Nickel difluoride

Carcinogenicity

Description of key information

INHALATION: Contrary to the views expressed by the authors of the 2008/2009 EU NICKEL SULPHATE RISK ASSESSMENT, the US National Toxicology Program study of the carcinogenicity potential of nickel sulfate after inhalation exposure is considered to be a guideline compliant, robust study demonstrating a lack of carcinogenicity in the experimental animals after inhalation.

ORAL: A well-conducted OECD 451 study in rats did not show any carcinogenic potential of nickel sulphate following oral administration. A summary document on this topic can be found in the attached document entitled, " Background-Oral Carcinogenicity for all Nickel Compounds" (Section 7.7 of IUCLID), where it is explained why data on nickel sulfate can be extrapolated to all soluble nickel compounds, including nickel fluoride.

DERMAL: The available data concerning dermal exposure are too limited for an evaluation of the carcinogenic potential in experimental animals. However, as oral exposure to nickel soluble compounds do not show any carcinogenic potential, there are good reasons to assume that cancer is not a relevant end-point with respect to dermal exposure either.

Studies via other routes of exposure and promoter studies provide at most limited evidence of carcinogenicity of nickel sulphate in animals.

As described in the attached  document entitled, " Background-Oral Carcinogenicity for all Nickel Compounds" (Section 7.7 of IUCLID)  Nickel sulfate hexahydrate represents a worst-case scenario for systemic absorption of nickel since nickel sulfate hexahydrate is readily solubilized in gastrointestinal fluid and results in the highest systemic absorption of Ni (II) ions compared to less soluble nickel-containing substances (Ishimatsu et al., 1995; Hayman et al., 1984), such as Nickel fluoride.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Reference

Endpoint:

carcinogenicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

not reported

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Guideline study

Reason / purpose for cross-reference:

reference to same study

Qualifier:

according to guideline

Guideline:

OECD Guideline 451 (Carcinogenicity Studies)

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.4200 (Carcinogenicity)

Principles of method if other than guideline:

According to OECD/EPA standard guidelines

GLP compliance:

yes

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Inc., Raleigh, North Carolina.
- Age at study initiation: 6 weeks
- Weight at study initiation: 118 to 147 g for males and 93 to 112 g for females
- Fasting period before study: not reported
- Housing: housed individually in suspended stainless steel cages that were rotated in a regular fashion
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: acclimated to the laboratory conditions prior to in-life initiation
- Other: The results of the pretest health screen (gross necropsy and serological analyses) conducted prior to in-life initiation indicated that the population of animals was suitable for study use. Serological analyses of blood samples fromfive male and five female sentinel animals conducted by
BioReliance Corporation, Rockville, Maryland, during weeks 25, 51, 77 and 103 did not reveal the presence of any viral infections that would
negatively impact the results of this study.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 70 to 76 °F
- Humidity (%): 29 to 73%
- Air changes (per hr): 10 to 15 air changes per hour
- Photoperiod (hrs dark / hrs light): 12-h light/12-h dark cycle

IN-LIFE DATES: not reported

Route of administration:

oral: gavage

Type of inhalation exposure (if applicable):

other: not applicable

Vehicle:

water

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: a specified amount of the test article and vehicle was mixed weekly. The mixtures were stirred continuously throughout each exposure period. The appearance of each test article preparation was determined and documented as a clear colorless solution for groups 2 and 3 (10 and 30mg/kg/day) and a clear pale blue solution for group 4 (50 mg/kg/day).

DIET PREPARATION
- not applicable

VEHICLE
- water

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Analyses were conducted by KAR Laboratories, Inc. (Kalamazoo, Michigan) prior to study initiation, during week 51, and following study completion
to confirm the stability and purity of the test substance. Reverse osmosis deionized tap water was used for administration to control animals and in
the preparation of the test article mixtures. Analytical concentration verification analyses conducted throughout the study demonstrated that the
exposure solutions were stable and properly prepared. All analyses were within ±10% of the nominal concentration.

Duration of treatment / exposure:

104 weeks

Frequency of treatment:

Daily

Post exposure period:

none reported

Remarks:

Doses / Concentrations:
10, 30 and 50 mg/kg/day
Basis:
other: dose via oral gavage

No. of animals per sex per dose:

60 males/60 females per dose

Control animals:

yes, concurrent no treatment

Details on study design:

- Dose selection rationale: Exposures for the 90-day range finding study were selected based on previous gavage studies of nickel sulfate hexahydrate in rats. The 90-day range-finding study of nickel sulfate hexahydrate administered by gavage was conducted using exposures of 0, 50, 75, 100, 125, and 150 mg/kg. Findings from this study are reported in the Results section. Based on the data from the 90-day range-finding study, exposure levels of 10, 30 and 50 mg/kg/day were selected for the 2 year oral gavage carcinogenicity study.

- Rationale for animal assignment (if not random): Sixty female and sixty male animals were assigned to each exposure group using a computer randomization program.

Positive control:

none reported

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: General health/mortality/moribundity checks were performed twice daily.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Detailed clinical observations were performed weekly and on the day of scheduled euthanasia (weeks 104–105). Beginning on week 25, detailed clinical observations included a palpable mass examination (including the occurrence, size, location and description of any palpable masses) followed by persistence or disappearance of these masses being documented at the next weekly clinical observation.

BODY WEIGHT: Yes
- Time schedule for examinations: Individual body weights were recorded prior to randomization (day −3), on day 0 (i.e., the start of exposure), weekly during the first 13 weeks, once every 4 weeks thereafter and during week 103.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Individual food consumption (grams/animal/day) was recorded on day 0, weekly during the first 13 weeks and once every 4 weeks thereafter, with the final food consumption measurement during week 103.

HAEMATOLOGY: Yes
- Selected hematological parameters were measured in blood samples collected from 10 animals/sex/group during week 54 (via tail vein) and prior to scheduled euthanasia during week 104/105 (via orbital plexus). Hematology and clinical chemistry parameters were measured according to the OECD 451 protocol.

Sacrifice and pathology:

GROSS PATHOLOGY/HISTOPATHOLOGY:
All animals were subjected to a complete gross necropsy examination at the time of death or euthanasia. Tissues collected at necropsy from all
animals were processed for histopathological evaluation. Slides were prepared by Histo Techniques (Powell, Ohio) and Charles River Laboratories-
Pathology Associates (Frederick, Maryland) and were examined microscopically by a Charles River Laboratories board-certified veterinary
pathologist.

