Regulation (EC) No 1272/2008 of the European Parliament and of the Council of 16 December 2008 on classification, labelling and packaging of substances and mixtures, amending and repealing Directives 67/548/EEC and 1999/45/EC, and amending Regulation (EC) No 1907/2006 (Text with EEA relevance)

Note 1: Desensitised explosives shall be prepared so that they remain homogeneous and do not separate during normal storage and handling, particularly if desensitised by wetting. The manufacturer/supplier shall give information in the safety data sheet about the shelf-life and instructions on verifying desensitisation. Under certain conditions the content of desensitising agent (e.g. phlegmatiser, wetting agent or treatment) may decrease during supply and use, and thus, the hazard potential of the desensitised explosive may increase. In addition, the safety data sheet shall include advice on avoiding increased fire, blast or projection hazards when the substance or mixture is not sufficiently desensitised.

Note 2: Explosive properties of desensitised explosives shall be determined by test series 2 of the UN RTDG, Manual of Tests and Criteria, and shall be communicated in the safety data sheet.

Note 3: For the purposes of storage, supply and use, desensitised explosives do not fall additionally within the scope of Sections 2.1 (explosives), 2.6 (flammable liquids) and 2.7 (flammable solids).

2.17.3.   Hazard communication

Label elements shall be used for liquid or solid substances or mixtures meeting the criteria for classification in this hazard class in accordance with Table 2.17.2.

Table 2.17.2.

Label elements for desensitised explosives

	Category 1	Category 2	Category 3	Category 4
GHS Pictogram	Image omitted; see official source	Image omitted; see official source	Image omitted; see official source	Image omitted; see official source
Signal word	Danger	Danger	Warning	Warning
Hazard statement	H206 Fire, blast or projection hazard; increased risk of explosion if desensitising agent is reduced	H207 Fire or projection hazard; increased risk of explosion if desensitising agent is reduced	H207 Fire or projection hazard; increased risk of explosion if desensitising agent is reduced	H208: Fire hazard; increased risk of explosion if desensitising agent is reduced
Precautionary statement Prevention	P210 P212 P230 P233 P280	P210 P212 P230 P233 P280	P210 P212 P230 P233 P280	P210 P212 P230 P233 P280
Precautionary Statement Response	P370 + P380+ P375	P370 + P380+ P375	P370 + P380+ P375	P371 + P380 + P375
Precautionary Statement Storage	P401	P401	P401	P401
Precautionary Statement Disposal	P501	P501	P501	P501

2.17.4.   Additional classification considerations

Figure 2.17.1.

Desensitised explosives

Image omitted; see official source

Text of image

No

Explosive

Division 1.1

Explosive

Division 1.1

Hazard class “Explosives” (see criteria in Section 2.1)

Yes

No

Not classified as a desensitised explosive

May fall within the scope of other physical hazard classes

Yes

Yes

Danger

Danger

Yes

Is the result a mass explosion?

Test 6(a), 6(b)

Is the exothermic decomposition energy less than 300 J/g?

Does it contain an explosive substance or mixture which is phlegmatised to suppress the explosive properties?

The substance/mixture is a solid or liquid?

No

Yes

No

AC > 1 200 kg/min?

Is the result a mass explosion?

Burning rate test

(Part V, sub-section 51.4)

Image omitted; see official source

Text of image

AC ≥ 60 kg/min but < 140 kg/min

Category 4

Category 3

Category 2

AC < 60 kg/min

Warning

Yes

No

AC ≥ 140 kg/min but < 300 kg/min

No

Warning

Danger

Danger

Category 1

Yes

Yes

Yes

AC ≥ 300 kg/min but < 1 200 kg/min

No

No

• 2.17.4.1. The classification procedure for desensitised explosives does not apply if:

• (a) The substances or mixtures contain no explosives according to the criteria in Section 2.1; or

• (b) The exothermic decomposition energy is less than 300 J/g.

• 2.17.4.2. The exothermic decomposition energy shall be determined using the explosive already desensitised (i.e.: the homogenous solid or liquids mixture formed by the explosive and the substance(s) used to suppress its explosive properties). The exothermic decomposition energy may be estimated using a suitable calorimetric technique (see Section 20, sub-section 20.3.3.3 in Part II of the UN RTDG, Manual of Tests and Criteria).

3. PART 3: HEALTH HAZARDS

3.1.   Acute toxicity

3.1.1.   Definitions

• 3.1.1.1.Acute toxicity means serious adverse health effects (i.e., lethality) occurring after a single or short-term oral, dermal or inhalation exposure to a substance or mixture.

• 3.1.1.2.The hazard class Acute Toxicity is differentiated into:

• — Acute oral toxicity;

• — Acute dermal toxicity;

• — Acute inhalation toxicity.

3.1.2.   Criteria for classification of substances as acutely toxic

• 3.1.2.1.Substances can be allocated to one of four hazard categories based on acute toxicity by the oral, dermal or inhalation route according to the numeric cut-off criteria as shown in the table below. Acute toxicity values are expressed as (approximate) LD50 (oral, dermal) or LC50 (inhalation) values or as acute toxicity estimates (ATE). While some in vivo methods determine LD50/LC50 values directly, other newer in vivo methods (e.g. using fewer animals) consider other indicators of acute toxicity, such as significant clinical signs of toxicity, which are used as a reference to assign the hazard category. Explanatory notes are shown following Table 3.1.1.

Table 3.1.1

Acute toxicity estimate (ATE) values and criteria for acute toxicity hazard categories.

Exposure route	Exposure route	Category 1	Category 2	Category 3	Category 4
Oral (mg/kg bodyweight)	Oral (mg/kg bodyweight)	ATE ≤ 5	5 < ATE ≤ 50	50 < ATE ≤ 300	300 < ATE ≤ 2 000
See:	Note (a) Note (b)	ATE ≤ 5	5 < ATE ≤ 50	50 < ATE ≤ 300	300 < ATE ≤ 2 000
Dermal (mg/kg bodyweight)	Dermal (mg/kg bodyweight)	ATE ≤ 50	50 < ATE ≤ 200	200 < ATE ≤ 1 000	1 000 < ATE ≤ 2 000
See:	Note (a) Note (b)	ATE ≤ 50	50 < ATE ≤ 200	200 < ATE ≤ 1 000	1 000 < ATE ≤ 2 000
Gases (ppmV [^E0029])	Gases (ppmV [^E0029])	ATE ≤ 100	100 < ATE ≤ 500	500 < ATE ≤ 2 500	2 500 < ATE ≤ 20 000
see:	Note (a) Note (b) Note (c)	ATE ≤ 100	100 < ATE ≤ 500	500 < ATE ≤ 2 500	2 500 < ATE ≤ 20 000
Vapours (mg/l)	Vapours (mg/l)	ATE ≤ 0,5	0,5 < ATE ≤ 2,0	2,0 < ATE ≤ 10,0	10,0 < ATE ≤ 20,0
see:	Note (a) Note (b) Note (c) Note (d)	ATE ≤ 0,5	0,5 < ATE ≤ 2,0	2,0 < ATE ≤ 10,0	10,0 < ATE ≤ 20,0
Dusts and mists (mg/l)	Dusts and mists (mg/l)	ATE ≤ 0,05	0,05 < ATE ≤ 0,5	0,5 < ATE ≤ 1,0	1,0 < ATE ≤ 5,0
see:	Note (a) Note (b) Note (c)	ATE ≤ 0,05	0,05 < ATE ≤ 0,5	0,5 < ATE ≤ 1,0	1,0 < ATE ≤ 5,0

Gas concentrations are expressed in parts per million per volume (ppmV).

Notes to Table 3.1.1:

• (a) The acute toxicity estimate (ATE) for the classification of a substance is derived using the LD50/LC50 where available.

