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EC number: 233-279-4 | CAS number: 10102-90-6
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
Data source
Reference
- Reference Type:
- publication
- Title:
- Unnamed
- Year:
- 1 993
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- EU Method B.26 (Sub-Chronic Oral Toxicity Test: Repeated Dose 90-Day Oral Toxicity Study in Rodents)
- Deviations:
- yes
- Remarks:
- See below.
- Principles of method if other than guideline:
- The deviations are as follows:
No recovery group was included. General eye examinations of the control and high dose group were not carried out. Sensory activity and signs of neurotoxicity were not determined. It was not reported if animals were fasted overnight prior to blood sampling. Heamatological examinations did not include a measure of blood clotting time/potential. Determinations of plasma or serum did not include sodium, potassium or total cholesterol analysis. Signs of reproductive toxicity were included in the test methodology. - GLP compliance:
- yes
Test material
- Reference substance name:
- copper sulphate pentahydrate
- IUPAC Name:
- copper sulphate pentahydrate
Constituent 1
- Specific details on test material used for the study:
- Lot/Batch number: 533344
Description: Blue, crystalline solid
Purity: Not reported
Stability: Stable at room temperature
solid: crystalline
Test animals
- Species:
- mouse
- Strain:
- B6C3F1
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- Species: Mouse
Strain: B6C3F1
Source: Simonsen Laboratories, Gilroy, California, USA
Sex: Male and Female
Age/weight at study initiation: Test animals were approximately 6 weeks old at study initiation. Male mean bodyweights ranged from 20.9-21.6 g, mean female bodyweights ranged from 17.1-18.6 g.
Number of animals per group: In the study, groups of 10
animals per sex were tested at each dose level.
Control animals: Yes (10 males and 10 females).
Administration / exposure
- Route of administration:
- oral: feed
- Details on oral exposure:
- Feed mix was available ad libitum throughout the study period. Doses were based on a preliminary 2-week feed study.
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Preparation of active ingredient in feed: Copper sulphate was mixed with NIH-07 Open Formula Diet in meal form.
Homogeneity analysis were conducted on the copper sulphate feed mixture using inductively coupled plasma-atomic emission spectroscopy. Samples taken prior to study initiation and twice during the study, confirmed homogeneity between feed mixtures. - Duration of treatment / exposure:
- 92 days
- Frequency of treatment:
- 7 days per week
Doses / concentrationsopen allclose all
- Dose / conc.:
- 1 000 ppm
- Remarks:
- estimated intake (nominal in diet)
male: 44 mg Cu/kg bw/day
female: 52 mg Cu/kg bw/day
- Dose / conc.:
- 2 000 ppm
- Remarks:
- estimated intake (nominal in diet)
male: 97 mg Cu/kg bw/day
female: 126 mg Cu/kg bw/day
- Dose / conc.:
- 4 000 ppm
- Remarks:
- estimated intake (nominal in diet)
male: 187 mg Cu/kg bw/day
female: 267 mg Cu/kg bw/day
- Dose / conc.:
- 8 000 ppm
- Remarks:
- estimated intake (nominal in diet)
male: 398 mg Cu/kg bw/day
female: 536 mg Cu/kg bw/day
- Dose / conc.:
- 16 000 ppm
- Remarks:
- estimated intake (nominal in diet)
male: 815 mg Cu/kg bw/day
female: 1058 mg Cu/kg bw/day
- No. of animals per sex per dose:
- 10
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- Post-exposure period: none
Examinations
- Observations and examinations performed and frequency:
- Clinical signs:
Yes - test animals were observed weekly for clinical signs
Mortality:
Yes - test animals were observed twice daily for mortality/morbidity.
Body weight:
Yes - Individual bodyweights were recorded prior to the start of the study, on Day 1 and weekly thereafter.
Food consumption:
Yes - test animals were observed once weekly for food consumption.
Water consumption:
Not reported.
Ophthalmoscopic examination:
See histological examinations.