Other examinations:

Near the end of the study (week 103), additional biological sampling was performed to provide data on nickel in urine, feces and blood. Immediately
following exposure on 1 day during week 103, five females and five males from each exposure group were placed in urine collection cages equipped with fecal collection screens, and an ice bath for cooling collected urine samples. Blood was collected from the orbital plexus of each animal
approximately 30 min and 24 h post-exposure and sent to WIL Research Laboratories, Inc. (Ashland, Ohio) for analysis of blood nickel
concentration. Urine and fecal samples were collected from each cage approximately 24 h post-exposure and sent to KAR Laboratories, Inc. for
urine and fecal analysis of nickel concentrations. Urine was analyzed also for creatinine and albumin concentrations. Other standard hematology
and clinical chemistry parameters for blood as well as other standard urinalysis parameters for urine were measured by Charles River Laboratories.

Statistics:

In-life data: The data were initially tested for normality using Levene's test for equality of variance followed by the Shapiro–Wilks test for normality.
A p≤0.001 level of significance was required for either test to reject the assumptions. If both assumptions were fulfilled, a singlefactor
ANOVA was applied, with animal grouping as the factor, utilizing a p≤0.05 level of significance. If the parametric ANOVA was significant at p≤0.05,
Dunnett's test was used to identify statistically significant differences between the control group and each nickel sulfate-treated group at the 0.05,
0.01 and 0.001 levels of significance. If either of the parametric assumptions was not satisfied, then the Kruskal–Wallis nonparametric ANOVA
procedure was used to evaluate intergroup differences (p≤0.05). The Dunn's multiple comparison test was applied if this ANOVA was significant,
again utilizing significance levels of p≤0.05, 0.01 and 0.001.

Survival Data: Kaplan–Meier estimates of group survival rates were calculated, by sex, and shown graphically. A log-rank dose response trend test
of survival rates was performed utilizing dose coefficients. In addition, a log-rank test for survival was used to make pairwise comparisons of each
treated group with the control group. Both the trend test and pairwise comparisons were conducted at the 0.05 significance level.

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

no effects observed

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

no effects observed

Details on results:

MORTALITY:
Group (Dose) Males (deaths/N, % mortality) Females(deaths/N, % mortality)
1 (0 mg/kg/day) 36/60 (60) 14/60 (23)
2 (10 mg/kg/day) 29/60 (48) 20/60 (33)
3 (30 mg/kg/day) 30/60 (50) 26/60 (43)
4 (50 mg/kg/day) 34/60 (57) 27/60 (45)

BODY WEIGHT AND WEIGHT GAIN:
Body weights decreased in a exposure-dependent manner, with significantly decreased body weights observed in the two highest exposure groups for males and females. Reductions in weight gain relative to controls at study week 103 reached the level of biological significance (i.e., >10% decrease) in the group 3 and 4 males and the group 4 females. This significant weight reduction indicates that the Maximum Tolerated Dose was reached in this study for both males and females.

HAEMATOLOGY:
A few statistically significant differences in the hematology data were observed in the nickel sulfate-treated males and females. However, none of these differences was suggestive of a hyperplastic (i.e., leukemia) response and none of these changes was considered toxicologically meaningful since they were small and did not follow a consistent exposure-related pattern.

GROSS PATHOLOGY/HISTOPATHOLOGY:
Gross necropsy and histopathology observations: Numerous gross necropsy findings were observed for animals in the control and nickel
sulfate-treated groups but the type and incidence of these findings observed for the treated animals were comparable to those observed in the
control group, and were consistent with findings commonly seen in aging rats in a longterm study. None of the neoplastic or non-neoplastic
microscopic findings was considered to be related to the experimental exposures. The non-neoplastic findings were either considered to
be secondary to toxicity or incidental background occurrences rather than a direct effect of nickel sulfate.

The pathology report, pathology peer-review and the pathology working group concurred that nickel sulfate hexahydrate did not
cause any carcinogenic effects in this study. Analysis of the tumor data revealed only one statistically significant (p<0.001) increase in tumors
corresponding to keratoacanthoma (tail) in the group 2 males. However, this finding is of questionable toxicologic significance since there was no
exposure–response relationship, the incidence rate in the group 2 males (15%) was only slightly higher than the upper end of Haseman's historical
control incidence for this tumor type (0–14%) and the incidence rate in the remaining control and treated groups (0–7%) was within the range of the
CRL-Ohio historical incidence (0–2%) and the Haseman historical incidence (0–14%). No other tumor finding in this study was statistically significant.

No notable differences were observed between controls and treated animals for the hematology, biochemistry and urinalysis parameters measured
during the toxicokinetic satellite study.

Dose descriptor:

NOAEL

Effect level:

11 other: mg Ni/kg bw/day

Sex:

male/female

Basis for effect level:

other: No observed tumors at the MTD

Remarks on result:

other: Effect type: carcinogenicity (migrated information)

Dose descriptor:

NOAEL

Effect level:

2.2 other: mg Ni/kg bw/day

Sex:

male/female

Basis for effect level:

other: Significant decrease in body weight

Remarks on result:

other: Effect type: toxicity (migrated information)

Dose descriptor:

LOAEL

Effect level:

6.7 other: mg Ni/kg bw/day

Sex:

male/female

Basis for effect level:

other: Significant decrease in body weight

Remarks on result:

other: Effect type: toxicity (migrated information)

Conclusions:

The present study indicated that nickel sulfate hexahydrate does not have the potential to cause carcinogenicity by the oral route of exposure in the Fischer 344 rat.

Executive summary:

STUDY RATED BY AN INDEPENDENT REVIEWER.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

50 mg/kg bw/day

Species:

rat

Carcinogenicity: via inhalation route

Link to relevant study records

Reference

Reference 1

Endpoint:

carcinogenicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

May 1988 to May 1990

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Reason / purpose for cross-reference:

reference to same study

Qualifier:

no guideline followed

Principles of method if other than guideline:

A standard Test Guideline was not specified in this study.