• (b) The acute toxicity estimate (ATE) for the classification of a substance in a mixture is derived using:
• — the LD50/LC50 where available,
• — the appropriate conversion value from Table 3.1.2 that relates to the results of a range test, or
• — the appropriate conversion value from Table 3.1.2 that relates to a classification category.

• (c) The ranges of the acute toxicity estimates (ATE) for inhalation toxicity used in the Table are based on 4-hour testing exposures. Conversion of existing inhalation toxicity data which have been generated using a 1-hour exposure can be carried out by dividing by a factor of 2 for gases and vapours and 4 for dusts and mists.

• (d) For some substances the test atmosphere will not just be a vapour but will consist of a mixture of liquid and vapour phases. For other substances the test atmosphere may consist of a vapour which is near the gaseous phase. In these latter cases, classification shall be based on ppmV as follows: Category 1 (100 ppmV), Category 2 (500 ppmV), Category 3 (2 500 ppmV), Category 4 (20 000 ppmV). The terms ‘dust’, ‘mist’ and ‘vapour’ are defined as follows:
• — dust: solid particles of a substance or mixture suspended in a gas (usually air),
• — mist: liquid droplets of a substance or mixture suspended in a gas (usually air),
• — vapour: the gaseous form of a substance or mixture released from its liquid or solid state. Dust is generally formed by mechanical processes. Mist is generally formed by condensation of supersaturated vapours or by physical shearing of liquids. Dusts and mists generally have sizes ranging from less than 1 to about 100 μm.

3.1.2.2.   Specific considerations for classification of substances as acutely toxic

• 3.1.2.2.1.The preferred test species for evaluation of acute toxicity by the oral and inhalation routes is the rat, while the rat or rabbit are preferred for evaluation of acute dermal toxicity. When experimental data for acute toxicity are available in several animal species, scientific judgement shall be used in selecting the most appropriate LD50 value from among valid, well-performed tests.

3.1.2.3.   Specific considerations for classification of substances as acutely toxic by the inhalation route

• 3.1.2.3.1.Units for inhalation toxicity are a function of the form of the inhaled material. Values for dusts and mists are expressed in mg/l. Values for gases are expressed in ppmV. Acknowledging the difficulties in testing vapours, some of which consist of mixtures of liquid and vapour phases, the table provides values in units of mg/l. However, for those vapours which are near the gaseous phase, classification shall be based on ppmV.

• 3.1.2.3.2. Of particular importance in classifying for inhalation toxicity is the use of well articulated values in the highest hazard categories for dusts and mists. Inhaled particles between 1 and 4 microns mean mass aerodynamic diameter (MMAD) will deposit in all regions of the rat respiratory tract. This particle size range corresponds to a maximum dose of about 2 mg/l. In order to achieve applicability of animal experiments to human exposure, dusts and mists would ideally be tested in this range in rats.

• 3.1.2.3.3.In addition to classification for inhalation toxicity, if data are available that indicates that the mechanism of toxicity was corrosivity, the substance or mixture shall also be labelled as ‘corrosive to the respiratory tract’ (see note 1 in 3.1.4.1). Corrosion of the respiratory tract is defined by destruction of the respiratory tract tissue after a single, limited period of exposure analogous to skin corrosion; this includes destruction of the mucosa. The corrosivity evaluation can be based on expert judgment using such evidence as: human and animal experience, existing (in vitro) data, pH values, information from similar substances or any other pertinent data.

3.1.3.   Criteria for classification of mixtures as acutely toxic

• 3.1.3.1.The criteria for classification of substances for acute toxicity as outlined in section 3.1.2 are based on lethal dose data (tested or derived). For mixtures, it is necessary to obtain or derive information that allows the criteria to be applied to the mixture for the purpose of classification. The approach to classification for acute toxicity is tiered, and is dependent upon the amount of information available for the mixture itself and for its ingredients. The flow chart of Figure 3.1.1 outlines the process to be followed.

• 3.1.3.2.For acute toxicity each route of exposure shall be considered for the classification of mixtures, but only one route of exposure is needed as long as this route is followed (estimated or tested) for all components and there is no relevant evidence to suggest acute toxicity by multiple routes. When there is relevant evidence of toxicity by multiple routes of exposure, classification is to be conducted for all appropriate routes of exposure. All available information shall be considered. The pictogram and signal word used shall reflect the most severe hazard category and all relevant hazard statements shall be used.

• 3.1.3.3.In order to make use of all available data for purposes of classifying the hazards of the mixtures, certain assumptions have been made and are applied where appropriate in the tiered approach:

• (a) the ‘relevant ingredients’ of a mixture are those which are present in concentrations of 1 % (w/w for solids, liquids, dusts, mists and vapours and v/v for gases) or greater, unless there is a reason to suspect that an ingredient present at a concentration of less than 1 % is still relevant for classifying the mixture for acute toxicity (see Table 1.1).

• (b) where a classified mixture is used as an ingredient of another mixture, the actual or derived acute toxicity estimate (ATE) for that mixture may be used, when calculating the classification of the new mixture using the formulas in section 3.1.3.6.1 and paragraph 3.1.3.6.2.3.

• (c) If the converted acute toxicity point estimates for all components of a mixture are within the same category, then the mixture should be classified in that category.

• (d) When only range data (or acute toxicity hazard category information) are available for components in a mixture, they may be converted to point estimates in accordance with Table 3.1.2 when calculating the classification of the new mixture using the formulas in sections 3.1.3.6.1 and 3.1.3.6.2.3.

Figure 3.1.1

Tiered approach to classification of mixtures for acute toxicity

Image omitted; see official source

Text of image

Test data on the mixture as a whole

No

Yes

Sufficient data available on similar mixtures to estimate classification hazards

Yes

Apply bridging principles outlined in section 1.1.3.

CLASSIFY

No

Available data for all ingredients

Yes

Apply formula in section 3.1.3.6.1

CLASSIFY

No

Other data available to estimate conversion values for classification

Yes

Apply formula in section 3.1.3.6.1

CLASSIFY

No

Convey hazards of the known ingredients

• Apply formula in section 3.1.3.6.1. (unknown ingredients equal or below 10 %)

• Apply formula in paragraph 3.1.3.6.2.3. (unknown ingredients > 10 %)

CLASSIFY

3.1.3.4.   Classification of mixtures where acute toxicity data are available for the complete mixture

• 3.1.3.4.1.Where the mixture itself has been tested to determine its acute toxicity, it shall be classified according to the same criteria as those used for substances, presented in Table 3.1.1. If test data for the mixture are not available, the procedures presented under sections 3.1.3.5 and 3.1.3.6 shall be followed.

3.1.3.5.   Classification of mixtures where acute toxicity data are available for the complete mixture: bridging principles

• 3.1.3.5.1.Where the mixture itself has not been tested to determine its acute toxicity, but there are sufficient data on the individual ingredients and similar tested mixtures to adequately characterise the hazards of the mixture, these data shall be used in accordance with the bridging rules set out in section 1.1.3.

• 3.1.3.5.2.If a tested mixture is diluted with a diluent that has an equivalent or lower toxicity classification than the least toxic original components, and which is not expected to affect the toxicity of other components, then the new diluted mixture may be classified as equivalent to the original tested mixture. Alternatively, the formula explained in section 3.1.3.6.1 can be applied.

3.1.3.6.   Classification of mixtures based on ingredients of the mixture (Additivity formula)

3.1.3.6.1.   Data available for all ingredients

In order to ensure that classification of the mixture is accurate, and that the calculation need only be performed once for all systems, sectors, and categories, the acute toxicity estimate (ATE) of ingredients shall be considered as follows:

• (a) include ingredients with a known acute toxicity, which fall into any of the acute hazard categories shown in Table 3.1.1;

• (b) ignore ingredients that are presumed not acutely toxic (e.g., water, sugar);

• (c) ignore components if the data available are from a limit dose test (at the upper threshold for Category 4 for the appropriate route of exposure as provided in Table 3.1.1) and do not show acute toxicity.

