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3.9.2.: Classification criteria for substances
3.9.2.1.
Substances are classified as specific target organ toxicants following repeated exposure 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 which take into account the duration of exposure and the dose/concentration which produced the effect(s), (see 3.9.2.9), and are placed in one of two categories, depending upon the nature and severity of the effect(s) observed (Table 3.9.1).
Table 3.9.1
Categories for specific target organ toxicity-repeated exposure
|
Categories |
Criteria |
|
Category 1 |
Substances that have produced significant toxicity in humans or that, on the basis of evidence from studies in experimental animals, can be presumed to have the potential to produce significant toxicity in humans following repeated exposure. Substances are classified in Category 1 for target organ toxicity (repeat exposure) on the basis of: — reliable and good quality evidence from human cases or epidemiological studies; or — observations from appropriate studies in experimental animals in which significant and/or severe toxic effects, of relevance to human health, were produced at generally low exposure concentrations. Guidance dose/concentration values are provided below (see 3.9.2.9), to be used as part of a weight-of- evidence evaluation. |
|
Category 2 |
Substances that, on the basis of evidence from studies in experimental animals can be presumed to have the potential to be harmful to human health following repeated exposure. Substances are classified in category 2 for target organ toxicity (repeat exposure) on the basis of observations from appropriate studies in experimental animals in which significant toxic effects, of relevance to human health, were produced at generally moderate exposure concentrations. Guidance dose/concentration values are provided below (see 3.9.2.9) in order to help in classification. In exceptional cases human evidence can also be used to place a substance in Category 2 (see 3.9.2.6). |
Note
Attempts shall be made to determine the primary target organ of toxicity and classify for that purpose, such as hepatotoxicants, neurotoxicants. One shall carefully evaluate the data and, where possible, not include secondary effects (a hepatotoxicant can produce secondary effects in the nervous or gastro-intestinal systems).
3.9.2.2.
The relevant route or routes of exposure by which the classified substance produces damage shall be identified.
3.9.2.3.
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.
3.9.2.4.
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. This taps the considerable body of industrial toxicology data collected over the years. Evaluation shall be based on all existing data, including peer-reviewed published studies and additional acceptable data.
3.9.2.5.
The information required to evaluate specific target organ toxicity comes either from repeated 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 28 day, 90 day or lifetime studies (up to 2 years) that include haematological, clinicochemical and detailed macroscopic and microscopic examination to enable the toxic effects on target tissues/organs to be identified. Data from repeat dose studies performed in other species shall also be used, if available. Other long-term exposure studies, such as on carcinogenicity, neurotoxicity or reproductive toxicity, may also provide evidence of specific target organ toxicity that could be used in the assessment of classification.
3.9.2.6.
In exceptional cases, based on expert judgement, it is appropriate to place certain substances with human evidence of specific 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.
3.9.2.7.
Effects considered to support classification for specific target organ toxicity following repeated exposure
3.9.2.7.1.
Reliable evidence associating repeated exposure to the substance with a consistent and identifiable toxic effect demonstrates support for the classification.
3.9.2.7.2.
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.
3.9.2.7.3.
Evidence from appropriate studies in experimental animals can furnish much more detail, in the form of clinical observations, haematology, clinical chemistry, 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, shall be taken into consideration in the classification process, including but not limited to the following toxic effects in humans and/or animals:
(a)
morbidity or death resulting from repeated or long-term exposure. Morbidity or death may result from repeated exposure, even to relatively low doses/concentrations, due to bioaccumulation of the substance or its metabolites, and/or due to the overwhelming of the de-toxification process by repeated exposure to the substance or its metabolites;
(b)
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);
(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 (e.g., severe fatty change in the liver);
(g)
evidence of appreciable cell death (including cell degeneration and reduced cell number) in vital organs incapable of regeneration.
3.9.2.8.
Effects considered not to support classification for specific target organ toxicity following repeated exposure
3.9.2.8.1.
It is recognised that effects may be seen in humans and/or animals that do not justify classification. Such effects include, but are not limited to:
(a)
clinical observations or small changes in bodyweight gain, food consumption or water intake that have 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.
3.9.2.9.
Guidance values to assist with classification based on the results obtained from studies conducted in experimental animals
3.9.2.9.1.
In studies conducted in experimental animals, reliance on observation of effects alone, without reference to the duration of experimental exposure and dose/concentration, omits a fundamental concept of toxicology, i.e. all substances are potentially toxic, and what determines the toxicity is a function of the dose/concentration and the duration of exposure. In most studies conducted in experimental animals the test guidelines use an upper limit dose value.
