Nickel bis(sulphamidate)

Exposure related observations in humans: other data

Administrative data

Endpoint:

exposure-related observations in humans: other data

Type of information:

experimental study

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.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Nickel ion (stable isotope 61Ni)

IUPAC Name:

Nickel ion (stable isotope 61Ni)

Method

Ethical approval:

confirmed, but no further information available

Details on study design:

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). Nickel dose in drinking water was 12 ug Ni/kg body weight. Six different time intervals between nickel-supplemented drinking water and the intake of food were chosen to represent varying degrees of fasting and non-fasting condititions. 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: Twenty nickel-sensitized and 20 non-nickel-sensitized women with current vesicular hand eczema were dosed dosed with 12 ug Ni/kg body weight in drinking water udner fasting conditions. Fasting was continued for 4 hours after dosing. Urine samples were colected 12 hour before dosing, and then at 3 hour intervals until 12 hours after dosing, followed by 12 hour intervals until 72 hours after dosing. Blood samples were collected 24 hours before dosing and then 0, 1, 2, 5, 8, 24, 48, and 72 hours after dosing. Total nickel and nickel isotope measurements were made for each of the urine and blood samples.

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: The nickel dose from the prepared drinking water was 12 ug/kg body wt; with a nickel concentration of 3 ug/ml.
- 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.

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.

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.

Study 1:
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

Study 2:
Serum nickel concentrations show a peak 3 h after administration when nickel was ingested in water.
The cumulated excretion in urine was 10.82% (1.79-29.46) for nickel-sensitized individuals and 11.26% (4.03-25.14) for controls.

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.

Executive summary:

STUDY RATED BY AN INDEPENDENT REVIEWER