Nickel(III) oxy hydroxide

Exposure related observations in humans: other data

Administrative data

Endpoint:

exposure-related observations in humans: other data

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Study period:

not reported

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Meets generally accepted scientific standards, well documented and acceptable for assessment

Cross-reference

Cross-reference 1

Reason / purpose for cross-reference:

reference to same study

Cross-reference 2

Reason / purpose for cross-reference:

reference to other study

Data source

Reference

Reference Type:

publication

Title:

Absorption and retention of nickel from drinking water in relation to food intake and nickel sensitivity.

Author:

Nielsen GD, Søderberg U, Jørgensen PJ, Templeton DM, Rasmussen SN, Andersen KE, Grandjean P

Year:

1999

Bibliographic source:

Toxicol Appl Pharmacol 154, 67-75.

Materials and methods

Type of study / information:

Toxicokinetics, absorption and retention of nickel from drinking water or food intake

Endpoint addressed:

basic toxicokinetics

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Test examined the influence of fasting and food intake on the absorption and retention of nickel in drinking water. Test methods described in the
following sections.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Nickel ion

IUPAC Name:

Nickel ion

Details on test material:

- Name of test material (as cited in study report): Stable isotope 61Ni
- Molecular formula (if other than submission substance): Not different than submission substance
- Molecular weight (if other than submission substance): Not different than submission substance
- Smiles notation (if other than submission substance): Not different than submission substance
- InChl (if other than submission substance): Not different than submission substance
- Structural formula attached as image file (if other than submission substance): Not different than submission substance.
- Substance type: Pure substance
- Physical state: Liquid
- Storage condition of test material: The isotope was dissolved and diluted to a concentration of 500 ug/ml and then diluted to 3 ug/ml before use
- All other details on test material not reported or not applicable.

Method

Ethical approval:

confirmed, but no further information available

Details on study design:

TEST SUBJECTS:
Study 1: Healthy men without known nickel sensitization were recruited. The eight volunteers were nonsmokers who did not use any medication
or alcohol at least 2 days prior to or during the study period. The age ranged from 21 to 30 years (median, 27 years), and the body weight varied
between 66 and 81 kg (median, 75 kg). The volunteers were tested for nickel sensitization after termination of the study using patch tests with nickel sulfate 5% in petrolatum (Hermal, Reinbek, Germany) applied for 2 days in Finn Chambers (Epitest Ltd., Helsinki, Finland) on Scanpor (Norgesplaster
AIS, Oslo, Norway) and read on the third day according to ICDRG recommendations (Wahlberg, 1995). No reactions were recorded in any of the
volunteers.

- Number of subjects exposed: 8
- Sex: Male
- Age: 21 to 30 years (median, 27 years)
- Race: Not reported
- Demographic information: Not reported
- Other: body weight varied between 66 and 81 kg (median, 75 kg).

Study 2: two age matched (+5 years) groups, each consisting of 20 women with current vesicular hand eczema (pompholyx type). They had no
history or clinical signs of atopic dermatitis. The nickel-sensitized subjects had a history of dermatitis from skin contact with white metal objects
and a positive patch test to 5% nickel sulfate in petrolatum within the last 2 years. The controls had no history of dermatitis from skin contact with
white metal objects and had a negative patch test to nickel. The nickel-sensitized group varied in age from 20 to 65 years (median, 39.5 years), while controls were 19-69 years (median, 36.5 years). Body weights were similar in the two groups and varied between 50 and 84 kg (median, 67 kg). If a
previous patch testing had not been performed within the last 2 years, retesting for confirmation was performed after termination of the
experimental study as described above. Reactions graded + to + + + were considered nickel-sensitized.

- Number of subjects exposed: 20 nickel-sensitised, 20 control
- Sex: Female
- Age: nickel-sensitised (20-65, median = 39.5 years), control (19-69, median = 36.5 years)
- Race: Not reported
- Demographic information: Not reported
- Other: body weight varied between 50 and 84 kg (median, 67 kg).

