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Guidelines on Handling Chemical
Carcinogens, Teratogens and Mutagens
1995 New Edition incorporating requirements of CoSHH 1994 1. Background, Scope and Purpose of the Code
The Control of Substances Hazardous to Health Regulations 1994 (section 7)introduced specific legal duties relating to the use of carcinogens, including a hierarchyof precautions which are MANDATORY . In addition the Approved Code of Practice onthe use of carcinogens was revised and anyone who is responsible for determiningdepartmental policy is strongly advised to obtain a copy.
The purpose of this document is to provide Heads of Departments and othersresponsible for the use of known or suspected carcinogens, teratogens and mutagensguidelines for use. These guidelines can be incorporated, where appropriate, intodepartmental policies and specific experimental procedures.
2. Definitions
Carcinogens are agents which cause cancer.
They can be categorised according to the degree of certainty that they cause cancer: • known carcinogens• suspected carcinogens• agents of undetermined carcinogenicity• non-carcinogens This document relates to known and suspected carcinogens, although all undeterminedagents must be handled with caution.
The statutory requirements relate specifically to those agents which must be labelled"carcinogenic - category 1" or "carcinogen - category 2" under the Chemicals (HazardInformation and Packaging) Regulations 1993 (CHIP) - (Appendix 2 of this document)and to any substances listed in Schedule 8 of the CoSHH Regulations 1994. (Appendix1 of this document).
Teratogens produce abnormalities in the growing embryo or foetus Mutagens damage the genes causing heritable abnormalities in offspring.
For the purposes of the University Guidelines, no further distinction is drawn betweenthese three categories. The guidelines concentrate on carcinogens but the proceduralrequirements apply equally to teratogens and mutagens.
3. Classes of Chemical Carcinogens
The following classes of chemicals are know to contain carcinogens: • aromatic amines• N-nitroso compounds• azo dyes• alkylating agents• some naturally occurring compounds Some known carcinogens in these categories are listed in Appendix 3: the list is notcomprehensive and the omission of any compound does not imply that it is free fromcarcinogenic activity.
If an investigator is uncertain about the carcinogen risk of any agent, the availableliterature must be adequately surveyed before the substance is brought onto Universitypremises. Producers and suppliers of chemicals are often a good source of information.
The CHIP lists also provide a useful source of reference on carcinogens, teratogens andmutagens.
4. Background Information of Carcinogenesis
Carcinogenesis is the name given to the process by which cancer develops from normaltissues and their constituent cells. Irrespective of the nature of the causative agents,the process is characterised by certain general properties which are stated herebecause they illustrate some of the problems encountered in the identification of acarcinogenic hazard.
Cancer is a common condition and is thought to be most often due to environmentalcauses rather than arising spontaneously. Important known associations with anincreased risk of cancer in humans include smoking (lung cancer), sexual promiscuity (cancer of the cervix) and low-fibre diet (large bowel cancer).
Some carcinogens are extremely potent and can induce cancer at very low doselevels in a susceptible species. There is often no knowledge available about thelower threshold of dose below which cancer will not occur. The probability thatcancer will result is usually proportional to the dose, except that very high dosesmay have more immediate toxic effects.
Unlike radiation protection control, there is no simple way of monitoringindividual exposure to chemical carcinogens. A single exposure to a carcinogenmay be sufficient to induce cancer.
With carcinogens, there is no immediate indication that harm has resulted fromexposure, unless the agent has some other toxic effect. Long intervals elapsebetween exposure to carcinogens and the appearance of tumours resultingtherefrom. Intervals of two or three decades are not unusual.
Some carcinogenic agents are unable to produce cancer alone. Subsequentexposure to another agent is necessary to amplify or promote the initialcarcinogenic injury.
Carcinogens can enter the human body by the following routes: • by mouth into the gut• by inhalation into the lungs• by skin contact The resulting cancers do not necessarily appear at the site of entry, becausecarcinogens require chemical transformation in the body into their active form.