Components that fall within the scope of this section are considered to be components with a known acute toxicity estimate (ATE). See note (b) to Table 3.1.1 and section 3.1.3.3 for appropriate application of available data to the equation below, and section 3.1.3.6.2.3.

The ATE of the mixture is determined by calculation from the ATE values for all relevant ingredients according to the following formula for Oral, Dermal or Inhalation Toxicity:

Image omitted; see official source

where:

Ci	=	concentration of ingredient i ( % w/w or % v/v)
---	---	---
i	=	the individual ingredient from 1 to n
---	---	---
n	=	the number of ingredients
---	---	---
ATEi	=	Acute Toxicity Estimate of ingredient i.

3.1.3.6.2.   Classification of mixtures when data are not available for all components

• 3.1.3.6.2.1.Where an ATE is not available for an individual ingredient of the mixture, but available information, such as that listed below, can provide a derived conversion value such as those laid out in Table 3.1.2, the formula in section 3.1.3.6.1 shall be applied.

• This includes evaluation of:

• (a) extrapolation between oral, dermal and inhalation acute toxicity estimates ([^E0030]). Such an evaluation could require appropriate pharmacodynamic and pharmacokinetic data;

• (b) evidence from human exposure that indicates toxic effects but does not provide lethal dose data;

• (c) evidence from any other toxicity tests/assays available on the substance that indicates toxic acute effects but does not necessarily provide lethal dose data; or

• (d) data from closely analogous substances using structure/activity relationships.

• This approach generally requires substantial supplemental technical information, and a highly trained and experienced expert (expert judgement, see section 1.1.1), to reliably estimate acute toxicity. If such information is not available, proceed to paragraph 3.1.3.6.2.3.

• 3.1.3.6.2.2.In the event that a component without any useable information for classification is used in a mixture at a concentration ≥ 1 %, it is concluded that the mixture cannot be attributed a definitive acute toxicity estimate. In this situation the mixture shall be classified based on the known components only, with the additional statement on the label and in the SDS that ‘x per cent of the mixture consists of component(s) of unknown acute toxicity’, taking into account the provisions set out in section 3.1.4.2.

• 3.1.3.6.2.3.If the total concentration of the relevant ingredient(s) with unknown acute toxicity is ≤ 10 % then the formula presented in section 3.1.3.6.1 shall be used. If the total concentration of the relevant ingredient(s) with unknown toxicity is > 10 %, the formula presented in section 3.1.3.6.1 shall be corrected to adjust for the percentage of the unknown ingredient(s) as follows:

Image omitted; see official source

Table 3.1.2

Conversion from experimentally obtained acute toxicity range values (or acute toxicity hazard categories) to acute toxicity point estimates for use in the formulas for the classification of mixtures

Exposure routes	Classification Category or experimentally obtained acute toxicity range estimate	Converted acute toxicity point estimate (see Note 1)
Oral (mg/kg bodyweight)	0 < Category 1 ≤ 5 5 < Category 2 ≤ 50 50 < Category 3 ≤ 300 300 < Category 4 ≤ 2 000	0,5 5 100 500
Dermal (mg/kg bodyweight)	0 < Category 1 ≤ 50 50 < Category 2 ≤ 200 200 < Category 3 ≤ 1 000 1 000 < Category 4 ≤ 2 000	5 50 300 1 100
Gases (ppmV)	0 < Category 1 ≤ 100 100 < Category 2 ≤ 500 500 < Category 3 ≤ 2 500 2 500 < Category 4 ≤ 20 000	10 100 700 4 500
Vapours (mg/l)	0 < Category 1 ≤ 0,5 0,5 < Category 2 ≤ 2,0 2,0 < Category 3 ≤ 10,0 10,0 < Category 4 ≤ 20,0	0,05 0,5 3 11
Dust/mist (mg/l)	0< Category 1 ≤ 0,05 0,05 < Category 2 ≤ 0,5 0,5 < Category 3 ≤ 1,0 1,0 < Category 4 ≤ 5,0	0,005 0,05 0,5 1,5

Note 1

These values are designed to be used in the calculation of the ATE for classification of a mixture based on its components and do not represent test results.

3.1.4.   Hazard Communication

• 3.1.4.1.Label elements shall be used for substances or mixtures meeting the criteria for classification in this hazard class in accordance with Table 3.1.3.  Without prejudice to Article 27, combined hazard statements may be used in accordance with Annex III.

Table 3.1.3

Acute toxicity label elements

Classification	Category 1	Category 2	Category 3	Category 4
GHS Pictograms	Image omitted; see official source	Image omitted; see official source	Image omitted; see official source	Image omitted; see official source
Signal Word	Danger	Danger	Danger	Warning
Hazard Statement: — Oral	H300: Fatal if swallowed	H300: Fatal if swallowed	H301: Toxic if swallowed	H302: Harmful if swallowed
—  Dermal	H310:Fatal in contact with skin	H310:Fatal in contact with skin	H311: Toxic in contact with skin	H312: Harmful in contact with skin
—  Inhalation (see Note 1)	H330:Fatal if inhaled	H330: Fatal if inhaled	H331: Toxic if inhaled	H332: Harmful if inhaled
Precautionary Statement Prevention (oral)	P264 P270	P264 P270	P264 P270	P264 P270
Precautionary Statement Response (oral)	P301 + P310 P321 P330	P301 + P310 P321 P330	P301 + P310 P321 P330	P301 + P312 P330
Precautionary Statement Storage (oral)	P405	P405	P405
Precautionary Statement Disposal (oral)	P501	P501	P501	P501
Precautionary Statement Prevention (dermal)	P262 P264 P270 P280	P262 P264 P270 P280	P280	P280
Precautionary Statement Response (dermal)	P302 + P352 P310 P321 P361 + P364	P302 + P352 P310 P321 P361 + P364	P302 + P352 P312 P321 P361 + P364	P302 + P352 P312 P321 P362 + P364
Precautionary Statement Storage (dermal)	P405	P405	P405
Precautionary Statement Disposal (dermal)	P501	P501	P501	P501
Precautionary Statement Prevention (inhalation)	P260 P271 P284	P260 P271 P284	P261 P271	P261 P271
Precautionary Statement Response (inhalation)	P304 + P340 P310 P320	P304 + P340 P310 P320	P304 + P340 P311 P321	P304 + P340 P312
Precautionary Statement Storage (inhalation)	P403 + P233 P405	P403 + P233 P405	P403 + P233 P405
Precautionary Statement Disposal (inhalation)	P501	P501	P501

Note 1

In addition to classification for inhalation toxicity, if data are available that indicates that the mechanism of toxicity is corrosivity, the substance or mixture shall also be labelled as EUH071: ‘corrosive to the respiratory tract’ — see advice at 3.1.2.3.3. In addition to an appropriate acute toxicity pictogram, a corrosivity pictogram (used for skin and eye corrosivity) may be added together with the statement ‘corrosive to the respiratory tract’.

Note 2

In the event that an ingredient without any useable information at all is used in a mixture at a concentration of 1 % or greater, the mixture shall be labelled with the additional statement that ‘x percent of the mixture consists of ingredient(s) of unknown toxicity’ — see advice at 3.1.3.6.2.2.

