Nickel difluoride

Endpoint summary

Description of key information

Oral: A 2-year oral carcinogenicity study reported a NOAEL of 10 mg/kg body weight/day (2.2 mg Ni/kg bw/day) and a LOAEL of 30 mg/kg body weight/day (6.7 mg Ni/kg bw/day), as tested with the related substance NiSO4 (Heim et al. 2007). The LOAEL of 6.7 mg Ni/kg bw/day based on reduced body weight and increased mortality together with a NOAEL of 2.2 mg Ni/kg bw/day is taken forward to the risk characterisation. A summary on this topic is included in a background document in section 7.5.1 of the IUCLID file.

Inhalation: A carcinogenicity study via inhalation was performed with the related substance NiSO4 (NTP, 1996). Chronic lung inflammation including lung fibrosis results from long-term exposure via inhalation to a concentration of 0.056 mg Ni/m³ or 0.25 mg nickel sulphate hexahydrate/m³. A NOAEC of 0.12 mg/m³ (0.027 mg Ni/m³, MMAD = 2.5 µm) was identified for these effects (Dunnick et al., 1995). A summary on this topic is included in section 7.5.2 of the IUCLID file.

Dermal: It was not possible to determine a NOAEL/LOAEL for the dermal route based on the available information. Testing by the dermal route has been waived as Nickel is already classified as skin sensitising and data are available for a second route of exposure, i.e. inhalation.

 

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

repeated dose toxicity: oral, other

Remarks:

oral carcinogenicity study

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:

other: OECD 451 (Carcinogenicity Studies)

Qualifier:

according to guideline

Guideline:

other: EPA OPPTS 870.4200 (Carcinogenicity)

GLP compliance:

yes

Limit test:

no

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

Vehicle:

water

Details on oral 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

Dose / conc.:

10 mg/kg bw/day (nominal)

Remarks:

dose via oral gavage

Dose / conc.:

30 mg/kg bw/day (nominal)

Remarks:

dose via oral gavage

Dose / conc.:

50 mg/kg bw/day (nominal)

Remarks:

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.

Key result

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

Key result

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

Key result

Critical effects observed:

not specified

Conclusions:

A 2-year oral carcinogenicity study reported a NOAEL of 10 mg/kg body weight/day (2.2 mg Ni/kg bw/day) and a LOAEL of 30 mg/kg bw/day (6.7 mg/kg bw/day), as tested with the related substance NiSO4. The LOAEL of 6.7 mg Ni/kg bw/day based on reduced body weight and increased body weight and increased mortality together with a NOAEL of 2.2 mg Ni/kg bw/day is taken forward to the risk characterisation.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Study duration:

chronic

Species:

rat

System:

urinary

Organ:

kidney

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Reference

Reference 1

Endpoint:

chronic toxicity: inhalation

Remarks:

combined repeated dose and carcinogenicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1995

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Comparable to guideline study (OECD 453)

Reason / purpose for cross-reference:

reference to same study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)

Deviations:

no

Principles of method if other than guideline:

not applicable

GLP compliance:

not specified

Limit test:

no

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
- Housing: Hazleton 2000 whole-body chambers
- Diet (e.g. ad libitum): ad libitum during non-exposure periods
- Water (e.g. ad libitum): ad libitum

ENVIRONMENTAL CONDITIONS
- Photoperiod (hrs dark / hrs light): 12 hr dark, 12 hr light

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

whole body

Vehicle:

other: no data

Remarks on MMAD:

MMAD / GSD: MMAD =2.08-2.52 um

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Hazieton 1000 (mice) and Hazleton 2000 (rats) whole-body chambers (Lab Products, Inc., Maywood, NJ)
- Method of holding animals in test chamber: not reported
- Source and rate of air: not reported
- Method of conditioning air: not reported
- System of generating particulates/aerosols: Nickel sulfate aerosols were generated by nebulization of nickel sulfate solutions
- Temperature, humidity, pressure in air chamber: not reported
- Air flow rate: not reported
- Air change rate: not reported
- Method of particle size determination: Aerosol concentration was determined by taking three 2-h filter samples throughout the exposure day.
Real-time determination of aerosol concentration was made using real time aerosol monitor - model S units. Aerosol size was determined using cascade impactors. (The range of mass median aerodynamic diameters and GSD obtained throughout the study were 2.2-2.5 um and GSD=2.2)
- Treatment of exhaust air: not reported