GLP compliance:

yes

Species:

mouse

Strain:

B6C3F1

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Simonsen Laboratories, Gilroy, CA, USA.  
- Age at study initiation: 6-week old 
- Weight at study initiation: ~23 g
- Fasting period before study: not reported
- Housing: individually housed
- Diet (e.g. ad libitum): ad libitum, except during exposure
- Water (e.g. ad libitum): ad libitum, except during exposure
- Acclimation period:

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17.2-29.6 deg. C
- Humidity (%): 8-99%
- Air changes (per hr): 9-21/hour
- Photoperiod (hrs dark / hrs light): 12-h light/dark  photo cycle

IN-LIFE DATES: May 1988 to May 1990

Route of administration:

inhalation

Type of inhalation exposure (if applicable):

whole body

Vehicle:

other: distilled and deionized water

Details on exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Stainless steel multitiered whole exposure chambers (Hazleton, Aberdeen, MD, USA)
- Method of holding animals in test chamber: not reported
- Source and rate of air: High-efficiency particulate air filter (Flanders, Washington, DC)
- Method of conditioning air: not reported
- System of generating particulates/aerosols: The test compound was generated from aqueous solutions (62.1 g/L in distilled and deionized water) and atomized.  
- Temperature, humidity, pressure in air chamber: Temp. 17.2-29.6 deg. C; humidity 8-99%
- Air flow rate: The aerosol was mixed with additional dilution air to achieve the proper concentration and flow rate.
- Air change rate: not reported
- Method of particle size determination: cascade impactor, the mass median aerodynamic diameter (MMAD) ranged from 2.3-2.5 um for all exposure concentrations.
- Treatment of exhaust air: not reported

TEST ATMOSPHERE
- Brief description of analytical method used: aerosol concentrations determined gravimetrically
- Samples taken from breathing zone: yes

VEHICLE: water

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

aerosol concentrations were monitored by collecting three 2-hour filter samples (3 Wmin flow rate) from each exposure chamber.

Duration of treatment / exposure:

2 years

Frequency of treatment:

6 hours/day, 5 days/week, for 104 weeks

Post exposure period:

none reported

Remarks:

Doses / Concentrations:
0, 0.25, 0.5, 1 mg/m3 (equivalent to 0, 0.056, 0.11, 0.22 mg Ni/m3)
Basis:
nominal conc.

No. of animals per sex per dose:

80 males and 80 females per group

Control animals:

yes, concurrent no treatment

Details on study design:

- Dose selection rationale: not reported
- Rationale for animal assignment (if not random): distributed randomely into groups of approximately equal initial mean body weights

Positive control:

none reported

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Animals were observed twice daily. 

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: conducted at the start of the study, weekly for 13 weeks, monthly during the remainder of the study, and at the end of the study period.

BODY WEIGHT: Yes
- Time schedule: conducted at the start of the study, weekly for 13 weeks, monthly during the remainder of the study, and at the end of the study period.

HAEMATOLOGY: Yes
- Blood was collected from the retroorbital sinus of as many as five male and five female mice at the 15-month interim evaluation.
- Hematology: hematocrit, hemoglobin, erythrocytes, mean erythrocyte volume, mean erythrocyte hemoglobin, mean erythrocyte hemoglobin concentration, reticulocytes, total leukocytes and differential, and nucleated erythrocytes.

Sacrifice and pathology:

GROSS PATHOLOGY/HISTOPATHOLOGY: Yes
Necropsy was performed on all animals.  
The following organs were weighed at 7- and 15-months: brain, right kidney, liver, lung, spleen, and thymus.

Complete histopathology was performed on all mice.  Gross lesions and tissues examined included: adrenal gland, bone, brain, clitoral gland,  
epididymis or oviduct, esophagus, heart, gallbladder, large intestine (including cecum, colon, rectum), small intestine (including duodenum,  
jejunum, ileum), kidneys, larynx, liver, lung, lymph nodes, mammary gland, nose, ovary, pancreas, parathyroid gland, pituitary gland,  
preputial gland, prostate, salivary gland, seminal vesicle, skin, spleen, stomach, testis, thymus, thyroid gland, trachea, urinary bladder, and uterus.

Other examinations:

Ni levels in lung and kidney tissues were analyzed.

Statistics:

The probability of survival was estimated by the product-limit procedure of Kaplan and Meier (1958).  Dose-related effects were analyzed using  
Cox's (1972) method for testing two groups for equality, and Tarone's (1975) life table test to identify dose-related trends.  Organ and body  
weight data were analyzed using the parametric multiple comparison procedures of Dunnett (1955) and Williams (1971, 1972).

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

no effects observed

Details on results:

CLINICAL SIGNS AND MORTALITY:
Survival rates of exposed mice were similar to controls.  

BODY WEIGHT AND WEIGHT GAIN:
Mean body weights of 1 mg/m3 males and of all Ni-exposed females were lower than control animals during year 2 of the study.

ORGAN WEIGHTS
Significant organ weight changes reported: -increased absolute lung weights of 1 mg/m3 males and females at 15-month evaluation.
-increased relative lung weight of 1 mg/m3 females at 15-month evaluation.

HAEMATOLOGY:
There were no substance-related hematology differences or clinical findings reported.
Tissue Ni burden levels were below the level of detection at the 7- and 15-month evaluation periods.

HISTOPATHOLOGY: NON-NEOPLASTIC
Significantly increased incidences of non-neoplastic lung lesions reported for 2-year study:
-chronic active lung inflammation of 0.5 and 1 mg/m3 male mice, and 0.25, 0.5, and 1 mg/m3 female mice.
-macrophage hyperplasia of 0.5 and 1 mg/m3 male mice, and 0.25, 0.5, and 1 mg/m3 female mice.
-bronchialization of 0.5 and 1 mg/mg3 male mice, and 0.25, 0.5, and 1   mg/m3 female mice.
-interstitial infiltration of 1 mg/m3 male mice, and 0.5 and 1 mg/m3  female mice.
-alveolar proteinosis of 1 mg/m3 male mice, and 0.5 and 1 mg/m3 female mice.
-bronchial lymphoid hyperplasia of 1 mg/m3 male and female mice.
-bronchial macrophage hyperplasia of 0.5 and 1 mg/m3 male and female mice.
The incidence of atrophy of the olfactory epithelium at the end of the 2-year study was significantly increased in 0.5 and 1 mg/m3 male mice,  
and in 1 mg/m3 female mice.

HISTOPATHOLOGY: NEOPLASTIC
No nickel sulfate hexahydrate-related neoplasms (alveolar/bronchiolar adenoma or carcinoma) were found in male or female mice exposed to the  
test substance via whole body inhalation for 2 years.