• 3.1.4.2.The acute toxicity hazard statements differentiate the hazard based on the route of exposure. Communication of acute toxicity classification should also reflect this differentiation. If a substance or mixture is classified for more than one route of exposure then all relevant classifications should be communicated on the safety data sheet as specified in Annex II to Regulation (EC) No 1907/2006 and the relevant hazard communication elements included on the label as prescribed in section 3.1.3.2. If the statement ‘x % of the mixture consists of ingredient(s) of unknown acute toxicity’ is communicated, as prescribed in section 3.1.3.6.2.2, then, in the information provided in the safety data sheet, it can also be differentiated based on the route of exposure. For example, ‘x % of the mixture consists of ingredient(s) of unknown acute oral toxicity’ and ‘x % of the mixture consists of ingredient(s) of unknown acute dermal toxicity’.

3.2.   Skin corrosion/irritation

3.2.1.   Definitions and general considerations

• 3.2.1.1. Skin corrosion means the production of irreversible damage to the skin; namely, visible necrosis through the epidermis and into the dermis occurring after exposure to a substance or mixture.

Skin irritation means the production of reversible damage to the skin occurring after exposure to a substance or mixture.

• 3.2.1.2. In a tiered approach, emphasis shall be placed upon existing human data, followed by existing animal data, followed by in vitro data and then other sources of information. Classification results directly when the data satisfy the criteria. In some cases, classification of a substance or a mixture is made on the basis of the weight of evidence within a tier. In a total weight of evidence approach all available information bearing on the determination of skin corrosion/irritation is considered together, including the results of appropriate validated in vitro tests, relevant animal data, and human data such as epidemiological and clinical studies and well-documented case reports and observations (see Annex I, Part 1, Sections 1.1.1.3, 1.1.1.4 and 1.1.1.5).

3.2.2.   Classification criteria for substances

Substances shall be allocated to one of the following two categories within this hazard class:

• (a) Category 1 (skin corrosion) This category is further subdivided in three sub-categories (1A, 1B, 1C). Corrosive substances shall be classified in Category 1 where data is not sufficient for sub-categorisation. When data are sufficient, substances shall be classified in one of the three sub-categories 1A, 1B, or 1C (see Table 3.2.1.)

• (b) Category 2 (skin irritation) (see Table 3.2.2).

3.2.2.1.   Classification based on standard animal test data

3.2.2.1.1.   Skin corrosion

• 3.2.2.1.1.1.A substance is corrosive to skin when it produces destruction of skin tissue, namely, visible necrosis through the epidermis and into the dermis in at least one tested animal after exposure for up to 4 hours.

• 3.2.2.1.1.2.Corrosive substances shall be classified in Category 1 where data is not sufficient for sub-categorisation.

• 3.2.2.1.1.3.When data are sufficient substances shall be classified in one of the three sub-categories 1A, 1B, or 1C in accordance with the criteria in Table 3.2.1.

• 3.2.2.1.1.4.Three sub-categories are provided within the corrosion category: sub-category 1A — where corrosive responses are noted following up to 3 minutes exposure and up to 1 hour observation; sub-category 1B — where corrosive responses are described following exposure greater than 3 minutes and up to 1 hour and observations up to 14 days; and sub-category 1C — where corrosive responses occur after exposures greater than 1 hour and up to 4 hours and observations up to 14 days.

Table 3.2.1

Skin corrosion category and sub-categories

Category	Criteria
Category 1 [^E0031]	Destruction of skin tissue, namely, visible necrosis through the epidermis and into the dermis, in at least one tested animal after exposure ≤ 4 h
Sub-Category 1A	Corrosive responses in at least one animal following exposure ≤ 3 min during an observation period ≤ 1 h
Sub-Category 1B	Corrosive responses in at least one animal following exposure > 3 min and ≤ 1 h and observations ≤ 14 days
Sub-Category 1C	Corrosive responses in at least one animal after exposures > 1 h and ≤ 4 h and observations ≤ 14 days

See the conditions for the use of Category 1 in paragraph (a) of Section 3.2.2.

• 3.2.2.1.1.5.The use of human data is discussed in Sections 3.2.1.2 and 3.2.2.2 and also in Sections 1.1.1.3, 1.1.1.4 and 1.1.1.5.

3.2.2.1.2.   Skin irritation

• 3.2.2.1.2.1.A substance is irritant to skin when it produces reversible damage to the skin following its application for up to 4 hours. The major criterion for the irritation category is that at least 2 of 3 tested animals have a mean score of ≥ 2,3 and ≤ 4,0.

• 3.2.2.1.2.2.A single irritation category (Category 2) is presented in Table 3.2.2, using the results of animal testing.

• 3.2.2.1.2.3.Reversibility of skin lesions is also considered in evaluating irritant responses. When inflammation persists to the end of the observation period in 2 or more test animals, taking into consideration alopecia (limited area), hyperkeratosis, hyperplasia and scaling, then a material shall be considered to be an irritant.

• 3.2.2.1.2.4.Animal irritant responses within a test can be variable, as they are with corrosion. A separate irritant criterion accommodates cases where there is a significant irritant response but less than the mean score criterion for a positive test. For example, a test material might be designated as an irritant if at least 1 of 3 tested animals shows a very elevated mean score throughout the study, including lesions persisting at the end of an observation period of normally 14 days. Other responses could also fulfil this criterion. However, it should be ascertained that the responses are the result of chemical exposure.

Table 3.2.2

Skin irritation category [^E0032]

Category

Criteria

Irritation (Category 2)

(1) Mean score of ≥ 2,3 and ≤ 4,0 for erythema/eschar or for oedema in at least 2 of 3 tested animals from gradings at 24, 48 and 72 hours after patch removal or, if reactions are delayed, from grades on 3 consecutive days after the onset of skin reactions; or (2) Inflammation that persists to the end of the observation period normally 14 days in at least 2 animals, particularly taking into account alopecia (limited area), hyperkeratosis, hyperplasia, and scaling reactions; or (3) In some cases where there is pronounced variability of response among animals, with very definite positive effects related to chemical exposure in a single animal but less than the criteria above .

Grading criteria are understood as described in Regulation (EC) No 440/2008.

• 3.2.2.1.2.5.The use of human data is discussed in Sections 3.2.1.2 and 3.2.2.2 and also in Sections 1.1.1.3, 1.1.1.4 and 1.1.1.5.

3.2.2.2.   Classification in a tiered approach

• 3.2.2.2.1. A tiered approach to the evaluation of initial information shall be considered, where applicable, recognising that not all elements may be relevant.

• 3.2.2.2.2. Existing human and animal data including information from single or repeated exposure shall be the first line of evaluation, as they give information directly relevant to effects on the skin.

• 3.2.2.2.3. Acute dermal toxicity data may be used for classification. If a substance is highly toxic by the dermal route, a skin corrosion/irritation study is not practicable since the amount of test substance to be applied considerably exceeds the toxic dose and, consequently, results in the death of the animals. When observations are made of skin corrosion/irritation in acute toxicity studies and are observed up through the limit dose, these data may be used for classification, provided that the dilutions used and species tested are equivalent. Solid substances (powders) may become corrosive or irritant when moistened or in contact with moist skin or mucous membranes.

• 3.2.2.2.4. In vitro alternatives that have been validated and accepted shall be used to make classification decisions.

• 3.2.2.2.5. Likewise, pH extremes like ≤ 2 and ≥ 11,5 may indicate the potential to cause skin effects, especially when associated with significant acid/alkaline reserve (buffering capacity). Generally, such substances are expected to produce significant effects on the skin. In the absence of any other information, a substance is considered as corrosive to skin (Skin Corrosion Category 1) if it has a pH ≤ 2 or a pH ≥ 11,5. However, if consideration of acid/alkaline reserve suggests the substance may not be corrosive despite the low or high pH value, this needs to be confirmed by other data, preferably by data from an appropriate validated in vitro test.

