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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP-status not known, guideline not known, published in a regulatory document. Only a summary of the study is available, limitations in design and/or reporting but otherwise adequate for assessment.

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
Screening-level hazard characterisation: Lubricating grease thickeners category
Author:
US Environmental Protection Agency
Year:
2011
Bibliographic source:
Hazard characterisation document
Reference Type:
publication
Title:
Robust summary of information on grease thickeners
Author:
American Petroleum Institute
Year:
2008
Bibliographic source:
Petroleum High Production Volume (HPV) Testing Group (www.petroleumhpv.org/pages/greases)
Reference Type:
publication
Title:
Magnesium stearate given perorally to rats: A short term study
Author:
Sondergaard D, Meyer O, Wurtzen G
Year:
1980
Bibliographic source:
Toxicology, vol. 17, pp. 51-55 cited in API (2008)

Materials and methods

Principles of method if other than guideline:
- Method: Magnesium stearate was added to rat semi-synthetic diets in replacement of carbohydrates for 12 weeks and weight gain and necroscopic observations were recorded.
GLP compliance:
not specified
Limit test:
no

Test material

Constituent 1
Reference substance name:
Magnesium stearate
IUPAC Name:
Magnesium stearate
Constituent 2
Chemical structure
Reference substance name:
Magnesium distearate
EC Number:
209-150-3
EC Name:
Magnesium distearate
Cas Number:
557-04-0
Molecular formula:
C18H36O2.1/2Mg
IUPAC Name:
magnesium dioctadecanoate
Test material form:
not specified
Details on test material:
No data reported

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
- Age at test initiation: 6 weeks

Administration / exposure

Route of administration:
oral: feed
Vehicle:
not specified
Details on oral exposure:
- Administration: For three months, magnesium stearate was administered via the diet at 0, 5, 10 and 20 % in substitution of the carbohydrates.
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No data reported
Duration of treatment / exposure:
- Exposure period: 3 months (12 weeks)
Frequency of treatment:
No data reported
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
~2500 mg/kg-bw/day
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
~5000 mg/kg-bw/day
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
~10000 mg/kg-bw/day
Basis:
nominal in diet
No. of animals per sex per dose:
- Number of animals: 20 /sex/dose
Control animals:
yes
Details on study design:
- Diet: Rats were fed a semi-synthetic diet in which casein was replaced with sodium caseinate. The 0, 5, 10 and 20 % magnesium stearate diets contained 67.3, 62.3, 57.3 and 47.8% carbohydrates respectively. Acidified water (pH 3.5) were available ad libitum.
Positive control:
No data reported

Examinations

Observations and examinations performed and frequency:
- Observations: Body weights were measured weekly. Blood samples of 8 male and 8 females were taken at test initiation, 8 weeks and test termination and clinical and hematological chemistry was recorded.
- Hematological observations: Hemoglobin, packed cell volume, red cell count, total white cell count, reticulocyte count, differential white cell count
- Clinical chemistry observations: Glucose, urea, aspartate amino transferase, alkaline phosphatase
Sacrifice and pathology:
- Observations: At test termination, organ weights were recorded and microscopic examination was undertaken of the organs and tissues of the highest treatment and control.
- Organ weight measurements: Thymus, liver, kidneys, adrenals, testes/ovaries, heart, lungs, brain and pituitary
- Tissue samples for light microscopy: urinary bladder, stomach, duodenum, pancrease, jejunum, cecum, colon, thyroid, parathyroid, triceps, brachial muscle, ischiadic nerve, axillar lymph node, uterus, sternum, eye, Harderian gland, skin and submandibular gland
Other examinations:
No data reported
Statistics:
No data reported