5. Prohibitions Relating to Certain Substances
The use of the following substances are banned under the Control of SubstancesHazardous to Health Regulations 1994: • 2-naphthylamine• benzidine• 4-aminodiphenyl• 4-nitrodiphenyl The ban includes their salts and any other substance containing more that 0.1% ofthem.
The use of benzene is also prohibited for most purposes. Although its use in researchand analysis is permitted under law, it is the University policy to ban its use unlessspecific permission for a given procedure has been obtained from Safety Services.
6. Assessment of Procedures
There is a requirement under CoSHH to assess any procedure involving a hazardoussubstance before the commencement of work. This is particularly vital with carcinogenssince there is unlikely to be any early warning of adverse effects. The general UniversityCoSHH form B should be used as a guide.
The results of the assessment should include at least details of: • the nature, hazard and extent of potential exposure • any workers who may be particularly at risk, including the possible risk to • whether substitution by a less hazardous substance is reasonably practicable• the control measures to be applied• operating procedures to ensure minimum exposure• procedures for maintenance and emergencies• use of personal protective equipment• monitoring procedures (if appropriate)• health surveillance (if appropriate)• arrangements for information and training• The assessment should be reviewed:• if there is any indication that control measures are not working efficiently• at least every year 7. Recording of Procedures
All work involving known or suspected carcinogens must be pursued according towritten departmental procedures. Specific procedures for each operation will be drawnup in the light of the assessments.
8. Use of Alternative Substances
Investigators should find out whether suitable, safer alternatives exist before using areagent which is a known or suspected carcinogen. Obviously if the experimentinvolves carcinogenesis, then there can be no alternative but to use the material. Saferalternatives may exist if the agent is being used for other laboratory purposes.
In chemical synthesis, due consideration should be given to the possible carcinogenicproperties of starting materials, intermediates, reaction products and by-products.
Unfamiliar techniques should be practised using a non-carcinogen before commencingwork with the carcinogen(s) and with due regard for the Home Office regulations in thecase of animal work.
9. Approval for the Work
The Head of Department or person with designated authority must approve all new andexisting procedures involving known or suspected carcinogens. They must be satisfiedthat the use of the agent is essential, that the proposed scale of the work is justified,that adequate facilities exist for use, storage and disposal, and that the investigator incharge of the project is competent to work with the agent. A written record of theproject summary, the known or suspected carcinogen, the quantity used, handling anddisposal procedure, and the name(s) of the user must be kept in the departmentalrecords for 40 years. If the department ceases to exist, the record must be deposited ina suitable archive.
10. Use of Carcinogens for Teaching Purposes
The use of carcinogens, particularly those regulated by law, for teaching purposesshould be avoided. If it is considered that their use in a teaching procedure isunavoidable, the need and conditions of use must be reviewed annually by the Head ofDepartment. In any case, all the legally required safety precautions must be followed.
11. Notification and Records
Heads of Department or responsible staff designated by them must be notified beforeany known or suspected carcinogen is brought into the department. Heads ofDepartment or responsible staff designated by them must keep written records of theacquisition and use of any known or suspected carcinogens in their department.
• the full chemical name of the carcinogen, along with any trade names or short • the title of the project• quantity issued, used and disposed of• names of approved users The records must be kept for 40 years and must be available for inspection by theDirector of Safety Services or his delegated authority at any time. Staff additionallyexposing themselves to known carcinogenic hazards (eg smoking, use of snuff, use oforal tobacco) must be recorded as doing so.
All personnel associated with the procedure must be informed in advance that a knownor suspected carcinogen is being used. This includes animal house staff, who must bebriefed about the material and potential hazards. Due regard must also be paid to anyother personnel who could be involved, such as those who may be exposed duringdisposal, maintenance or emergencies.
12. Storage
Heads of Department must ensure that all substances listed in Appendices 1 and 2 ofthis document are kept in secure, locked storage except when in immediate use.
Access to the store must be restricted to named, authorised staff. Carcinogens must bestored in appropriate, closed, clean and clearly labelled containers. Over-stockingshould be avoided.
