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Acute Toxicity: oral

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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-referenceopen allclose all
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
2008
Report Date:
2008
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:
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

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
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 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:
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 mg/kg (3 animals): prior to death, animals were hypoactive and/or exhibited hunched posture and piloerection
Body weight:
175 mg/kg (1 animal): gained body weight
500 mg/kg (3 animals): gained body weight
2000 mg/kg (3 animals): not applicable
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
 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