronchoalveolar lavage fluids);
(c)
the symptoms observed in humans shall also be typical of those that would be produced in the exposed population rather than being an isolated idiosyncratic reaction or response triggered only in individuals with hypersensitive airways. Ambiguous reports simply of ‘irritation’ shall be excluded as this term is commonly used to describe a wide range of sensations including those such as smell, unpleasant taste, a tickling sensation, and dryness, which are outside the scope of classification for respiratory irritation;
(d)
there are currently no validated animal tests that deal specifically with RTI, however, useful information may be obtained from the single and repeated inhalation toxicity tests. For example, animal studies may provide useful information in terms of clinical signs of toxicity (dyspnoea, rhinitis etc) and histopathology (e.g. hyperemia, edema, minimal inflammation, thickened mucous layer) which are reversible and may be reflective of the characteristic clinical symptoms described above. Such animal studies can be used as part of weight of evidence evaluation;
(e)
this special classification would occur only when more severe organ effects including in the respiratory system are not observed.
3.8.2.2.2
Criteria for narcotic effects
The criteria for classifying substances as Category 3 for narcotic effects are:
(a)
central nervous system depression including narcotic effects in humans such as drowsiness, narcosis, reduced alertness, loss of reflexes, lack of coordination, and vertigo are included. These effects can also be manifested as severe headache or nausea, and can lead to reduced judgment, dizziness, irritability, fatigue, impaired memory function, deficits in perception and coordination, reaction time, or sleepiness;
(b)
narcotic effects observed in animal studies may include lethargy, lack of coordination, loss of righting reflex, and ataxia. If these effects are not transient in nature, then they shall be considered to support classification for Category 1 or 2 specific target organ toxicity single exposure.