TEST ATMOSPHERE
- Brief description of analytical method used: Aerosol concentration was determined by taking three 2-h filter samples throughout the exposure day.
Real-time determination of aerosol concentration was made using real time aerosol monitor - model S units. Aerosol size was determined using cascade impactors. (The range of mass median aerodynamic diameters and GSD obtained throughout the study were 2.2-2.5 um and GSD=2.2)
- Samples taken from breathing zone:not reported

VEHICLE (if applicable)
- water

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Aerosol concentration was determined by taking three 2-h filter samples throughout the exposure day.
Real-time determination of aerosol concentration was made using real time aerosol monitor-model S units.

Duration of treatment / exposure:

6 hr/day

Frequency of treatment:

5 d/wk, 2 yr

Dose / conc.:

0 mg/m³ air (nominal)

Dose / conc.:

0.125 mg/m³ air (nominal)

Dose / conc.:

0.25 mg/m³ air (nominal)

Dose / conc.:

0.5 mg/m³ air (nominal)

Dose / conc.:

1 mg/m³ air

No. of animals per sex per dose:

Groups of 63 to 65 male and 63 to 64 female rats

Control animals:

yes

Details on study design:

- Dose selection rationale: based on previous 13-week study

Positive control:

Not applicable

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: every 4 weeks

BODY WEIGHT: Yes
- Time schedule for examinations: every 4 weeks

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data

WATER CONSUMPTION: No data

OPHTHALMOSCOPIC EXAMINATION: No data

HAEMATOLOGY: No data

CLINICAL CHEMISTRY: No data

URINALYSIS: No data

NEUROBEHAVIOURAL EXAMINATION: No data

OTHER: Lung Ni burden

Sacrifice and pathology:

GROSS PATHOLOGY: Yes, organ weights
HISTOPATHOLOGY: Yes. Complete histopathology was performed on high-exposure and control groups and to a no-effect level in target tissues.

Other examinations:

lung Ni concentration

Statistics:

Tests of significance included pairwise comparisons of each exposed group with controls and a test for overall exposure-related trends. Organ and body weight data were analyzed using parametric multiple comparison procedures, and lung burden data were analyzed using nonparametric multiple comparison methods. The reported values were considered significant at the P < 0.05 level.

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

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

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

effects observed, treatment-related

Details on results:

GROSS PATHOLOGY/HISTOPATHOLOGY:
Complete necropsies were done on all animals. At necropsy, all organs and tissues were examined for grossly visible lesions, and all major
tissues and lesions were preserved in 10% neutral-buffered formalin, embed ded in paraffin, sectioned, and stained with hematoxylin and
eosin for microscopic examination.

Additional animals were added for lung burden determinations at 7 or 15 months, Ni analyzed by atomic absorption spectroscopy.

MORTALITY & BODY WEIGHT:
Survival and body weights were similar to in exposed mice and rats to controls.

ORGAN WEIGHTS:
At 15-months, the lung weight in the high-exposure nickel sulfate mice was 30-37% more than control lung weight, and in the rats, 33-41% more than controls.

GROSS & HISTOPATHOLOGY:
A spectrum of exposure-related nonneoplastic respiratory tract lesions included: focal alveolar/bronchiolar hyperplasia, inflammation, and/or
fibrosis of the lung and lymph oid hyperplasia of the lung-associated lymph nodes, and atrophy of the olfactory epithelium.

There were no increases in lung neoplasms in rats or mice exposed to nickel sulfate. The A/B neoplasms that were observed in the exposed
groups were similar in incidence and morphology to those observed in controls.

OTHER FINDINGS:
The lung burden at 7 or 15 months in rats and mice was 1-2 ug Ni/g lung for nickel sulfate.

