clp classification of e-liquids -...

CLP CLASSIFICATION AND LABELLING

REQUIREMENTS OF NICOTINE CONTAINING

E-LIQUIDS

Prepared by

Dr Dilip Arvind Bhuva Document created: January, 2015

1st update: August, 2015

2nd update: October, 2015

This document is a property of Xyfil Ltd.

CLP Classification of e-liquids Dr Dilip Arvind Bhuva, Xyfil Ltd.

of 54

This document has been made public by Xyfil Ltd. as many manufacturers of the e-

liquids include hazard pictograms and statements that are – at most times – irrelevant

and therefore supplying misleading information about the CLP classification of these

products. This document is intended for sharing information on the CLP classification of

e-liquids and is intended for our customers, e-cigarette users and other manufacturers

and businesses that operate in the e-cigarette industry. This document can be cited as:

Bhuva, D.A. 2015. CLP classification and labelling requirements of nicotine containing e-

liquids. Xyfil Ltd. Available from: [insert web link to the document]

Legal Disclaimer

The information provided in this document is accurate and represents the best

information available to us – and believed to be reliable – at the time of publication. This

information is given in good faith without any representation or warranty, expressed or

implied, regarding its accuracy or correctness and we assume no liability – legal,

personal or otherwise – resulting from its use.

Although the information given in this document is used for designing the products

manufactured by Xyfil Ltd., any manufacturer, supplier, or distributor must satisfy

themselves that the information on their product and their labels are correct and

comply with all the relevant legislations. In no event shall Xyfil Ltd. be liable for any

claims, losses, or damages to any third party or for lost profits or any special, indirect,

incidental, consequential or exemplary damages, howsoever arising, even if Xyfil Ltd.

has been advised of the possibility of such damages. We advise that the information

provided in this document should be used along with all the relevant legislation and/or

literature.


of 54

The CLP classification and selection of labelling information for our products is based

mainly on the assessment carried out according to:

a) “Regulation (EC) No 1272/2008 on classification, labelling and packaging (CLP)

of substances and mixtures”1 (this legislation is referred to as ‘CLP regulation’ in

this document);

b) Any subsequent “Adaptations to Technical Progress (ATP)” made to the CLP

regulations. As of August 2015, six amendments have been made to the CLP

regulations2.

c) “Guidance on the Application of the CLP Criteria” version 4.1, last updated on

June, 20153;

d) “Guidance on Labelling and Packaging in accordance with Regulation (EC) No

1272/2008”4.

e) The European Agreement concerning the International Carriage of Dangerous

Goods by Road (ADR). ECE/TRANS/242, Vol. I and II and corrigenda5 (this

legislation is referred to as ‘ADR-2015’ in this document).

f) Inland transport of dangerous goods (by air, road and inland waterway)

Directive 2008/68/EC6.

These can be downloaded from links below in the footnotes.

1 http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2008:353:0001:1355:EN:PDF 2 http://ec.europa.eu/enterprise/sectors/chemicals/documents/classification/index_en.htm#h2-4 3 http://echa.europa.eu/documents/10162/13562/clp_en.pdf 4 https://echa.europa.eu/documents/10162/13562/clp_labelling_en.pdf 5 http://www.unece.org/trans/danger/publi/adr/adr2015/15contentse.html 6 http://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:02008L0068-20130515&from=EN

http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2008:353:0001:1355:EN:PDF

http://ec.europa.eu/enterprise/sectors/chemicals/documents/classification/index_en.htm#h2-4

http://echa.europa.eu/documents/10162/13562/clp_en.pdf

https://echa.europa.eu/documents/10162/13562/clp_labelling_en.pdf

http://www.unece.org/trans/danger/publi/adr/adr2015/15contentse.html

http://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:02008L0068-20130515&from=EN


of 54

List of Abbreviations

ATE Acute Toxicity Estimates

CLP Classification, labelling and packaging of substances and mixtures

EC50 Half maximal effective concentration

ECITA Electronic Cigarette Industry Trade Association

ErC50 The concentration at which a 50% inhibition of growth rate is observed

KOW Octanol-Water partition coefficient

LC50 The concentration (in air or water) at which 50% of the test population

died. i.e. The median lethal concentration.

LD50 The dose (amount of test material) at which 50% of the test population

died. i.e. The median lethal dose

LDLO The lowest lethal dose

mg/kg.bw milligram per kilo-body weight

NOEC No Observed Effect Concentration

pH Potential of Hydrogen

ppb Parts per billion

ppm Parts per million

TPD Tobacco Product Directive

TWA Time-Weighted Average

Notes: The phrase “CLP regulation” and Regulation “(EC) No 1272/2008” are used

interchangeably throughout this document and they both refer to the, same, European

Union CLP regulation that has regulation identity: “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” and came into force on 16th

December 2008 whilst amending and repealing ‘Directives 67/548/EEC’ and ‘Directives

1999/45/EC’, and amending regulation (EC) No 1907/2006.


of 54

Contents

Legal Disclaimer ............................................................................................................................................. 2

List of Abbreviations ..................................................................................................................................... 4

1. INTRODUCTION ....................................................................................................................................... 7

2. NICOTINE .................................................................................................................................................... 9

2.1 Animal Toxicity Data for Nicotine .............................................................................................. 10

2.2 Major/relevant Human Toxicity data for Nicotine: ............................................................ 11

2.3 Carcinogenicity, Genotoxicity & Reproductive Toxicity .................................................... 12

2.4 Specific Risk Groups ........................................................................................................................ 12

2.5 Eco-Toxicity Data ............................................................................................................................. 13

2.6 Environmental Fate ......................................................................................................................... 14

2.7 Additional Hazards .......................................................................................................................... 14

3. PROPYLENE GLYCOL ........................................................................................................................... 15

3.1 Animal Toxicity Data for Propylene Glycol ............................................................................ 16



3.5 Eco-toxicity Data for Propylene Glycol .................................................................................... 19



4. GLYCEROL (VEGETABLE GLYCERINE) ........................................................................................ 21

4.1 Animal Toxicity Data for Glycerol .............................................................................................. 22

4.2 Major Human Toxicity Data for Glycerol ................................................................................. 23



4.5 Eco-toxicity Data for Glycerol ...................................................................................................... 25



5. 7.2% (W/V) NICOTINE IN PROPYLENE GLYCOL ................................................................... 27

5.1 Physical Hazards ............................................................................................................................... 27

5.2 Health Hazard Classification ........................................................................................................ 27

5.3 Environmental Hazards ................................................................................................................. 29

5.4 Conclusion ........................................................................................................................................... 31


of 54

6. SUMMARY TABLES FOR CLP CLASSIFICATION OF NICOTINE SOLUTIONS. ............. 32

7. TRANSPORT LABELS ........................................................................................................................... 38

7.1 Hazard class of nicotine solutions for transport purposes .............................................. 38

7.2 Do you require a transport label? .............................................................................................. 40

8. CONCLUSIONS ......................................................................................................................................... 42

APPENDIX A .................................................................................................................................................. 43

APPENDIX B .................................................................................................................................................. 48

B.1 Boundaries of classification for acute toxicity hazards ..................................................... 48

B.2 Contents of the label ....................................................................................................................... 50

B.3 General rules for the application of labels.............................................................................. 51

B.4 Location of information on the label ........................................................................................ 51

B.5 Dimensions and make-up of the label elements .................................................................. 52

B.6 Allowed (relevant) exceptions .................................................................................................... 52

B.7 Interplay between Transport and CLP labelling system .................................................. 54


of 54

1. INTRODUCTION

There is a lot of debate among e-cigarette (here after referred to as e-cigs) industry

stakeholders on the CLP classification of nicotine containing solutions that are intended

to be used with e-cigs (referred to as e-liquid(s) here after). Some stake holders argue

that since e-liquids (or e-cigs) have nicotine in them and since nicotine has legally

binding harmonised classification in the EU, all e-liquids should carry the same

classification as that of pure nicotine along with all the hazard pictograms and warning

statements7,8. Whilst others argue that EU CLP experts have got the classification of

pure nicotine wrong (i.e. wrongly classified as toxic) and thus any product containing

nicotine should not be classified under CLP regulations in the first place9,10. Such

misconception is also evident among trading standards with some trading standard

agencies going to the extent of declaring that those products (containing nicotine ≤2.5%

w/w) that do not carry GHS06 and/or GHS09 and relevant risk phrases are liable to be

seized for non-compliance with the CLP regulations11,12,13. To the best of our knowledge,

to date only ‘Bibra proposal’ has come close to correctly classifying the e-liquids

according to the CLP classification (classification carried out by a chemical company

named ‘Bibra Ltd.’ on behalf of ECITA)14. The ‘Bibra proposal’ has taken – in general – a

correct approach of using the acute toxicity estimate (ATE) values (as described for

classification of mixtures) for assessing the CLP classification of e-liquids; and their

approach for selection of the LD50 values is appropriate (for oral and dermal toxicity).

However, their assessment completely ignored the other toxicity categories such as

aquatic toxicity (even though nicotine has harmonised classification in this category),

the implications of weight/weight and weight/volume solutions, and transport label

considerations. Thus in order to address these differences of opinion and to provide

complete assessment of e-liquids for labelling purposes, Xyfil Ltd. has undertaken CLP

classification of e-liquids and findings are presented in this document.

7 http://hibiscus-plc.co.uk/blog/e-cigarettes-clp-labelling-and-tactile-warning-labels/ 8 http://www.totallywicked-eliquid.co.uk/blog/2101/e-liquid-is-it-really-all-that-toxic/ 9 http://ecigintelligence.com/e-liquids-not-as-dangerous-as-regulators-think/ 10 http://escape-ecigarettes.co.uk/blog/EU-to-remove-toxic-warning-labels-from-e-cigarettes 11 https://www.google.co.uk/url?sa=t&rct=j&q=&esrc=s&source=web&cd=3&cad=rja&uact=8&ved=0CDEQFjACahUKEwjz88S02eDIAhVJuBQKHRO3C1M&url=https%3A%2F%2Fwww.sheffield.gov.uk%2Fdms%2Fscc%2Fmanagement%2Fcorporate-communications%2Fdocuments%2Fbusiness-industry%2Ftrading-standards%2FElectronic_Cigarettes_Guidance.pdf&usg=AFQjCNGblUDQrJuZAIQIadIvqbO3FweApA&bvm=bv.105841590,d.bGQ 12 http://www.darlington.gov.uk/media/540498/E-Cigarette_-_Trader_Guidance.pdf 13 http://www3.hants.gov.uk/tradingstandards/tradingstandards-business/ts-business-safety/tsguide-electronic-cigarettes.htm 14 http://www.ecita.org.uk/ise/07-qs-chapter-4-classification-labelling-and-packaging-clp-regulations-2010

https://www.google.co.uk/url?sa=t&rct=j&q=&esrc=s&source=web&cd=3&cad=rja&uact=8&ved=0CDEQFjACahUKEwjz88S02eDIAhVJuBQKHRO3C1M&url=https%3A%2F%2Fwww.sheffield.gov.uk%2Fdms%2Fscc%2Fmanagement%2Fcorporate-communications%2Fdocuments%2Fbusiness-industry%2Ftrading-standards%2FElectronic_Cigarettes_Guidance.pdf&usg=AFQjCNGblUDQrJuZAIQIadIvqbO3FweApA&bvm=bv.105841590,d.bGQ







of 54

We manufacture e-liquids that are intended to be used in electronic cigarette (e-cigs)

devices. An e-liquid contains specific concentrations of nicotine, propylene glycol,

glycerol and other flavour ingredients that impart taste to the e-liquid and subsequent

smoke generated from its use in e-cig devices (commonly referred to as “vapour” or

“vaping” in the industry). The classification should be performed for each type of e-

liquid product as the mixtures may have different toxicity properties – and thus

different CLP classification; however, TPD2 regulations may not allow use of flavour

ingredients/additives that would pose a (higher) risk to human health when compared

to that of nicotine15. Thus it is likely that the finalised e-liquid products that are placed

on the market post TPD2 may have the same CLP classification as the base nicotine

solution (i.e. without any additives such as flavourings).

