Carcinogens and mutagens

Go to: What are carcinogens and mutagens? What to do? Classification Related legislation and policies References List of substances according to Regulation 1272/2008 List of substances according to IARC List of substances according to other sources List of substances according to SSI -breast cancer

What are carcinogens and mutagens?

A carcinogen is a substance that may cause cancer or increase its incidence by inhalation, ingestion or skin absorption.

Cancer is a disease characterized by uncontrolled growth and division of cells. These cells have the ability to invade the organ where they originate, to travel through the blood and lymph fluid to other organs and grow in them.

More than 200 different types of diseases (malignant tumours) are included under the term cancer.

The latency period of the disease, i.e. the time that elapses between exposure to a carcinogen and clinical detection of resulting cancer can extend for several years.

Mutagens are substances and mixtures which, if inhaled, swallowed or absorbed through the skin, may induce heritable genetic damage or increase its incidence.

Former Dangerous Substances Directive, known as DSD (67/548/EEC) and the new Regulation 1272/2008 (commonly known as CLP) identify carcinogenic and mutagenic substances with the following risk phrases (R) and hazard statements (H):

• R45 or H350 May cause cancer


• R46 or H340 May cause heritable genetic damage


• R49 or H350i May cause cancer by inhalation


• R40 or H351 Limited evidence of a carcinogenic effect


• R68 or H341 Possible risk of irreversible effects

What to do?

There is not a safe environmental or occupational exposure dose to carcinogens.

Due to the severity of harm from exposure to carcinogens and mutagens they should be regarded as substances of very high concern, and their elimination/substitution should be promoted as a precautionary measure, following the principles of preventive action according to Directive 89/391/EEC on the safety and health of workers at work.

In addition, Directive 2004/37/EC on the protection of workers from the risks related to exposure to carcinogens at work, establishes the employers’ obligation to substitute carcinogens and mutagens by other non hazardous or less hazardous substances whenever it is technically feasible. This obligation applies only to chemicals that meet the criteria for classification as carcinogens or mutagens of categories 1A or 1B (according to CLP Regulation) or 1 or 2 (according to DSD).

Substances that meet the classification criteria as 1 and 2A according to the International Agency for Research of Cancer (IARC), are also substances of particular concern, and should be substituted.

If the substitution of the carcinogen or mutagen is not technically possible, the employer shall ensure then the prevention and reduction of workers’ exposure (Article 5, Directive 2004/37/EC) and shall include specific measures of personal hygiene and individual protection (Article 10, Directive 2004/37/EC), such as:

• Prohibit eating, drinking or smoking in work areas with exposure risk to carcinogens and mutagens.


• Provide separate storage locations for protective work clothes.


• The employer is responsible for cleaning and decontamination of working clothes.

Occupational exposure limit values assigned to some carcinogens do not constitute a reference to guarantee health protection.

Additionally, when pregnant or breastfeeding workers are in risk of exposure, the employer must:

1. Take the necessary measures to prevent exposure through the adaptation of working conditions of affected workers.


2. Transfer the affected workers to a workstation compatible with her condition whenever the adaptation of working conditions is not possible.


3. Subsidised job suspension due to risks during pregnancy or breast feeding when changes of the workplace are not technically feasible.

Classification

Many national authorities, international agencies and even professional associations have developed lists of carcinogens according to their own classification criteria, which often do not coincide.

• Regulation 1272/2008 (CLP) on classification, labelling and packaging of substances and mixtures (in force since January 20, 2009).

It defines as a carcinogen: a substance or a mixture of substances which induce cancer or increase its incidence. Substances which have induced benign and malignant tumours in well performed experimental studies on animals are also considered to be presumed or suspected human carcinogens unless there is strong evidence that the mechanism of tumour formation is not relevant for humans.

Carcinogenic substances are classified in three categories according to the following criteria (see Annex I, point 3.6.2.)

Category 1: Category 1A and Category 1B
Known or presumed human carcinogens A substance is classified in Category 1 for carcinogenicity on the basis of epidemiological and/or animal data. A substance may also be included in category 1A if it is known that it is a human carcinogen, based on the existence of human testing, or category 1B if it is supposed to be a human carcinogen, based on the existence of animal testing. The classification in Category 1A and 1B is based on the strength of evidence and others. This evidence may come from: human studies that establish a causal relationship between human exposure to a substance and the development of cancer (known human carcinogen); or animal experiments for which there is sufficient evidence to demonstrate animal carcinogenicity (presumed human carcinogen). In addition, on a case-by-case basis, scientific judgment may warrant a decision of presumed human carcinogenicity derived from studies showing limited evidence of carcinogenicity in humans together with limited evidence of carcinogenicity in experimental animals.	Danger
	H350 May cause cancer (indicate exposure route if it is conclusively proven that the danger is not caused by any other route)

