Nickel bis(2-ethylhexanoate)

Repeated dose toxicity: dermal

Administrative data

Endpoint:

sub-chronic toxicity: dermal

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

not reported

Reliability:

3 (not reliable)

Rationale for reliability incl. deficiencies:

other: oral exposure cannot be ruled out

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference Type:

publication

Title:

Effect of nickel sulfate on male rats.

Author:

Mathur, A.K., K.K. Datta, S.K. Tandon, and T.S.S. Dikshith.

Year:

1977

Bibliographic source:

Bulletin of Environmental Contamination and Toxicology. 17(2):241-248.

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

A particular Test Guideline was not specified in this study.

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Nickel sulphate

EC Number:

232-104-9

EC Name:

Nickel sulphate

Cas Number:

7786-81-4

Molecular formula:

H2O4S.Ni

IUPAC Name:

Nickel sulfate

Details on test material:

- Name of test material (as cited in study report): Nickel sulfate hexahydrate, 10101-97-0
- 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

Test animals

Species:

rat

Strain:

other: albino

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: obtained from Industrial Toxicology Research Centre (Lucknow, India)
- Age at study initiation: not reported
- Weight at study initiation: 160 +/- 10 g
- Fasting period before study: not reported
- Housing: not reported
- Diet (e.g. ad libitum): not reported
- Water (e.g. ad libitum): not reported
- Acclimation period: not reported

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23-27 deg C
- Humidity (%): 60-70%
- Air changes (per hr): not reported
- Photoperiod (hrs dark / hrs light): not reported

IN-LIFE DATES: not reported

Administration / exposure

Type of coverage:

not specified

Vehicle:

other: saline

Details on exposure:

TEST SITE
- Area of exposure: A 4x4-cm patch of fur was shaved on the lateroabdominal area of each animal.  
- % coverage: not reported
- Type of wrap if used: patch
- Time intervals for shavings or clipplings: shaved on the lateroabdominal area of each animal.  

REMOVAL OF TEST SUBSTANCE: not reported

TEST MATERIAL
Appropriate amounts of the test substance were dissolved in normal saline to prepare nominal test concentrations of 40, 60, and 100 mg Ni/kg.
Animals in Group 1 were treated dermally with 40 mg Ni/kg; Group 2 with 60 mg Ni/kg; Group 3 with 100 mg Ni/kg; and Group 4 (control group) 
with 0.25 ml untreated saline.  The test and control concentrations were administered at a volume of 0.25 ml.  Dermal applications continued daily 
for the entire 30-day exposure period.  

VEHICLE: normal salive

USE OF RESTRAINERS FOR PREVENTING INGESTION: not reported

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

not reported

Duration of treatment / exposure:

30 days

Frequency of treatment:

daily

Doses / concentrations

Remarks:

Doses / Concentrations:
40, 60, and 100 mg Ni/kg
Basis:
nominal per unit body weight

No. of animals per sex per dose:

8

Control animals:

yes, concurrent vehicle

Details on study design:

no other details reported

Positive control:

none reported

Examinations

Observations and examinations performed and frequency:

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: not reported

BODY WEIGHT: Yes
- Time schedule for examinations: not reported

-Other examinations not reported

Sacrifice and pathology:

GROSS PATHOLOGY/HISTOPATHOLOGY: After 15 days of treatment, 4 animals from each group were sacrificed,  with the remaining 4 animals sacrificed at the end of the 30-day exposure period.  Gross and histopathological examinations of the skin, liver, kidney, and testis of each animal were conducted.

Other examinations:

none reported

Statistics:

none reported

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Dermal irritation:

not specified

Mortality:

no mortality observed

Body weight and weight changes:

not specified

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 examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

not specified

Details on results:

CLINICAL SIGNS AND MORTALITY:
No mortality or symptoms of poisoning were noted during the exposure period.

GROSS PATHOLOGY:
There were no gross changes to the liver, skin, kidneys, or testis of the exposed rats, after either 15- or 30-days of exposure.
The results of microscopic examination of the skin, liver, kidneys, and testis of exposed rats are summarized by treatment group:

DERMAL EXAMINATIONS:
Group 1 (40 mg Ni/kg): Day 15 - all tissues normal.  Day 30 - slight hyperkeratinization and distortion of the epidermis was noted.  No  
abnormal changes to the liver or testis.

Group 2 (60 mg Ni/kg): Day 15 - testis and skin normal; liver hepatocytes swollen with some degeneration.  Day 30 - tubular damage, degenerated  
sperm, and edematous fluid in testis; slight distortion and hyperkeratinization of the skin; focal necrosis, dilatation of the  sinusoids, and 
vacuolation of the liver.

Group 3 (100 mg Ni/kg): Day 15 - testis normal; distortion of the dermis and epidermis of the skin; liver hepatocytes swollen with some  
degeneration.  Day 30 - increased tubular degeneration and edema of the testis, necrotic tubules with a few giant cells in one rat, and  
distortion of the seminiferous tubules; atrophy or acanthosis of the  epidermis, epidermal cells disordered, increasing hyperkeratinization;  
focal necrosis, dilatation of the sinusoids, and vacuolation of the liver.