Key result

Dose descriptor:

NOAEC

Effect level:

ca. 0.027 other: mg Ni/m³ (as Ni sulfate hexahydrate)

Sex:

male/female

Basis for effect level:

other: chronic active lung inflammation

Key result

Dose descriptor:

LOAEC

Effect level:

0.056 other: mg Ni/m³ (as Ni sulfate hexahydrate)

Sex:

male/female

Basis for effect level:

other: Chronic active lung inflammation

Key result

Critical effects observed:

not specified

Conclusions:

Chronic lung inflammation including lung fibrosis results from long-term exposure via inhalation to a concentration of 0.056 mg/m³ or 0.25 mg nickel sulphate hexahydrate/m³. A NOAEC of 0.12 mg/m³ (0.027 mg Ni/m³, MMAD = 2.5 µm) was identified for these effects

Reference 2

Endpoint:

chronic toxicity: inhalation

Remarks:

combined repeated dose and carcinogenicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Comparable to guideline study (OECD 453)

Reason / purpose for cross-reference:

reference to same study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)

Deviations:

not specified

Principles of method if other than guideline:

not applicable

GLP compliance:

not specified

Limit test:

no

Species:

mouse

Strain:

B6C3F1

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Simonsen Laboratories, Gilroy, CA
- Housing: Hazleton 1000 whole-body chambers
- Diet (e.g. ad libitum): ad libitum during non-exposure periods
- Water (e.g. ad libitum): ad libitum


ENVIRONMENTAL CONDITIONS
- Photoperiod (hrs dark / hrs light): 12 hr dark, 12 hr light

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

whole body

Vehicle:

other: no data

Remarks on MMAD:

MMAD / GSD: MMAD = 2.02-2.53 um

Details on inhalation 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 1.8-3.1 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 concentration was determined by taking three 2-h filter samples throughout the exposure day.
Real-time determination of aerosol concentration was made using real time aerosol monitor-model S units.

Duration of treatment / exposure:

6 hr/day

Frequency of treatment:

5 d/wk, 2 yr

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, 80 females

Control animals:

yes

Details on study design:

- Dose selection rationale: based on previous 13-week study

Positive control:

Not applicable

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: every 4 weeks

BODY WEIGHT: Yes
- Time schedule for examinations: every 4 weeks

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data

WATER CONSUMPTION: No data

OPHTHALMOSCOPIC EXAMINATION: No data

HAEMATOLOGY: No data

CLINICAL CHEMISTRY: No data

URINALYSIS: No data

NEUROBEHAVIOURAL EXAMINATION: No data

OTHER: Lung Ni burden

Sacrifice and pathology:

GROSS PATHOLOGY: Yes, organ weights
HISTOPATHOLOGY: Yes. Complete histopathology was performed on high-exposure and control groups and to a no-effect level in target tissues.

Other examinations:

lung Ni concentration

Statistics:

Tests of significance included pairwise comparisons of each exposed group with controls and a test for overall exposure-related trends. Organ and body weight data were analyzed using parametric multiple comparison procedures, and lung burden data were analyzed using nonparametric multiple comparison methods. The reported values were considered significant at the P < 0.05 level.

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

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

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

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:

not specified

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.

Dose descriptor:

LOAEC

Effect level:

0.056 other: mg Ni/m3 (as Ni sulfate hexahydrate)

Sex:

male/female

Basis for effect level:

other: chronic active lung inflammation

Critical effects observed:

not specified

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.

Conclusions:

Noncarcinogenic effects included alveolar/bronchiolar (A/B) hyperplasia, inflammation, fibrosis, and lymphoid hyperplasia of the lung-associated lymph nodes.Qualitatively, the effects were similar across the three nickel compounds, but were generally considered by the authors as more severe for NiO and Ni3S2; however, effects in mice were considered less sensitive than rats.

Executive summary:

As part of a study on the toxicity and carcinogenicity of NiSO4, Ni3S2 and NiO, Dunnick et al. (1995) described the toxicity of inhaled Ni3S2 in B6C3F1 mice exposed for 6 hr/d, 5 d/wk, for 2 years (0.15, and 1 mg Ni3S2 /m3; 0.11 and 0.73 mg Ni/m3). Chamber concentrations and aerosol size were determined analytically (MMAD: 2.1 μm; GSD 2.0). Noncarcinogenic effects examined included clinical signs, body and organ weights, tissue histopathology, and lung burden (note: carcinogenic effects and lung burden are described in the Carcinogenicity and Basic Toxicokinetics sections, respectively). No significant differences in mortality were observed between control and treated animals. Bodyweights of exposed animals were said to be within 5-10% of control animals and were not considered characterized as adverse effects. Lung weights in exposed animals were greater than controls and were considered to be due to inflammatory responses. By 7 months, lung weight was significantly increased in males at 1.2 mg/m3 and in females at 0.6 mg/m3. At 15 months, the lung weight was about 0.4 g in male mice treated at either dose versus 0.23 g in control males. In female mice, the lung weights were 0.26, 0.39, and 0.5 g in control mice and the mice treated at low and high doses of Ni3S2 . Noncarcinogenic effects included alveolar/bronchiolar (A/B) hyperplasia, inflammation, fibrosis, and lymphoid hyperplasia of the lung-associated lymph nodes. Qualitatively, the effects were similar across the three nickel compounds, but were generally considered by the authors as more severe for NiO and Ni3S2; however, mice were considered less sensitive than rats. This investigation was part of a comprehensive bioassay conducted by the National Toxicology Program (1996). STUDY RATED BY AN INDEPENDENT REVIEWER