Category 2
Suspected human carcinogens. The placing of a substance in Category 2 is done on the basis of evidence obtained from human and/or animal studies, but which is not sufficiently convincing to place the substance in Category 1A or 1B, based on strength of evidence together with additional considerations. Such evidence may be derived either from limited evidence of carcinogenicity in human studies or from limited evidence of carcinogenicity in animal studies.	Warning
	H351 Suspected of causing cancer (state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard)

Regulation 1272/2008 (CLP) defines mutation as a permanent change in the amount or structure of the genetic material in a cell. The term ‘mutation’ applies both to heritable genetic changes that may be manifested at the phenotypic level and to the underlying DNA modifications when known (including specific base pair changes and chromosomal translocations). The term ‘mutagenic’ and ‘mutagen’ will be used for agents giving rise to an increased occurrence of mutations in populations of cells and/or organisms.

For the purpose of classification for germ cell mutagenicity, substances are allocated to one of two categories:

Category 1: Category 1A and Category 1B
Substances known to induce heritable mutations or to be regarded as if they induce heritable mutations in the germ cells of humans. Substances known to induce heritable mutations in the germ cells of humans. The classification in Category 1A is based on positive evidence from human epidemiological studies. Substances to be regarded as if they induce heritable mutations in the germ cells of humans. The classification in Category 1B is based on: Positive result(s) from in vivo heritable germ cell mutagenicity tests in mammals; or Positive result(s) from in vivo somatic cell mutagenicity tests in mammals, in combination with some evidence that the substance has potential to cause mutations to germ cells. It is possible to derive this supporting evidence from mutagenicity/genotoxicity tests in germ cells in vivo, or by demonstrating the ability of the substance or its metabolite(s) to interact with the genetic material of germ cells; or Positive results from tests showing mutagenic effects in the germ cells of humans, without demonstration of transmission to progeny; for example, an increase in the frequency of aneuploidy in sperm cells of exposed people.	Danger
	H340 May cause genetic defects(state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard)

Category 2
Substances which cause concern for humans owing to the possibility that they may induce heritable mutations in the germ cells of humans The classification in Category 2 is based on: Positive evidence obtained from experiments in mammals and/or in some cases from in vitro experiments, obtained from: Somatic cell mutagenicity tests in vivo, in mammals; or Other in vivo somatic cell genotoxicity tests which are supported by positive results from in vitro mutagenicity assays. Note: Substances which are positive in invitro mammalian mutagenicity assays, and which also show chemical structure activity relationship to known germ cell mutagens, shall be considered for classification as Category 2 mutagens.	Warning
	H341 Suspected of causing genetic defects (state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard)

• Former Directive 67/548/EEC relating to the classification, packaging and labelling of dangerous substances (DSD, in force until 1^st December of 2010, with the exemption of substances already in the market before the cited date, for these substances, there will be no obligation to re-label or repackage until 1^st December, 2012).

DSD defines as carcinogenic substances and mixtures: substances or preparations which, if they are inhaled or ingested or if they penetrate the skin, may induce cancer or increase its incidence;

DSD classifies carcinogens in three categories according to the following criteria (see Annex VI, section 4.2.1.):

Category 1
Substances known to be carcinogenic to man. There is sufficient evidence to establish a causal association between human exposure to a substance and the development of cancer.	T: Tóxic
	R45 May cause cancer R49 May cause cancer by inhalation

Category 2
Substances which should be regarded as if they are carcinogenic to man. There is sufficient evidence to provide a strong presumption that human exposure to a substance may result in the development of cancer, generally on the basis of: appropriate long-term animal studies, other relevant information.	T: Tóxic
	R45 May cause cancer R49 May cause cancer by inhalation

Category 3
Substances which cause concern for man owing to possible carcinogenic effects but in respect of which the available information is not adequate for making a satisfactory assessment. There is some evidence from appropriate animal studies, but this is insufficient to place the substance in Category 2.	Xn: Harmful
	R40 Limited evidence of a carcinogenic effect

DSD classifies mutagens in three categories according to the following criteria (see Annex VI, section 4.2.2.):

Category 1
Substances known to be mutagenic to man. There is sufficient evidence to establish a causal association between human exposure to a substance and heritable genetic damage.	T: Tóxic
	R46 May cause heritable genetic damage

Category 2
Substances which should be regarded as if they are mutagenic to man. There is sufficient evidence to provide a strong presumption that human exposure to the substance may result in the development of heritable genetic damage, generally on the basis of: appropriate animal studies, other relevant information.	T: Tóxic
	R46 May cause heritable genetic damage

Category 3
Substances which cause concern for man owing to possible mutagenic effects. There is evidence from appropriate mutagenicity studies, but this is insufficient to place the substance in Category 2.	Xn: Harmful
	R68 Possible risk of irreversible effects

Annex I of DSD includes a list of carcinogen and mutagen substances classified according to the previous criteria.