Thus here the CLP classification is based on the nicotine, propylene glycol and glycerol.

However, the CLP classification will be revisited for each and every product during the

notification process of the e-liquids under TPD2 even though they are likely to carry the

same classification as that of these ‘base nicotine solutions’.

15 Clause 36.7 of the Draft statutory instrument: The Tobacco and Related Products Regulations 2016. https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/440989/SI_tobacco_products_acc.pdf

https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/440989/SI_tobacco_products_acc.pdf

https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/440989/SI_tobacco_products_acc.pdf


of 54

PART A: Gathering and Analysing Relevant Information.

2. NICOTINE

General Name Nicotine IUPAC Name 3-(N-methyl-2-pyrrolidinyl)pyridine EC No 200-193-3 CAS No 54-11-5 Molecular Weight 162.23156 g/mol Molecular Formula C10H14N2 XLogP3 1.2 Boiling Point 247 oC at atmospheric pressure16 Melting Point -79 oC at atmospheric pressure16 Flash Point 111 oC17 Auto Ignition 244 oC Vapour Density (air=1) 5.6118 Vapour Pressure 0.038 mm Hg at 25 oC19 (8.83 Pa) Log Kow 1.1720 pH 10.2 (for 0.05 Molar solution) TWA (mg/m3) 0.5 (skin) Harmonised Classification Index No (ISO) 614-001-00-4 Harmonised Classification21 (ISO) Acute Tox. 1; H310 (dermal/skin)

Acute Tox. 3 *; H301 (Oral) Aquatic Chronic 2; H411

Harmonised Labelling10 (ISO) GHS06; H310 GHS09; H301 Dgr; H411

* This is the minimum classification (for pure nicotine) given by the Harmonised

classification under CLP ((EC) No 1727/2008). If the evaluator has more data that

classify the substance in a more hazardous class, then the higher toxicity class needs to

be chosen.

Although the toxicity classification of nicotine has been harmonised under the CLP

regulation, the classification is for the pure form. However in the electronic cigarettes

and e-liquids, the nicotine used is highly diluted with either propylene glycol or glycerol

16 Lide, D.R. CRC Handbook of Chemistry and Physics 88TH Edition 2007-2008. CRC Press, Taylor & Francis, Boca Raton, FL 2007, p. 3-386 17 Experimental determination according to EU method A.9 (Flash-Point). 2014. 18 Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982., p. 2741 19 Boublik, T., Fried, V., and Hala, E., The Vapour Pressures of Pure Substances. Second Revised Edition. Amsterdam: Elsevier, 1984. 20 Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. Washington, DC: American Chemical Society., 1995., p. 76 21 Table 3.1 List of harmonised classification and labelling of hazardous substances to Annex VI of CLP Regulation (EC) No 1272/2008.


of 54

or both (along with flavour ingredients). Thus the CLP classification of the nicotine

containing mixtures (e-liquid) need to be evaluated by using the classification criteria

for mixtures as laid down in the CLP regulation ((EC) No 1272/2008).

2.1 Animal Toxicity Data for Nicotine

Model Route Dose Comments Reference

Rat Skin 140mg/kg.bw LD50 22 Rat Oral 50 mg/kg.bw LD50 23 Rat subcutaneous 25mg/kg.bw LD50 24 Rat Intraperitoneal 14.56

mg/kg.bw LD50 25

Rat intramuscular 15mg/kg.bw LDLO. Behavioural: convulsions or effect on seizure threshold; ataxia; Peripheral nerve and sensation: flaccid paralysis without anaesthesia (usually neuromuscular blockage)

26

Rat Intravenous 2.8 mg/kg.bw LD50 27 Rat parenteral 34mg/kg.bw LDLO. Lungs, thorax, or respiration:

other changes

28

Rabbit Skin 50 mg/kg.bw LD50. Respiratory depression; convulsions or effect on seizure threshold

29

Rabbit Intraperitoneal 14mg/kg.bw LD50 30

Rabbit Intramuscular 30mg/kg.bw LDLO. Behavioural: convulsions or effect on seizure threshold; ataxia; Peripheral nerve and sensation: flaccid paralysis without anaesthesia (usually neuromuscular blockage)

31

Rabbit Intravenous 6.25mg/kg.bw LD50 32

22 World Review of Pest Control. Vol. 9, Pg. 119, 1970. 23 Sine C (1993). Nicotine. In: Farm chemicals handbook '93, p. C245. 24 Farmakologiya i Toksikologiya Vol. 47(5), Pg. 85, 1984. 25 Journal of Pharmacology and Experimental Therapeutics. Vol. 124, Pg. 350, 1958. 26 Science. Vol. 127, Pg. 1054, 1958. 27 Drugs in Japan Vol. -, Pg. 916, 1995. 28 Journal of Pharmacology and Experimental Therapeutics. Vol. 48, Pg. 317, 1933. 29 Trochimowicz HJ, Kennedy GL Jr and Krivanek ND. Heterocyclic and miscellaneous nitrogen compounds. 1994. 30 Proceedings of the Society for Experimental Biology and Medicine. Vol. 58, Pg. 231, 1945. 31 Science. Vol. 127, Pg. 1054, 1958. 32 Proceedings of the Society for Experimental Biology and Medicine. Vol. 58, Pg. 231, 1945.


of 54

2.2 Major/relevant Human Toxicity data for Nicotine:

Type Dose Comments References

Effect on Human foetus

4 mg nicotine chewing gum

Gum increased significantly maternal heart rate, systolic and diastolic blood pressure. There was no influence on foetal heart rate or foetal blood flow.

33

Oral ingestion 5 gm of concentrated nicotine pesticide solution (concentration not specified)

17 year old smoker; committed and collapsed, pulseless. The patient was hospitalised and died 64 hr after ingestion

34

Dermal Nicotine patch Two patients developed vasculitis after 3 days use of nicotine patches. They recovered fully after these were stopped. On challenge, the symptoms reappeared confirming the casual link between nicotine patches use and development of vasculitis

35

Epidemiology study

Nicotine patch Meta-analysis/review. In total the study included data from 5501 patients using nicotine patches and 3752 patients receiving placebo. Several minor effects were elevated among nicotine patch users, these included sleep disturbances, nausea or vomiting, localised skin irritation and respiratory symptoms. However, the background rate and risk ratios varied widely among different studies

36

Case study Pure nicotine base

Splash of pure nicotine base in the eye caused severe pain, much conjunctival reaction & corneal infiltration. Eventually, eye healed with partial opacification of cornea.

37

33 Lindblad A, Marsal K; J Perinat Med 15 (1): 13-9 (1987) 34 Krieger, R. (ed.). Handbook of Pesticide Toxicology. Volume 1, 2nd ed. 2001. Academic Press, San Diego, California., p. 120 35 Van der Klauw MM et al; Br J Dermatol 134 (2): 361-4 (1996) 36 Greenland S et al; Drug Saf. 1998 Apr;18(4):297-308 37 Grant, W. M. Toxicology of the Eye. 2nd ed. Springfield, Illinois: Charles C. Thomas, 1974., p. 747


of 54

2.3 Carcinogenicity, Genotoxicity & Reproductive Toxicity

Nicotine can rapidly cross placenta and enter the foetus. In some reports, nicotine in

higher doses interfered with osteogenesis in mice and chick embryos. Chronic nicotine

treatments of pregnant rats throughout the gestation period produced subtle

neurological changes that exhibited as behavioural or electrophysiological alterations.

Although smoking (traditional cigarettes) is generally associated with impaired growth

and other congenital defects in a foetus, nicotine itself is not thought to be involved in

these processes38. Furthermore, literature reports indicate that nicotine is neither an

initiator nor a promoter of tumours in mice39. In the Ames and mammalian cell

cytogenic assays, nicotine did not exhibit any significant genotoxic activity. In one

report, nicotine has been shown to be teratogenic in mice treated cutaneously with a

dose of 25 mg/kg.bw27. Thus, nicotine – especially in the concentrations used in e-liquid

– may not exhibit any carcinogenicity, teratogenicity, genotoxicity or reproductive

toxicity.

2.4 Specific Risk Groups

Nicotine has been associated with a decrease in breathing movement if the mother is

exposed to nicotine in the last trimester. Nicotine also passes freely into the breast milk

but the concentrations would generally be clinically non-significant (average: 91 ppb in

one study). However, heavy smoking (20-30 cigarettes per day) may alter the supply of

milk and cause nausea and vomiting in the infant. Thus pregnant and breast feeding

women can be regarded as a specific risk group that needs to exercise caution when

using e-cigs.

38 US Department of Health and Human Services (1988). A Report of the Surgeon General, The Health consequences of smoking. Nicotine addiction. US Department of Health and Human Services, Public Health Service. Office of the Assistant Secretary for Health, on Smoking and Health 32-33: 601-602 39 PDR (1987) Physician's desk reference. 41st ed. Barnhart E. 1070-72


of 54

2.5 Eco-Toxicity Data

Model Dose Comments Reference

Xenopus laevis 136 mg/L for 96 hr; 100% purity

LC50. Conditions: freshwater, renewal, 23-24 oC, without metabolic activation system

40

Daphnia magna (age: <24 hr neonate)

0.035 mmol/L for 24 hr

EC50. Effect: intoxication, immobilization; Conditions: freshwater, static, 21 oC, pH 7.6.