Cupboards and refrigerators containing carcinogens must be labelled with a"carcinogen" sign.
Carcinogenic waste products must be clearly labelled and stored safely until disposedof in the manner designated by the written procedure.
13. Control of Exposure
If the use of a carcinogen is deemed to be essential, then adequate control of exposuremust be ensured. All the following control measures are legally required.
13.1 The process and handling systems must be totally enclosed unless this is not 13.2 The use of plant, processes and systems of work which minimise the generation of, or suppress and contain, spills, leaks, fumes and vapours of carcinogens.
13.3 The limitation of the quantity of carcinogen in the workplace.
13.4 The keeping of the number of persons who might be exposed to a carcinogen to a minimum. Non-essential personnel should be excluded. This will apply as muchin an emergency situation as during routine work.
13.5 The prohibition of eating, drinking and smoking in areas that may be contaminated by carcinogens. Similarly, the use of snuff, the application ofcosmetics and finger-mouth contact is inappropriate.
13.6 The provision of hygiene measures including adequate washing facilities. All users should wash their hands in luke-warm (rather than hot) water before leaving thelaboratory or work area.
13.7 The regular cleaning of walls and surfaces.
13.8 The designation of those areas and installations which may be contaminated by carcinogens, and the use of suitable and sufficient warning signs.
13.9 The safe storage, handling and disposal of carcinogens and the use of closed and If the above measures do not provide adequate control, the use of suitablepersonal protective equipment shall, in addition to the above measures, beobligatory.
ii) It is however University policy that regardless of whether control measures are deemed to be adequate, a laboratory coat and suitable impervious glovestogether with safety spectacles must be worn whenever carcinogens are inuse.
iii) Protective clothing must not be worn outside the area designated for handling iv) The possibility of exposure to carcinogens by inhalation should normally be controlled by engineering means. It would be regarded as very exceptional fora worker to require the use of personal respiratory protective equipment. Ifthe use of a cartridge mask is required then the user must hold a currenttraining voucher.
14. High Risk Operations
This list is NOT to be regarded as definitive and may be extended in the light ofindividual experience or knowledge.
• Any process which can produce aerosols, vapours or dusts of carcinogenic • Synthesis of carcinogens using for example distillation, crystallisation, filtration, • Storage and manipulation of carcinogenic gases, volatile carcinogens and compounds that decompose spontaneously evolving a carcinogen • Weighing of carcinogens and the preparation of solutions containing them• Recovery of carcinogens from TLC plates• Changing of traps and exhaust filters• Husbandry of animals treated with carcinogens Careful thought must be given to preventing exposure during these operations. Sincethey all involve standard techniques, it is easy to forget their risk potential. However,concern over the long-term hazards of carcinogens must not be allowed to divertattention from the precautions essential for protecting against most immediate hazardssuch as acute toxicity, fire etc.
15. Disposal of Carcinogens
The procedure for the safe disposal of carcinogens and materials contaminated bythem must be determined before the agent is taken into the department. Known orsuspected carcinogens must be disposed of safely: this is normally by incineration orby disposal to a specialist contractor. These agents must not be washed down thedrains or placed in the general waste bins. Waste litter from the cages of animalsexposed to known or suspected carcinogens must be emptied into plastic bags andincinerated unopened. Safety Services may be able to advise on the procedure forspecific agents and on disposal by specialist contractors.
It should be noted that the disposal of toxic waste is a costly exercise and appropriatebudgetary arrangements must be made during the planning stages of the procedure.
Decontamination methods used for experimental residues and glassware should ensurecomplete chemical conversion into non-carcinogenic substances. Only named personswho have been specifically instructed in the appropriate safe procedures should beemployed to wash-up contaminated glassware.
16. Monitoring of the Workplace
Because exposure to carcinogens can result in serious health effects, considerationshould be given to monitoring procedures. This should take two forms: a) A regular check at pre-determined intervals that procedures are being followed andare effective.
b) Where there is possibility that containment may not be effective and a suitableenvironmental monitoring procedure is available, departments should undertakechecks on a regular basis.