ENVIRONMENTAL CONDITIONS: Not applicable
IN-LIFE DATES: Not applicable

Exposure assessment:

measured

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: The isotope was dissolved and diluted to a concentration of 500 ug/ml and then further diluted to the final
concentration of 3 ug/ml just before use. This concentration was verified by atomic absorption measurements.

DIET PREPARATION
Study 1: Two days before and during each schedule, all volunteers avoided the following food items naturally high in nickel content: cocoa, soya
beans and other dried legumes, nuts, oat meal, and sweets. Further, water from the tap was allowed to run for 1 min before consumption. Before
each nickel intake, the volunteers fasted for 12 h (overnight). The nickel dose from the prepared drinking water was 12 ug/kg body wt; with a
nickel concentration of 3 ug/ml, the required water intake of each individual was 4 ml/kg body wt. For the eight male volunteers, the food intake
consisted of a standardized 1400-kj portion of scrambled eggs prepared in a microwave oven for 2.5 min from two eggs, 50 ml water, 2.5 g wheat
flour, and 15 g butter. Six different time intervals between the nickel-supplemented water intake and the intake of food were chosen. The nickel in
either water or scrambled eggs was taken on a Tuesday morning at 9 a.m. In each schedule, 12-h urine samples were collected from Monday at
9 p.m. until nickel intake at 9 a.m. the next morning. The following four urine samples were at 3-h intervals and were followed by five 12-h urine
samples, the last one completed at 9 a.m. Friday morning. Blood samples were taken (schedules 3,4, and 5) 24 h before nickel ingestion and at times 0, 1, 3, 8,24,48, and 72 h afterward.

Study 2: Prior to the nickel ingestion and daily during the study, all patients were examined clinically by the same dermatologist who was blinded
regarding nickel allergy. The status of hand eczema was evaluated according to the following clinical parameters: vesicles, erythema, scaling, and
fissures; the number of vesicles was counted on the lateral surfaces of the fingers and on the palm of the hand with the highest number of vesicles.
The grading system used the following categories: slight (0-30 vesicles), moderate (31-70 vesicles), or severe (more than 70 vesicles). During the
study period, none of the patients took systemic drugs that might influence the eczema. The patients were advised to continue using their skin care
product and to increase topical steroid treatment if a flare-up of eczema was noted.

- Rate of preparation of diet (frequency): The nickel solution (12 ug/kg body wt) was ingested on a Tuesday morning at 9 a.m., and fasting was then maintained for another 4 h.
- Mixing appropriate amounts with (Type of food): Food preparations described above
- Storage temperature of food: Not reported

VEHICLE
- Details on vehicle (water) not reported

HOMOGENEITY AND STABILITY OF TEST MATERIAL: Not reported

PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: Urine and blood sampled
- Time and frequency of sampling: A baseline 12-h urine sample was collected from 9 p.m. on Monday evening. Subsequent to nickel ingestion, four
3-h urine samples, followed by five 12-h urine samples, were collected, the last one being finished by Friday morning at 9 a.m. Blood samples were
taken 24 h before, and 0, I, 2, 5, 8, 24, 48, and 72 h after nickel ingestion. Blood specimens for lymphocyte isolation were obtained twice from each
volunteer, right before nickel intake and 5 h later. Intercellular fluid was collected during 1.5 h before administration of nickel and was initiated again 4 h after nickel intake.

STATISTICS:
The nonparametric Wilcoxon signed ranks test was used to test possible differences in the paired samples from the eight males, and the
Mann-Whitney U-test to test possible differences between the two matched groups of female volunteers.

Results and discussion

Results:

Excretion:
During the predose periods of Study 1, the total range of baseline nickel levels in the 12-h urine samples was 0.07-3.48 ug Ni/g creatinine, with
medians varying between 0.36 and 2.09. Baseline nickel concentrations in serum ranged from 0.07 ug/L to 1.45 ug/L, with medians varying between 0.26 ug/L and 0.62 ug/L.