41

Daphnia pulex (age: <24 hrs) 0.00857 mM for 24 hr

EC50. Effect: intoxication, immobilization; Conditions: freshwater, static, 20 oC;

42

Daphnia pulex Effective concentration: 0.242 mg/L. used >97% pure nicotine; liquid; for 48 hr.

EC50. Mobility test. Method according to ASTM E729-80 and US EPA 660/3-75-009. Conditions: static fresh water, 20 oC, pH=7.60 to 8.0, dissolved oxygen=60-100%, no aeration

43

Desmodesmus subspicatus Tested: 1.0; 3.2; 10; 32; and 100 mg/L. Liquid nicotine (pure form). For 72 hrs.

EC50. NOEC=3.2 mg/L; LOEC=10 mg/L; EC10=5.2mg/L; EC50=37mg/L (based on growth rate) & 11mg/L (based on Yield). Method according to EU Method C.3 (Algal Inhibition test) and OECD Guideline 201 (Alga, Growth Inhibition Test). Conditions: static fresh water, 22.6±1.0 oC, pH=8.3-8.4

32

Oncorhynchus mykiss (new or recent hatch)

5 mg/L for 60 days; >98% purity

LC50. Conditions: freshwater, flow through, 10-11 oC, pH 8.2, hardness 140 mg/L CaCO3, conductivity 260 μmhos/cm, dissolved oxygen 90% (70-100%).

44

Culex pipiens molestus (4 instar larvae)

0.938 mM for 24 hr; 100% purity

LC50. Conditions: freshwater, static, 18-20 oC

45

Dugesia dorotocephala (Turbellarian, flatworm, asexual, 15-18 mm)

(50,000-75,000) μg/L for 10 days

LC50. Conditions: freshwater, renewal

46

40 Dawson DA et al; Teratog Carcinog Mutagen 8 (6): 329-38 (1988) 41 Lilius H et al; Aquat Toxicol 30: 47-60 (1994) 42 Lilius H et al; Environ Toxicol Chem 14 (12): 2085-8 (1995) 43 Perry and Smith. Bull. Environ. Contam. Toxicol., 41, 604-608 (1998) 44 Passino-Reader DR et al; J Gt Lakes Res 21 (3): 373-83 (1995) 45 Corbet SA et al; Entomol Exp Appl 94 (3): 295-307 (2000) 46 Best JB, Morita M; Hydrobiologia 227: 375-83 (1991)


of 54

2.6 Environmental Fate

An estimated Koc value of 100, determined from a log Kow of 1.17 and a regression-

derived equation47, indicates that nicotine is expected to have high mobility in soil and

is not expected to adsorb to suspended solids and sediments. However, the pKb1 and

pKb2 values of 6.16 and 10.9648 indicate that this compound will exist - almost entirely -

in the cation form. The cations generally adsorb more strongly to soils containing

organic carbon and clay than their neutral counterparts49. Volatilization of nicotine from

moist soil surfaces and/or water is not expected to be an important fate process given

an estimated Henry's Law constant of 3.0x10-9 atm-cu m/mole, determined using a

fragment constant estimation method50. Similarly, nicotine is not expected to volatilize

from dry soil surfaces based upon a vapour pressure of 0.038 mm of Hg at 25 oC. If

released to air, a vapour pressure of 0.038 mm of Hg at 25 oC indicates nicotine will

exist solely as a vapour in the atmosphere. Vapour-phase nicotine will be degraded in

the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-

life for this reaction in air is estimated to be 4 hours. Nicotine does not contain

chromophores that absorb at wavelengths >290 nm and therefore is not expected to be

susceptible to direct photolysis by sunlight51. An estimated BCF score of 3 was

calculated in fish, using a log Kow of 1.17 and a regression-derived equation, which

suggests that the potential for bio-concentration in aquatic organisms is low. Lastly, it

has been experimentally determined ‒ using OECD Guideline 301 B ‒ that nicotine has

ready biodegradability under aerobic conditions; and the degradation at the end of 10-

day period was 72%.

2.7 Additional Hazards

No additional hazards to report.

47 Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9 (1990) 48 Tomlin C; The Pesticide Manual. 10th Ed, Surrey,UK: Crop Protection Pub, p. 735 (1994) 49 Doucette WJ; pp. 141-188 in Handbook of Property Estimation Methods for Chemicals. Boethling RS, Mackay D, eds. Boca Raton, FL: Lewis Publ (2000) 50 Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999) (7) Maeda S et al; Agric Biol Chem 42: 1455-60 (1978) 51 Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 8-12 (1990)


of 54

3. PROPYLENE GLYCOL

General Name Propylene Glycol IUPAC Name Propane-1,2-diol EC No 200-338-0 CAS No 57-55-6 Molecular Weight 76.09442 g/mol Molecular Formula C3H8O2 XLogP3 -0.9 Boiling Point 187.6 oC at atmospheric pressure52 Melting Point -60 oC at atmospheric pressure52 Flash Point 104 oC53 Auto Ignition 371 oC Vapour Density (air=1) 2.6 Vapour Pressure 0.13 mm Hg at 25 oC (Extrapolated) Log Kow -0.92 pH Unknown TWA (mg/m3) Not Established Harmonised Classification Index No Not classified Harmonised Classification Not classified Harmonised Labelling Not classified

52 Lide, D.R. CRC Handbook of Chemistry and Physics 88TH Edition 2007-2008. CRC Press, Taylor & Francis, Boca Raton, FL 2007, p. 3-444 53 Martin AE, Murphy FH; Glycols, Propylene Glycols. Kirk-Othmer Encyclopedia of Chemical Technology (1994). John Wiley & Sons, Inc. Online Posting Date: December 4, 2000


of 54

3.1 Animal Toxicity Data for Propylene Glycol


Rat Oral 22000mg/kg.bw LD50 54 Rat Subcutaneous 22500mg/kg.bw LD50 55 Rat Intraperitoneal 6660mg/kg.bw LD50 56 Rat Intramuscular 14000mg/kg.bw LD50 57 Rat Intravenous 6423mg/kg.bw LD50 58 Rabbit Skin 20800mg/kg.bw LD50 59

Rabbit Oral 18000mg/kg.bw LD50 60

Rabbit Intramuscular 6300mg/ml LDLo. Coma, respiratory stimulation, somnolence.

61

Rabbit Intravenous 3099mg/kg.bw LD50 62

3.2 Major Human Toxicity Data for Propylene Glycol


Patch testing Pads containing propylene glycol (100%) attached to forearm for 2 hr.

Observation duration: 7 days; n = 6 humans. No irritation of the skin observed/reported.

63

Patch testing Semi-occlusive or occlusive epicutaneous application. (Amount not specified; 100% purity)

n > 300 humans. The study demonstrates that it is not irritating to skin or eye and does not cause skin sensitisation by skin contact.

64

Topical (skin) Cream containing n = 204 humans. Conclusion: Not sensitising or 65

54 Organization for Economic Cooperation and Development; Screening Information Data Set for 1,2-Dihydroxypropane (57-55-6) p.6 (2001). 55 Interagency Collaborative Group on Environmental Carcinogenesis, National Cancer Institute, Memorandum, June 17, 1974Vol. 17JUN1974. 56 Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 3061. 57 Interagency Collaborative Group on Environmental Carcinogenesis, National Cancer Institute, Memorandum, June 17, 1974Vol. 17JUN1974. 58 Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 3061. 59 European Commission, ESIS; IUCLID Dataset, Propane-1,2-diol (57-55-6) p.45 60 Amdur, M.O., J. Doull, C.D. Klaasen (eds). Casarett and Doull's Toxicology. 4th ed. New York, NY: Pergamon Press, 1991., p. 705. 61 Journal of Pharmacology and Experimental Therapeutics. Vol. 44, Pg. 109, 1932. 62 European Commission, ESIS; IUCLID Dataset, Propane-1,2-diol (57-55-6) p.53 63 Organization for Economic Cooperation and Development; Screening Information Data Set for 1,2-Dihydroxypropane (57-55-6) p.56 (2001). 64 Organization for Economic Cooperation and Development; Screening Information Data Set for 1,2-Dihydroxypropane (57-55-6) p.17 (2001).


of 54

application 12% propylene glycol.

irritating to the skin.

Inhalation (mist)

Geometric mean of 309 mg/cu m (range 176-851 mg/cu m). Exposure for 1 minute

n = 27 humans, non-asthmatic. Exposed during realistic training conditions. The included an estimate of tear film stability break up time, nasal patency by acoustic rhinometry, dynamic spirometry, and a doctor's administered questionnaire on symptoms. Conclusion: short exposure to PG mist may cause acute ocular and upper airway irritation in non-asthmatic subjects. A few may also react with cough and slight airway obstruction.

66

Patch testing 100% Propylene glycol

N = 1556 humans. 194 subjects were observed with positive reactions with 4 patients identified as having “true allergy”. These patients were later tested with lower concentrations (3.2, 10 & 32%) of propylene glycol and only 9, 12 and 20 patients showed positive reactions respectively.

67

PC12 cells 0.2 to 20% v/v Concentrations above 1% produced significant increase in dopamine release.

68

Meta-analysis/review

--- Ocular exposure causes mild ocular irritation with hyperaemia. Gastrointestinal disturbances, nausea and vomiting have been observed after ingestion. (No dose specified).

69

Inhalation (smoke from theatrical fog generators)

Surveillance study conducted over 2 years on population frequently exposed to such glycol smoke

439 actors from 16 musicals were studied for irritant effects to the respiratory tract and eyes by employing a baseline questionnaire, daily checklists, and medical evaluation. No clinically significant adverse impact on pulmonary function or in rates of asthma associated with exposure to propylene glycol was noted. However, there was an increased reporting of respiratory, throat, and nasal symptoms, and vocal folds inflammation in cases of elevated localized air concentrations following release of glycol smoke. It was recommended that exposures to propylene glycol by actors not exceed peak or ceiling concentrations of 40 mg/cu m.

70

65 Organization for Economic Cooperation and Development; Screening Information Data Set for 1,2-Dihydroxypropane (57-55-6) p.60 (2001). 66 Wieslander G et al; Occup Environ Med 58 (10): 649-55 (2001) 67 Cosmetic Ingredient Review Expert Panel; J Am Coll Toxicol 13 (6): 437-91 (1994) 68 Hattori T et al; Res Commun Mol Pathol Pharmacol 107 (3-4): 323-9 (2000) 69 Poisons Information Monograph 443: Propylene glycol (May 1994). 70 DHHS/NTP-CERHR; NTP-CERHR Monograph on the Potential Human Reproductive and Developmental Effects of Propylene Glycol (March 2004) NIH Pub No. 04-4482 p.II-29 .


of 54


Propylene Glycol has been used in many consumer products worldwide for decades and

no cancer risk has been associated with exposure to propylene glycol. Many extensive

studies have been conducted in the laboratory – including lifetime studies – on a variety

of species and none reported an associated increase in tumour rates. There is a general

consensus that there is no cancer risk associated with exposure to propylene glycol and

this is in agreement with the American Chemistry Council’s report71.