Result (carcinogenicity): negative

On the basis of chronic active lung inflammation, the LOAEL was determined to be 0.056 mg Ni/m3 (0.25 mg nickel sulfate hexahydate/m3).   
No NOAEL could be determined. The authors reported "no evidence of carcinogenic activity of nickel sulfate hexahydrate in male or 
female B6C3F1 mice exposed to 0, 0.25,  0.5, or 1 mg/m3" under the conditions of the 2-year inhalation study.

Dose descriptor:

LOAEL

Effect level:

0.056 other: mg Ni/m3

Sex:

male/female

Basis for effect level:

other: chronic active lung inflammation

Remarks on result:

other: Effect type: toxicity (migrated information)

Conclusions:

The authors reported "no evidence of carcinogenic activity of nickel sulfate hexahydrate in male or female B6C3F1 mice exposed to 0, 0.25,  0.5, or 1 mg/m3" under the conditions of the 2-year inhalation study.

Executive summary:

STUDY RATED BY AN INDEPENDENT REVIEWER.

ROBUST SUMMARY DEVELOPED BY AN INDEPENDENT REVIEWER.

Robust Summary for NTP (1996):

Male and female B6C3F1 mice were obtained from Simonsen Laboratories, Gilroy, CA, USA.  Groups of mice (80 males + 80 females) were  

individually housed and provided food and water ad libitum, except during exposure.  6-week old mice were exposed to the test substance via whole  

body inhalation chambers.  Chambers were maintained at a temperature of 17.2-29.6 deg. C, a relative humidity of 8-99%, and a 12-h light/dark  

photo cycle.  Chamber air changes were 9-21/hour.

The test compound was generated from aqueous solutions (62.1 g/L in distilled and deionized water) and atomized.  The aerosol was mixed with  

additional dilution air to achieve the proper concentration and flow rate.  The mass median aerodynamic diameter (MMAD) ranged from 1.8-3.1 um  

for all exposure concentrations.

Nickel sulfate hexahydrate concentrations tested were: 0, 0.25, 0.5, or 1 mg/m3 (equivalent to 0, 0.056, 0.11, or 0.22 mg Ni/m3 ).

Animals were observed twice daily.  Body weight and clinical observations were conducted at the start of the study, weekly for 13 weeks, monthly  

during the remainder of the study, and at the end of the study period.

Necropsy was performed on all animals.  The following organs were weighed at 7- and 15-months: brain, right kidney, liver, lung, spleen, and thymus.

Hematology parameters measured at 15 months from 5 males and 5 females: hematocrit, hemoglobin, erythrocytes, mean erythrocyte volume, mean  

erythrocyte hemoglobin, mean erythrocyte hemoglobin concentration, reticulocytes, total leukocytes, and differential and nucleated erythrocytes.

Complete histopathology was performed on all mice.  Gross lesions and tissues examined included: adrenal gland, bone, brain, clitoral gland,  

epididymis or oviduct, esophagus, heart, gallbladder, large intestine (including cecum, colon, rectum), small intestine (including duodenum,  

jejunum, ileum), kidneys, larynx, liver, lung, lymph nodes, mammary gland, nose, ovary, pancreas, parathyroid gland, pituitary gland,  

preputial gland, prostate, salivary gland, seminal vesicle, skin, spleen, stomach, testis, thymus, thyroid gland, trachea, urinary bladder, and uterus.

Ni levels in lung and kidney tissues were analyzed.

The probability of survival was estimated by the product-limit procedure of Kaplan and Meier (1958).  Dose-related effects were analyzed using  

Cox's (1972) method for testing two groups for equality, and Tarone's (1975) life table test to identify dose-related trends.  Organ and body  

weight data were analyzed using the parametric multiple comparison procedures of Dunnett (1955) and Williams (1971, 1972).

Survival rates of exposed mice were similar to controls.  Mean body weights of 1 mg/m3 males and of all Ni-exposed females were lower than  

control animals during year 2 of the study.

Significant organ weight changes reported:
-increased absolute lung weights of 1 mg/m3 males and females at 15 -month evaluation.
-increased relative lung weight of 1 mg/m3 females at 15-month evaluation.

There were no substance-related hematology differences or clinical findings reported.

Tissue Ni burden levels were below the level of detection at the 7- and 15-month evaluation periods.

No nickel sulfate hexahydrate-related neoplasms (alveolar/bronchiolar adenoma or carcinoma) were found in male or female mice exposed to the  

test substance via whole body inhalation for 2 years.

Significantly increased incidences of non-neoplastic lung lesions reported for 2-year study:
-chronic active lung inflammation of 0.5 and 1 mg/m3 male mice, and 0.25, 0.5, and 1 mg/m3 female mice.
-macrophage hyperplasia of 0.5 and 1 mg/m3 male mice, and 0.25, 0.5, and 1 mg/m3 female mice.
-bronchialization of 0.5 and 1 mg/mg3 male mice, and 0.25, 0.5, and 1 mg/m3 female mice.
-interstitial infiltration of 1 mg/m3 male mice, and 0.5 and 1 mg/m3 female mice.
-alveolar proteinosis of 1 mg/m3 male mice, and 0.5 and 1 mg/m3 female mice.

-bronchial lymphoid hyperplasia of 1 mg/m3 male and female mice.
-bronchial macrophage hyperplasia of 0.5 and 1 mg/m3 male and female mice.

The incidence of atrophy of the olfactory epithelium at the end of the 2-year study was significantly increased in 0.5 and 1 mg/m3 male mice,  

and in 1 mg/m3 female mice.

On the basis of chronic active lung inflammation, the LOAEL was determined to be 0.056 mg Ni/m3 (0.25 mg nickel sulfate hexahydate/m3).   

No NOAEL could be determined.

The authors reported "no evidence of carcinogenic activity of nickel sulfate hexahydrate in male or female B6C3F1 mice exposed to 0, 0.25,  

0.5, or 1 mg/m3" under the conditions of the 2-year inhalation study.

Reference 2

Endpoint:

carcinogenicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

June 1988 to Jun 1990

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Comparable to guideline study

Reason / purpose for cross-reference:

reference to same study

Qualifier:

no guideline followed

Principles of method if other than guideline:

A standard Test Guideline was not specified in this study.

