Reaction mass of aluminium fluoride and chromium trifluoride and nickel difluoride

Carcinogenicity

Description of key information

Nickel compounds are considered as human carcinogens based on epidemiological studies. Although physico-chemical data tend to indicate that PBN1 mixture is a non-reactive inert substance and that its size and structure can not allow its absorption by skin or airways, a worst case approach has been chosen  by considering  the data for nickel chloride and nickel fluoride contained at a content of 4.5 and 9.5% respectively in PBN1 mixture.

Justification for classification or non-classification

According to the Annex I of Directive 67/548/EEC, nickel fluoride (CAS No.: 10028 -18 -9) and nickel chloride (CAS No.: 7718 -54 -9) are classified Carcinogenic Category 1; R49 (by inhalation). As they are both present at 9.5 and 4.5% respectively in the mixture, and taking into account the classification criteria of Directive 1999/45/EC for carcinogenicity, PBN1 mixture should be classified as Carcinogenic Category 1; R49, or classified Carcinogenic cat. 1A (H350) according to Directive 1272/2008/EC (CLP), for the risk of causing lung and nasal cancer following respiratory exposure.

Additional information

Exposure to nickel in the workplace (nickel mines or refineries) has been associated with an increase in lung and nasal sinus tumours. In the final report from the International Committee on Nickel Carcinogenesis in Man (ICNCM), quantitative exposure estimates were introduced for four forms of nickel (water-soluble, sulphidic, oxidic, and metallic nickel), with the aim to identify which form(s) of nickel that contributed to the cancer risk in exposed humans (Doll et al., 1990). An increased risk for lung and nasal sinus cancers was particularly noted in refinery work involving roasting, sintering, and calcining processes that converted impure nickel-copper matte to an oxide.

The analyses were based on calculation of standardised mortality ratios from lung cancer and nasal cancer according to duration of work in different departments and to cumulative exposures to the four forms of nickel. The variables were used in a categorical form, and the workers were cross-classified according to dichotomised nickel exposure variables (low or high exposure). Multivariable regression analyses or continuous variables were not used. Although a standardized strategy of analysis was used, the uncertainty and variation in the exposure measures made it difficult to compare across cohorts. Somewhat more confidence was put in comparisons made between groups at the same refinery. The most informative cohorts of nickel exposed workers proved to be the Welsh, the Norwegian, and some of the Canadian cohorts. Lung and nasal cancer mortality is summarized in the Table 1 below.

Table 1: Summary of lung and nasal cancer mortality in the studied cohorts

15 or more years since first exposure (from Doll et al., 1990)

Cohort	Lung cancer				Nasal cancer
	O	E	SMR	95% CI	O	E	SMR	95% CI
Mond/INCO (Clydach)^a	166	42.30	393***	335-457	72	0.32	22513***	17615-23852
Falconbridge (Ontario)	98	76.63	128*	104-157	1	0.65	154	4-858
Hanna Nickel Mining Company	18	12.38	145	86-229	-	0.09	0	0-5953
Huntington Alloys, Inc.
Cohort 1 (hired before 1947)	72	72.64	99	78-125	2	0.86	233	28-843
Cohort 2 (hired in 1947 or later)	18	17.74	101	60-160	-	0.28	0	0-1376
INCO
Sudbury sinter
Copper Cliff	63	20.51	307***	238-396	6	0.17	3617***	1327-7885
Coniston	8	2.67	292**	126-576	-	0.02	0	0-28375
Sudbury nonsinter	493	444.68	111**	101-121	4	3.50	114	31-293
Port Colborne
Leaching, calcining, sintering	72	30.04	239***	187-302	19	0.24	7776***	4681-12144
Non leaching, calcining, sintering	30	32.32	93	63-133	-	0.25	0	0-1472
Falconbridge (Kristiansand)	67	22.38	299***	233-382	3^b	0.45	669*	138-1953
Oak Ridge Gaseous Diffusion Plant	9	15.10	60	27-113	-	0.18	0	0-2943
Outokumpu Oy (Finland)	1	-^c	-	-	1	-^c	-	-
Société le Nickel (New-Caledonia)	-	-	90^d	-	-	-	-	-
Henry Wiggin Company	19	20.06	95	57-148	-	0.11	0	0-4816
O: Observed number of deaths      E: Expected number of deaths        SMR: Standardized Mortality ratio 95% CI = 95% confidence interval ^a  Workers hired before 1930 ^b  Four other nasal cancers occurred in men who were still alive and had 15 or more years since first exposure at the time of publication ^c  129 men ^d  Relative risk x 100 based on ratio of cumulative incidences of the nickel-exposed workers and the New-Caledonia population * p<0.05              ** p<0.01            *** p<0.001

