Appendix 5 Classification of substances and preparations, Danish Environmental Protection Agency

Environmental Factors and Health

Appendix 5
Classification of substances and preparations

Classification of substances

The criteria for classifying chemical substances are based on results from laboratory tests specified in the regulations. Practical experience is also taken into consideration if this information shows that the properties and the potential hazard to man differ from what is observed in the tests. Information may derive from epidemiological studies of human exposure to chemicals, workplace exposures or reported accidents. Deliberate testing of humans with the purpose of classifying a substance is not allowed. The test results and general experience are used to determine:

the type of danger, as expressed through the danger categories

the degree of danger, i.e. how pronounced the related effects are (e.g. if the substance should be classified as very toxic, toxic or harmful by ingestion)

the certainty of the effect (or strength of evidence) in relation to chronic toxicity, carcinogenicity, mutagenicity and reproductive toxicity as these properties can be difficult to demonstrate with absolute certainty. If a substance is a known carcinogen in humans or very likely to cause cancer in humans, it is labelled toxic and assigned one of the following the risk phrases: R45 (May cause cancer) or R49 (May cause cancer by inhalation). If there is more limited evidence, but still a reason to suspect a possible carcinogenic effect in humans based on relevant animal studies, the substance is labelled as harmful and assigned the risk phrase R40 (Possible risk of irreversible effect).

Annex I to the substance directive includes a list of chemical substances and groups of substances for which the classification has been agreed by the Commission. These classifications must be followed in the EU countries. The annexes to the directive, including Annex I, are regularly adapted to technical progress as a result of increased scientific knowledge and more substances are added. With the 26th adaptation, the list now includes approximately 5,000 substances and substance groups.

Substances which are not included in the list must be evaluated against the criteria specified in the directive and classified accordingly. These criteria are briefly outlined in Table 1.

Table 1
Criteria for classification of substances based on toxicological properties

Category of danger	Symbol letter	Indication of danger	Criteria for classification
Very toxic	Tx	Very toxic	Acute toxicity Oral:LD₅₀ Ł 25 mg/kg or <100% survival at 5 mg/kg Dermal:LD₅₀ Ł 25 mg/kg Inhalation: LC₅₀ Ł 0.25 mg/L/4h, (aerosols and particles) LC₅₀ Ł 0.5 mg/L/4h (gasses and vapours) Non-lethal irreversible effects after a single exposure Irreversible effects on e.g. liver or kidney. No specific test method. Experience from short-term tests can be used following the same dose intervals as shown above.
Toxic	T	Toxic	Acute toxicity Oral: 25 mg/kg < LD₅₀Ł 200 mg/kg or critical dose 5 mg/kg Dermal:50 mg/kg < LD₅₀ Ł 400 mg/kg Inhalation: 0.25 mg/kg < LC₅₀ Ł 1 mg/L/4h, (aerosols and particles) 0.5 mg/kg < LC₅₀ Ł 2 mg/L/4h (gasses and vapours) Non-lethal irreversible effects after a single exposure Irreversible effects on e.g. liver or kidney. No specific test method. Experience from short-term tests can be used following the same dose intervals as shown above. Severe effects after repeated or prolonged exposure Functional disturbances or morphological changes seen in subacute (28 days) or subchronic (90 days) animal tests. Dose levels 10 times lower than for acute toxicity (shown above).
Harmful	Xn	Harmful	Acute toxicity Oral: 200 mg/kg < LD₅₀Ł 2000 mg/kg or < 100% survival at 500 mg/kg or critical dose 500 mg/kg Dermal: 400 mg/kg < LD₅₀ Ł 2000 mg/kg Inhalation: 1 mg/kg < LC₅₀ Ł 5 mg/L/4h, (aerosols and particles) 2 mg/kg < LC₅₀ Ł 20 mg/L/4h (gasses and vapours) Liquid substances, which because of low visco-sity, may cause *aspiration* into the lungs with the risk of chemical pneumonitis when swallowed. Non-lethal irreversible effects after a single exposure Irreversible effects on e.g. liver or kidney. No specific test method. Experience from short-term tests can be used following the same dose intervals as shown above. Severe effects after repeated or prolonged exposure Functional disturbances or morphological changes seen in subacute (28 days) or subchronic (90 days) animal tests. Dose levels 10 times lower than for acute toxicity (shown above).
Corrosive	C	Corrosive	Substances, which cause destruction of skin tissue in undamaged animal skin in the skin irritation test, or can be predicted to cause this effect (e.g. because of pH Ł 2 or pH ł 11.5).
Irritant	Xi	Irritant	Non-corrosive substances which, through immediate, prolonged or repeated contact with the skin or mucous membrane, can cause inflammation. Various criteria exist for skin, eye and respiratory irritation.
Sensitising with R42 [1] with R43[1]	Xi Xn	Harmful Irritant	Inhalation: Available documetation of specific sensitisation. Positive results from animal experiments. The substance is an isocyanate, unless it can be documented that the substance is not sensitising. Dermal: Practical experience showing that the substance causes sensitisation in a large number of persons. Positive results from animal experiments.
Carcinogenic Carc 1 and Carc 2: Carc 3:	T Xn	Toxic Harmful	Carc 1: Available documentation proving the correlation between exposure and development of cancer in humans, i.e. results from epidemiological studies. Carc 2: Documentation from animal studies in two different species or one species including information on mutagenicity, toxico-kinetics, etc. Carc 3: Suspected carcinogenic potential, but inadequate documentation from animal studies. Available information not sufficient to classify as Carc 2.
Mutagenic Mut 1 and Mut 2: Mut 3:	T Xn	Toxic Harmful	Mut 1: Available documentation proving the correlation between exposure and hereditary damage to genetic material in humans, i.e. results from epidemiological studies. Mut 2: Mutagen effect in germ cells from mammals in vivo.Other cellular effects i mammal germ cells in vivo, which may be caused by mutagenicity. Mutagen effect in somatic cells in vivo and evidence that the substance or a relevant metabolite reaches the germ cells. Mut 3: Mutagen effect or other cellular effects in vivo in somatic cells, preferably supplemeted with evidence from positive in vitro studies.
Toxic to reproduction Rep 1 and Rep 2: Rep 3:	T Xn	Toxic Harmful	Rep 1 Fertility Available documentation proving the correlation between exposure and reduced fertility in humans, i.e. results from epidemiological studies investigating sexual behaviour, spermatogenesis, agonesis, hormonal activity, reproduction Embryotoxicity Positive documentation from epidemiological studies in humans. Rep 2: Fertility Positive results from animal studies in at least one species and additional information about mechanism of action supporting the relevance for humans. Embryotoxicity Positive results from animal experiments in one or more species, showing adverse effects on the offspring at dose levels without effects on the mother animal, or specific adverse effects on the offspring which are not secondary effects of toxic effects on the mother animal. Rep 3: Fertility Suspected reprotoxic potential, but inadequate documentation from animal studies. Available information not sufficient to classify as Rep 2. Embryotoxicity Information from inadequate animal experiments, e.g. where dose levels or toxico-kinetic differences between the animal and humans make predictions of human effects less certain