Hyperosmolarity and lactic acidosis, both of which occur most frequently in

patients (specifically Infant and neonatal age) with consumption of large

quantities of propylene glycol. Symptoms were also observed on administration

of propylene glycol to children under age of 4, pregnant women, and patients

with hepatic or renal failure.72

Adverse effects from propylene glycol may occur in patients treated with

disulfiram or metronidazole.73

Propylene glycol is metabolized in the liver by the alcohol and aldehyde

dehydrogenase enzyme pathway, and the possibility exists that young infants,

patients with renal or hepatic impairment, and certain patient groups (females,

Asians, Native Alaskans, Native Americans) may be at increased risk of

propylene glycol-associated adverse effects if they receive amprenavir oral

solution because of diminished ability to metabolize propylene glycol (due to

alcohol dehydrogenase polymorphism). Estimated dose: ~1650

mg/kg.bw/day.74

In a patient with renal failure who was unable to excrete propylene glycol in the

urine, such retention caused severe central nervous system depression. In

addition, lactic acidosis was a prominent feature in this patient; with a large

anion gap and a lactic acid level of 80 mEq/l.75

Patients with impaired liver or kidney function would be at increased risk for

developing propylene glycol toxicity. In patients with renal insufficiency, high

propylene glycol levels have been associated with lactic acidosis

71http://msdssearch.dow.com/PublishedLiteratureDOWCOM/dh_0046/0901b80380046c80.pdf?filepath=propyleneglycol/pdfs/noreg/117-01656.pdf&fromPage=GetDoc 72 Rowe, R.C., Sheskey, P.J., Quinn, M.E.; (Eds.), Handbook of Pharmaceutical Excipients 6th edition Pharmaceutical Press, London, England 2009, p. 593. 73 Rowe, R.C., Sheskey, P.J., Quinn, M.E.; (Eds.), Handbook of Pharmaceutical Excipients 6th edition Pharmaceutical Press, London, England 2009, p. 593. 74 McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 2003. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2003 (Plus Supplements)., p. 626. 75 Haddad, L.M., Clinical Management of Poisoning and Drug Overdose. 2nd ed. Philadelphia, PA: W.B. Saunders Co., 1990., p. 700.


of 54

(hyperlactemia). Propylene glycol has been found in the blood of alcoholics with

cirrhosis of the liver without detectable measurable blood alcohol levels.76

3.5 Eco-toxicity Data for Propylene Glycol


Selenastrum capricornutum 19000 mg/l for 96 hr

EC50. 14 day growth rate 77

Daphnia magna (age 6-24hr) >10000 mg/l for 24, 48 hr

EC50. Conditions: fresh water, static, 20 oC, pH≥7.0

78

Skeletonema costatum ErC50=19300 mg/l for 72 hr. 5300, 12000, 25000, 51000 and 97000 mg/l.

ErC50. 14 day NOEC=<5300 mg/L. Method according to OECD Guideline 201. 14 day growth inhibition test. Conditions: static, saltwater (salinity 30ppm), 19.1-20.6 oC, pH=7.8-8.2.

79

Carassius auratus >5000 mg/l for 24 hr

LC50. Conditions: static 80

Cyprinodon variegatus 48000 ppm for 96 hr

LC50. 81

Daphnia magna 43500 mg/l for 48 hr


Mysidopsis bahia 18800 mg/l for 96 hr


Oncorhynchus mykiss 51600 mg/l for 96 hr


Oryzias latipes >1000 mg/l for 24 & 48 hr

LC50. Conditions: freshwater, static, 10, 20, 30 oC

85

Pimephales promelas (age: ≤7 days)

29485-39339 mg/L for 96 hrs

LC50. Conditions: freshwater, renewal, 20 oC

86

76 Monograph on the Potential Human Reproductive and Developmental Effects of Propylene Glycol (March 2004) NIH Pub No. 04-4482 p.II-44. 77 Organization for Economic Cooperation and Development; Screening Information Data Set for 1,2-Dihydroxypropane (57-55-6) p.6 (2001). 78 Kuhn R et al; Water Res 23 (4): 495-9 (1989) as cited in the ECOTOX database. 79 Organization for Economic Cooperation and Development; Screening Information Data Set for 1,2-Dihydroxypropane (57-55-6) p.6 (2001). 80 European Commission, ESIS; IUCLID Dataset, Propane-1,2-diol (57-55-6) p.36 (2000 CD-ROM edition). 81 USEPA/Office of Pesticide Programs; Reregistration Eligibility Decision Document - Propylene glycol and Dipropylene glycol p.13 EPA-739-R-06-002 (September 2006). 82 Organization for Economic Cooperation and Development; Screening Information Data Set for 1,2-Dihydroxypropane (57-55-6) p.5 (2001). 83 Organization for Economic Cooperation and Development; Screening Information Data Set for 1,2-Dihydroxypropane (57-55-6) p.6 (2001). 84 Organization for Economic Cooperation and Development; Screening Information Data Set for 1,2-Dihydroxypropane (57-55-6) p.5 (2001). 85 Tsuji S et al; J Hyg Chem (Eisei Kagaku) 32 (1): 46-53 (1986) as cited in the ECOTOX database. 86 Cornell JS et al; Environ Toxicol Chem 19 (6): 1465-72 (2000) as cited in the ECOTOX database.


of 54


Propylene glycol does not contain chromophores that absorb at wavelengths

>290 nm and therefore is not expected to be susceptible to direct photolysis by

sunlight.

If released to soil, propylene glycol is expected to have very high mobility based

on an estimated Koc of 1, determined from a log Kow of -0.92 and a regression-

derived equation.87

If released into water, propylene glycol is not expected to adsorb to suspended

solids and sediment based on the estimated Koc of 1.

Volatilization from moist soil or water surfaces is not expected to be an

important fate process based on an estimated Henry's Law constant of 1.3x10-8

atm-cu m/mole, derived from its vapour pressure of 0.13 mm of Hg, and

assigned value for water solubility of 1x106 mg/L (miscible).88

Vapour-phase propylene glycol is degraded in the atmosphere by reaction with

photochemically-produced hydroxyl radicals; the half-life for this reaction in air

is estimated to be 32 hours, calculated from its rate constant of 1.2x10-11 cu

cm/molecule-sec at 25 oC89

Propylene glycol was mineralized (73-78%) in laboratory studies conducted

using an agricultural soil over a 51 day incubation period, suggesting

biodegradation will be an important environmental fate process in soil.

An estimated BCF of 3, calculated from log Kow of -0.92 and a regression-derived

equation, suggests the potential for bio concentration in aquatic organisms is

low.


None to report

87 Estimation Program Interface (EPI) Suite. Ver. 4.11. Nov, 2012. 88 Yalkowsky SH, He Y; Handbook of Aqueous Solubility Data: An Extensive Compilation of Aqueous Solubility Data for Organic Compounds Extracted from the AQUASOL dATAbASE. Boca Raton, FL: CRC Press LLC, (2003). 89 Atkinson R; J Phys Chem Ref Data Monograph 1 (1989) (4) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 8-12 (1990).


of 54

4. GLYCEROL (VEGETABLE GLYCERINE)

General Name Glycerol (Glycerine/Glycerin)

IUPAC Name propane-1,2,3-triol

EC No 200-289-5

CAS No 56-81-5

Molecular Weight 92.09382 g/mol

Molecular Formula C3H8O3

XLogP3 -1.8

Boiling Point 290 oC at atmospheric pressure (decomposes)90

Melting Point 18.1 oC at atmospheric pressure91

Flash Point 177 oC (open cup)92

Auto Ignition 393 oC 93

Vapour Density (air=1) 3.1794

Vapour Pressure 1.68x10-4 mm Hg at 25 oC95

Log Kow -1.7696

pH Neutral to litmus test97

TWA (mg/m3) 5 mg/m3 (respirable fraction) & 15 mg/m3 (total dust)

Harmonised Classification Index No Not classified

Harmonised Classification Not classified

Harmonised Labelling Not classified

90 O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 774. 91 Lide, D.R. CRC Handbook of Chemistry and Physics 88TH Edition 2007-2008. CRC Press, Taylor & Francis, Boca Raton, FL 2007, p. 3-268. 92 International Labour Office. Encyclopedia of Occupational Health and Safety. Vols. I&II. Geneva, Switzerland: International Labour Office, 1983., p. 971. 93 Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993, p. 566 94 Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984., p. 1479. 95 Daubert, T.E., R.P. Danner. Physical and Thermodynamic Properties of Pure Chemicals Data Compilation. Washington, D.C.: Taylor and Francis, 1989.. 96 Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. Washington, DC: American Chemical Society., 1995., p. 7. 97 O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 774.


of 54

4.1 Animal Toxicity Data for Glycerol


Rat Oral 12.6 gm/kg.bw LD50. Behavioural: general anaesthetic, muscle weakness. Liver: other changes

98

Rat Subcutaneous 0.1 gm/kg.bw LD50 99 Rat Intraperitoneal 4.42 gm/kg.bw LD50. Cardiac: Other changes;

behavioural: toxic psychosis; kidney, ureter, & bladder: other changes

100

Rat Intravenous 5.57 gm/kg.bw LD50 101 Rat Inhalation >570 mg/cu m/1

hr LC50 102

Rat (Sprague-Dawley-derived (Cr1:CD))

Inhalation Mean aerosol concentrations of 0, 1.93, 3.91 or 7.0 mg glycerol/L of filtered room air for 6 hr/day for 2 weeks. AND, 0.033, 0.167, or 0.662 mg glycerol/L of filtered room air for 6 hr/day for 13 weeks.

