Nickel bis(sulphamidate)

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2008

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP guideline study

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 1

Reference Type:

study report

Title:

Unnamed

Year:

2008

Report date:

2008

Reference 2

Reference Type:

publication

Title:

Acute Oral Toxicity of Nickel Compounds

Author:

Henderson RG, Durando J, Oller A, Merkel DJ, Marone PA, and Bates HK.

Year:

2012

Bibliographic source:

Regul Toxicol and Pharmacol (doi.org/10.1016/j.yrtph.2012.02.002)

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 425 (Acute Oral Toxicity: Up-and-Down Procedure)

Deviations:

not specified

Remarks:

regarding limit test

Principles of method if other than guideline:

Not Applicable

GLP compliance:

yes

Test type:

up-and-down procedure

Test material

Test material information

Constituent 1

Reference substance name:

Nickel bis(sulphamidate)

EC Number:

237-396-1

EC Name:

Nickel bis(sulphamidate)

Cas Number:

13770-89-3

Molecular formula:

Ni(NH2SO3)2

IUPAC Name:

nickel(2+) disulfamate

Constituent 2

Reference substance name:

124594-15-6

Cas Number:

124594-15-6

IUPAC Name:

124594-15-6

Details on test material:

- Name of test material (as cited in study report): Nickel sulfamate (nickel sulfamate tetrahydrate), Code #N104-PTL
- Physical state: green crystals
- Analytical purity: nickel sulfamate tetrahydrate 100%
- Storage condition of test material: under nitrogen
- Stability: expected to be stable for the duration of the testing
- Solubility: soluble in water
- Other: EPSL Reference Number 080707-38H

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Received from Ace Animals, Inc, Boyertown, PA
- Age at study initiation: young adult (9-12 weeks)
- Weight at study initiation: 175-231 grams
- Fasting period before study: overnight
- Housing: singly in suspended stainless steel caging with mesh floors; litter paper was placed beneath the cage and changed at least three times/week
- Diet (e.g. ad libitum): Purina Rodent Chow #5012
- Water (e.g. ad libitum): ad libitum, filtered tap supplied by an automatic water dispensing system
- Acclimation period: 10-30 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-21
- Humidity (%): 56-86 (the humidity was above the targeted upper limit of 70% during the study due to exceptionally high, seasonal humidity; portable dehumidifiers were used to lower the humidity levels during this time)
- Photoperiod (hrs dark / hrs light): 12 hour light/dark cycle

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 60% w/w mixture in distilled water
- Other: preliminary solubility testing conducted by EPSL indicated that mixtures in excess of 60% were too viscous to be administered properly.


MAXIMUM DOSE VOLUME APPLIED:
- Individual doses were calculated based on the initial body weights, taking into account the specific gravity (determined by EPSL) and concentration of the test mixture.


CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: the Main Test was conducted using a default starting dose level of 175 mg/kg

Doses:

A Main Test was conducted using a default starting dose level of 175 mg/kg; remaining doses were determined using the Up and Down procedure (a dose of 550 or 2000 mg/kg was administered to the remaining animals). The decision to proceed with the next animal was based on the survival of the previous animal following dosing.

No. of animals per sex per dose:

175 mg/kg: 1 female
550 mg/kg: 3 females
2000 mg/kg: 3 females

See table for dosing sequence.

Control animals:

no

Details on study design:

DETAILS ON STUDY DESIGN
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: multiple observations within the first several hours post-dosing; at least once daily thereafter. Body weight was recorded prior to test substance administration and again on Days 7 and 14 following dosing or after death.
- Necropsy of survivors performed: yes; gross necropsies were performed on all decedents and euthanized animals, tissues and organs of the thoracic and abdominal cavities were examined
- Other examinations performed: mortality, signs of gross toxicity, behavioral changes, gross evaluation of skin and fur, eyes and mucous membranes, respiratory, circulatory, autonomic and central nervous systems, somatomotor activity and behavior pattern. Particular attention was directed to observation of tremors, convulsions, salivation, diarrhea, and coma.