GLP compliance:

yes

Species:

rat

Strain:

other: F344/N

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source:  Taconic Farms, Germantown, NY, USA.
- Age at study initiation: 6-week old
- Weight at study initiation: ~108-133 g
- Fasting period before study: not reported
- Housing: individually housed
- Diet (e.g. ad libitum): ad libitum, except during exposure
- Water (e.g. ad libitum): ad libitum, except during exposure
- Acclimation period:

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17.2-29.6 deg. C
- Humidity (%): 8-99%
- Air changes (per hr): 9-21/hour
- Photoperiod (hrs dark / hrs light): 12-h light/dark photo cycle

IN-LIFE DATES: June 1988 to June 1990

Route of administration:

inhalation

Type of inhalation exposure (if applicable):

whole body

Vehicle:

other: distilled and deionized water

Details on exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Stainless steel multitiered whole exposure chambers (Hazleton, Aberdeen, MD, USA)
- Method of holding animals in test chamber: not reported
- Source and rate of air: High-efficiency particulate air filter (Flanders, Washington, DC)
- Method of conditioning air: not reported
- System of generating particulates/aerosols: The test compound was generated from aqueous solutions (62.1 g/L in distilled and deionized water) and atomized.
- Temperature, humidity, pressure in air chamber: Temp. 17.2-29.6 deg. C; humidity 8-99%
- Air flow rate: The aerosol was mixed with additional dilution air to achieve the proper concentration and flow rate.
- Air change rate: not reported
- Method of particle size determination: cascade impactor, the mass median aerodynamic diameter (MMAD) ranged from 2.1-2.4 um for all exposure concentrations.
- Treatment of exhaust air: not reported

TEST ATMOSPHERE
- Brief description of analytical method used: aerosol concentrations determined gravimetrically
- Samples taken from breathing zone: yes

VEHICLE: water

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

aerosol concentrations were determined gravimetrically from two 3-hour samples (4.5 Wmin flow rate) for the 0.12 and 0.25 mg/m3
exposure chambers and from three 2-hour filter samples for the higher concentration.

Duration of treatment / exposure:

2 years

Frequency of treatment:

6 hours/day, 5 days/week, for 104 weeks

Post exposure period:

not reported

Remarks:

Doses / Concentrations:
0, 0.12, 0.25, 0.5 mg/m3 (equivalent to 0, 0.027, 0.056, 0.11 mg Ni/m3)
Basis:
nominal conc.

No. of animals per sex per dose:

63-65 males
63-64 females

Control animals:

yes, concurrent no treatment

Details on study design:

- Dose selection rationale: not reported
- Rationale for animal assignment (if not random): distributed randomely into groups of approximately equal initial mean body weights

Positive control:

none reported

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Animals were observed twice daily.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: conducted at the start of the study, weekly for 13 weeks, monthly during the remainder of the study, and at the end of the study period.

BODY WEIGHT: Yes
- Time schedule: conducted at the start of the study, weekly for 13 weeks, monthly during the remainder of the study, and at the end of the study period.

HAEMATOLOGY: Yes
- Blood was collected from the retroorbital sinus of as many as five male and five female mice at the 15-month interim evaluation.
- Hematology: hematocrit, hemoglobin, erythrocytes, mean erythrocyte volume, mean erythrocyte hemoglobin, mean erythrocyte hemoglobin concentration, reticulocytes, total leukocytes and differential, and nucleated erythrocytes.

Sacrifice and pathology:

GROSS PATHOLOGY/HISTOPATHOLOGY: Yes
Necropsy was performed on all animals.
The following organs were weighed at 7- and 15-months: brain, right kidney, liver, lung, spleen, and thymus.

Complete histopathology was performed on all mice. Gross lesions and tissues examined included: adrenal gland, bone, brain, clitoral gland,
epididymis or oviduct, esophagus, heart, gallbladder, large intestine (including cecum, colon, rectum), small intestine (including duodenum,
jejunum, ileum), kidneys, larynx, liver, lung, lymph nodes, mammary gland, nose, ovary, pancreas, parathyroid gland, pituitary gland,
preputial gland, prostate, salivary gland, seminal vesicle, skin, spleen, stomach, testis, thymus, thyroid gland, trachea, urinary bladder, and uterus.

Other examinations:

Ni levels in lung tissues were analyzed.

Statistics:

The probability of survival was estimated by the product-limit procedure of Kaplan and Meier (1958).  Dose-related effects were analyzed using  
Cox's (1972) method for testing two groups for equality, and Tarone's (1975) life table test to identify dose-related trends.  Organ and body  
weight data were analyzed using the parametric multiple comparison procedures of Dunnett (1955) and Williams (1971, 1972).

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Details on results:

CLINICAL SIGNS AND MORTALITY:
Survival rates of exposed rats were similar to controls.  Slight (6-9%) decrease in final mean body weights of females exposed to 0.5 mg/m3.   

BODY WEIGHT AND WEIGHT GAIN:
Final mean body weights of males at all exposed levels and of females at 0.12 and 0.25 mg/m3 were similar to control animals.

ORGAN WEIGHTS:
Significant organ weight changes reported: -increased relative lung weights of 0.25 and 0.5 mg/m3 males at 7-month evaluation.
-increased relative and absolute lung weights of 0.5 mg/m3 females at 7-month evaluation.
-increased relative and absolute lung weights of 0.5 mg/m3 males and   females at 15-month evaluation.

HAEMATOLOGY:
There were no substance-related hematology differences or clinical findings reported. Lung Ni levels were significantly higher in Ni-exposed rats 
relative to  the control animals.  Lung Ni levels increased with increasing Ni exposure levels.

HISTOPATHOLOGY: NON-NEOPLASTIC
Significantly-increased incidences of non-neoplastic lung lesions reported for 2-year study:
-chronic active lung inflammation of 0.25 and 0.5 mg/m3 rats.
-macrophage hyperplasia of 0.25 and 0.5 mg/m3 rats.
-alveolar proteinosis of 0.25 and 0.5 mg/m3 rats.
-fibrosis of 0.25 and 0.5 mg/mg3 rats.

HISTOPATHOLOGY: NEOPLASTIC
No nickel sulfate hexahydrate-related neoplasms (squamous cell carcinoma or alveolar/bronchiolar adenoma or carcinoma) were found in male or  
female rats exposed to the test substance via whole body inhalation  chambers for 2 years.

Result (carcinogenicity): negative

The incidence of atrophy of the olfactory epithelium at the end of the 2-year study was significantly increased in 0.5 mg/m3 male and female rats.
Chronic active lung inflammation was the most serious adverse effect detected.   The LOAEL was determined to be 0.056 mg Ni/m3 
(0.25 mg nickel sulfate hexahydate/m3) and the NOAEL was 0.027 mg Ni/m3 (0.12 mg nickel sulfate hexahydate/m3).