Nose only inhalation. For 2 weeks (n=10 rats), all three concentrations of glycerol exhibited minimal to mild squamous metaplasia of the epithelium lining the base of the epiglottis. For 13 weeks (n=75 rats), results were same as those for 2 week exposure period

103

Mouse Oral 4.1 gm/kg.bw LD50 104 Mouse Subcutaneous 0.091 gm/kg.bw LD50 105 Mouse Intraperitoneal 8.70 gm/kg.bw LD50. Behavioural: altered

sleep time (including change in righting reflex)

106

Mouse Intravenous 4.25 gm.kg.bw LD50 107 Rabbit Skin >10 gm/kg.bw LD50 108 Rabbit Oral 27 gm/kg.bw LD50 109 Guinea Pig Oral 7.75 gm/kg.bw LD50 110

98 Federation Proceedings, Federation of American Societies for Experimental Biology. Vol. 4, Pg. 142, 1945. 99 Drugs in Japan Vol. 6, Pg. 215, 1982. 100 Research Communications in Chemical Pathology and Pharmacology. Vol. 56, Pg. 125, 1987. 101 Arzneimittel-Forschung. Drug Research. Vol. 26, Pg. 1581, 1976. 102 BIOFAX Industrial Bio-Test Laboratories, Inc., Data Sheets. Vol. 9-4/1970. 103 Renne et al., 2-week and 13-week inhalation studies of aerosolized glycerol in rats. Inhalation Toxicology: International Forum for Respiratory Research, Vol. 4, 2, 1992. 104 Farmatsevtichnii Zhurnal Vol. (6), Pg. 56, 1977. 105 Drugs in Japan Vol. 6, Pg. 215, 1982. 106 Arzneimittel-Forschung. Drug Research. Vol. 28, Pg. 1579, 1978. 107 Journal of the American Pharmaceutical Association, Scientific Edition. Vol. 39, Pg. 583, 1950. 108 BIOFAX Industrial Bio-Test Laboratories, Inc., Data Sheets. Vol. 9-4/1970. 109 Delaware State Medical Journal. Vol. 31, Pg. 276, 1959.


of 54

4.2 Major Human Toxicity Data for Glycerol


Oral 1.428 gm/kg.bw Behavioural: headache. Gastrointestinal: nausea or vomiting

111

Fertility (sperm quality)

64 male employees of glycerol manufacturer

No significant differences were observed between the test and control (63 workers) groups indicating that glycerol may not cause decrease sperm quality

112

Closed skin patch test

0.05 ml or 10% solution for 21 consecutive days.

Slightly irritating in case of 0.05ml/closed patch test. Furthermore, the participants assigned a maximum irritation score of 4 (on a scale of 9) at 14th day during the 21 days test period.

Oral Acute or chronic (42 days). Exact concentration/quantity not specified

Increased serum glyceride concentration was observed with males showing significantly higher increase

Oral 30ml of 95% glycerol (mixed with orange juice)

14 volunteers (10 men, 4 women). No obvious signs of toxicity or effect on food consumption.

Eye exposure (drops)

100% glycerol Specular microscopy showed extensive changes in the appearance of the endothelium most of which disappeared within 90 minutes after the exposure ended.

Oral Average daily intake of 24 gm/kg.bw per day, for 50 days

10 men & 4 women. No toxic effects reported with a slight tendency towards an increase in body weight.

113


Glycerol has been tested for its carcinogenic or genotoxicity effects in few studies and

no studies have reported a link between glycerol exposure and carcinogenicity. A

standard mutation test, Ames test, showed no induced mutations in the bacteria (with

or without metabolic activation). In other tests that involved mammalian cell gene

mutation test and chromosomal aberration tests (using Chinese hamster ovary and rat

bone marrow), glycerol did not induce any statistically significant mutation of

chromosomal aberrations and these incidences were not concentration dependent

110 Journal of Industrial Hygiene and Toxicology. Vol. 23, Pg. 259, 1941. 111 "Toxicology of Drugs and Chemicals," Deichmann, W.B., New York, Academic Press, Inc., 1969Vol. -, Pg. 288, 1969. 112 European Chemicals Bureau; IUCLID Dataset, Glycerol (56-81-5) (2000 CD-ROM edition). 113 WHO/FAO: Expert Committee on Food Additives. Summary of Toxicological Data of Certain Food Additives Series 48: Aliphatic acyclic diols, triols, and related substances (56-81-5) (2002).


of 54

indicating that the results are of no biological relevance114. Thus glycerol is not

considered to induce any carcinogenicity, genotoxicity or reproductive toxicity.


Chances of dehydration are increased in patients with geriatric, senile, or

already dehydrated patients115.

Moreover, caution needs to be exercised when geriatric patients are given

glycerol as these patients may have age-related renal function impairment116.

However, no such relationship of age to the adverse effects of glycerol has been

established.

When metabolised, glycerol may cause slight hyperglycaemia and glycosuria and

thus caution must be observed during oral administration in diabetic

patients117.

Risk-benefit should be considered when Glycerol is administered to patients

with severe dehydration, cardiac, renal or hepatic disease, since shift in body

water may aggravate these conditions and may lead to pulmonary oedema

and/or congestive heart failure104, 105.

No specific, age-related effects of glycerol are expected in paediatric population.

114 United Nations Environment Programme: Screening Information Data Sheets on Glycerol (56-81-5) (March 2002) Available from, as of July 14, 2009. 115 McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993)., p. 1774. 116 US Pharmacopeial Convention; US Pharmacopeia Dispensing Information (USP DI); Drug Information for the Health Care Professional 12th ed, V.I p.1456 (1992). 117 McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993)., p. 1774.


of 54

4.5 Eco-toxicity Data for Glycerol


Microcystis aeruginosa 2900 mg/l Toxicity threshold (cell multiplication inhibition test)

118

Entosiphon sulcatum 3200 mg/l Toxicity threshold (cell multiplication inhibition test)

Carassius auratus >5000 mg/L for 24 hr

LC50

Daphnia magna >10000 mg/L for 24 hr

LC50. Conditions: freshwater, static, 20-22 deg C

119

Scenedesmus quadricauda EC3 (3% effective concentration) = >10,000 mg/L (for 8 days)

Conditions: Static, freshwater, pH=7.0 before adding test material.

120


Glycerol does not contain chromophores that absorb (sun) light at wavelengths

>290 nm and therefore it is not expected to be susceptible to direct photolysis by

sunlight121.

If released to soil, glycerol is expected to have very high mobility based upon an

estimated Koc of 1, determined from a structure estimation method122.

If released into water, glycerol is not expected to adsorb to suspended solids and

sediment based upon the estimated Koc of 1.

Volatilization from moist soil or water surfaces is not expected to be an

important fate process based upon an estimated Henry's Law constant of 1.7x10-

8 atm-cu m/mole123.

According to a model of gas/particle partitioning of semi-volatile organic

compounds in the atmosphere124, glycerol is expected to exist in both, vapour

and particulate, phases given that it has vapour pressure of 1.68x10-4 mm Hg at

25 oC125.

118 Verschueren, K. Handbook of Environmental Data of Organic Chemicals. 2nd ed. New York, NY: Van Nostrand Reinhold Co., 1983., p. 695. 119 Bringmann G, Kuhn R; Z Wasser-Abwasser-Forsch 10 (5): 161-1 (1977) as cited in the ECOTOX database. Available from, as of July 7, 2011. 120 Bringmann and Kuehn. Mitt. Internat. Verein. Limnol. 21: 275-284 (1980) 121 Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 8-12 (1990). 122 Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (3) Hine J, Mookerjee PK; J Org Chem 40: 292-8 (1975). 123 Hine J, Mookerjee PK; J Org Chem 40: 292-8 (1975). 124 Bidleman TF; Environ Sci Technol 22: 361-367 (1988). 125 Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals Data Compilation. Washington, DC: Taylor and Francis (1989).


of 54

Vapour-phase glycerol is degraded in the atmosphere by reaction with

photochemically-produced hydroxyl radicals; the half-life for this reaction in air

is estimated to be 7 hours, calculated from its rate constant of 1.9x10-11 cu

cm/molecule-sec at 25 oC126.

Glycerol, present at 100 mg/L, reached 63% of its theoretical BOD in 2 weeks

using an activated sludge inoculum at 30 mg/L in the Japanese MITI test127.

Aerobic biodegradation rate constants of 0.258/day and 0.200/day in

respirometric test systems employing activated sludge have also been reported,

corresponding to 68% and 78% degradation, respectively128. This suggests that

biodegradation is an important and major fate of glycerol in the environment.

An estimated BCF of 3, calculated from log Kow of -1.76129 and a regression-

derived equation130, suggests the potential for bio concentration in aquatic

organisms is low.


None to report

126 Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993). 127 NITE; Chemical Risk Information Platform (CHRIP). Biodegradation and Bioconcentration. Tokyo, Japan: Natl Inst Tech Eval. 128 Reuschenbach P et al; Water Res 37: 1571-1582 (2003). 129 Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. 7 (1995). 130 US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Jan, 2010.


of 54

PART B: CLP CLASSIFICATION OF PRODUCTS

5. 7.2% (W/V) NICOTINE IN PROPYLENE GLYCOL

5.1 Physical Hazards

From all the available physical information, the mixtures under classification do not

pose any physical hazards and does not require classification (or cannot be classified)

under this category. The only important and relevant note is that the given nicotine

mixtures are believed to be combustible and thus care should be taken to avoid

exposure to open flames.

5.2 Health Hazard Classification

According to CLP regulations (EC No 1272/2008), if the data is not available on the

mixture itself or on similar mixtures, then the hazard in this category can be calculated

from the summation formula as given in the Annex I: 3.1.3.6.1 of CLP regulation (EC

1272/2008), provided the toxicity values are available for all the ingredients.

The Acute Toxicity Estimate (ATE) of the mixture is determined by calculation from the ATE values (or LD50) for all relevant ingredients according to the following formula for Oral, Dermal or Inhalation Toxicity:

100

ATE𝑚𝑖𝑥= ∑

C𝑖

ATE𝑖𝑛

............. Equation 1 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.

In order to apply this to the 7.2% (w/v) nicotine mixtures, the w/v percentage will first

need to be converted to w/w percentage and most appropriate acute animal toxicity

doses need to be selected for solving the summation equation.

𝑤

𝑤% =

𝑎𝑚𝑜𝑢𝑛𝑡 𝑜𝑓 𝑠𝑢𝑏𝑠𝑡𝑎𝑛𝑐𝑒 𝑖𝑛 𝑔𝑚 𝑝𝑒𝑟 𝑚𝑙

𝑆𝑝𝑒𝑐𝑖𝑓𝑖𝑐 𝑔𝑟𝑎𝑣𝑖𝑡𝑦 × 100

...............Equation 2

Given that the specific gravity of the mixture/solution is 1.038 (determined

experimentally) and substituting all the values in equation 2 we get,

𝑤

𝑤% =

7.2 × 10−2𝑔𝑚

1.038 × 100 = 6.94%


of 54

Therefore, 7.2% (w/v) nicotine in propylene glycol is equivalent to 6.94% (w/w)

nicotine in propylene glycol solution. Similarly, 7.2% (w/v) nicotine in glycerol is

equivalent to 6.01% (w/w) nicotine in glycerol as the specific gravity for this solution is

1.198 (determined experimentally; calculations not shown).

Furthermore, the CLP regulations states that “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”. Also, if more than one reliable toxicity

end points are available, a conservative approach should be used in selecting the ATE

values. The list of selected values for calculation is given below in the Table 5.1.