Haematology
No haematology parameters were investigated
Clinical Chemisty
No clinical chemistry parameters were investigated
Urinalysis
No urinalysis investigation was carried out - Sacrifice and pathology:
- Organ Weights:
liver, kidneys, adrenals, testes, epididymides, uterus, ovaries, thymus, spleen, brain, heart
Gross and histopathology:
Number of animals: Complete necropsies were performed on all animals in the control and high dose groups and on all other animals that died early
Time point: See above
Parameters: adrenal glands, brain (three sections), esophagus, eyes (if grossly abnormal) femur with marrow, gross lesions, heart, intestines (large: cecum, colon, rectum: small: duodenum, jejunum. Ileum), kidneys, liver, lung/mainstream bronchi, lymph nodes (mandibular, mesenteric) mammary gland, nasal cavity and turbinates (three sections), ovaries, pancreas, parathyroid glands, pharynx (if grossly abnormal), pituitary gland, preputial or
clitoral glands, prostate gland, salivary glands, spinal cord/sciatic nerve (if neurological signs were present), spleen, stomach (forestomach, glandular stomach), testes (with epididymis) thymus, thyroid gland, trachea, urinary bladder and uterus.Other examinations
Supplemental histological examination:
To characterise the distribution of copper in the liver and kidney, sections of both organs from selected males and females were stained for copper using the rhodanine method.
In order to determine the nature of the proteinaceous droplets (see in previous study on rats) sections from selected animals were stained for carbohydrate (PAS method), protein (Mallory-Heidenhain method), lipofuscin (AFIP method) and a-2-microglobulin (immunochemistry). Perl's stain for iron was used to stain sections of spleen from mice in all groups . - Other examinations:
- Sperm morphology and vaginal cytology:
Sperm morphology and vaginal cytology evaluations were performed on rats from the 0, 500, 200 and 4000 ppm groups (10 animals per sex and dose group). The method employed was as follows:
National Toxicology Program (NTP) 1987. Technical Protocol for Sperm Morphology and Vaginal Cytology Evaluations in Toxicity Testing for Rats and Mice, 10/31/82 version. Research Triangle Park, N.C.
Females: 12 days prior to sacrifice, the vaginal vaults of 10 individuals per dose group were lavaged and the aspirated lavage fluid and cells stained with Toluidine Blue. Relative numbers of leukocytes, nucleated epithelial cells and large squamous epithelial cells were determined and used to ascertain estrous cycle stage.
Males: Sperm motility was evaluated at necropsy. The left testis and epididymis were weighed, the tail of the epididymis was removed from the epididymis body and weighed. Test yolk was applied to slides and a small incision made in the cauda. The sperm effluxing from the incision were dispersed in the buffer on the slides, and the number of motile and non-motile spermatozoa counted for five microscopic fields per slide. Following motility determination, each left cauda were placed in phosphate buffered saline solution for sperm density determination with a hemacytometer. - Statistics:
- The following statistical procedures were followed:
Dunnet, C.W. 1955. A multiple comparison procedure for comparing several treatments with a control. J. Am. Stat. Assoc. 50, 1095-1121
Williams, D. A. 1971. Biometrics, 27, 103-117
Williams, D.A. 1972. The comparison of several dose levels with a zero dose control. Biometrics 28, 519-531
Shirley, E. 1977. A nonparametric equivalent of William's test for contrasting increasing dose levels of a treatment. Biometrics 33, 386-389
Dun, O.J. 1964. Multiple comparisons using rank sums. Technometrics 6, 241-252
Jonckheere, A.R. 1954. A distribution free k-sample test against ordered alternatives. Biometrika, 41, 133-145
Dixon & Massay 1951 Introduction to Statistical Analysis, McGraw-Hill Book Co.
Results and discussion
Results of examinations
- Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- 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:
- effects observed, treatment-related
- Gross pathological findings:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Histopathological findings: neoplastic:
- no effects observed
- Details on results:
- Clinical signs:
No clinical signs of toxicity, considered to be substance related, were observed in male or female mice during the course of the study.
Mortality:
No mice in any of the dose groups died or were killed before the end of the 13-week study.
Body weight gain:
Mice exhibited a dose-related growth depression which resulted in more severe body weight depression at higher dose levels. Final mean bodyweights and bodyweight gains were slightly lower than those of the control group for males in the 4000 ppm group and were significantly lower for males and females in the 8000 and 16,000 ppm groups. See attached Table 1.
Food consumption and compound intake:
For both sexes in all dose groups, the average daily feed consumption was similar to, or exceeded that of the controls. The average daily compound consumption increased proportionally with increasing concentrations of copper sulphate pentahydrate in the feed. See attached Table 1.