The authors reported "no evidence of carcinogenic activity of nickel  sulfate hexahydrate in male or female F344/N rats exposed to 0, 0.12,  
0.25, or 0.5  mg/m3" under the conditions of the 2-year inhalation study.

Dose descriptor:

NOAEC

Effect level:

0.027 other: mg Ni/m3

Sex:

male/female

Basis for effect level:

other: Chronic active lung inflammation 

Remarks on result:

other: Effect type: toxicity (migrated information)

Dose descriptor:

LOAEC

Effect level:

0.056 other: mg Ni/m3

Sex:

male/female

Basis for effect level:

other: Chronic active lung inflammation 

Remarks on result:

other: Effect type: toxicity (migrated information)

Conclusions:

The authors reported "no evidence of carcinogenic activity of nickel  sulfate hexahydrate in male or female F344/N rats exposed to 0, 0.12,  
0.25, or 0.5  mg/m3" under the conditions of the 2-year inhalation study.

Executive summary:

STUDY RATED BY AN INDEPENDENT REVIEWER.

ROBUST SUMMARY DEVELOPED BY AN INDEPENDENT REVIEWER.

Robust Summary for NTP (1996):

Male and female F344/N rats were obtained from Taconic Farms, Germantown, NY, USA.  Groups of rats (63-65 males + 63-64 females) were individually  

housed and provided food and water ad libitum, except during exposure.  6-week old rats were exposed to the test substance via whole body  

inhalation chambers.  Chambers were maintained at a temperature of 17.2-29.6 deg. C, a relative humidity of 8-99%, and a 12-h light/dark  

photo cycle.  Chamber air changes were 9-21/hour.

The test compound was generated from aqueous solutions (62.1 g/L in distilled and deionized water) and atomized.  The aerosol was mixed with  

additional dilution air to achieve the proper concentration and flow rate.  The mass median aerodynamic diameter (MMAD) ranged from 1.8-3.1 um  

for all exposure concentrations.

Nickel sulfate hexahydrate concentrations tested were: 0, 0.12, 0.25, or 0.5  mg/m3 (equivalent to 0, 0.027, 0.056, or 0.11mg Ni/m3).

Animals were observed twice daily.  Body weight and clinical observations were conducted at the start of the study, weekly for 13 weeks, monthly  

during the remainder of the study, and at the end of the study period.

Necropsy was performed on all animals.  The following organs were weighed at 7- and 15-months: brain, right kidney, liver, lung, spleen, right  

testis (at 7 months), and thymus.

Hematology parameters measured at 15 months from 5 males and 5 females:  hematocrit, hemoglobin, erythrocytes, mean erythrocyte volume, mean  

erythrocyte hemoglobin, mean erythrocyte hemoglobin concentration, reticulocytes, total leukocytes, and differential and nucleated erythrocytes.

Complete histopathology was performed on all rats.  Gross lesions and tissues examined included: adrenal gland, bone, brain, clitoral gland,  

epididymis or oviduct, esophagus, heart, large intestine (including cecum, colon, rectum), small intestine (including duodenum, jejunum,  

ileum), kidneys, larynx, liver, lung, lymph nodes, mammary gland, nose, ovary, pancreas, parathyroid gland, pituitary gland, pancreatic islets,  

preputial gland, prostate, salivary gland, seminal vesicle, skin, spleen, stomach, testis, thymus, thyroid gland, trachea, urinary bladder, and uterus.

Ni levels in lung tissues were analyzed.

The probability of survival was estimated by the product-limit procedure of Kaplan and Meier (1958).  Dose-related effects were analyzed using  

Cox's (1972) method for testing two groups for equality, and Tarone's (1975) life table test to identify dose-related trends.  Organ and body  

weight data were analyzed using the parametric multiple comparison procedures of Dunnett (1955) and Williams (1971, 1972).

Survival rates of exposed rats were similar to controls.  Slight (6-9%) decrease in final mean body weights of females exposed to 0.5 mg/m3.   

Final mean body weights of males at all exposed levels and of females at 0.12 and 0.25 mg/m3 were similar to control animals.

Significant organ weight changes reported:
-increased relative lung weights of 0.25 and 0.5 mg/m3 males at 7-month evaluation.
-increased relative and absolute lung weights of 0.5 mg/m3 females at 7-month evaluation.
-increased relative and absolute lung weights of 0.5 mg/m3 males and females at 15-month evaluation.

There were no substance-related hematology differences or clinical findings reported.

Lung Ni levels were significantly higher in Ni-exposed rats relative to the control animals.  Lung Ni levels increased with increasing Ni exposure levels.

No nickel sulfate hexahydrate-related neoplasms (squamous cell carcinoma or alveolar/bronchiolar adenoma or carcinoma) were found in male or  

female rats exposed to the test substance via whole body inhalation chambers for 2 years.

Significantly-increased incidences of non-neoplastic lung lesions reported for 2-year study:
-chronic active lung inflammation of 0.25 and 0.5 mg/m3 rats.
-macrophage hyperplasia of 0.25 and 0.5 mg/m3 rats.
-alveolar proteinosis of 0.25 and 0.5 mg/m3 rats.
-fibrosis of 0.25 and 0.5 mg/mg3 rats.

The incidence of atrophy of the olfactory epithelium at the end of the 2-year study was significantly increased in 0.5 mg/m3 male and female rats.

Chronic active lung inflammation was the most serious adverse effect detected.  The LOAEL was determined to be 0.056 mg Ni/m3 (0.25 mg nickel  

sulfate hexahydate/m3) and the NOAEL was 0.027 mg Ni/m3 (0.12 mg nickel  sulfate hexahydate/m3).

The authors reported "no evidence of carcinogenic activity of nickel sulfate hexahydrate in male or female F344/N rats exposed to 0, 0.12,  

0.25, or 0.5  mg/m3" under the conditions of the 2-year inhalation study.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEC

0.5 mg/m³

Species:

rat

Carcinogenicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

Ni fluoride belongs to the group 028 -029 -00 -4 in the 1st ATP to the CLP Regulation category and it has been classified as Carc. Cat. 1 and Carc. 1A; H350i .
Ni sulphate has been classified as Carc. 1A; H350i in the 1st ATP to the CLP Regulation. Background information regarding this classification is provided in the discussion section above. In addition, a background document that discusses the potential of Ni compounds to cause cancer via the oral route of exposure can be found in Appendix B1 of the CSR). In summary, absence of oral carcinogenicity of the nickel (II) ion demonstrates that the possible carcinogenic effects of nickel-containing substances in humans are limited to the inhalation route of exposure and the associated organ of entry (i. e., the respiratory tract). After inhalation, respiratory toxicity limits the systemic absorption of Ni (II) ion to levels below those that can be achieved via oral or dermal exposure.