The results of any environmental monitoring should be compared with prescribedstandards (Maximum exposure limits and/or Occupational Exposure Standards), whereavailable.
Environmental monitoring is mandatory, by law, in the case of any procedure usingvinyl chloride monomer.
Records of monitoring should be made available to those involved in the procedure andshould be kept for at least 40 years.
17. Health Advice and Surveillance
Health surveillance is appropriate in the case of all carcinogenic substances unlessexposure is not significant.
It is required by law in the case of persons using: • vinyl chloride• 1-naphthylamine and its salts• orthotoluidine and its salts• dianisidine and its salts• dichlobenzidine and its salts Females who are pregnant must not handle suspected carcinogens: the risk ofteratogenic effects is greatest in the early stage of pregnancy. Female staff who workwith known or suspected carcinogens and who are contemplating pregnancy shouldseek medical advice from the Occupational Health Unit or their own GeneralPractitioner.
18. Accidents
A record must be kept of all accidents involving known or suspected carcinogens, evenif there is no apparent injury. Each accident must be reported to Safety Servicesfollowing the usual procedure. Records must be kept for 40 years.
Contact with skin, eyes or any body surface must be followed by liberal washing withcold water (not using soap) and medical advice sought on subsequent steps.
19. Information, Instruction and Training
Appropriate instruction, information and training must be given, by law, to all users ofcarcinogens. Because the manifestations of exposure may be delayed for severaldecades it is vital that such instruction and training is to a very high standard. Everyoneusing carcinogenic materials should be fully aware of the risks, the correct proceduresfor the use of such materials and the action to take in an emergency.
Appendix One
Substances and Processes Defined in the Approved Code of Practice (Schedule 8) towhich the definition "carcinogen" relates.
Bichromate manufacture involving the roasting of chromite ores Electrolytic chromium processes, excluding passivation, which involve hexavalentcompounds Mustard gas (B,B'Dichlorodiethyl sulphate) Calcining, sintering or smelting of nickel copper matte or acid leaching orelectrorefining of roasted matte Coal soots, coal tar, pitch and coal tar fumes • unrefined and mildly refined vacuum distillates• catalytically cracked petroleum oils with final boiling point above 320oC• used engine oils Leather dust in boot and shoe manufacture Isopropyl alcohol manufacture (strong acid process) Note that any substance defined as "carcinogen - category 1" and "carcinogen -category 2" under the Chemicals (Hazard Information and Packaging) Regulations 1993also attract the legal provisions under the Control of Substances Hazardous to HealthRegulations 1994 Appendix Two
Carcinogens Listed under CHIP 2
Note that this list is frequently amended and you are strongly advised to check the
most recently published document.
Category 1
Category 2
Arsenic acid and its saltsArsenic pentoxide 2-Nitropropane3,3'-Dimethoxybenzidine and salts3,3'-Diethylbenzidine3,3'Dimethylbenzidine salts3-Propanolide 4,4'Diaminophenylmethane4-Amino-3-fluorophenol4-Aminoazobenzene4-Methyl-m-phenylenediamine4-Nitrobiphenyl4-o-Tolylazo-o-toluidine5-NitroacenaphtheneAcrylamideAcrylonitrileBenzo[a]anthraceneBenzo[a]pyreneBenzo[b]fluorantheneBenzo[j]fluorantheneBenzo[k]fluorantheneBeryllium and Beryllium CompoundsCadmium chlorideCadmium oxideCadmium sulphateCalcium chromateCaptafol (iso)Carbadox (Inn) Chromium III chromateDiazomethaneDibenz(a,h)anthraceneDichlorobenzidine and saltsDiethyl sulphateDimethyl carbomyl chlorideDimethyl sulphateDimethylsulfamoylchlorideDirect Brown (CI)Ethylene OxideEthyleneimineExtracts (Petroleum) heavyExtracts (Petroleum) lightHexachlorobenzeneHexamethylphosphoric TriamideHydrazineHydrazine Bis (3-Carboxy-4-Hydroxybenzenesulfonate)HydrazobenzeneHydrocarbons (C22-55) Arom. richMethyl acrylamidoglycolateMethyl acrylamidomethoxyacetateMethyl-onn-azoxymethyl acetateN-NitrososodiummethylamineNitrofen (iso)NitrosodipropylamineO-ToluidinePotassium bromatePropylene oxideSalts of hydrazineStrontium chromateStyrene oxideSulphallate - isoThioacetamidea a a TrichlorotolueneUrethane (Inn) Appendix Three
A. Examples of Known or Suspected Carcinogens
This list gives only a few examples. It is not comprehensive and the omission of anyagent from this list does not deem it to be free of carcinogenic activity.