Statistics:

The Acute Oral Toxicity (Guideline 425) Statistical Program (Weststat, version 1.0, May 2001) was used for all data analyses including: dose progression selections, stopping criteria determinations, and/or LD50 and confidence limit calculations.

Results and discussion

Preliminary study:

Not Applicable

Effect levels

Sex:

female

Dose descriptor:

LD50

Effect level:

1 098 mg/kg bw

95% CL:

ca. 500 - ca. 2 000

Mortality:

175 mg/kg (1 animal): survived
500 mg/kg (3 animals): survived
2000 mg/kg (3 animals): died

Clinical signs:

other: 175 mg/kg (1 animal): appeared active and healthy during the study 500 mg/kg (3 animals): apart from one female exhibiting reduced fecal volume on Day 1, there were no other signs of gross toxicity, adverse pharmacologic effects, or abnormal behavior 2000

Gross pathology:

175 mg/kg (1 animal): no signs of gross toxicity, adverse pharmacologic effects, or abnormal behavior
500 mg/kg (3 animals): no gross abnormalities were noted for any of the animals when necropsied at the conclusion of the observation period
2000 mg/kg (3 animals): red intestines were observed at necropsy

Other findings:

Not Applicable

Any other information on results incl. tables

Dosing Sequence	Animal No.	Dose Level (mg/kg)	Short-Term Outcome	Long-Term Outcome
1	3101	175	S	S
2	3102	550	S	S
3	3103	2000	D	D
4	3104	550	S	S
5	3105	2000	D	D
6	3106	550	S	S
7	3107	2000	D	D

S= Survived

D = Death

Applicant's summary and conclusion

Conclusions:

Under the conditions of this study, the acute oral LD50 of nickel sulfamate crystals (nickel sulfamate tetrahydrate) is estimated to be 1,098 mg/kg body weight in female rats with an approximate 95% confidence interval of 550 mg/kg (lower) to 2,000 mg/kg (upper). A NOAEL of 550 mg/kg bw (or 96 mg Ni/kg bw/day) was observed.

Executive summary:

Eurofins Product Safety Laboratory (EPSL) conducted an acute toxicity up and down procedure in female rats according to OECD Test # 425 guidelines and using GLP standards. This test allows for the estimation of an LD50 with a confidence interval and the results allow a substance to be classified for acute toxicity according to the Globally Harmonized System of classification and labeling of chemicals. Information regarding a limit test was not provided, thus it is not clear if such was conducted; however, the maximum dose in this study was 2000 mg/kg which is the OECD limit and thus the study is within guidelines. For the main test, a young female rat was exposed to a single default starting dose (175 mg/kg) of green nickel sulfamate crystals (nickel sulfamate tetrahydrate) administered via gavage as a 60% w/w mixture in distilled water. Remaining doses were determined using the Up and Down procedure (a dose of 550 or 2000 mg/kg was administered to the remaining animals, 3 animals per dose level). The decision to proceed with the next animal was based on the survival of the previous animal following dosing (a total of 7 animals were exposed in the following dose sequence: 175, 550, 2000, 550, 2000, 550, 2000 mg/kg). All animals were observed for mortality, signs of gross toxicity, and behavioral changes at least once daily; body weight was monitored prior to dosing and again on Days 7 and 14, and all animals were necropsied following death or at study termination (Day 14). Animals exposed to 175 or 550 mg/kg of the test substance survived, gained weight, and generally did not demonstrate any signs of gross toxicity, adverse effects, or abnormal behavior throughout the 14-day observation period. Additionally, no abnormalities were noted when these animals were necropsied. All three animals exposed to 2000 mg/kg died within three hours; these animals exhibited hypoactive and/or hunched posture and piloerection prior to death. Red intestines were noted upon necropsy. The oral LD50 was calculated using the maximum likelihood method and was estimated to be 1098 mg/kg bodyweight in female rats (95% CI of 550 mg/kg to 2000 mg/kg). STUDY RATED BY AN INDEPENDENT REVIEWER