When nickel was ingested in water 4 and 1.5 h after intake of eggs, the peak nickel excretion rate in urine was 12.2 times and 3.5 times, respectively, above the corresponding value when nickel in water and eggs were taken simultaneously. Likewise, when the nickel containing water was taken 0.5 and 1 h prior to the eggs, the peak nickel excretion levels were 10.0 times and 9.8 times, respectively, above the corresponding values when they were
taken together.

When nickel was ingested in water taken together with the eggs, the urinary nickel excretion was significantly higher during the interval from 12 to 60 h after intake compared to when the nickel was mixed into the eggs during the meal preparation, but the difference corresponded to a factor of only 1.3-1.5.

When the eggs were taken 4 h prior to nickel in drinking water, a total of 23.2% of the administered dose appeared in the urine collected, whereas only 7.1% was found if the eggs were taken 1.5 h prior to the nickel intake. When the eggs were taken 0.5 or 1 h after the nickel in water 12.8% and 16.7%,
respectively, were detected in the urine, and a significant difference between the two was observed from 9 h after the nickel intake. When water and
eggs were taken together or if they were mixed together, cumulative amounts of 3.4% and 2.3%, respectively, were detected in the urine.

Serum nickel concentrations show a peak 1 h after administration when nickel was ingested in water 0.5 and 1 h prior to the intake of eggs, and in
both cases it corresponded to 12.8 times the value at the same time when nickel in water and eggs were taken simultaneously, where a delayed peak was observed 3 h after the administration.

The range of median half-times of urinary excretion for the six schedules was 19.92-26.65 h, with a range of individual means of 21.00-35.78 h.
When the eggs were taken 4 h prior to nickel in drinking water, a cumulative median amount of 25.81% (25.00 +/- 11.02) of the administered dose
was excreted, while 2.51% (2.95 +/- 1.32) was excreted when the nickel was mixed into the eggs.

Toxicokinetic parameters:
Range of median Ni serum clearance = 8.15 - 8.40 ml/min
Range of median Ni creatinine clearance = 89.34 - 95.23 ml/min
Range of median Ni half-times of urinary excretion = 19.92 - 26.65 hours

In the second study, 17 controls had a slight hand eczema, three had a moderate eczema, and all remained unchanged during the study period. In the nickel-sensitized group, 9 showed a flare-up of symptoms after nickel intake, and they also reported increased use of topical steroids. All excacerbations started within 12 h after nickel administration.

The first serum sample from the female volunteers and the first 24-h urine sample before nickel administration showed nickel concentrations very similar to the first study. The serum analyses then showed a steep increase during the first couple of hours after nickel ingestion, followed by a decline. By 72 h, the nickel concentrations had not yet returned to the level before nickel ingestion. The highest nickel excretion was seen during the first 3 h after nickel ingestion, and the elimination remained increased 72 h later.

Following nickel ingestion, intercellular nickel concentrations increased by a factor of about eight in both groups. Two individuals showed a slightly lower nickel concentration at the second sampling, but otherwise clear increases were found. The nickel concentration in the cell pellets did not seem to reflect the changes revealed by the other parameters.

Applicant's summary and conclusion

Conclusions:

When nickel was ingested in water 30 min or 1 h prior to a meal, peak Ni concentrations in serum occurred 1 h after the water intake, and the peak
was 13-fold higher than the one seen 1 h after simultaneous intake of Ni containing water and scrambled eggs. Median urinary nickel excretion
half-times varied between 19.9 and 26.7 h. Within 3 days, the amount of nickel excreted corresponded to 2.5% of the nickel ingested when it was
mixed into the scrambled eggs. Increasing amounts were excreted as the interval between the water and the meal increased, with 25.8% of the
administered dose being excreted when the eggs were served 4 h prior to the nickel containing drinking water.