As a guide to the hazard, the following designations are used: * Carcinogenicity established, but little hazard if careful (no mark) Carcinogenicity weak or possible 1. Aromatic Amines
Benzidine (4,4'diaminobiphenyl), 2-naphthylamine and 4-aminobiphenyl areestablished causes of bladder cancer in industrial workers. They were banned fromBritish industry by the Carcinogenic Substances Regulations 1967 (now superseded byCoSHH). Some related 2- and 3- ring aromatic amines are also carcinogenic, and somewere controlled by the Regulations. Some activity has been detected in some single ringamines.
Benzidine has had many uses in analytical chemistry and safer alternatives should beused. 3,3', 5,5'-tetramethylbenzidine and 3,3',4,4'-tetra-aminobiphenyl(diaminobenzidine) are free of significant activity, but o-toluidine and 3-amino-9-ethylcarbazole are carcinogenic. The carcinogenicity of 1-naphthylamine appears to beentirely due to contamination with 2-naphthylamine.
H*** 2-naphthylamineH 1-naphthylamineH*** 4-aminobiphenylH*** benzidine** o-toluidine** 3,3'-dichlorobenzidine* 3,3'-dimethoxybenzidine (o-dianisidine)4,4'-methylene dianiline* 4,4'-methylenebis (2-chloroaniline)*** 2-aminofluorene*** 2-acetamidofluorene** 4-aminostilbene** 3-amino-9-ethylcarbazole * quinoline* diphenylamine (if contaminated with 4- aminobiphenyl)aniline (main risk from toxicity) ethidium bromide (carcinogenicity unknown, but is a potent mutagen) 2. Aromatic nitro compounds
Those corresponding to carcinogenic aromatic amines should be assumed to becarcinogenic.
*** 4-nitrobiphenyl*** 4,4'-dinitrobiphenyl** 2-nitronaphthalene** 2-nitrofluorene** many substituted 2-nitrofurans** 4-nitroquinoline 1-oxide and related compounds* nitro derivative of polycyclic aromatic hydrocarbons A number of azo and other dyes are carcinogenic for experimental animals. Methyl ormethoxy groups can markedly increase activity. Many commercial dyes are of very lowpurity.
* 4-dimethylaminoazobenzene (Butter yellow or Methyl yellow)* o-aminoazotoluenechrysoidines (2,4-diaminoazobenzenes; methyl derivatives are more mutagenic and may be more carcinogenic)?H auramine (some bladder cancer cases in manufacturing workers)magenta (some bladder cancer cases in manufacturing workers but no evidence that 4. Alkylating Agents
These interact directly (ie without prior metabolism) with biological materials andcommonly have irritant, toxic, mutagenic and carcinogenic actions. They includechemicals of major industrial importance, and also various drugs used for thetreatment of cancer. Mustard gas and bis(chloromethyl) ether (BCME) have causedoccupational lung cancer, while human cancer has also occurred in some patientstreated with alkylating agent drugs. Any reactive alkylating agent should be assumed tobe potentially carcinogenic in addition to its other hazards.
BCME may arise unintentionally from interaction of formaldehyde with hydrogenchloride. Amounts formed in air appear to be generally very small, but high levels havebeen detected from Friedel-Craft mixtures containing formaldehyde, and commercialchloralkylation may have led to some lung cancer cases.