3.9.2.9.2.
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. Also, repeated-dose studies conducted in experimental animals are designed to produce toxicity at the highest dose used in order to optimise the test objective and so most studies will reveal some toxic effect at least at this highest dose. What is therefore to be decided is not only what effects have been produced, but also at what dose/concentration they were produced and how relevant is that for humans.
3.9.2.9.3.
Thus, in animal studies, when significant toxic effects are observed that indicate classification, consideration of the duration of experimental exposure and the dose/concentration at which these effects were seen, in relation to the suggested guidance values, can provide useful information to help assess the need to classify (since the toxic effects are a consequence of the hazardous property(ies) and also the duration of exposure and the dose/concentration).
3.9.2.9.4.
The decision to classify at all can be influenced by reference to the dose/concentration guidance values at or below which a significant toxic effect has been observed.
3.9.2.9.5.
The guidance values refer to effects seen in a standard 90-day toxicity study conducted in rats. They 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, which states essentially that the effective dose is directly proportional to the exposure concentration and the duration of exposure. The assessment shall be done on a case-by-case basis; for a 28-day study the guidance values below is increased by a factor of three.
3.9.2.9.6.
Thus classification in Category 1 is applicable, when significant toxic effects observed in a 90-day repeated-dose study conducted in experimental animals are seen to occur at or below the guidance values (C) as indicated in Table 3.9.2:
Table 3.9.2
Guidance values to assist in Category 1 classification
|
Route of exposure |
Units |
Guidance values (dose/concentration) |
|
Oral (rat) |
mg/kg body weight/day |
C ≤ 10 |
|
Dermal (rat or rabbit) |
mg/kg body weight/day |
C ≤ 20 |
|
Inhalation (rat)gas |
ppmV/6h/day |
C ≤ 50 |
|
Inhalation (rat)vapour |
mg/litre/6h/day |
C ≤ 0,2 |
|
mg/litre/6h/day |
C ≤ 0,02 |
3.9.2.9.7.
Classification in Category 2 is applicable, when significant toxic effects observed in a 90-day repeated-dose study conducted in experimental animals are seen to occur within the guidance value ranges as indicated in Table 3.9.3:
Table 3.9.3
Guidance values to assist in Category 2 classification
|
Route of Exposure |
Units |
Guidance Value Ranges: (dose/concentration) |
|
Oral (rat) |
mg/kg body weight/day |
10 < C ≤ 100 |
|
Dermal (rat or rabbit) |
mg/kg body weight/day |
20 < C ≤ 200 |
|
Inhalation (rat) gas |
ppmV/6h/day |
50 < C ≤ 250 |
|
Inhalation (rat)vapour |
mg/litre/6h/day |
0,2 < C ≤ 1,0 |
|
mg/litre/6h/day |
0,02 < C ≤ 0,2 |
3.9.2.9.8.
The guidance values and ranges mentioned in paragraphs 3.9.2.9.6 and 3.9.2.9.7 are intended only for guidance purposes, i.e. to be used as part of the weight of evidence approach, and to assist with decisions about classification. They are not intended as strict demarcation values.
3.9.2.9.9.
Thus it is feasible that a specific profile of toxicity occurs in repeat-dose animal studies at a dose/concentration below the guidance value, such as < 100 mg/kg bw/day by the oral route, however the nature of the effect, such as nephrotoxicity seen only in male rats of a particular strain known to be susceptible to this effect may result in the decision not to classify. Conversely, a specific profile of toxicity may be seen in animal studies occurring at or above a guidance value, such as ≥ 100 mg/kg bw/day by the oral route, and in addition there is supplementary information from other sources, such as other long-term administration studies, or human case experience, which supports a conclusion that, in view of the weight of evidence, classification is the prudent action to take.
3.9.2.10.
Other considerations
3.9.2.10.1.
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.
3.9.2.10.2.
When well-substantiated human data are available showing a specific target organ toxic effect that can be reliably attributed to repeated or prolonged 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 no specific target organ toxicity was seen at or below the dose/concentration guidance value for animal testing, if subsequent human incident data become available showing a specific target organ toxic effect, the substance shall be classified.
3.9.2.10.3.
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.
3.9.2.10.4.
Saturated vapour concentration shall be considered, where appropriate, as an additional element to provide for specific health and safety protection