Group 4 (control; 0.25 ml saline): Days 15 and 30 - all tissues normal. Based on the results presented, there is evidence that the test substance  
was absorbed through intact skin.  Testicular changes were observed at an application of >= 60 mg Ni/kg, after exposure for 30 days.  Minor 
changes to the liver and skin were observed at 60 and 100 mg Ni/kg, respectively,  following 15 days of continuous exposure.  Microscopic 
changes to the  testis, liver, and skin became more severe following 30 days of  continuous exposure.

Effect levels

Dose descriptor:

NOAEL

Effect level:

40 other: mg Ni/kg

Sex:

male

Basis for effect level:

histopathology: non-neoplastic

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

There were no clinical symptoms of poisoning or mortality among experimental animals due to the dermal application of nickel sulphate. No gross changes were noticed in the skin, liver, kidney or testis of rats painted with nickel sulphate. There was no liver enlargement and the weight of liver showed no significant difference from those of controls. The testis did not show any marked atrophy or hypertrophy. The colour and weight of testes did not differ significantly from those of controls.

 

The results of microscopic examination on skin, liver and testis of control animals and those of 40, 60 and 100 mg Ni/kg groups after 15 and 30 days of exposure to nickel demonstrated that a NOAEL of 40 mg Ni/kg existed for effects on skin testis, and liver of nickel sulfate painted rats. No abnormality was observed in kidney of nickel sulphate treated rats.

Only males were included in the study. Exposure via the oral route of exposure could not be ruled out, preventing a conclusive assessment of the NOAEL for dermal exposure, based on these results. In addition, only selected endpoints were measured. Effects on body weights are unknown. Due to the limitations of the study a clear NOAEL for dermal exposure cannot be derived from this study.

Applicant's summary and conclusion

Conclusions:

In the study, 40 mg Ni/kg bw/day was a NOAEL for liver and testis degenerative changes, and a LOAEL for local effects on the skin. This study has limitations in experimental design and reporting. E.g., the group size in the study is small, only male animals were included, and only a limited number of organs were examined. Information on food intake and body weight were not given in the publication.

Executive summary:

STUDY RATED BY AN INDEPENDENT REVIEWER.

ROBUST SUMMARY DEVELOPED BY AN INDEPENDENT REVIEWER.

Robust Summary for Mathur et al.(1977):

Appropriate amounts of the test substance were dissolved in normal saline to prepare nominal test concentrations of 40, 60, and 100 mg Ni/kg.  Male  

albino rats (160 +/- 10 g), obtained from Industrial Toxicology Research Centre (Lucknow, India), were divided into 4 groups of 8.  A 4x4-cm patch  

of fur was shaved on the lateroabdominal area of each animal.  Animals in Group 1 were treated dermally with 40 mg Ni/kg; Group 2 with 60 mg Ni/kg;  

Group 3 with 100 mg Ni/kg; and Group 4 (control group) with 0.25 ml untreated saline.  The test and control concentrations were administered  

at a volume of 0.25 ml.  Dermal applications continued daily for the entire 30-day exposure period.  The test was conducted under constant  

conditions of temperature (25 +/- 2 deg. C) and relative humidity  (60-70%).  Animals were observed for mortality.

After 15 days of treatment, 4 animals from each group were sacrificed, with the remaining 4 animals sacrificed at the end of the 30-day exposure  

period.  Gross and histopathological examinations of the skin, liver, kidney, and testis of each animal were conducted.

No mortality or symptoms of poisoning were noted during the exposure period.

There were no gross changes to the liver, skin, kidneys, or testis of the exposed rats, after either 15- or 30-days of exposure.

The results of microscopic examination of the skin, liver, kidneys, and testis of exposed rats are summarized by treatment group:

Group 1 (40 mg Ni/kg): Day 15 - all tissues normal.  Day 30 - slight hyperkeratinization and distortion of the epidermis was noted.  No abnormal changes to the liver 

or testis.

Group 2 (60 mg Ni/kg): Day 15 - testis and skin normal; liver hepatocytes swollen with some degeneration.  Day 30 - tubular damage, degenerated  

sperm, and edematous fluid in testis; slight distortion and hyperkeratinization of the skin; focal necrosis, dilatation of the sinusoids, and vacuolation of the liver.

Group 3 (100 mg Ni/kg): Day 15 - testis normal; distortion of the dermis and epidermis of the skin; liver hepatocytes swollen with some  

degeneration.  Day 30 - increased tubular degeneration and edema of the testis, necrotic tubules with a few giant cells in one rat, and  

distortion of the seminiferous tubules; atrophy or acanthosis of the epidermis, epidermal cells disordered, increasing hyperkeratinization;  

focal necrosis, dilatation of the sinusoids, and vacuolation of the liver.

Group 4 (control; 0.25 ml saline): Days 15 and 30 - all tissues normal.

Based on the results presented, there is evidence that the test substance was absorbed through intact skin.  Testicular changes were observed at an  

application of >= 60 mg Ni/kg, after exposure for 30 days.  Minor changes to the liver and skin were observed at 60 and 100 mg Ni/kg, respectively,  

following 15 days of continuous exposure.  Microscopic changes to the testis, liver, and skin became more severe following 30 days of continuous exposure.