Methylation with diazomethane is known to be hazardous. Also it forms precursorsmethylnitrosourea, N-methyl-N'-nitroso-N-nitro-guanidine (MNNG) andespeciallymethylnitrosourethane are potent carcinogens, though methylnitroso-p-toluenesulphonamide is not. The methylating agent fluorosulphate ("magic methyl") hasbeen reported to cause rapid death after a relatively small laboratory spillage; in suchcases possible carcinogenic risks are hardly relevant.
H*** bis(2-chloroethyl) sulphide (mustard gas)H*** bis(chloromethyl) ether (BCME)*** chloromethyl methyl ether (normally contains some BCME)H*** various nitrogen mustard derivatives** alkyl methanesulphonates** dimethyl sulphate*** methyl fluorosulphate (very high toxicity)** dimethylcarbam(o)yl chloride* triethylene phosphoramide (TEPA)* triethylene thiophosphoramide (thioTEPE)** tris(2,3-dibromopropyl)phosphate (former clothing flameproofer)** 2,3-dibromo-1-chloropropane (has caused sterility)** 2,3-dibromopropan-1-olbromomethane (methyl bromide)iodomethane (methyl iodide)?H * benzotrichloride** beta-propiolactone* propane sultrone?H some aziridines (ethyleneamines)* ethylene oxideother epoxides where the ring is unstable 5. Other organic halides etc
Compounds with a very stable carbon-halogen bond may still be metabolised to acarcinogenic species, including vinyl chloride which led to liver blood-vessel cancer inheavily-exposed workers. Various polyhalogenated chemicals are of considerableconcern because of their persistence in the environment and the body, toxic effectsand association with highly toxic polychlorinated dibenzodioxins and dibenzofurans;relatively little is known about the carcinogenic risk. For halogenated solvents seesection B.
H* chloroethene (vinyl chloride)* chloropreneH** cyclophosphamidepolychlorinated biphenyls (PCBs)polybrominated biphenyls (PBBs)some polychlorinated pesticides 6. N-Nitroso compounds and hydrazines
A very high proportion of nitrosamines (RR'N.NO) tested are potent experimentalcarcinogens, with a very wide range of body organs being affected.
The initial discovery resulted from the occurrence of severe liver poisoning from theuse of N-nitrosodimethylamine as a solvent by laboratory workers. Risks of many areincreased by their volatile nature. Related carcinogens include alkylnitrosamides (egmethylnitrosourea), 1,2-dialkylhydrazines, diazoalkanes, and guanidines such as thestrong mutagen MNNG. Involvement of some N-nitroso compounds in some humancancers is strongly suspected but not firmly established.
*** N-nitrosodimethylamine (dimethylnitrosamine)*** N-nitrosodiethylamine (diethylnitrosamine)** most other compounds RR'N.NO with some exceptions (N-nitrosodiphenylamine andthose with a tert-butyl group)* N-nitrosodiethanolamine (found in engineering oils based on ethanolamines with nitrite inhibitor)** N-nitrosopiperidine** N-nitrosopiperazine** N-nitrosomorpholine* N-alkyl-N-nitrosoureas, H2N.CO.N(NO)R, also N- nitroso di- and tri- alkylureas*** N-alkyl-N-nitrosourethanes (powerful local carcinogens)** N-alkyl-N'-nitro-N-nitrosoguanidines (eg MNNG)** 1,2-dialkylhydrazines, RNH.NHR'* procarbazine (drug - substituted 1,2- dimethylhydrazine)** azoalkanes, R.N-N.R'** azoxyalkanes, R.NO-N.R'* methylazomethanol* 1-phenyl-3,3-dimethyltriazene and analogues 7. Polycyclic aromatic hydrocarbons and heterocycles
Many such compounds containing 4 and 6 aromatic rings are potent carcinogens, theirrisks being increased by their likely persistence in the body. Benzo(a)pyrene is amongthe complex mixtures of such compounds formed during incomplete combustion oforganic matter and is held responsible for occupational scrotal and skin cancer inworkers in contact with soots, tars and mineral oils. Their role in other forms of humancancer is uncertain, but they may well be one of the factors in lung cancer caused bysmoking.