Table 5.1: Selected ATE for health hazard calculations

Chemical Oral (LD50; Rat) Dermal (LD50; Rabbit)

Inhalation (LC50; Rat)

Nicotine 50 mg/kg.bw 50 mg/kg.bw Not available Propylene Glycol 22,000 mg/kg.bw 20,800 mg/kg.bw Not available Glycerol 12,600 mg/kg.bw >10,000 mg/kg.bw No reliable data

available. The LD50 values for Propylene glycol and Glycerol will be ignored during the calculation (i.e. solving ............. Equation 1) as these values are above 2,000 mg/kg.bw.

Acute Oral Toxicity

Solving ............. Equation 1 we get,

100


C𝑖

ATE𝑖𝑛

100 (%𝑤𝑤)

ATE𝑚𝑖𝑥=

6.94 (%𝑤𝑤)

50 (𝑚𝑔

𝑘𝑔. 𝑏𝑤)

ATE𝑚𝑖𝑥 = 50 × 100

6.94= 720.46

𝑚𝑔

𝑘𝑔. 𝑏𝑤

Thus, the estimated ATE for 7.2% (w/v) nicotine in Propylene glycol or glycerol is

720.46 mg/kg.bw, which indicates that the given mixture is classified into category 4 for

this toxicity category, based on Table 3.1.1 of CLP regulation (see Appendix A).

Similarly, calculations can be done - by using values given in table 1 and solving

equation 1 – for 7.2% nicotine in Glycerol which would classify the mixture in category

4 for oral toxicity since the derived ATE value is 831.95 mg/kg.bw.


of 54

Acute Dermal Toxicity

Solving ............. Equation 1 for 7.2% (w/v) nicotine in glycerol we get,

100


C𝑖

ATE𝑖𝑛

100 (%𝑤𝑤)

ATE𝑚𝑖𝑥=

6.01 (%𝑤𝑤)

50 (𝑚𝑔

𝑘𝑔. 𝑏𝑤)

ATE𝑚𝑖𝑥 = 50 × 100

6.01= 831.95

𝑚𝑔

𝑘𝑔. 𝑏𝑤

Thus, the derived ATE value for acute dermal toxicity of 7.2% (w/v) nicotine in glycerol

is 831.95 mg/kg.bw. Similarly, the derived ATE value for 7.2% (w/v) nicotine in

propylene glycol would be 720.46 mg/kg.bw. These derived ATE values place both the

products in category 3 for dermal toxicity (see table 3.1.3 of CLP regulation).

Acute Inhalation Toxicity

Classification under this toxicity category is not possible due to lack of sufficient and

reliable evidence.

5.3 Environmental Hazards

For environmental hazards, the assessment of a mixture – which itself hasn’t been

tested for environmental toxicity - can be based on ‘bridging principles’ or ‘summation

method’. Since there are no environmental data available on similar mixtures, bridging

principles are not applicable (according to Annex I, 4.1.3.4 of CLP regulation) and the

summation method should be used (Annex I, 4.1.3.5 of CLP regulation). Furthermore,

since nicotine (pure form) is classified under EU harmonised system for its aquatic

toxicity (Chronic category 2), the additivity formula given in Annex I, 4.1.3.5.2 cannot be

used and summation method given in Annex I, 4.1.3.5.5 of CLP regulations can be

directly applied in this case. In the mixtures under classification, the propylene glycol

and glycerol are considered as not having any substantial acute or chronic aquatic

toxicity (as evident from ATE values in Table 5.2; calculations not shown) and thus

these components are ignored while employing the summation method.


of 54

Table 5.2: Selected ATE for Environmental calculations

Chemical ErC50 (acute) NOEC

Dose Model Dose Model

Nicotine 37 mg/L Desmodesmus subspicatus (algae); 72 hrs

3.2 mg/L Desmodesmus subspicatus (algae); 72 hrs

Propylene Glycol

19300 mg/L Skeletonema costatum (algae); 72 hrs

≤5300 mg/L Skeletonema costatum (algae); 72 hrs

Glycerol 2900 mg/L Microcystis aeruginosa (Cyanobacteria); not specified

EC3 = ~10,000 mg/L

Scenedesmus quadricauda (algae); 8 days

Acute Aquatic Toxicity

Nicotine is neither classified as having an acute aquatic toxicity under harmonised

classification nor does the aquatic toxicity data suggest that nicotine has a potential of

acute aquatic toxicity. Moreover, nicotine is determined to be rapidly degraded in the

environment and has very low potential for bioaccumulation (Kow=1.17; >70%

degradation in 28 days; however, NOEC is ≥1 mg/mL and therefore chronic

implications) further supporting the notion that nicotine may not pose any significant

acute toxicity threat to the aquatic ecosystem. Thus the mixtures under consideration

are not classified under this toxicity category.

Chronic Aquatic Toxicity

Pure nicotine is classified as having chronic aquatic toxicity category 2 under

harmonised classification and labelling of hazardous substances (Annex VI, table 3.1 of

regulation (EC) No 1272/2008); and this is a legally binding classification – for this

particular toxicity category – to all the manufacturers, importers and all downstream

users (see clause 17 of the introductory notes of CLP regulation). Using this

classification and applying summation method given in Annex I, 4.1.3.5.5 and table 4.1.2

(see Appendix A) we get following classification:


of 54

Mixture Percentage of components from chronic category 2

Multiplication factor

Adjusted sum of all toxic components with aquatic toxicity

Results for classification

7.2% (w/v) nicotine propylene glycol

6.93% (w/w) None 6.93% Cannot classify under category 2 as the sum is <25%.

10 69.3% Chronic aquatic category 3.

7.2% (w/v) nicotine Glycerol

6.01% (w/w) None 6.01% Cannot classify under category 2 as the sum is <25%.

10 60.1% Chronic aquatic toxicity 3

Please note, no M factors (within the definition of CLP regulations) are applicable as

none of the components are classified as acute or chronic aquatic toxicity category 1.

5.4 Conclusion

Thus, based on the assessment presented here, 7.2% (w/v) nicotine in propylene glycol

and/or in glycerol is classified as category 4 for oral toxicity, category 3 for dermal

toxicity and category 3 for chronic aquatic toxicity. Similarly, assessment can be done

for any other concentration of nicotine solution and a summary is provided in the

section 6 of this documents. However, no assessment or calculations are shown for this

to keep this document concise.


of 54

6. SUMMARY TABLES FOR CLP CLASSIFICATION OF NICOTINE

SOLUTIONS.

As shown in the previous sections, nicotine is classified in three distinct hazard classes

(oral, dermal and aquatic) and the categorisation into these hazard classes depend on

the nicotine concentration in the mixture that is required to be classified. The three

tables presented in this section allow step-wise selection of appropriate toxicity

categories and labelling information for nicotine containing solutions. Full list of

relevant hazard pictograms and statements are included in the appendix B of this

document. Based on the nicotine concentration in the mixture, appropriate

classification categories should be selected from all three tables (one category from

each table) and care should be taken to ensure:

a) Correct nicotine percentage is selected and whether the given concentration is in

weight/volume or weight/weight

b) Except nicotine, propylene glycol, and glycerol, no other components in the

mixture should be classified into a toxicity category that is higher than that of

nicotine (at concentrations present in the mixture to be classified) and should

not increase the overall toxicity of the mixture under any toxicity category. If this

is the case then the information given in the tables may not be sufficient for

appropriate CLP classification and the classification of such mixtures needs to be

re-evaluated as per CLP regulations (EC No 1272/2008).

c) Inclusions of all hazard statements on the product label are mandatory unless

there is evident duplication or redundancy.

d) All significant/appropriate precautionary statements should also be included

(usually no more than six), unless there is evident duplication or redundancy.

Where the substance or mixture is supplied to the general public, one

precautionary statement addressing the disposal of that substance or mixture as

well as the disposal of packaging shall appear on the label, unless not required

under Article 22 (for legal text, see Article 22 & 28 of CLP regulation).

a) Redundancy or precedence principle is also applicable to the signal word and

hazard pictogram such that where the signal word ‘Danger’ is used, the signal

word ‘Warning’ shall not appear on the label; similarly when ‘GHS06’ is used,

‘GHS07’ should not be included on the label (see Article 26(1)(b) of CLP

regulation).

Lastly, following specific risk groups have been identified during the classification

process. These are the groups of people that need to exercise caution while using e-

cigarette devices. These specific risk groups can be included as additional information in

the product information booklet and should NOT be included in the labels of products

that are classified under CLP.

For nicotine containing mixtures: Pregnant and breast feeding women


of 54

For propylene glycol containing mixtures: Children under the age of 4, pregnant

women, patients with hepatic or renal failure, and patients treated with

disulfiram or metronidazole.

For glycerol containing mixtures: Diabetic patients; geriatric, senile, or already

dehydrated patients.


of 54

Table 6.1 Oral toxicity classification of nicotine containing solutions

Nicotine in Propylene Glycol Nicotine in Glycerol Hazard Class and Category

Labelling

w/v % w/w % (considering specific gravity of 1.038)


Pictogram code & Signal word

Hazard statement codes (Mandatory)

Relevant Precautionary statement codes

χ ≥ 17.3% χ ≥ 16.7% χ ≥ 20% χ ≥ 16.7% Acute Oral 3

GHS06; Danger

H301 P270

P264

P301+P310

P102†

P405

P501

2.6% ≤ χ <17.3% 2.5% ≤ χ <16.7% 3.0% ≤ χ <20% 2.5% ≤ χ <16.7% Acute Oral 4

GHS07; Warning

H302 P270 P264

P301+P312

P102†

P501

χ < 2.6% χ < 2.5% χ < 3.0% χ < 2.5% NOT CLASSIFIED P102†

† Please note that although P102 statement is not required to be included as part of the CLP classification of these mixtures, it is

advisable to include this ‘P’ statement to reduce the risk of child poisoning by e-liquid. This is considering the fact that recently few news

reports of child poisoning – and even death in one of the cases – have surfaced that were related to ingestion of nicotine containing e-

liquids.