 

Additional information

ENDPOINT SUMMARY INFORMATION FROM THE 2008/2009 EU NICKEL SULPHATE RISK ASSESSMENT:

 

Inhalation studies with nickel sulphate hexahydrate (MMAD = 2.1-2.5 µm; GSD ~ 2) have been performed in rats and mice (NTP 1996a). No exposure related neoplasms were observed in rats (F344/N) or in mice (B6C3F1) after exposure for two years at concentrations up to 0.11 mg Ni/m³ or 0.22 mg Ni/m³, respectively. These results are in contrast to those obtained with crystalline nickel subsulphide and green (high calcining temperature) nickel oxide. Inhalation studies with nickel oxide (NTP, 1996b) and nickel subsulphide (NTP, 1996c) showed some evidence and clear evidence, respectively, for carcinogenic activity following inhalation exposure in rats, and there was equivocal evidence for nickel oxide in female mice.

 

The different results obtained with nickel sulphate, nickel oxide, and nickel subsulphide raise questions as to whether these compounds differ in their mode of action or carcinogenic potency. The role of respiratory toxicity on carcinogenicity is also an important consideration. Water soluble nickel compounds are some of the most toxic of the nickel compounds for the respiratory tract but induced no tumors even at exposure levels corresponding to the maximum tolerated dose. A possible model for tumor initiation based on the Ni bioavailability at critical intracellular sites has been described to help reconcile all these possibilities (Goodman et al., 2009). It is postulated that there are many factors that can affect the bioavailability of nickel at key intracellular sites and that if these factors preclude Ni to be available at nuclear sites in sufficient amounts, no tumors will be induced. This could be the case for soluble nickel compounds that are very toxic to the lungs, and this toxicity limits the exposure levels that can be tolerated. In addition, these compounds are cleared from the lungs very quickly, and the Ni ion released extracellularly is very poorly taken up by the cells. The possibility that exposure to soluble nickel compounds may enhance the development of tumors initiated by other carcinogens cannot be excluded based on the data from animals experiments with single exposures.

 

The carcinogenicity of nickel sulphate following oral administration has been studied in rats and dogs and no neoplasms were observed in either of these two animal species (see Ambrose et al., 1976; IUCLID, section 7.7). However, these studies were old and not guideline compliant; therefore some uncertainties remained. A recent 2-year carcinogenicity study in rats by oral gavage has been completed (Heim et al., 2007). This study was performed according to OECD 451 guidance and it did not show a carcinogenic potential for exposure to nickel sulphate following oral administration. In conclusion, there is sufficient oral carcinogenicity data to show that nickel sulphate does not show a carcinogenic potential in experimental animals following oral administration. The negative results from the oral study are consistent with the negative results from the inhalation study in rats and provide supporting evidence for the low intracellular uptake and rapid excretion of water soluble nickel compound.

 

No data regarding carcinogenicity following dermal contact to nickel sulphate in experimental animals have been located. In conclusion, the available data are too limited for an evaluation of the carcinogenic potential in experimental animals following dermal contact to water soluble nickel compounds. As oral exposure does not show carcinogenicity, it seems reasonable to assume that cancer is not a relevant endpoint for dermal exposure.

 

Studies on the carcinogenicity of nickel sulphate following intramuscular or intraperitoneal injections have been performed in rats. The results have either been negative (e.g., Kasprzak et al., 1983) or have shown low incidence of injection site tumors at very high exposure levels (e.g., Pott et al., 1989). It should be noted that these routes of administration are irrelevant for human beings who will only be exposed via inhalation, oral intake or dermal contact to nickel sulphate.

 

Three studies with nickel sulphate in experimental animals suggest a promoter effect of nickel sulphate, if applied locally to the nasopharynx or the oral cavity, or by the feed to pups from initiated dams; however, the indications are rather weak. Goodman et al. (2009) considered these data and concluded that although several possible non-genotoxic effects of the nickel ion have been described, it is not clear whether soluble nickel compounds can elicit these effects in vivo or whether these effects, if elicited, would result in tumor promotion.

 

A background document that discusses the potential of Ni compounds to cause cancer via the oral route of exposure can be found in Appendix B1 of the CSR (and IUCLID Section 7.7).

 

In conclusion, the available data show that nickel compounds, with a few exceptions, produce local tumours following injection at various sites to experimental animals. It should be noted that these routes of administration are irrelevant for human beings who will only be exposed via inhalation, oral intake or dermal contact to nickel fluoride. However, the positive findings in these studies might be considered as part of the weight of the evidence when evaluating the carcinogenic potential of nickel fluoride to human beings. No other data considered as being relevant for the conclusion on the carcinogenicity of nickel sulphate in experimental animals following inhalation have been located. In conclusion, the available data on carcinogenicity of various nickel compounds, is considered as being insufficient for a conclusion on the carcinogenic potential of nickel fluoride in experimental animals following inhalation.

 

Epidemiology Data

As discussed in the European Union Risk Assessment for Nickel Sulphate (2008-2009), epidemiological studies from at least three nickel refineries processing sulphidic nickel ores have demonstrated elevated risk of lung and nasal cancer in workers exposed to dust containing nickel sulphate in the presence of variable amounts of water insoluble nickel compounds. These refineries were: the Clydach refinery in Wales, UK; the Kristiansand refinery in Norway; and the Harjavalta refinery in Finland. Among electrolysis workers at the Port Colborne refinery in Canada the association between respiratory cancer and exposure to nickel sulphate was not observed.