For exposure to water soluble nickel compounds, strong evidence of a dose related increase in lung cancer risk came from the electrolysis workers in the Norwegian cohort. These workers had only low exposure to less soluble forms of nickel. Some evidence, but slightly less convincing, was found in the Welsh cohort. Both the Norwegian and the Welsh cohorts gave evidence that water-soluble nickel increased the lung cancer risk associated with exposure to oxidic nickel, the Welsh also for the combination of water-soluble and sulphidic nickel. The lack of evidence of risk associated with water-soluble nickel among the Port Colborne electrolysis workers was explained by lower exposures to water-soluble as well as to less soluble forms. The results from Wales suggested a separate effect on lung cancer risk from sulphidic nickel, but no support was found for this view in the other cohorts. Some evidence from the Norwegian and Welsh cohort suggested a lung cancer risk from exposure to oxidic nickel, although a possible contribution from water-soluble nickel could not be excluded in the Welsh data. A potential effect from the concomitant exposure to copper oxides was also discussed. No evidence was found of increased lung cancer risk from exposure to metallic nickel.

As an overall conclusion, much of the lung cancer was ascribed to high exposures to the combination of nickel oxides and nickel sulphides, or to high levels of oxidic nickel in the absence of sulphidic nickel. Water-soluble nickel was found to increase the risk of lung cancer alone or together with less soluble forms. Much of the respiratory cancer risk was attributed to exposure to a mixture of oxidic and sulfidic nickel. In the absence of sulfidic nickel, exposure to large concentrations of oxidic nickel was also associated with increased lung and nasal sinus cancer risks. There was evidence that exposure to soluble nickel salts increased the risk of lung and nasal sinus cancer and that it may enhance risks associated with exposure to less soluble forms of nickel. There was no evidence that metallic nickel was associated with increased lung and nasal sinus cancer risks. There was no evidence to suggest that exposure to metallic nickel or any of its compounds was likely to produce cancers elsewhere than in the lung or nose. No exposure-specific estimates of risks for individual nickel species could be provided. However, the evidence from these studies suggest that respiratory cancer risks in "high-risk" cohorts (occupationally exposed to nickel) are primarily related to exposure to water-soluble nickel concentrations in excess of 1 mg Ni/m3 and to exposure to less soluble forms at concentrations greater than 10 mg Ni/m3.

A cancer update of the Norwegian nickel workers was analysed using the exposure estimates and the cohort sample from the ICNCM study extended with workers who had 3 years service or more from the years before 1946 (Andersen et al., 1996). The cohort consisted of 379 workers with first employment 1916 -1940 and at least 3 years of employment, and 4385 workers with at least 1 year of employment 1946 -1983. Data on smoking (ever or never) were available for almost 95% of the cohort. Standardized incidence ratios were calculated and internal comparisons performed in multivariable analyses with Poisson regression including cumulative exposure to water-soluble and oxidic nickel, age, observation period, and smoking habits. During the 1953 -1993 follow-up, 203 new cases of lung cancer were observed versus 68 expected, with a standardised incidence ratio (SIR) of 3.0 (95% confidence interval 2.6 -3.4), and 32 cases of nasal cancer versus 1.8 expected, with a SIR of 18.0 (95% confidence interval 12 -25). The Poisson regression analysis showed an excess risk of lung cancer in association with exposure to soluble forms of nickel, with a 3 -fold increase in relative risk (p<0.001). The effect of the combination of smoking and nickel exposure seemed to fit into a multiplicative pattern. The relative risks were 1.1 (95% confidence interval 0.2 -5.1) for exposed workers who had never smoked and 5.1 (95% confidence interval 1.3 -20.5) for exposed workers who smoked.

From a regulatory perspective, the European Directive 2004/107 sets a target limit concentration of 20 ng Nickel/m3 in ambient air, compatible with limiting the excess lifetime cancer risk to not more than one in a million.

Literature references:

• Andersen A, Berge SR, Engeland A, Norseth T. Exposure to nickel compounds and smoking in relation to incidence of lung and nasal cancer among nickel refinery workers. Occup Environ Med 53: 708-713, 1996.
• Doll R, Andersen A, Cooper WC, Cosmatos I, Cragle DL et al. Report of the International Committee on Nickel Carcinogenesis in Man. Scand J Work Environ Health 16: 1-82, 1990.
• Directive 2004/107/EC of the European Parliament and of the Council of 15 December 2004 relating to arsenic, cadmium, mercury, nickel and polycyclic aromatic hydrocarbons in ambient air

Carcinogenicity: via inhalation route (target organ): respiratory: lung; respiratory: nose