• International Agency for Research on Cancer (IARC)




The International Agency for Research on Cancer is part of the World Health Organization. It is the international reference organization for this topic and publishes and regularly updates a list of carcinogens and a list of activities that may cause cancer, according to the following criteria:

		Combinations of evidences for each group
IARC Group	Group description	Epidemiological Evidences	Evidences in animals	Others evidences
1	The agent (mixture, work activity) is carcinogenic to humans	Sufficient	Any	Any
		Less than sufficient	Sufficient	Strong positive
2A	The agent (mixture, work activity) is probably carcinogenic to humans	Limited	Sufficient	Less than strong positive
		Inadequate or not available	Sufficient	Strong positive
2B	The agent (mixture, work activity) is possibly carcinogenic to humans	Limited	Less than sufficient	Any
		Inadequate or not available	Sufficient	Less than strong positive
		Inadequate or not available	Limited	Strong positive
3	The agent (mixture, work activity) is not classifiable as to its carcinogenicity to humans	Inadequate or not available	Limited	Less than strong positive
			Not elsewhere classified
4	The agent (mixture, work activity) is probably not carcinogenic to humans	Suggesting lack of carcinogenicity	Suggesting lack of carcinogenicity	Any
		Inadequate or not available	Suggesting lack of carcinogenicity	Strong negative

Others agencies that have developed lists of carcinogens are:

• American Conference of Governmental Industrial Hygienists (ACGIH)

The American hygienists’ professional association is an international recognised organization whose threshold limit values (TLV) are used as a reference all over Europe.

A1	Confirmed human carcinogen
A2	Suspected human carcinogen
A3	Confirmed animal carcinogen with unknown relevance to humans
A4	Not classifiable as a human carcinogen
A5	Not suspected as a human carcinogen

• Occupational Safety and Health Administration (OSHA)
  

  Carcinogenic list of the U.S Occupational Safety and Health Administration.

  
  


• National Toxicology Program (NTP)
  

  The National Toxicology Program of the U.S. Department of Health and Human Services is mandated to produce a biennial Report on Carcinogens. It classifies carcinogens into two groups:
  





1	Known to be a human carcinogen
2	Reasonably anticipated to be a human carcinogen




• California Proposition 65 (CP65)
  

  List of chemicals known by the California state to cause cancer.
  



• Substances that cause breast cancer

These substances are included at the database Environment and Breast Cancer: Science Review developed by the US Silent Spring Institute. The Science Review database includes information on 216 chemicals that increase mammary gland tumours in animal studies conducted by the US National Toxicology Program (NTP) or included in the International Agency for Research on Cancer (IARC) Monographs, 11th Report on Carcinogens (11th ROC), Carcinogenic Potency Database (CPDB), or Chemical Carcinogenesis Research Information System (CCRIS) database.



For each chemical, the database Environment and Breast Cancer: Science Review includes:





• carcinogenic potential


• ability to cause gene mutations


• exposure in the general population and for women at work


• other characteristics of chemical use, sources, and regulation.

Related legislation and policies

• Council Directive 89/391/EEC, of 12 June 1989 on the introduction of measures to encourage improvements in the safety and health of workers at work.


• Regulation 1272/2008 (CLP), on classification, labelling and packaging of substances and mixtures.


• Council Directive 67/548/EEC, of 27 June 1967 on the approximation of laws, regulations and administrative provisions relating to the classification, packaging and labelling of dangerous substances.


• Council Directive 98/24/EC of 7 April 1998 on the protection of the health and safety of workers from the risks related to chemical agents at work.


• Directive 2004/37/EC of 28 June 1990 on the protection of workers from the risks related to exposure to carcinogens at work


• Council Directive 97/42/EC of 27 June 1997 amending for the first time Directive 90/394/EEC on the protection of workers from the risks related to exposure to carcinogens at work


• Council Directive 1999/38/EC of 29 April 1999 amending for the 2nd time Directive 90/394/EEC on the protection of workers from the risks related to exposure to Carcinogens at work and extending it to Mutagens


• Regulation (EC) No 1907/2006 of the European Parliament and of the Council of 18 December 2006, concerning the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH)


• Council Directive 92/85/EEC of 19 October 1992 concerning the implementation of measures to encourage improvements in the safety and health of pregnant workers, workers who have recently given birth and women who are breastfeeding (Tenth individual Directive within the meaning of Article 16(1) of Directive 89/391/EECT)

References

The sources consulted for the preparation of this list are:

List	Source	Publication date
Regulation 1272/2008 (CLP)	Annexes I, VI and VII	January 2011
IARC	IARC Databases	2017
Breast Cancer	Environment and Breast Cancer: Science Review	June 2010
Other sources	University of California
	NTP-2011
	California Proposition (CP65)

Last update

June 2017