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Study duration:

chronic

Species:

rat

Organ:

lungs

Repeated dose toxicity: inhalation - local effects

Link to relevant study records

Reference

Reference 1

Endpoint:

chronic toxicity: inhalation

Remarks:

combined repeated dose and carcinogenicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Comparable to guideline study (OECD 453)

Reason / purpose for cross-reference:

reference to same study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)

Deviations:

not specified

Principles of method if other than guideline:

not applicable

GLP compliance:

not specified

Limit test:

no

Species:

mouse

Strain:

B6C3F1

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Simonsen Laboratories, Gilroy, CA
- Housing: Hazleton 1000 whole-body chambers
- Diet (e.g. ad libitum): ad libitum during non-exposure periods
- Water (e.g. ad libitum): ad libitum


ENVIRONMENTAL CONDITIONS
- Photoperiod (hrs dark / hrs light): 12 hr dark, 12 hr light

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

whole body

Vehicle:

other: no data

Remarks on MMAD:

MMAD / GSD: MMAD = 2.02-2.53 um

Details on inhalation 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 1.8-3.1 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 concentration was determined by taking three 2-h filter samples throughout the exposure day.
Real-time determination of aerosol concentration was made using real time aerosol monitor-model S units.

Duration of treatment / exposure:

6 hr/day

Frequency of treatment:

5 d/wk, 2 yr

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, 80 females

Control animals:

yes

Details on study design:

- Dose selection rationale: based on previous 13-week study

Positive control:

Not applicable

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: every 4 weeks

BODY WEIGHT: Yes
- Time schedule for examinations: every 4 weeks

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data

WATER CONSUMPTION: No data

OPHTHALMOSCOPIC EXAMINATION: No data

HAEMATOLOGY: No data

CLINICAL CHEMISTRY: No data

URINALYSIS: No data

NEUROBEHAVIOURAL EXAMINATION: No data

OTHER: Lung Ni burden

Sacrifice and pathology:

GROSS PATHOLOGY: Yes, organ weights
HISTOPATHOLOGY: Yes. Complete histopathology was performed on high-exposure and control groups and to a no-effect level in target tissues.

Other examinations:

lung Ni concentration

Statistics:

Tests of significance included pairwise comparisons of each exposed group with controls and a test for overall exposure-related trends. Organ and body weight data were analyzed using parametric multiple comparison procedures, and lung burden data were analyzed using nonparametric multiple comparison methods. The reported values were considered significant at the P < 0.05 level.

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

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

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

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:

not specified

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.

Dose descriptor:

LOAEC

Effect level:

0.056 other: mg Ni/m3 (as Ni sulfate hexahydrate)

Sex:

male/female

Basis for effect level:

other: chronic active lung inflammation

Critical effects observed:

not specified

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.

Conclusions:

Noncarcinogenic effects included alveolar/bronchiolar (A/B) hyperplasia, inflammation, fibrosis, and lymphoid hyperplasia of the lung-associated lymph nodes.Qualitatively, the effects were similar across the three nickel compounds, but were generally considered by the authors as more severe for NiO and Ni3S2; however, effects in mice were considered less sensitive than rats.

