BACKGROUND• In the rubber industry most accelerators based on secondary amines can produce

N-nitrosamines as a by-product during the vulcanisation reaction. Many

N-nitrosamines are carcinogenic, therefore they are highly regulated in final rubber

articles and during manufacture.

• Substitution of the traditional amino compounds by safe amines give compounds

that are still active as accelerators, but do not form carcinogenic N-nitrosamines.

Not all safe amines give effective rubber accelerators or produce accelerators that

are easy to synthesise and are economically viable.

• Safe amines are characterised by their toxicity and potential carcinogenicity.

• Animal testing studies for carcinogenicity require a scientifically sound rationale as to

why the study is needed and additional reasoning is needed to satisfy animal welfare

guidelines. It also involves time consuming testing and is expensive.

OBJECTIVES• Develop an effective method of prediction for the non-carcinogenicity of

N-nitrosamines, as an alternative to intensive animal studies for carcinogenicity.

• Design new N-nitrosamine safe rubber accelerator molecules. For example: Robac

TINTD and Robac ARBESTAB Z (Zinc diisononyldithiocarbamate).

METHODQuantitative structure–activity relationship (QSAR) Study

• Wishnok et al. developed a predictive equation to demonstrate a significant

correlation between carcinogenic activity, water-hexane partition coefficients (π) and

electronic factors of substituents on the carbon atoms alpha to the N-nitroso group

(Taft σ*). See Figures 1 to 4.

• They described a relationship between carcinogenic doses of various N-nitrosamines

(log (1/D50)) and π plus Taft σ*. Here Taft σ* provides an indication of the

electron-donating or electron withdrawing properties of a substituent present on a

methylene group that is directly bound to a reaction centre. And π indicates the

ease of transport of the N-nitrosamine across the cell wall.

• The paper published values of Taft σ* and π for various R substituents for many

N-nitrosamines and calculated the log (1/D50) and compared this value to the

experimental log (1/D50) in order to derive a relationship between σ*, π and log

(1/D50), see equation 1. D50 is the lethal dose for 50% mortality rate for rats.

log (1/D50) = 1.74 – 0.26π² + 0.92π + 0.59σ* Equation 1

• This equation was based on data from 21 carcinogenic N-nitrosamines and had a

coefficient of determination (R²) of 0.84, where a value of 1.0 would be a perfect

correlation. The higher the value of log (1/D50) the greater is the carcinogenic

potency of the N-nitrosamine under test.

• In this work the above derived equation was used to predict whether

N-nitrosodiisononylamine is non-carcinogenic or not.

RESULTS• Figure 5 shows the relationship between the rubber accelerators, the nitrosamines

formed from them and their carcinogenicity.

• Figure 6 ranks accelerators based upon the nitrosamine formed during vulcanisation.

It can be seen that ARBESTAB Z and TINTD are in the non-carcinogen slot on the

graph.

• Figure 7 shows DNA mutation by N-nitrosamine transport across the cell wall.

• Figure 8 shows the performance of TINTD as a rubber accelerator and sulfur donor.

• N-nitrosodiisononylamine was predicted to be non-carcinogenic.

CONCLUSIONS• Many classes of accelerators generate potentially harmful N-nitrosamines.• N-nitrosamines may be mutagenic and/or carcinogenic.• Possible to predict carcinogenicity of N-nitrosamines by QSAR studies.• QSAR could replace expensive (~£1.5m) and time consuming (~2 years)

animal testing.• NDINA is non-mutagenic and calculated by QSAR to also be non-carcinogenic.• Robac ARBESTAB Z and now Robac TINTD, both based on DINA, are safer to

health than most conventional rubber accelerators.

Title:Subtitle

A Predictive Model, using N-nitrosamine Toxicological Data, for the Design of Safer Rubber Accelerators.

R.S. VIRDI and B.W. GROVERRobinson Brothers Limited, Phoenix Street, West Bromwich, B70 0AH, UK

J. S. Wishnok, M. C. Archer, A. S. Edelman, and W. M. Rand, Chem.-Biol. Interact., 20, 43, (1978).J. S. Wishnok and M. C. Archer, Br. J. Cancer, 33, 307, (1976).

REFERENCES

Figure 2. π vs number of carbon atoms in substituent chain

Figure 3. Taft σ* vs number of carbon atoms in substituent chain

Figure 4. Predicted carcinogenic potency, log(1/D50) vs carbon no.

Figure 7. DNA mutation by N-nitrosamine transport across cell wall

Figure 8. Performance of TINTD as an accelerator and sulfur donor in rubber

Figure 6. Accelerator ranking based upon the nitrosamine formed during vulcanisation

Figure 5. Relationship between rubber accelerators, nitrosamines formed and carcinogenicity

Figure 1. Data on N-nitrosamines generated by Wishnok et al.

Contact: Ranvir Virdi / Boyd GroverE:mail rsvirdi@robinsonbrothers.co.uk / bwgrover@robinsonbrothers.co.ukTelephone: +44 (0)121 553 2451

www.robinsonbrothers.co.uk

Compound Abbrev. R1=R2 No. of C Atoms σ* π

N-nitrosodi-n-methylamine NDMA CH3 1 0.49 0

N-nitrosodi-n-ethylamine NDEA CH3CH2 2 0 1.24

N-nitrosodi-n-propylamine NDProA CH3(CH2)2 3 -0.1 2.49

N-nitrosodi-n-butylamine NDBA CH3(CH2)3 4 -0.115 3.59

N-nitrosodi-n-pentylamine NDPeA CH3(CH2)4 5 -0.125 4.22

N-nitrosodi-n-hexylamine NDHA CH3(CH2)5 6 n/a n/a

N-nitrosodi-n-heptylamine NDHepA CH3(CH2)6 7 -0.135 n/a

N-nitrosodi-n-octylamine NDOA CH3(CH2)7 8 n/a n/a

N-nitrosodi-n-nonylamine NDNA CH3(CH2)8 9 n/a n/a

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