χ Represents Nicotine concentration in the mixture that needs to be classified according to CLP regulations.


of 54

Table 6.2 Dermal (skin) toxicity classification of nicotine containing solutions


Labelling w/v % w/w %

(considering specific gravity of 1.038)





χ = 100% (pure form)

---- χ = 100% (Pure form)

--- Acute Dermal 1

GHS06; Danger

H310 P262

P280

P302+P352

P310

P361

P363

P405

26% ≤ χ < 100% χ ≥ 25%

30% ≤ χ < 100% χ ≥ 25% Acute Dermal 2

GHS06; Danger

H310 Same as that of acute dermal 1

5.2% ≤ χ < 26% 5% ≤ χ <25% 6% ≤ χ < 30% 5% ≤ χ < 25% Acute Dermal 3

GHS06; Danger

H311 P280

P302+P352

P312

P361

P363

P405

2.6% ≤ χ < 5.2% 2.5% ≤ χ <5% 3% ≤ χ < 6% 2.5% ≤ χ < 5% Acute Dermal 4

GHS07; Warning

H312 P280

P302+P352

P312

χ < 2.6% χ < 2.5% χ < 3.0% χ < 2.5% NOT CLASSIFIED



of 54

Table 6.3 Aquatic toxicity classification of nicotine containing solutions


Labelling






χ ≥ 26% χ ≥ 25%

χ ≥ 30% χ ≥ 25% Chronic Aquatic 2

GHS09; No signal word is used

H411 P273

P391

P501

2.6% ≤ χ < 26% 2.5% ≤ χ < 25% 3% ≤ χ < 30% 2.5% ≤ χ < 25% Chronic Aquatic 3

No pictogram or signal words are used

H412 P273

P501

χ < 2.6% χ < 2.5% χ < 3.0% χ < 2.5% NOT CLASSIFIED



of 54

Table 6.4 Product identifier information in accordance with Article 18 of CLP regulations (see Appendix ??? for further details)

Product constituent Name Nicotine Propylene Glycol Vegetable Glycerol

IUPAC NAME 3-(N-methyl-2-

pyrrolidinyl)pyridine

Propane-1,2-diol Propane-1,2,3-triol

Other names Nicotine Propylene Glycol Glycerol; Glycerin; Glycerine; Vegetable Glycerine (only if extracted from vegetable sources)

Index no (Part 3 of Annex VI of CLP regulation)

614-001-00-4 Not Applicable Not Applicable

CAS number 54-11-5 57-55-6 56-81-5

EC number 200-193-3 200-338-0 200-289-5

7. TRANSPORT LABELS

Although CLP regulation is used for assessing and classifying the products and require

labelling according to the relevant provisions, they may also need to carry “Transport

labels” (on the outer packaging) if they are classified as “dangerous goods” according to

the rules on the transport of dangerous goods (ADR 2015 and Directive 2008/68/EC).

For legal text in CLP regulation where it specifies that the transport regulations (ADR,

2015) also apply to the products – independent of the CLP regulation – please see

Article 1(6) and Article 33 of the CLP regulation ((EC) No 1272/2008; also see appendix

B of this document). The interpretations and conclusions of these articles are presented

in a decision flow chart in Figure 8.1 of this document.

7.1 Hazard class of nicotine solutions for transport purposes

Based on chapter 2.1 of the ADR-2015 regulations, goods are categorised into nine

distinct classes of which the nicotine containing solutions will only be classified under

‘class 6.1-toxic substances’ and all the other classes do not apply to these nicotine

containing products (based on physical properties, literature and chapter 2 of ADR-

2015; discussion not provided). Moreover, similar to CLP classification, nicotine is

included in the ‘Dangerous goods list’ of Table A of chapter 3.2 of ADR-2015 which

defines all the major packing parameters for nicotine or related mixtures (see page 271-

276, 358 of ADR 2015).

Based on the 2.2.61.1.10 of ADR-2015, the LD50 (for oral as well as dermal toxicity) of

the nicotine solutions under considerations can be determined using the formula:

2.2.61.1.10.1

𝐿𝐷50 value of the preparation =𝐿𝐷50 𝑣𝑎𝑙𝑢𝑒 𝑜𝑓 𝑡ℎ𝑒 𝑎𝑐𝑡𝑖𝑣𝑒 𝑠𝑢𝑏𝑠𝑡𝑎𝑛𝑐𝑒

𝑃𝑒𝑟𝑐𝑒𝑛𝑡𝑎𝑔𝑒 𝑜𝑓 𝑎𝑐𝑡𝑖𝑣𝑒 𝑠𝑢𝑏𝑠𝑡𝑎𝑛𝑐𝑒 𝑏𝑦 𝑚𝑎𝑠𝑠× 100

……Equation 3

For 7.2% (w/v) nicotine in propylene glycol, substituting the values given in table 5.1 of

this document in equation 3 we get,

𝐿𝐷50 value of the preparation =50

𝑚𝑔𝑘𝑔

. 𝑏𝑤

6.94 (% 𝑤/𝑤)× 100

𝐿𝐷50 value of the preparation = 720.46mg

kg. bw


of 54

Thus, the estimated or computed LD50 value for 7.2% (w/v) nicotine in Propylene glycol

is 720.46 mg/kg.bw. Similarly, the LD50 value for 7.2% (w/v) nicotine in Glycerol can be

calculated and the resulting LD50 value would be 831.95 mg/kg.bw. Using the ‘packaging

group’ classification table given in section 2.2.61.1.7 of the ADR-2015 and the computed

LD50, we get no classification for the oral toxicity and packing group III (slightly toxic)

for dermal classification for both types of nicotine solutions/preparations. Calculations

can be done for any given concentration of the nicotine and the resulting LD50 values

can be used to determine the packing group based on the table given in 2.2.61.1.7 of the

ADR-2015. These calculations are omitted in this document to keep it concise. The

summary of the implications of the transport label requirements are given in the

following section.


of 54

7.2 Do you require a transport label?

Based on the calculations by Xyfil Ltd (undertaken by the author) and the ADR-2015

regulations, it is concluded that any nicotine preparation (liquid form) that has nicotine

percentage weight greater than or equal to 5% (w/w) would be required to carry an

appropriate transport labels, unless derogations of limited or excepted quantity applies

(discussed later). This 5% (w/w) is equivalent to 5.2% (w/v) of nicotine in propylene

glycol and 6% (w/v) of nicotine in Glycerol/glycerine. All the nicotine solutions (in PG

or VG) that require transport labels are classified as following:

UN No: 3144

Name and description (aka proper shipping name)

NICOTINE PREPARATION, LIQUID, N.O.S.

Toxicity class 6.1

Classification code T1 (organic liquid without subsidiary risk(s))

Packing group II – for w/w solutions containing nicotine ≥25% III – for w/w solutions containing nicotine ≥5% but less than 25%. Note: For nicotine solutions (w/w) that has nicotine concentration of less than 5%, no transport labels are required as it does not fall under the scope of ADR-2015 regulations based on the evaluation of their LD50 values.

Labels 6.1 And Orientation arrows (see appendix B of this document) Unless shipping in limited or excepted quantities in which case their labels should be included.

Limit for exemption under ‘Limited quantities’ derogations

Maximum 100 ml per outer packaging Note: Packages qualifying for limited quantities need to be labelled with ‘Figure 3.4.7.1’ or ‘Figure 3.4.8.1’ of ADR-2015, whichever is appropriate. These are also given in Appendix B.

Limits for ‘excepted quantities’

Maximum 1 ml net quantity per inner package and maximum of 500 ml net per outer packaging. Note: Packages qualifying for limited quantities need to be labelled with ‘Figure 3.5.4.2’ along with the label number ‘6.1’. This is also provided in Appendix B of this document.

Maximum number of (outer) packages

The total number of packages in any vehicle or container shall not exceed 1000.

Packing instructions P001 (see 4.1.4 of ADR-2015) For IBCs: IBC02 (see 4.1.4.2 of ADR-2015) For mixed packaging: MP15 (see 4.1.10 of ADR-2015)


of 54

Along with this information, the decision diagram given in figure 8.1 shall be used to

determine if the package to be shipped requires the application of the transport label.

This is based on the legal wording given in the article 33 of the CLP regulations.

Figure 7.1 A decision flowchart for the application of CLP and transport labelling for single and

combination packaging based on the interpretation of Article 33 of CLP regulation. Adapted

from Guidance on Labelling and Packaging in accordance with Regulation (EC) No 1272/2008131.

131 Guidance on Labelling and Packaging in accordance with Regulation (EC) No 1272/2008.


of 54

8. CONCLUSIONS

Proper interpretation of CLP regulations clearly suggests that the classification of e-

liquids should be based on the strategy specified for “classification of mixtures” and that

this classification would be based on the final concentrations of the ingredients and

calculations based on their ATE values. Secondly, care should be taken to clarify the

correct type of mixture (i.e. weight/volume, weight/weight or volume/volume) and the

classification limits should be applied and/or defined accordingly.

Based on the assessment presented in this report, it is evident that all the e-liquids that

contain nicotine less than 2.5% (w/w) is not classified under CLP classification for any

of the hazard categories as defined by the CLP regulation. Any e-liquid (or any other

product) that contains nicotine in excess of 2.5% (w/w), are classified in one or more

hazard categories and this can be easily “looked-up” from the summary tables provided

in section 6 (table 6.1 to 6.3) of this document.


of 54

APPENDIX A

Relevant hazard pictograms (CLP system)

GHS06

GHS07

GHS09


of 54

Relevant hazard Statements (CLP system)

H301 Toxic if swallowed

H302 Harmful if swallowed

H310 Fatal in contact with skin

H311 Toxic in contact with skin

H312 Harmful in contact with skin

H411 Toxic to aquatic life with long lasting effects

H412 Harmful to aquatic life with long lasting effects

Relevant Precautionary Statements (CLP system)

P102 Keep out of reach of children

P262 Do not get in eyes, on skin, or on clothing

P264 Wash hands thoroughly after handling

P270 Do not eat, drink or smoke when using this product

P273 Avoid release to the environment

P280 Wear protective gloves and clothing*

P301+P310 IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician

P301+P312 IF SWALLOWED: Call a POISON CENTER or doctor/physician if you feel

unwell

P302+P350 IF ON SKIN: Gently wash with plenty of soap and water

P302+P352 IF ON SKIN: Wash with plenty of soap and water

P310 Immediately call a POISON CENTER or doctor/physician

P312 Call a POISON CENTER or doctor/physician if you feel unwell

P361 Remove/Take off immediately all contaminated clothing

P363 Wash contaminated clothing before reuse

P391 Collect spillage

P405 Store locked up

P501 Dispose of contents/container in accordance with your local regulations

* This statement includes only appropriate preventative action when handling nicotine

solutions.


of 54

Labelling in accordance with ADR-2015 (Transport labels)

Class 6.1 Hazard (toxic substances)

(Label number: 6.1)

Symbol (skull and cross bones): black in colour; background: White in colour; Figure ‘6’

in the bottom corner.

Orientation Arrows

Two black or red arrows on white or suitable contrasting background. The rectangular

border is optional. All features shall be in approximate proportion to those shown.

Marking for packages containing limited quantities (except for air transport)

For packages containing limited quantities of dangerous goods that is to be transported

by means other than by air, the marking shown in blow should be applied (figure 3.4.7.1

of ADR-2015). The marking shall be readily visible, legible and able to withstand open

weather exposure without a substantial reduction in effectiveness.