Executive summary:

As part of a study on the toxicity and carcinogenicity of NiSO4, Ni3S2 and NiO, Dunnick et al. (1995) described the toxicity of inhaled Ni3S2 in B6C3F1 mice exposed for 6 hr/d, 5 d/wk, for 2 years (0.15, and 1 mg Ni3S2 /m3; 0.11 and 0.73 mg Ni/m3). Chamber concentrations and aerosol size were determined analytically (MMAD: 2.1 μm; GSD 2.0). Noncarcinogenic effects examined included clinical signs, body and organ weights, tissue histopathology, and lung burden (note: carcinogenic effects and lung burden are described in the Carcinogenicity and Basic Toxicokinetics sections, respectively). No significant differences in mortality were observed between control and treated animals. Bodyweights of exposed animals were said to be within 5-10% of control animals and were not considered characterized as adverse effects. Lung weights in exposed animals were greater than controls and were considered to be due to inflammatory responses. By 7 months, lung weight was significantly increased in males at 1.2 mg/m3 and in females at 0.6 mg/m3. At 15 months, the lung weight was about 0.4 g in male mice treated at either dose versus 0.23 g in control males. In female mice, the lung weights were 0.26, 0.39, and 0.5 g in control mice and the mice treated at low and high doses of Ni3S2 . Noncarcinogenic effects included alveolar/bronchiolar (A/B) hyperplasia, inflammation, fibrosis, and lymphoid hyperplasia of the lung-associated lymph nodes. Qualitatively, the effects were similar across the three nickel compounds, but were generally considered by the authors as more severe for NiO and Ni3S2; however, mice were considered less sensitive than rats. This investigation was part of a comprehensive bioassay conducted by the National Toxicology Program (1996). STUDY RATED BY AN INDEPENDENT REVIEWER

Reference 2

Endpoint:

chronic toxicity: inhalation

Remarks:

combined repeated dose and carcinogenicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1995

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Comparable to guideline study (OECD 453)

Reason / purpose for cross-reference:

reference to same study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)

Deviations:

no

Principles of method if other than guideline:

not applicable

GLP compliance:

not specified

Limit test:

no

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
- Housing: Hazleton 2000 whole-body chambers
- Diet (e.g. ad libitum): ad libitum during non-exposure periods
- Water (e.g. ad libitum): ad libitum

ENVIRONMENTAL CONDITIONS
- Photoperiod (hrs dark / hrs light): 12 hr dark, 12 hr light

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

whole body

Vehicle:

other: no data

Remarks on MMAD:

MMAD / GSD: MMAD =2.08-2.52 um

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Hazieton 1000 (mice) and Hazleton 2000 (rats) whole-body chambers (Lab Products, Inc., Maywood, NJ)
- Method of holding animals in test chamber: not reported
- Source and rate of air: not reported
- Method of conditioning air: not reported
- System of generating particulates/aerosols: Nickel sulfate aerosols were generated by nebulization of nickel sulfate solutions
- Temperature, humidity, pressure in air chamber: not reported
- Air flow rate: not reported
- Air change rate: not reported
- Method of particle size determination: Aerosol concentration was determined by taking three 2-h filter samples throughout the exposure day.
Real-time determination of aerosol concentration was made using real time aerosol monitor - model S units. Aerosol size was determined using cascade impactors. (The range of mass median aerodynamic diameters and GSD obtained throughout the study were 2.2-2.5 um and GSD=2.2)
- Treatment of exhaust air: not reported

TEST ATMOSPHERE
- Brief description of analytical method used: Aerosol concentration was determined by taking three 2-h filter samples throughout the exposure day.
Real-time determination of aerosol concentration was made using real time aerosol monitor - model S units. Aerosol size was determined using cascade impactors. (The range of mass median aerodynamic diameters and GSD obtained throughout the study were 2.2-2.5 um and GSD=2.2)
- Samples taken from breathing zone:not reported

VEHICLE (if applicable)
- water

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Aerosol concentration was determined by taking three 2-h filter samples throughout the exposure day.
Real-time determination of aerosol concentration was made using real time aerosol monitor-model S units.

Duration of treatment / exposure:

6 hr/day

Frequency of treatment:

5 d/wk, 2 yr

Dose / conc.:

0 mg/m³ air (nominal)

Dose / conc.:

0.125 mg/m³ air (nominal)

Dose / conc.:

0.25 mg/m³ air (nominal)

Dose / conc.:

0.5 mg/m³ air (nominal)

Dose / conc.:

1 mg/m³ air

No. of animals per sex per dose:

Groups of 63 to 65 male and 63 to 64 female rats

Control animals:

yes

Details on study design:

- Dose selection rationale: based on previous 13-week study

Positive control:

Not applicable

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: every 4 weeks

BODY WEIGHT: Yes
- Time schedule for examinations: every 4 weeks

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data

WATER CONSUMPTION: No data

OPHTHALMOSCOPIC EXAMINATION: No data

HAEMATOLOGY: No data

CLINICAL CHEMISTRY: No data

URINALYSIS: No data

NEUROBEHAVIOURAL EXAMINATION: No data

OTHER: Lung Ni burden

Sacrifice and pathology:

GROSS PATHOLOGY: Yes, organ weights
HISTOPATHOLOGY: Yes. Complete histopathology was performed on high-exposure and control groups and to a no-effect level in target tissues.