Use of the pure compounds outside cancer research are (or should be) very limited, butthey require particular care in handling owing to their potency and likely persistencewithin the body.
*** benzo(a)pyrene*** 7,12-dimethylbenz(a)anthracene *** 3-methylcholanthrene*** dibenz(a,h)anthracene** certain benzacridines and similar heterocyclic compoundsH* cutting oils, lubricants, tars, soots, when contaminated with agents of this type 8. Naturally-occurring carcinogens
A variety of plants and micro-organisms produce carcinogenic metabolites. Havingcomplex structures, they are not very volatile, but some are highly potent and mayrepresent considerable hazard if handled as the isolated chemicals. Aflatoxins,metabolites of a fungus contaminating foodstuffs, may have contributed to the highlevel of liver cancer in parts of tropical Africa. Dusts encountered in the woodworkingand leather industries have caused cancer of the nasal sinuses in workers, but theagents responsible are not known.
?H** aflatoxin B1 and less active analogues (from Aspergillus)* sterigmatocystin (from Aspergillus)* griseofulvin (from Penicillin)* streptozotocin (from a Streptpmyces)* cycastin (from Cycads)* bracken fern** phorbol esters (potent tumour-promoting and co-carcinogenic constituents)H* dusts from certain hardwoods 9. Inorganic carcinogenic agents
Various processes involving mining, refining and uses of some metals, particularlynickel and chromium, have been associated with occupational cancers of therespiratory tract. Exposures to dusts and fumes have been complex and are ofuncertain relevance to work under laboratory conditions, where toxic hazards areprobably much more important.
H* nickel (dusts and fumes have caused lung and nasal sinus cancers in workers.
Various compounds, possibly only sparingly soluble ones are carcinogenic in animals,particularly nickel subsulphide Ni3S2 but not amorphous NiS) H* chromium (human and experimental lung carcinogen; apparently Cr(VI) compoundsonly) H* beryllium (human and experimental lung carcinogen) ?H cadmium (dubious evidence for small increase in risk of prostate cancer) H arsenic (inorganic compounds carcinogenic for human skin and lung in formermedicinal and agricultural use) H*** asbestos dust (major occupational health hazard, having led to cancer of lung,particularly in smokers, mesothelioma of the pleura and peritoneum and crippling fibrous degeneration of the lung. Uses and handling subject to strict legislative control) B. Toxicity and Carcinogenicity of Some Solvents and Other

Many solvents are used in particularly large quantities, and the volatility of manycontributed to the possibilities of extensive exposure. They vary very greatly in theirtoxicity, some show carcinogenicity in animals, and benzene is an acceptedoccupational carcinogen for man.
Toxicity high, bone-marrow poison, can cause severe fatal anaemia. Accepted cause ofleukaemia from high exposure of workers in various occupations. Toluene and otheralkylbenzenes are detoxified by metabolism of the alkyl group(s); they arecorrespondingly less toxic, with no suspicions of carcinogenic risk.
Dichloromethane (methylene chloride)Some evidence for weak carcinogenicity of borderline significance only.
Trichloromethane (chloroform)Toxicity high; has given slight evidence for experimental carcinogenicity.
Tetrachloromethane (carbon tetrachloride)Toxicity high. Experimental liver carcinogen, suspected in having caused liver cancer ina few heavily exposed workers.
Bromomethane (methyl bromide)Fumigant use has caused toxic effects and some deaths. Some experimental evidencefor carcinogenic action.
TrichloroethyleneReadily breaks down to more toxic agents in absence of an inhibitor. Very weak experimental carcinogen, by mechanisms not applicable.
Tetrachloroethylene (perchloroethylene)Evidence for weak carcinogenicity of borderline significance.