In Clydach (Doll et al., 1990; Easton et al., 1992; Sorahan and Williams, 2005; Grimsrud and Peto, 2006), elevated risk for death from lung or nasal cancer was found in workers employed in the hydrometallurgy department. Exposure to nickel sulphate also took place in other departments and there was evidence of a dose-response between soluble nickel exposure and increased cancer risk in workers with high oxidic and/or sulfidic exposure but not when oxidic and sulfidic exposures were low. At the Kristiansand refinery, both lung and nasal cancer mortality risks were elevated (Doll et al., 1990; Andersen et al., 1996; Grimsrud et al., 2002; 2003). A dose-response was demonstrated for lung cancer according to duration of work in the electrolysis departments. In a regression analysis, a dose-response for lung cancer and cumulative exposure to water-soluble nickel (nickel sulphate and nickel chloride) was observed after adjustment for age, smoking (ever smoker versus never smokers), and cumulative exposure to oxidic nickel. The effect from sulphidic nickel was not addressed but for oxidic nickel a modest increase in risk was also observed. The study suggested a multiplicative effect of smoking and nickel exposure. A 2002 case-control study within the same cohort, also demonstrated a dose-response between lung cancer and water-soluble nickel after adjustment for smoking (life-time habits). An increase in risk from exposures to other forms of nickel irrespective of dose could not be excluded.

The refinery in Harjavalta also treated a sulphidic nickel concentrate, as did the two refineries in Clydach and Kristiansand. Elevated risk for lung and nasal cancers was demonstrated in the group of workers with nickel sulphate exposures (Doll et al., 1990; Anttila et al., 1998). No adjustment for smoking could be performed in the analyses of lung cancer risk. No dose-response was found, but the number of cancer cases was low. The electrolysis workers at the Port Colborne refinery were exposed mainly to nickel sulphate until 1942 and from that year exposures contained a mixture of sulphate and chloride. In contrast to the three cohorts described above, lung cancer mortality risks were not elevated among the electrolysis workers with no exposure in leaching, calcining or sintering plant (Roberts et al., 1989a,b; Doll et al., 1990). In addition, there were no nasal cancer cases among these workers.

The European Union Risk Assessment for Nickel Sulphate (2008-2009) concluded that the epidemiological data demonstrated “a positive association in a dose-dependent manner between exposure to soluble nickel compounds (e.g., nickel sulphate) and increased respiratory cancer risk in at least three separate cohorts.”

The epidemiological evidence (without the animal data) was reviewed by the Specialised Experts at their in April, 2004. The Specialised Experts concluded that the epidemiological evidence was sufficient to classify nickel sulphate in Category 1, known to be carcinogenic to man. The Specialised Experts considered the data to be sufficient to establish a causal association between the human exposure to the substances and the development of lung cancer and they considered that there was supporting evidence for this conclusion from more limited data on nasal cancer (European Union Risk Assessment for Nickel Sulphate, 2008-2009).

A recent review of the carcinogenicity data for soluble nickel compounds applied the Bradford Hill criteria of causality to the epidemiological evidence in support of the carcinogenicity of soluble nickel compounds (Goodman et al.,2009). A weight of evidence analysis was later applied to the epidemiological, animal and mode of action data. Based on their evaluation, the authors considered that some epidemiological data, but not all, suggest that soluble nickel exposure leads to increased cancer risk in the presence of certain insoluble nickel compounds. In their opinion, there was only limited evidence for its carcinogenicity in humans. They note that although there is no evidence that soluble nickel acts as a complete carcinogen in animals, there is some evidence from the animal data that soluble nickel may act as a tumor promoter. Goodman et al..(2009) go on to state: “Finally, the mode-of-action data suggest that soluble nickel compounds are not able to cause genotoxic effects in vivo because they cannot deliver sufficient nickel ion to nuclear sites of target cells. Although the data do suggest several possible non-genotoxic effects of the nickel ion, it is unclear whether soluble nickel compounds can elicit these effects in vivo or whether these effects, if elicited, would result in tumor promotion. Overall, the mode-of-action data equally support soluble nickel as a promoter or as not being a causal factor in carcinogenesis at all.” Goodman and coworkers concluded: “The weight of evidence does not clearly support a role for soluble nickel alone in carcinogenesis.”

As discussed above, the Specialized Experts had concluded in 2004 that the epidemiological evidence was sufficient to classify nickel sulphate in Category 1, known to be carcinogenic to man.

The epidemiological evidence (without the animal data) was reviewed by the Specialised Experts at their in April, 2004. The Specialised Experts concluded that the epidemiological evidence was sufficient to classify nickel fluoride in Category 1, known to be carcinogenic to man. The Specialised Experts considered the data to be sufficient to establish a causal association between the human exposure to the substances and the development of lung cancer and they considered that there was supporting evidence for this conclusion from more limited data on nasal cancer (2008/2009 EU NICKEL SULPHATE RISK ASSESSMENT).

The 2008/2009 EU NICKEL SULPHATE RISK ASSESSMENT concluded that the epidemiological data demonstrated “a positive association in a dose-dependent manner between exposure to soluble nickel compounds (e.g., nickel fluoride) and increased respiratory cancer risk in at least three separate cohorts.”

 

The following information is taken into account for any hazard / risk assessment:

 

INHALATION: Data on respiratory carcinogenicity associated with inhalation exposure to nickel chloride and/or Ni sulphate (in mixed nickel exposures) from multiple human studies are considered (e.g., Oller et al., 2014; Grimsrud et al., 2002). Ni sulphate has been classified as Carc. 1A; H350i in the 1st ATP to the CLP Regulation.

ORAL: A well-conducted OECD 451 study in rats did not show any carcinogenic potential of nickel sulphate following oral administration.A summary document that discusses this topic can be found in Appendix B1 of the CSR (and IUCLID Section 7.7).

 

DERMAL: The available data concerning dermal exposure are too limited for an evaluation of the carcinogenic potential in experimental animals following dermal contact to nickel sulphate. However, as oral exposure to nickel sulphate does not show any carcinogenic potential, there are good reasons to assume that cancer is not a relevant end-point with respect to dermal exposure either.

Studies via other routes of exposure and promoter studies provide at most limited evidence of carcinogenicity of nickel sulphate in animals.

 

 

FOR AN EXTENSIVE DISCUSSION, REFER TO THE NICKEL SULFATE DOSSIER WHICH IS BASED ON THE CONCLUSIONS EXPLAINED IN THE 2008/2009 EUROPEAN UNION EXISITING SUBSTANCE RISK ASSESSMENT OF NICKEL (EU RAR) (EEC 793/93)

K1 and K2 studies included in the current version of the nickel sulphate dossier were reviewed and included. K3 and K4 studies from the NiSO4 dossier were not included in the NiF2 dossier if new studies were included in the last update of the NiSO4 dossier.