Other examinations:

lung Ni concentration

Statistics:

Tests of significance included pairwise comparisons of each exposed group with controls and a test for overall exposure-related trends. Organ and body weight data were analyzed using parametric multiple comparison procedures, and lung burden data were analyzed using nonparametric multiple comparison methods. The reported values were considered significant at the P < 0.05 level.

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

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

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

effects observed, treatment-related

Details on results:

GROSS PATHOLOGY/HISTOPATHOLOGY:
Complete necropsies were done on all animals. At necropsy, all organs and tissues were examined for grossly visible lesions, and all major
tissues and lesions were preserved in 10% neutral-buffered formalin, embed ded in paraffin, sectioned, and stained with hematoxylin and
eosin for microscopic examination.

Additional animals were added for lung burden determinations at 7 or 15 months, Ni analyzed by atomic absorption spectroscopy.

MORTALITY & BODY WEIGHT:
Survival and body weights were similar to in exposed mice and rats to controls.

ORGAN WEIGHTS:
At 15-months, the lung weight in the high-exposure nickel sulfate mice was 30-37% more than control lung weight, and in the rats, 33-41% more than controls.

GROSS & HISTOPATHOLOGY:
A spectrum of exposure-related nonneoplastic respiratory tract lesions included: focal alveolar/bronchiolar hyperplasia, inflammation, and/or
fibrosis of the lung and lymph oid hyperplasia of the lung-associated lymph nodes, and atrophy of the olfactory epithelium.

There were no increases in lung neoplasms in rats or mice exposed to nickel sulfate. The A/B neoplasms that were observed in the exposed
groups were similar in incidence and morphology to those observed in controls.

OTHER FINDINGS:
The lung burden at 7 or 15 months in rats and mice was 1-2 ug Ni/g lung for nickel sulfate.

Key result

Dose descriptor:

NOAEC

Effect level:

ca. 0.027 other: mg Ni/m³ (as Ni sulfate hexahydrate)

Sex:

male/female

Basis for effect level:

other: chronic active lung inflammation

Key result

Dose descriptor:

LOAEC

Effect level:

0.056 other: mg Ni/m³ (as Ni sulfate hexahydrate)

Sex:

male/female

Basis for effect level:

other: Chronic active lung inflammation

Key result

Critical effects observed:

not specified

Conclusions:

Chronic lung inflammation including lung fibrosis results from long-term exposure via inhalation to a concentration of 0.056 mg/m³ or 0.25 mg nickel sulphate hexahydrate/m³. A NOAEC of 0.12 mg/m³ (0.027 mg Ni/m³, MMAD = 2.5 µm) was identified for these effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Study duration:

chronic

Species:

rat

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: dermal

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: dermal

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

 