• 3.2.2.2.6. In some cases, sufficient information may be available from structurally related substances to make classification decisions.

• 3.2.2.2.7. The tiered approach provides guidance on how to organize existing information on a substance and to make a weight of evidence decision about hazard assessment and hazard classification.

Although information might be gained from the evaluation of single parameters within a tier (see Section 3.2.2.2.1.), consideration shall be given to the totality of existing information and making an overall weight of evidence determination. This is especially true when there is conflict in information available on some parameters.

3.2.3.   Classification criteria for mixtures

3.2.3.1.   Classification of mixtures when data are available for the complete mixture

• 3.2.3.1.1. The mixture shall be classified using the criteria for substances, taking into account the tiered approach to evaluate data for this hazard class.

• 3.2.3.1.2. When considering testing of the mixture, classifiers are encouraged to use a tiered weight of evidence approach as included in the criteria for classification of substances for skin corrosion and irritation (Sections 3.2.1.2 and 3.2.2.2), to help ensure an accurate classification as well as to avoid unnecessary animal testing. In the absence of any other information, a mixture is considered corrosive to skin (Skin Corrosion Category 1) if it has a pH ≤ 2 or a pH ≥ 11,5. However, if consideration of acid/alkaline reserve suggests the mixture may not be corrosive despite the low or high pH value, this needs to be confirmed by other data, preferably by data from an appropriate validated in vitro test.

3.2.3.2.   Classification of mixtures when data are not available for the complete mixture: bridging principles

• 3.2.3.2.1. Where the mixture itself has not been tested to determine its skin corrosion/irritation potential, but there are sufficient data on the individual ingredients and similar tested mixtures to adequately characterise the hazards of the mixture, these data shall be used in accordance with the bridging rules set out in Section 1.1.3.

3.2.3.3.   Classification of mixtures when data are available for all ingredients or only for some ingredients of the mixture

• 3.2.3.3.1. In order to make use of all available data for purposes of classifying the skin corrosion/irritation hazards of mixtures, the following assumption has been made and is applied where appropriate in the tiered approach:

The ‘relevant ingredients’ of a mixture are those which are present in concentrations ≥ 1 % (w/w for solids, liquids, dusts, mists and vapours and v/v for gases), unless there is a presumption (e.g., in the case of skin corrosive ingredients) that an ingredient present at a concentration < 1 % can still be relevant for classifying the mixture for skin corrosion/irritation.

• 3.2.3.3.2. In general, the approach to classification of mixtures as corrosive or irritant to skin when data are available on the ingredients, but not on the mixture as a whole, is based on the theory of additivity, such that each skin corrosive or skin irritant ingredient contributes to the overall skin corrosive or skin irritant properties of the mixture in proportion to its potency and concentration. A weighting factor of 10 is used for skin corrosive ingredients when they are present at a concentration below the generic concentration limit for classification with Category 1, but are at a concentration that will contribute to the classification of the mixture as skin irritant. The mixture is classified as corrosive or irritant to skin when the sum of the concentrations of such ingredients exceeds a concentration limit.

• 3.2.3.3.3. Table 3.2.3 provides the generic concentration limits to be used to determine if the mixture is considered to be corrosive or irritant to the skin.

• 3.2.3.3.4.1. Particular care must be taken when classifying certain types of mixtures containing substances such as acids and bases, inorganic salts, aldehydes, phenols, and surfactants. The approach explained in Sections 3.2.3.3.1 and 3.2.3.3.2 may not be applicable given that many such substances are corrosive or irritant to the skin at concentrations < 1 %.

• 3.2.3.3.4.2. For mixtures containing strong acids or bases the pH shall be used as a classification criterion (see Section 3.2.3.1.2) since pH is a better indicator of skin corrosion than the concentration limits in Table 3.2.3.

• 3.2.3.3.4.3. A mixture containing ingredients that are corrosive or irritant to the skin and that cannot be classified on the basis of the additivity approach (Table 3.2.3), due to chemical characteristics that make this approach unworkable, shall be classified as Skin Corrosion Category 1 if it contains ≥ 1 % of an ingredient classified as Skin Corrosion or as Skin Irritation (Category 2) when it contains ≥ 3 % of an skin irritant ingredient. Classification of mixtures with ingredients for which the approach in Table 3.2.3 does not apply is summarised in Table 3.2.4.

• 3.2.3.3.5. On occasion, reliable data may show that the skin corrosion/irritation hazard of an ingredient will not be evident when present at a level at or above the generic concentration limits mentioned in Tables 3.2.3 and 3.2.4 in Section 3.2.3.3.6. In these cases the mixture shall be classified according to that data (see also Articles 10 and 11). On other occasions, when it is expected that the skin corrosion/irritation hazard of an ingredient is not evident when present at a level at or above the generic concentration limits mentioned in Tables 3.2.3 and 3.2.4, testing of the mixture shall be considered. In those cases the tiered weight of evidence approach shall be applied, as described in Section 3.2.2.2.

• 3.2.3.3.6. If there are data showing that (an) ingredient(s) is/are corrosive or irritant to skin at a concentration of < 1 % (skin corrosive) or < 3 % (skin irritant), the mixture shall be classified accordingly.

Table 3.2.3

Generic concentration limits of ingredients classified as skin corrosion (Category 1, 1A, 1B or 1C)/skin irritation (Category 2) that trigger classification of the mixture as skin corrosion/skin irritation where the additivity approach applies

Sum of ingredients classified as:	Concentration triggering classification of a mixture as:	Concentration triggering classification of a mixture as:
	Skin corrosion	Skin irritation
	Category 1 (see note below)	Category 2
Skin corrosion Sub-Category 1A, 1B, 1C or Category 1	≥ 5 %	≥ 1 % but < 5 %
Skin irritation Category 2		≥ 10 %
(10 × Skin corrosion Sub-Category 1A, 1B, 1C or Category 1) + Skin irritation Category 2		≥ 10 %

Note:

The sum of all ingredients of a mixture classified as Skin Corrosion Sub-Category 1A, 1B, or 1C respectively, shall each be ≥ 5 % in order to classify the mixture as either Skin Corrosion Sub-Category 1A, 1B or 1C. If the sum of the ingredients classified as Skin Corrosion Sub-Category 1A is < 5 % but the sum of ingredients classified as Skin Corrosion Sub-Category 1A + 1B is ≥ 5 %, the mixture shall be classified as Skin Corrosion Sub-Category 1B. Similarly, if the sum of ingredients classified as Skin Corrosion Sub-Category 1A + 1B ingredients is < 5 % but the sum of ingredients classified as Sub-Category 1A + 1B + 1C is ≥ 5 % the mixture shall be classified as Skin Corrosion Sub-Category 1C. Where at least one relevant ingredient in a mixture is classified as Category 1 without sub-categorisation, the mixture shall be classified as Category 1 without sub-categorisation if the sum of all ingredients corrosive to skin is ≥ 5 %.

Table 3.2.4

Generic concentration limits of ingredients that trigger classification of the mixture as skin corrosion/skin irritation, where the additivity approach does not apply

Ingredient:	Concentration:	Mixture classified as:
Acid with pH ≤ 2	≥ 1 %	Skin corrosion Category 1
Base with pH ≥ 11,5	≥ 1 %	Skin corrosion Category 1
Other skin corrosive (Sub-Categories 1A, 1B, 1C or Category 1) ingredients	≥ 1 %	Skin corrosion Category 1
Other skin irritant (Category 2) ingredients, including acids and bases	≥ 3 %	Skin irritation Category 2

3.2.4.   Hazard Communication

• 3.2.4.1. Label elements shall be used for substances or mixtures meeting the criteria for classification in this hazard class in accordance with Table 3.2.5.