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Mortality was observed in 4 high-dose males due to stone formation in the lower urinary pathways.
Mortality:
mortality observed, treatment-related
Description (incidence):
Mortality was observed in 4 high-dose males due to stone formation in the lower urinary pathways.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
All high-dose males showed decreases in body weight gain.
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 specified
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
High-dose males showed statistically significant reductions in packed cell volume.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
High dose males showed a decrease in liver glycogen and high-dose males and females showed increases in iron in the liver.
Urinalysis findings:
not specified
Behaviour (functional findings):
effects observed, treatment-related
Description (incidence and severity):
All high-dose males showed increases in quietness, incontinence and unsteady movements.
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Statistically significant differences were observed at all dose levels in male relative liver weights and female relative kidney weights.
Gross pathological findings:
not specified
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
- Necroscopy: Changes were observed in the renal pelvis and lower urinary pathways during the autopsy at test termination of 5 surviving animals (4 males and 1 female) from the 20% treatment due to stone formation. Nephrocalcinosis was observed in 12/20 control males and all control females (with it considered to be severe in 18 females). In the 20% treatment group, 19/20 females showed slight to moderate nephrocalcinosis and 7/20 males were affected only slightly.
- Hematology: 20% treatment males showed statistically significant reductions were observed in packed cell volumes
- Organs: When compared to the controls, significant changes (p<0.05) in liver weight were observed in males at 5, 10 and 20% treatments and 20% treatment females. Significant changes in kidney weight were observed in males at the 10% treatment and in females at the 5, 10 and 20% treatment groups. Various amounts of iron deposition was observed in the kidneys and livers, though the males and females in the 20% group both showed increased iron deposition. The 20% treatment males showed a marked decrease in liver glyocgen but no differences were observed in the females. No effects were reported for reproductive organ weights or histology for treated males or females.
- Clinical signs: After 8 weeks, body weight gains were significantly lower in the 20% treatment males than in the controls. The highest treatment males also showed slow and unsteady movement with quiet behaviour and one male was incontinent. The surviving males showed receding symptoms in the last 4 weeks. No clinical effects were observed in any females in any groups.
- Mortality: Within the first 2 months, 4 males in the 20% treatment group died, with their deaths considered to be related to the stone formation observed in the lower urinary pathways of all 4 animals
- Comparison with controls: Nephrocalcinosis has been observed to be common in animals fed semi-synthetic diets and the reduction in nephrocalcinosis of high-dose animals compared to the control may be a result of increased magnesium in the diet. Diets with increased magnesium content have also previously been shown to be associated with greater incidence of stone formation in the lower part of the urinary track.

Effect levels

open allclose all
Dose descriptor:
LOAEL
Effect level:
ca. 10 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: According to US EPA (2011). Based on mortality and haematological effects in males and possible signs of liver toxicity in males and females. Corresponding to 20% magnesium stearate in the diet.
Dose descriptor:
NOAEL
Effect level:
ca. 5 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: According to US EPA (2011). Corresponding to 10% magnesium stearate in the diet.
Dose descriptor:
NOAEL
Effect level:
2 500 mg/kg diet
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: According to API (2008). Based on liver weight. Corresponding to 5% magnesium stearate in the diet.

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
A 3 month study of approximately 2500, 5000 and 10000 mg/kg-bw/day magnesium stearate administered via the diet to Wistar rats (20/sex/dose) led to a LOAEL of ~10,000 mg/kg-bw/day based on mortality and hematological effects in males and possible signs of liver toxicity in males and females and a NOAEL of ~5000 mg/kg-bw/day.
Executive summary:

A 3 month study repeated dose oral toxicity used approximately 2500, 5000 and 10000 mg/kg-bw/day magnesium stearate administered via the diet to Wistar rats (20/sex/dose). According to the US EPA (2011), this led to a LOAEL of ~10,000 mg/kg-bw/day, corresponding to 20% magnesium stearate in the diet, based on mortality and hematological effects in males and possible signs of liver toxicity in males and females and a NOAEL of ~5000 mg/kg-bw/day, corresponding to 10% magnesium stearate in the diet. According to the API (2008), the NOEAL was 2500 mg/kg body weight, corresponding to 5% magnsium stearate in the diet based on liver weight. Only a summary of the study is available, with no information on the test methods used. However, this information is taken from regulatory documents (US EPA 2011, API 2008) and can be considered adequate for use for this endpoint.

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