BLOOD ANALYSIS
Haematology: Not applicable
Clinical chemistry: Not applicable
Urinalysis: Not applicable
SACRIFICE AND PATHOLOGY
Organ weights:
Significant decreases in organ weights were noted for the heart and kidney of high dose (16,000 ppm) male mice and the thymus and kidney of the high does females. In addition, dose related decreases in absolute liver weights were noted for males and females, with significant decreases occurring
in both sexes in the 8000 and 16,000 ppm groups and the 4000 ppm group in males. Generally relative organ weights for males and females in all dosed groups were greater than that of the controls, and many of these increases were significant for the higher dose groups. These changes in
absolute and relative organ weights could be attributed to the lower final mean weights of mice in the higher doses. See attached Table 1.
Gross and histopathology:
Chemical related gross lesions were limited to the forestomach of seven male and four female mice in the 16,000 ppm groups. This lesion was characterised as a focal white discolouration of the squamous mucosa in the area of the limiting ridge where it forms a junction with the glandular gastric mucosa. Histopathological findings included minimal to mild squamous cell hyperplasia with hyperkeratosis of the forestomach mucosa at the site of the limiting ridge. This lesion was present in male and female mice receiving 4000 ppm test substance or greater. There was no evidence of inflammation or erosion/ulceration in the forestomach, and there was no increase in hyperplasia or hyperkeratosis in other portions of the forestomach mucosa. See attached Table 2.
Supplemental histological examination:
The livers and kidneys of male mice in all groups and female mice in the control group and 16,000 ppm were stained for the presence of copper. Positive staining was limited to the livers of high-dose male and female mice. Staining was extremely minimal and consisted of only a few positive
staining hepatocytes in the entire liver section. Hepatocytes staining positive for copper contained a maximum of approximately 10 red granules per cell. Due to limited number of cells stained, no distribution of copper was apparent. There was no staining of livers in the lower doses or in the controls, and no staining was present in the kidneys of any mice.
Because of the reduction in iron in the spleen of rats (see Rat Repeat Dose Toxicity), additional sections of spleen from four mice in each dosed and control group were stained for iron. There was no difference between dosed and control mice in the amount of iron-positive granules in the spleen.
Sperm Morphology and Vaginal Cytology:
No significant findings were noted in males or females in any dose group. See attached Table 3.
Effect levels
open allclose all
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No effects at this concentration (NOAEL).
- Key result
- Dose descriptor:
- LOAEL
- Effect level:
- 2 000 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- gross pathology
- histopathology: non-neoplastic
Target system / organ toxicity
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 2 000 ppm
- System:
- gastrointestinal tract
- Organ:
- stomach
- Treatment related:
- yes
Any other information on results incl. tables
The NOAEL for a dose-related depression in growth was 1000 ppm (44 mg Cu/kg bw/day) in males and 2000 ppm (126 Cu/kg bw/day) in females.
The histological NOAEL in both sexes, based on hyperplasia with hyperkeratosis of the epithelium on the limiting ridge separating the forestomach from the glandular stomach, was
2000 ppm (97 mg Cu/kg bw/day and 126 mg Cu/kg bw/day in males and females, respectively).
Reproductive parameters (sperm morphology and vaginal cytology) were evaluated in mice from the 0, 1000, 4000 and 8000 ppm groups. No significant findings were noted in either males or females from any group.
Applicant's summary and conclusion
- Conclusions:
- LOAEL: 2000 ppm for males and females
NOAEL: 1000 ppm for males and females - Executive summary:
Materials and Methods
The aim of the study was to examine the effect of copper sulphate (0,1000, 2000, 4000, 8000 or 16,000 ppm) administered to male and female B6C3F1mice in feed for 13 weeks. The test organisms were observed throughout the study for signs of clinical toxicity, mortality, bodyweight changes and food consumption. At the end of the study period all animals were sacrificed and subject to pathological examinations, sperm morphology and vaginal cytology. The study was conducted to a methodology developed by the US National Toxicology Program specifically for the test. The study was conducted in accordance with GLP.
Results and Discussion
There were no mortalities or signs of clinical toxicity observed in any of the test species during the duration of the study. Opthalmoscopic examinations revealed no abnormalities at any dose level tested. At gross pathology, significant decreases in heart and kidney weight were noted in the high dose males in the thymus and kidneys of high dose females. There was also a significant decrease in liver weights in both sexes in the 8000 and 16000 ppm dose groups. Chemical related gross lesions were limited to the forestomach of 7 male and 4 females in the 16000 ppm dose group. Histopathological findings included minimal to mild squamous cell hyperplasia with hyperkeratosis of the forestomach mucosa at the site of the limiting ridge. Minimal positive staining for copper was present in the liver and was limited to the high-dose male and female mice. No significant findings were noted following examination of the sperm morphology and vaginal cytology.
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