Table 3.2.5

Label elements for skin corrosion/irritation

Classification	Sub-Categories 1A/1B/1C and Category 1	Category 2
GHS Pictograms	Image omitted; see official source	Image omitted; see official source
Signal Word	Danger	Warning
Hazard Statement	H314: Causes severe skin burns and eye damage	H315: Causes skin irritation
Precautionary Statement Prevention	P260 P264 P280	P264 P280
Precautionary Statement Response	P301 + P330 + P331 P303 + P361 + P353 P363 P304 + P340 P310 P321 P305 + P351 + P338	P302 + P352 P321 P332 + P313 P362 + P364
Precautionary Statement Storage	P405
Precautionary Statement Disposal	P501

3.3.   Serious eye damage/eye irritation

3.3.1.   Definitions and general considerations

• 3.3.1.1. Serious eye damage means the production of tissue damage in the eye, or serious physical decay of vision, which is not fully reversible, occurring after exposure of the eye to a substance or mixture.

Eye irritation means the production of changes in the eye, which are fully reversible, occurring after the exposure of the eye to a substance or mixture.

• 3.3.1.2. In a tiered approach, emphasis shall be placed upon existing human data, followed by existing animal data, followed by in vitro data, and then other sources of information. Classification results directly when the data satisfy the criteria. In other cases, classification of a substance or a mixture is made on the basis of the weight of evidence within a tier. In a total weight of evidence approach all available information bearing on the determination of serious eye damage/eye irritation is considered together, including the results of appropriate validated in vitro tests, relevant animal data, and human data such as epidemiological and clinical studies and well-documented case reports and observations (see Annex I, Part 1, Section 1.1.1.3).

3.3.2.   Classification criteria for substances

Substances are allocated to one of the categories within this hazard class, Category 1 (serious eye damage) or Category 2 (eye irritation), as follows:

• (a) Category 1 (serious eye damage): substances that have the potential to seriously damage the eyes (see Table 3.3.1).

• (b) Category 2 (eye irritation): substances that have the potential to induce reversible eye irritation (see Table 3.3.2).

3.3.2.1.   Classification based on standard animal test data

3.3.2.1.1.   Serious eye damage (Category 1)

• 3.3.2.1.1.1.A single hazard category (Category 1) is adopted for substances that have the potential to seriously damage the eyes. This hazard category includes as criteria the observations listed in Table 3.3.1. These observations include animals with grade 4 cornea lesions and other severe reactions (e.g. destruction of cornea) observed at any time during the test, as well as persistent corneal opacity, discoloration of the cornea by a dye substance, adhesion, pannus, and interference with the function of the iris or other effects that impair sight. In this context, persistent lesions are considered those which are not fully reversible within an observation period of normally 21 days. Hazard classification as Category 1 also contains substances fulfilling the criteria of corneal opacity ≥ 3 or iritis > 1,5 observed in at least 2 of 3 tested animals, because severe lesions like these usually do not reverse within a 21-day observation period.

• 3.3.2.1.1.2.The use of human data is discussed in Section 3.3.2.2 and also in Sections 1.1.1.3, 1.1.1.4 and 1.1.1.5.

Table 3.3.1

Serious eye damage [^E0033]

Category

Criteria

Category 1

A substance that produces: (a) in at least one animal effects on the cornea, iris or conjunctiva that are not expected to reverse or have not fully reversed within an observation period of normally 21 days; and/or (b) in at least 2 of 3 tested animals, a positive response of: (i) corneal opacity ≥ 3; and/or (ii) iritis > 1,5; calculated as the mean scores following grading at 24, 48 and 72 hours after instillation of the test material.

Grading criteria are understood as described in Regulation (EC) No 440/2008.

3.3.2.1.2.   Eye irritation (Category 2)

• 3.3.2.1.2.1.Substances that have the potential to induce reversible eye irritation shall be classified in Category 2 (eye irritation).

• 3.3.2.1.2.2.For those substances where there is pronounced variability among animal responses, this information shall be taken into account in determining the classification.

• 3.3.2.1.2.3.The use of human data is addressed in Sections 3.3.2.2, and also in Sections 1.1.1.3, 1.1.1.4 and 1.1.1.5.

Table 3.3.2

Eye irritation [^E0034]

Category	Criteria
Category 2	Substances that produce in at least 2 of 3 tested animals a positive response of: (a) corneal opacity ≥ 1; and/or (b) iritis ≥ 1; and/or (c) conjunctival redness ≥ 2; and/or (d) conjunctival oedema (chemosis) ≥ 2 calculated as the mean scores following grading at 24, 48 and 72 hours after instillation of the test material, and which fully reverses within an observation period of normally 21 days.

Grading criteria are understood as described in Regulation (EC) No 440/2008.

3.3.2.2.   Classification in a tiered approach

• 3.3.2.2.1. A tiered approach to the evaluation of initial information shall be considered where applicable, recognizing that not all elements may be relevant.

• 3.3.2.2.2. Existing human and animal data shall be the first line of evaluation as they give information directly relevant to effects on the eye. Possible skin corrosion has to be evaluated prior to consideration of any testing for serious eye damage/eye irritation in order to avoid testing for local effects on eyes with skin corrosive substances. Skin corrosive substances shall be considered as leading to serious eye damage (Category 1) as well, while skin irritant substances may be considered as leading to eye irritation (Category 2).

• 3.3.2.2.3. In vitro alternatives that have been validated and accepted shall be used to make classification decisions.

• 3.3.2.2.4. Likewise, pH extremes like ≤ 2 and ≥ 11,5, may indicate serious eye damage, especially when associated with significant acid/alkaline reserve (buffering capacity). Generally such substances are expected to produce significant effects on the eyes. In the absence of any other information, a substance is considered to cause serious eye damage (Category 1) if it has a pH ≤ 2 or ≥ 11,5. However, if consideration of acid/alkaline reserve suggests the substance may not cause serious eye damage despite the low or high pH value, this needs to be confirmed by other data, preferably by data from an appropriate validated in vitro test.

• 3.3.2.2.5. In some cases sufficient information may be available from structurally related substances to make classification decisions.

• 3.3.2.2.6. The tiered approach provides guidance on how to organize existing information and to make a weight-of-evidence decision about hazard assessment and hazard classification. Animal testing with corrosive substances shall be avoided whenever possible. Although information might be gained from the evaluation of single parameters within a tier (see 3.3.2.1.1) consideration shall be given to the totality of existing information and making an overall weight of evidence determination. This is especially true when there is conflict in information available on some parameters.

3.3.3.   Classification criteria for mixtures

3.3.3.1.   Classification of mixtures when data are available for the complete mixture

• 3.3.3.1.1. The mixture shall be classified using the criteria for substances, and taking into account the tiered approach to evaluate data for this hazard class.

• 3.3.3.1.2. When considering testing of the mixture classifiers are encouraged to use a tiered weight of evidence approach as included in the criteria for classification of substances for skin corrosion and serious eye damage/eye irritation to help ensure an accurate classification, as well as to avoid unnecessary animal testing. In the absence of any other information, a mixture is considered to cause serious eye damage (Category 1) if it has a pH ≤ 2 or ≥ 11,5. However, if consideration of acid/alkali reserve suggests the mixture may not cause serious eye damage despite the low or high pH value, this needs to be confirmed by other data, preferably data from an appropriate validated in vitro test.

3.3.3.2.   Classification of mixtures when data are not available for the complete mixture: bridging principles

• 3.3.3.2.1. Where the mixture itself has not been tested to determine its skin corrosivity or potential to cause serious eye damage/eye irritation, but there are sufficient data on the individual ingredients and similar tested mixtures to adequately characterise the hazards of the mixture, these data shall be used in accordance with the bridging rules set out in Section 1.1.3.