1,2 Dichloroethane (ethylene dichloride)Has caused many cases of acute poisoning. Some evidence for experimentalcarcinogenicity.
** 1,2-Dibromoethane (ethylene dibromide)Toxicity high and is a potent experimental carcinogen, leading to increasingrestrictions on its commercial use.
1,1,1-Trichloroethane (methyl chloroform)No evidence for any carcinogenicity, but has caused fatalities through high industrialexposure and solvent abuse.
1,2-Dichlorobenzene (o-dichlorobenzene)Carcinogenicity tests have been negative.
isoPropanolFormer "strong acid" process of manufacture caused cases of nasal sinus cancer inworkers. No evidence that the solvent itself is carcinogenic.
1,4-DioxaneHigh exposures have caused deaths in workers. High dosage to rats and mice indrinking water were carcinogenic but there is no human evidence for carcinogenicity.
DimethylformamideHeavy occupational exposure has given rise to suspicions of testicular damage andcancer.
Dimethyl sulphoxide (DMSO)No reason to suspect carcinogenicity but may facilitate entry of more harmfulsubstances into the body.
*** Hexamethyl phosphoramide (hexametapol)Inhalation at extremely low levels has induced nasal cancer in rats. The mechanism ofthis may not be directly relevant to man, but pending further knowledge it must beassumed to be a significant carcinogenic hazard to man also.
Formaldehyde and FormalinHighly irritant and toxic. Inhalation at levels causing significant tissue damage causescancer in nasal sinuses of rats. To date, no reliable evidence that extensiveoccupational exposure has caused human cancer.
GlutaraldehydeHighly irritant and toxic. No evidence to date for carcinogenicity.
* ButadieneClearly carcinogenic for rats and mice inhaling high levels of the gas. No evidence thatlarge- scale industrial use has been carcinogenic for humans* AcrylamideToxicity high, including by skin contact. Accepted neurotoxin, with evidenceaccumulating that it may cause testicular damage and general effects. A weakexperimental carcinogen.
?H* AcrylonitrileHighly toxic for nervous system, with effects similar to cyanide. Some suspicions ofpossible occupational carcinogenesis.
* Ethyl carbamate (urethane)Experimental carcinogen, but most tests required the presence of a tumour promoteralso.
Appendix Four
Literature References to Chemical Carcinogens, Mutagens and Teratogens
This reference list is for general guidance only and the published literature on chemical
carcinogens is subject to continuous revision and addition.
IARC Monographs on the Evaluation of the Carcinogenic Risk to Man (International
Association for Research on Cancer, Lyons, France) Volumes 1 - 16 (1972 - 1978)
IARC Monographs on the Evaluation of the Carcinogenic Risk to Humans (International
Association for Research on Cancer, Lyons, France)
Volume 17 - (1978 to present)
US National Cancer Institute's Survey of Compounds Which Have Been Tested for
Carcinogenic Activity
(US Service Publication)
Volumes or supplements published in 1951, 1957, 1969, 1971, 1973, 1974 et seq.
"Handbook of Teratology" by J.G. Wilson & F.C. Fraser
Plenum Press NY, 1977 (4 volumes)
"Catalogue of Tetratogenic Agents" by T.H. Shepherd
John Hopkins University Press, Baltimore and London, 1983 (4th Edition)
"Reproductive Hazards of Industrial Chemicals: An Evaluation of Animal and Human
Data" by S.M. Barlow & F.M. Sullivan
Academic Press, London 1982
"Precautions for the Safe Handling of Cytotoxic Drugs"
Health & Safety Executive Guidance Note MS21
"Chemical Hazards to Human Reproduction" by I.C.T. Nisbet & N.J. Karch
Noyes Data Corp., New Jersey 1983
"Drugs as Teratogens" by J.L. Schardein
CRC Press 1976
On-Line Databases on Chemical Carcinogens, Tetratogens and Mutagens
Currently available on databases include:
HSELINE (Health & Safety Executive)
TOXLINE (US National Library of Medicine)
CANCERLINE (US National Library of Medicine)


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