All the elements and features of the label should be in the approximate proportions as

shown in the figure. The minimum dimensions shall be 100 mm X 100 mm and the

minimum width of the line forming the diamond shall be 2 mm. If the size of the

package so requires, the minimum outer dimensions may be reduced to be not less than


of 54

50 mm X 50 mm and the minimum width of the line forming diamond may be reduced

to a minimum of 1 mm. The symbol “Y” shall remain in approximate proportions.

Marking for packages containing limited quantities (for air transport only)

For packages containing limited quantities of dangerous goods and that is intended to

be transported by air, the package should comply with the provisions of Part 3, chapter

4 of the ICAO Technical Instructions and should bear the following marking (figure

3.4.8.1 of ADR-2015) to certify the package’s compliance.

The marking shall be readily visible, legible and able to withstand open weather

exposure without a substantial reduction in effectiveness. All the elements and features

of the label should be in the approximate proportions as shown in the figure. The

minimum dimensions shall be 100 mm X 100 mm and the minimum width of the line

forming the diamond shall be 2 mm. If the size of the package so requires, the minimum

outer dimensions may be reduced to be not less than 50 mm X 50 mm and the minimum

width of the line forming diamond may be reduced to a minimum of 1 mm. The symbol

“Y” shall remain in approximate proportions.


of 54

Marking for dangerous goods transported in excepted quantities


of 54

APPENDIX B

This section includes important and relevant excerpts from the CLP regulation (EC) No

1272/2008; and clause and article numbers referred to in this part reflects the actual

clause and/or article numbers in CLP regulation ((EC) No 1272/2008).

B.1 Boundaries of classification for acute toxicity hazards

Table 3.1.1 of Annex I of (EC) No 1272/2008 (aka CLP regulation).

Notes to Table 3.1.1

a) The acute toxicity estimate (ATE) for the classification of a substance or

ingredient 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.

b) Generic concentration limits for inhalation toxicity in the table are based on 4

hour testing exposures. Conversion of existing inhalation toxicity data which


of 54

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.

c) For some substances or mixtures the test atmosphere will not just be a vapour

but will consist of a mixture of liquid and vapour phases. For other substances or

mixtures 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.

Table 4.1.2 of Annex I of (EC) No 1272/2008 (aka CLP regulation).


of 54

B.2 Contents of the label

Article 17

1. A substance or mixture classified as hazardous and contained in packaging shall

bear a label including the following elements:

a. the name, address and telephone number of the supplier(s);

b. the nominal quantity of the substance or mixture in the package made available

to the general public, unless this quantity is specified elsewhere on the package;

c. product identifiers as specified in Article 18;

d. where applicable, hazard pictograms in accordance with Article 19;

e. where applicable, signal words in accordance with Article 20;

f. where applicable, hazard statements in accordance with Article 21;

g. where applicable, the appropriate precautionary statements in accordance with

Article 22;

h. where applicable, a section for supplemental information in accordance with

Article 25.

2. The label shall be written in the official language(s) of the Member State(s)

where the substance or mixture is placed on the market, unless the Member

State(s) concerned provide(s) otherwise.

Suppliers may use more languages on their labels than those required by the

Member States, provided that the same details appear in all languages used.

PLEASE NOTE: All these elements – for an e-liquid or nicotine containing

solutions – are provided in the tables 6.1, 6.2, 6.3 and 6.4 of this document.

Also Note:

For mixtures containing components of unknown acute or aquatic toxicity at a

concentration at 1% or greater, the statement “x percent of the mixture consists of

component(s) of unknown toxicity” should be included in the label and the Safety

Data Sheet, see point 3.1.3.6.2.2 of Annex I to CLP. In this connection, it may be

worthwhile to specify the statement as follows: “x percent of the mixture consists of

component(s) of unknown acute (oral/dermal/inhalation) toxicity” OR “Contains x

percent of components with unknown hazards to the aquatic environment”, in

particular where the substance is also classified for other hazards and where it is

important to specify the route of exposure (see the changes to point 4.1.3.6.1 of

Annex I to CLP, see also point 3.1.4.2 of the Guidance on the Application of the CLP

Criteria).


of 54

B.3 General rules for the application of labels

Article 31

1. Labels shall be firmly affixed to one or more surfaces of the packaging

immediately containing the substance or mixture and shall be readable

horizontally when the package is set down normally.

2. The colour and presentation of any label shall be such that the hazard pictogram

stands out clearly.

3. The label elements referred to in Article 17(1) shall be clearly and indelibly

marked. They shall stand out clearly from the background and be of such size

and spacing as to be easily read.

4. The shape, colour and the size of a hazard pictogram as well as the dimensions of

the label shall be as set out in section 1.2.1 of Annex I.

5. A label shall not be required when the label elements referred to in Article 17(1)

are shown clearly on the packaging itself. In such cases, the requirements of this

Chapter applicable to a label shall be applied to the information shown on the

packaging.

B.4 Location of information on the label

Article 32

1. The hazard pictograms, signal word, hazard statements and precautionary

statements shall be located together on the label.

2. The supplier may decide the order of the hazard statements on the label.

However, subject to paragraph 4, all hazard statements shall be grouped on the

label by language. The supplier may decide the order of the precautionary

statements on the label. However, subject to paragraph 4, all precautionary

statements shall be grouped on the label by language.

3. Groups of hazard statements and groups of precautionary statements referred to

in paragraph 2 shall be located together on the label by language.

4. The supplemental information shall be placed in the supplemental information

section referred to in Article 25, and shall be located with the other label

elements specified in Article 17(1)(a) to (g).

5. In addition to its use in hazard pictograms, colour may be used on other areas of

the label to implement special labelling requirements.


of 54

6. Label elements resulting from the requirements provided for in other

Community acts shall be placed in the section for supplemental information on

the label referred to in Article 25.

B.5 Dimensions and make-up of the label elements

Section 1.2.1 of Annex I of the CLP regulation

1.2.1.1. Hazard pictograms as laid down in Annex V (see Appendix 2 of this

document) shall have a black symbol on a white background with a red

frame sufficiently wide to be clearly visible.

1.2.1.2. Hazard pictograms shall be in the shape of a square set at a point. Each

hazard pictogram shall cover at least one fifteenth of the surface area of

the harmonised label but the minimum area shall not be less than 1 cm2.

1.2.1.3. The dimensions of the label shall be as follows:

B.6 Allowed (relevant) exceptions

The CLP regulations allow few exceptions or relaxation from labelling

requirements for special cases and the relevant excerpts from CLP regulation are

quoted below.

Article 29

Exemptions from labelling and packaging requirements

1. Where the packaging of a substance or a mixture is either in such a shape or

form or is so small that it is impossible to meet the requirements of Article 31

for a label in the languages of the Member State in which the substance or

mixture is placed on the market, the label elements in accordance with the first

subparagraph of Article 17(2) shall be provided in accordance with section 1.5.1

of Annex I.


of 54

2. If the full label information cannot be provided in the way specified in paragraph

1 the label information may be reduced in accordance with section 1.5.2 of

Annex I.

1.5.1. Exemptions from Article 31 [(Article 29(1))]

1.5.1.1. Where Article 29(1) applies, the label elements mentioned in Article 17

may be provided in one of the following ways:

(a) in fold-out labels; or

(b) on tie-on tags; or

(c) on an outer packaging.

1.5.1.2. The label on any inner packaging shall contain at least hazard pictograms,

the product identifier referred to in Article 18 and name and telephone

number of the supplier of the substance or mixture.

1.5.2. Exemptions from Article 17 [(Article 29(2)]

1.5.2.1. Labelling of packages where the contents do not exceed 125 ml

1.5.2.1.1. The hazard statements and the precautionary statements linked to the

hazard categories listed below may be omitted from the label elements

required by Article 17 where:

(a) the contents of the package do not exceed 125 ml; and

(b) the substance or mixture is classified in one or more of the following

hazard categories:

11) Acute toxicity of category 4, if the substances or mixtures are not

supplied to the general public;

17) Hazardous to the aquatic environment — Chronic of category 1

or 2.

PLEASE NOTE: The clause 1.5.2.1.1 and classification provided in tables 6.1, 6.2 and 6.3

would imply that only the nicotine containing solutions (e-liquid or ‘base nicotine

solution’) that are supplied in quantity of less than 125 ml and have nicotine

concentration of ≤ 5% (weight/weight) and are NOT supplied to the general public (i.e.

only exchanged between two businesses/suppliers) qualify for this exemption.


of 54

B.7 Interplay between Transport and CLP labelling system

Article 33

Specific rules for labelling of outer packaging, inner packaging and single packaging

1. Where a package consists of an outer and an inner packaging, together with any

intermediate packaging, and the outer packaging meets labelling provisions in

accordance with the rules on the transport of dangerous goods, the inner and any

intermediate packaging shall be labelled in accordance with this Regulation (i.e. CLP

regulation). The outer packaging may also be labelled in accordance with this

Regulation. Where the hazard pictogram(s) required by this Regulation relate to the

same hazard as in the rules for the transport of dangerous goods, the hazard

pictogram(s) required by this Regulation need not appear on the outer packaging.

2. Where the outer packaging of a package is not required to meet labelling provisions

in accordance with rules on the transport of dangerous goods, both the outer and

any inner packaging, including any intermediate packaging, shall be labelled in

accordance with this Regulation. However, if the outer packaging permits the inner

or intermediate packaging labelling to be clearly seen, the outer packaging need not

be labelled.

3. Single packages that meet the labelling provisions in accordance with the rules on the

transport of dangerous goods shall be labelled both in accordance with this

Regulation and the rules on the transport of dangerous goods. Where the hazard

pictogram(s) required by this Regulation relate to the same hazard as in rules on the

transport of dangerous goods, the hazard pictogram(s) required by this Regulation

need not appear.

PLEASE NOTE: “The assumption underlying the provisions of CLP Article 33(2) is that

only one substance or mixture is contained in single or combined outer packaging.

Therefore, in cases where the rules on the transport of dangerous goods do not

apply and where more than one substance or mixture with different hazard

classifications are packed together in the same outer packaging then the rules of CLP

Article 33(2) should be applied with care: where the outer packaging carries

different labels which relate to different packaged substances or mixtures, then the

whole set of individual labels on the outer packaging may not provide coherent

hazard information and safety advice, e.g. in case one substance is hazardous to the

aquatic environment, the other is a carcinogen, the third one is flammable and the

last one is a non-hazardous mixture”. (Taken from section 5.4 of Guidance on

Labelling and Packaging in accordance with Regulation (EC) No 1272/2008).

clp classification of e-liquids -...

Documents