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

Oral Exposure
In a 3-6-month drinking water study by Vyskocil et al. (1994a), increased urinary albumin was detected in female rats exposed to 6.8 mg Ni/kg bw/day. In a 13-week study conducted by Obone et al. (1999), a LOAEL of 11 mg Ni/kg bw/day was identified for nickel sulphate hexahydrate given in drinking water. At this exposure level, a 4% reduction in body weight and increases in relative organ weights were observed. The NOAEL for these effects was 4.5 mg Ni/kg bw/day. A more recent 90-day study, by gavage, showed 8% body weight reduction at 7-11 mg Ni/kg bw/day (Benson et al., 2002). A 2-year chronic rat study conducted by Ambrose et al. (1976) examined the effects of nickel sulphate hexahydrate administered to rats in the diet. Effects on body weights were also observed in this study, with a NOAEL of 10 mg Ni/kg bw/day and a LOAEL of 100 mg Ni/kg bw/day identified for these effects. The same researchers conducted a 2-year study in dogs (Ambrose et al., 1976), and identified a NOAEL of 75 mg Ni/kg bw/day and a LOAEL of 188 mg Ni/kg bw/day for decreased body weight, lung granulomas, and bone marrow hyperplasia. However, because of the small group size (3 dogs/sex) it is possible that this study missed effects at the lower dose exposure levels.
A more recent 2-year OECD 451 carcinogenicity study found decreased body weight gains ranging from 4% to 12% in rats (males and females combined) following oral gavage administration of 2.2 to 11 mg Ni/kg bw/day. Survival was reduced in a dose-related manner, achieving statistical significance at the two highest dose levels in females (Heim et al., 2007).
The kidney has been identified as a target organ for oral toxicity of nickel (e.g., albuminuria) although marked histopathological kidney damage after oral exposure has not been observed (TERA, 1999). A mouse study showed mild tubular nephropathy but at higher dose levels. The increases in urinary albumin were observed at approximately the same dose level as the reduction in body weight. Various effects on the immune system have also been reported after oral exposure to nickel sulphate. The immune effects have been observed at dose levels above those causing body weight loss. Therefore, the LOAEL of 6.7 mg Ni/kg bw/day based on reduced body weight and increased mortality together with a NOAEL of 2.2 mg Ni/kg bw/day from the chronic Heim et al. (2007) study is taken forward to the risk characterisation for oral repeated dose toxicity.
A summary of the chronic oral toxicity of Ni compounds can be found in Section 7.5.1 of IUCLID.

Inhalation exposure
There are several inhalation studies ranging from 12 days to 24 months of exposure that have examined the effects of repeated exposure to nickel sulphate in rats and mice. These studies identified the target organ for toxicity effects of inhalation exposure to nickel sulphate as the respiratory tract, with effects seen in the nose and the lungs.
Following inhalation of nickel sulphate the most serious toxicity effects observed in the respiratory tract are chronic inflammation and fibrosis. The most relevant and sensitive studies to assess chronic effects are the 2-year rat inhalation studies with nickel sulphate hexahydrate (NTP, 1996a; Dunnick et al., 1995). Rats appeared to be more sensitive to the toxicity effects of nickel sulphate by inhalation than mice. Chronic lung inflammation in rats including lung fibrosis was observed at a concentration of 0.056 mg Ni/m³ or 0.25 mg nickel sulphate hexahydrate/m³, with a NOAEC of 0.027 mg Ni/m³ identified for these effects. Although macrophage hyperplasia was detected at the exposure level of 0.027 mg Ni/m³, this effect was considered an adaptive effect and not an adverse toxicity effect. The LOAEC for repeated dose toxicity via inhalation of 0.056 mg Ni/m³ and the NOAEC of 0.027 mg Ni/m³ are used in the risk characterization of nickel sulphate.

Nickel sulphate fulfils the criteria for classification for repeated dose toxicity via inhalation since chronic lung inflammation including lung fibrosis results from long-term exposure via inhalation to a concentration of 0.056 mg Ni/m³ or 0.25 mg nickel sulphate hexahydrate/m³. Ni sulfate was classified as STOT RE 1;H372 in the 1st ATP to the CLP.

Dermal exposure
One set of studies describing toxicity effects after repeated exposure through the skin has been identified (Mathur et al. 1977; 1991; 1992; 1993; 1994) A NOAEL of 40 mg Ni/kg was identified in the Mathur et al. (1977) study for local effects on skin and systemic effects in testis and liver. However, due to the methodological limitations of this study, a NOAEL for toxicity effects via the dermal route is not carried forward to the risk characterisation. It was not possible to determine a NOAEL/LOAEL for the dermal route based on the available information, Therefore testing for chronic dermal toxicity has been waived. It should also be considered that Nickel fluoride is already classified as skin sensitiser. Risk measures to protect workers from exposure cover also the risk of dermal contact.

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.

Justification for classification or non-classification

There are several studies that have investigated the repeated toxicity of nickel sulphate via oral and inhalation routes of exposure. Only one set of studies investigating the effects of repeated exposure via the dermal route was identified. The target organ for toxicity caused by repeated exposure to nickel sulphate depends on the route of exposure.

Based on these results, the test substance is classified as STOT RE 1; H372 in the 1st ATP to the CLP Regulation. Background information regarding this classification is provided in the discussion section above.