Classification of preparations

Preparations are classified in the same categories of danger as substances. Classification based on toxicological effects can follow two different approaches:

either the conventional method using concentration limits,
or the same methods and criteria as used for classification of substances.

When both methods have been applied, results from 2) shall be used except in the case of carcinogenic, mutagenic and reprotoxic effects.

The conventional method rests on the principle that the toxicological properties of a product can be derived from the health hazardous properties and the concentration of the individual substances in the preparation. Another important principle is the assumption that a product must contain a certain amount of a hazardous substance before the product itself is hazardous - the so-called concentration limits.

General concentration limits are assigned to the different danger categories. The concentration limits depend on the severity of the effect. For some substances, which have been shown to exhibit hazardous effects in lower concentrations than the general concentration limit, individual concentration limits are assigned. These limits appear in the list of dangerous substances. As an example the general concentration limits for preparations containing only one classified substance with acute lethal effects are shown below.

Classification of the substance¹	Tx with R26, R27 and/or R28	T with R23, R24 and/or R25	Xn with R20, R21 and/or R22
Concen- tration of the substance in the preparation (w/w%)
0 % < conc. < 0.1 %
0.1 % Ł conc. < 1 %	Xn with R20, R21 and/or R22
1 % Ł conc. < 3 %	T with R23, R24 and/or R25
3 % Ł conc. < 7 %		Xn with R20, R21 and/or R22
7 % Ł conc. < 25 %	Tx with R26, R27 and/or R28
25 % Ł conc.		T with R23, R24 and/or R25	Xn with R20, R21 and/or R22

If preparations contain more chemical substances with the same effect, the concentrations of each of these substances are added in certain situations, and the sum is used for the final classification. Evaluated effects are based on addition:

acute toxic effects

corrosive effects

irritant effects

When adding the acute lethal effects, very toxic and toxic substances in individual concentrations below the concentration limits for classifying the preparation as very toxic or toxic, are added to the harmful substances. The following calculation should be done in this case:

; where

P_Tx	is the percentage by weight of each very toxic substance in the preparation
P_T	is the percentage by weight of each toxic substance in the preparation
P_Xn	is the percentage by weight of each harmful substance in the preparation
L_Xn	is the limit specified for each very toxic, toxic or harmful substance expressed as a percentage

Likewise, the corrosive substances below the concentration limit are added to the irritant substances. Every contribution is divided by the corresponding concentration limit related to the specific category of danger and risk phrase.

Effects which are evaluated individually:

sensitising effects

non-lethal irreversible effects after a single exposure

severe effects after repeated or prolonged exposure

carcinogenic effects

mutagenic effects

effects toxic to reproduction

When using the conventional method, it is important also to evaluate the product as a whole, as some constituents may inactivate each other (acid and base), polymerise or react in other ways. Synergistic and antagonistic effects should also be considered. As an example, some detergents can enhance the irritant effect on eyes of other substances and chelating substances can bind heavy metals and counteract the health hazardous effects of the metal.

Where more than one danger symbol expressing the health hazards are assigned to the preparation, only the symbol expressing the highest degree of danger should be applied.

¹	R26: Very toxic by inhalation; R27: Very toxic in contact with skin; R28: Very toxic if swallowed; R23: Toxic by inhalation; R24: Toxic in contact with skin; R25: Toxic if swallowed; R20: Harmful by inhalation; R21: Harmful in contact with skin; R22: Harmful if swallowed.