3.3.3.3.   Classification of mixtures when data are available for all ingredients or only for some ingredients of the mixture

• 3.3.3.3.1. In order to make use of all available data for purposes of classifying the serious eye damage/eye irritation properties of the mixtures, the following assumption has been made and is applied where appropriate in the tiered approach:

The ‘relevant ingredients’ of a mixture are those which are present in concentrations ≥ 1 % (w/w for solids, liquids, dusts, mists and vapours and v/v for gases), unless there is a presumption (e.g. in the case of skin corrosive ingredients) that an ingredient present at a concentration < 1 % can still be relevant for classifying the mixture for serious eye damage/eye irritation.

• 3.3.3.3.2. In general, the approach to classification of mixtures as seriously damaging to the eye/eye irritant when data are available on the ingredients, but not on the mixture as a whole, is based on the theory of additivity, such that each skin corrosive or serious eye damaging/eye irritant ingredient contributes to the overall serious eye damage/eye irritation properties of the mixture in proportion to its potency and concentration. A weighting factor of 10 is used for skin corrosive and serious eye damaging ingredients when they are present at a concentration below the generic concentration limit for classification with Category 1, but are at a concentration that will contribute to the classification of the mixture as eye irritant. The mixture is classified as seriously damaging to the eye or eye irritant when the sum of the concentrations of such ingredients exceeds a concentration limit.

• 3.3.3.3.3. Table 3.3.3 provides the generic concentration limits to be used to determine if the mixture shall be classified as seriously damaging to the eye or as eye irritant.

• 3.3.3.3.4.1. Particular care must be taken when classifying certain types of mixtures containing substances such as acids and bases, inorganic salts, aldehydes, phenols, and surfactants. The approach explained in Sections 3.3.3.3.1 and 3.3.3.3.2 might not work given that many such substances are seriously damaging to the eye/eye irritant at concentrations < 1 %.

• 3.3.3.3.4.2. For mixtures containing strong acids or bases the pH shall be used as classification criterion (see Section 3.3.3.1.2) since pH will be a better indicator of serious eye damage (subject to consideration of acid/alkali reserve) than the generic concentration limits in Table 3.3.3.

• 3.3.3.3.4.3. A mixture containing skin corrosive or serious eye damaging/eye irritating ingredients that cannot be classified based on the additivity approach (Table 3.3.3) due to chemical characteristics that make this approach unworkable, shall be classified as Serious Eye Damage (Category 1) if it contains ≥ 1 % of a skin corrosive or serious eye damaging ingredient and as Eye Irritation (Category 2) when it contains ≥ 3 % of an eye irritant ingredient. Classification of mixtures with ingredients for which the approach in Table 3.3.3 does not apply is summarised in Table 3.3.4.

• 3.3.3.3.5. On occasion, reliable data may show that the effects of serious eye damage/eye irritation of an ingredient will not be evident when present at a level at or above the generic concentration limits mentioned in Tables 3.3.3 and 3.3.4 in Section 3.3.3.3.6. In these cases the mixture shall be classified according to those data (see also Articles 10 and 11). On other occasions, when it is expected that the skin corrosion/irritation hazards or the effects of serious eye damage/eye irritation of an ingredient will not be evident when present at a level at or above the generic concentration limits mentioned in Tables 3.3.3 and 3.3.4, testing of the mixture shall be considered. In those cases, the tiered weight of evidence approach shall be applied.

• 3.3.3.3.6. If there are data showing that (an) ingredient(s) may be corrosive to the skin or seriously damaging to the eye/eye irritating at a concentration of < 1 % (corrosive to the skin or seriously damaging to the eye) or < 3 % (eye irritant), the mixture shall be classified accordingly.

Table 3.3.3

Generic concentration limits of ingredients classified as skin corrosion (Category 1, 1A, 1B or 1C) and/or serious eye damage (Category 1) or eye irritation (Category 2) that trigger classification of the mixture as serious eye damage/eye irritation where the additivity approach applies

Sum of ingredients classified as:	Concentration triggering classification of a mixture as:	Concentration triggering classification of a mixture as:
Sum of ingredients classified as:	Serious eye damage	Eye irritation
Sum of ingredients classified as:	Category 1	Category 2
Skin corrosion Sub-Category 1A, 1B, 1C or Category 1 + Serious eye damage (Category 1) [^E0035]	≥ 3 %	≥ 1 % but < 3 %
Eye irritation (Category 2)		≥ 10 %
10 × (Skin corrosion Sub-Category 1A, 1B, 1C or Skin corrosion Category 1 + Serious eye damage (Category 1)) + Eye irritation (Category 2)		≥ 10 %

If an ingredient is classified as both Skin Corrosion Sub-Category 1A, 1B, 1C or Category 1 and Serious Eye Damage (Category 1), its concentration is considered only once in the calculation.

Table 3.3.4

Generic concentration limits of ingredients that trigger classification of the mixture as serious eye damage (Category 1) or eye irritation (Category 2), where the additivity approach does not apply

Ingredient	Concentration	Mixture classified as:
Acid with pH ≤ 2	≥ 1 %	Serious eye damage (Category 1)
Base with pH ≥ 11,5	≥ 1 %	Serious eye damage (Category 1)
Other ingredient classified as skin corrosion (Sub-Category 1A, 1B, 1C or Category 1) or serious eye damage (Category 1)	≥ 1 %	Serious eye damage (Category 1)
Other ingredient classified as eye irritation (Category 2)	≥ 3 %	Eye irritation (Category 2)

3.3.4.   Hazard Communication

• 3.3.4.1. Label elements shall be used for substances or mixtures meeting the criteria for classification in this hazard class in accordance with Table 3.3.5.

Table 3.3.5

Label elements for serious eye damage/eye irritation [^E0036]

Classification	Category 1	Category 2
GHS Pictograms	Image omitted; see official source	Image omitted; see official source
Signal Word	Danger	Warning
Hazard Statement	H318: Causes serious eye damage	H319: Causes serious eye irritation
Precautionary Statement Prevention	P280	P264 P280
Precautionary Statement Response	P305 + P351 + P338 P310	P305 + P351 + P338 P337 + P313
Precautionary Statement Storage
Precautionary Statement Disposal

Where a chemical is classified as skin corrosion Sub-Category 1A, 1B, 1C or Category 1, labelling for serious eye damage/eye irritation can be omitted as this information is already included in the hazard statement for skin corrosion Category 1 (H314).

3.4.   Respiratory or skin sensitisation

3.4.1.   Definitions and general considerations

• 3.4.1.1.Respiratory sensitisation means hypersensitivity of the airways occurring after inhalation of a substance or a mixture.

• 3.4.1.2.Skin sensitisation means an allergic response occurring after skin contact with a substance or a mixture.

• 3.4.1.3.For the purpose of section 3.4, sensitisation includes two phases: the first phase is induction of specialised immunological memory in an individual by exposure to an allergen. The second phase is elicitation, i.e. production of a cell-mediated or antibody-mediated allergic response by exposure of a sensitised individual to an allergen.

• 3.4.1.4.For respiratory sensitisation, the pattern of induction followed by elicitation phases is shared in common with skin sensitisation. For skin sensitisation, an induction phase is required in which the immune system learns to react; clinical symptoms can then arise when subsequent exposure is sufficient to elicit a visible skin reaction (elicitation phase). As a consequence, predictive tests usually follow this pattern in which there is an induction phase, the response to which is measured by a standardised elicitation phase, typically involving a patch test. The local lymph node assay is the exception, directly measuring the induction response. Evidence of skin sensitisation in humans normally is assessed by a diagnostic patch test.

• 3.4.1.5.Usually, for both skin and respiratory sensitisation, lower levels are necessary for elicitation than are required for induction. Provisions for alerting sensitised individuals to the presence of a particular sensitiser in a mixture can be found  in Annex II, section 2.8..

• 3.4.1.6.The hazard class Respiratory or Skin Sensitisation is differentiated into:

• — Respiratory Sensitisation  and;

• — Skin Sensitisation.

3.4.2.   Classification criteria for substances

3.4.2.1.   Respiratory sensitisers

3.4.2.1.1.   Hazard categories

• 3.4.2.1.1.1. Respiratory sensitisers shall be classified in Category 1 where data are not sufficient for sub-categorisation.

• 3.4.2.1.1.2. Where data are sufficient a refined evaluation according to 3.4.2.1.1.3 shall allow the allocation of respiratory sensitisers into sub-category 1A, strong sensitisers, or sub-category 1B for other respiratory sensitisers.

• 3.4.2.1.1.3. Effects seen in either humans or animals will normally justify classification in a weight of evidence approach for respiratory sensitisers. Substances may be allocated to one of the two sub-categories 1A or 1B using a weight of evidence approach in accordance with the criteria given in Table 3.4.1 and on the basis of reliable and good quality evidence from human cases or epidemiological studies and/or observations from appropriate studies in experimental animals.

• 3.4.2.1.1.4. Substances shall be classified as respiratory sensitisers in accordance with the criteria in Table 3.4.1:

Table 3.4.1

Hazard category and sub-categories for respiratory sensitisers

Category	Criteria
Category 1	Substances shall be classified as respiratory sensitisers (Category 1) where data are not sufficient for sub-categorisation in accordance with the following criteria: (a) if there is evidence in humans that the substance can lead to specific respiratory hypersensitivity; and/or (b) if there are positive results from an appropriate animal test.
Sub-category 1A:	Substances showing a high frequency of occurrence in humans; or a probability of occurrence of a high sensitisation rate in humans based on animal or other tests [^E0037]. Severity of reaction may also be considered.
Sub-category 1B:	Substances showing a low to moderate frequency of occurrence in humans; or a probability of occurrence of a low to moderate sensitisation rate in humans based on animal or other tests [^E0037]. Severity of reaction may also be considered.

At present, recognised and validated animal models for the testing of respiratory hypersensitivity are not available. Under certain circumstances, data from animal studies may provide valuable information in a weight of evidence assessment.

3.4.2.1.2.   Human evidence

• 3.4.2.1.2.1. Evidence that a substance can lead to specific respiratory hypersensitivity will normally be based on human experience. In this context, hypersensitivity is normally seen as asthma, but other hypersensitivity reactions such as rhinitis/conjunctivitis and alveolitis are also considered. The condition will have the clinical character of an allergic reaction. However, immunological mechanisms do not have to be demonstrated.

• 3.4.2.1.2.2. When considering the human evidence, it is necessary for a decision on classification to take into account, in addition to the evidence from the cases:

• (a) the size of the population exposed;

• (b) the extent of exposure.

The use of human data is discussed in sections 1.1.1.3, 1.1.1.4 and 1.1.1.5.

• 3.4.2.1.2.3. The evidence referred to above could be:

• (a) clinical history and data from appropriate lung function tests related to exposure to the substance, confirmed by other supportive evidence which may include:
• (i) in vivo immunological test (e.g. skin prick test);
• (ii) in vitro immunological test (e.g. serological analysis);
• (iii) studies that indicate other specific hypersensitivity reactions where immunological mechanisms of action have not been proven, e.g. repeated low-level irritation, pharmacologically mediated effects;
• (iv) a chemical structure related to substances known to cause respiratory hypersensitivity;

• (b) data from one or more positive bronchial challenge tests with the substance conducted according to accepted guidelines for the determination of a specific hypersensitivity reaction.

• 3.4.2.1.2.4. Clinical history shall include both medical and occupational history to determine a relationship between exposure to a specific substance and development of respiratory hypersensitivity. Relevant information includes aggravating factors both in the home and workplace, the onset and progress of the disease, family history and medical history of the patient in question. The medical history shall also include a note of other allergic or airway disorders from childhood, and smoking history.

• 3.4.2.1.2.5. The results of positive bronchial challenge tests are considered to provide sufficient evidence for classification on their own. It is however recognised that in practice many of the examinations listed above will already have been carried out.

3.4.2.1.3.   Animal studies

• 3.4.2.1.3.1. Data from appropriate animal studies ([^E0038]) which may be indicative of the potential of a substance to cause sensitisation by inhalation in humans ([^E0039]) may include:

• (a) measurements of Immunoglobulin E (IgE) and other specific immunological parameters, for example in mice;

• (b) specific pulmonary responses in guinea pigs.

3.4.2.2.   Skin sensitisers

3.4.2.2.1.   Hazard categories

• 3.4.2.2.1.1. Skin sensitisers shall be classified in Category 1 where data are not sufficient for sub-categorisation.

• 3.4.2.2.1.2. Where data are sufficient a refined evaluation according to section 3.4.2.2.1.3 allows the allocation of skin sensitisers into sub-category 1A, strong sensitisers, or sub-category 1B for other skin sensitisers.

• 3.4.2.2.1.3. Effects seen in either humans or animals will normally justify classification in a weight of evidence approach for skin sensitisers as described in section 3.4.2.2.2. Substances may be allocated to one of the two sub-categories 1A or 1B using a weight of evidence approach in accordance with the criteria given in Table 3.4.2 and on the basis of reliable and good quality evidence from human cases or epidemiological studies and/or observations from appropriate studies in experimental animals according to the guidance values provided in sections 3.4.2.2.2.1 and 3.4.2.2.3.2 for sub-category 1A and in sections 3.4.2.2.2.2 and 3.4.2.2.3.3 for sub-category 1B.

• 3.4.2.2.1.4. Substances shall be classified as skin sensitisers in accordance with the criteria in Table 3.4.2:

Table 3.4.2

Hazard category and sub-categories for skin sensitisers

Category	Criteria
Category 1	Substances shall be classified as skin sensitisers (Category 1) where data are not sufficient for sub-categorisation in accordance with the following criteria: (a) if there is evidence in humans that the substance can lead to sensitisation by skin contact in a substantial number of persons; or (b) if there are positive results from an appropriate animal test (see specific criteria in section 3.4.2.2.4.1).
Sub-category 1A:	Substances showing a high frequency of occurrence in humans and/or a high potency in animals can be presumed to have the potential to produce significant sensitisation in humans. Severity of reaction may also be considered.
Sub-category 1B:	Substances showing a low to moderate frequency of occurrence in humans and/or a low to moderate potency in animals can be presumed to have the potential to produce sensitisation in humans. Severity of reaction may also be considered.

3.4.2.2.2.   Human evidence

• 3.4.2.2.2.1. Human evidence for sub-category 1A can include:

• (a) positive responses at ≤ 500 μg/cm² (HRIPT, HMT — induction threshold);

• (b) diagnostic patch test data where there is a relatively high and substantial incidence of reactions in a defined population in relation to relatively low exposure;

• (c) other epidemiological evidence where there is a relatively high and substantial incidence of allergic contact dermatitis in relation to relatively low exposure.

• 3.4.2.2.2.2. Human evidence for sub-category 1B can include:

• (a) positive responses at > 500 μg/cm2 (HRIPT, HMT — induction threshold);

• (b) diagnostic patch test data where there is a relatively low but substantial incidence of reactions in a defined population in relation to relatively high exposure;

• (c) other epidemiological evidence where there is a relatively low but substantial incidence of allergic contact dermatitis in relation to relatively high exposure.

The use of human data is discussed in sections 1.1.1.3, 1.1.1.4 and 1.1.1.5.

3.4.2.2.3.   Animal studies