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EC number: 285-597-8 | CAS number: 85117-47-1
- 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
Endpoint summary
Administrative data
Description of key information
Key value for chemical safety assessment
Repeated dose toxicity: via oral route - systemic effects
Link to relevant study records
- Endpoint:
- short-term repeated dose toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Study conducted to OECD guidelines to to GLP, and therefore meets the requirements for Klimisch code 1.
- Guideline:
- OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- Deviations:
- yes
- Remarks:
- A fuctional observation battery for neurotoxicity was not performed since this test was not part of the OECD 407 guideline at the time the study was performed
- GLP compliance:
- yes
- Limit test:
- no
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories
- Age at study initiation: 41 days
- Weight at study initiation: males, 179-215g; female 141-170g
- Housing: hanging stainless steel wire-bottom cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 14 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-23°C
- Humidity (%): 48-66%
- Photoperiod (hrs dark / hrs light): 12 hour light/dark cycle - Route of administration:
- oral: gavage
- Vehicle:
- peanut oil
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS: Mixed weekly weight/volume in peanut oil
DIET PREPARATION
- Rate of preparation of diet (frequency): weekly
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Chemical analysis of dosing solutions was conducted to confirm that they were homogeneous and met the desired concentrations.
- Duration of treatment / exposure:
- 29 day treatment duration with a 14 day recovery period.
- Frequency of treatment:
- 7 days/week.
- Remarks:
- Doses / Concentrations:
gavage doses of 0, 100, 500 or 1000 mg/kg/bw/day
Basis:
actual ingested - No. of animals per sex per dose:
- 6
- Control animals:
- yes
- Details on study design:
- - Dose selection rationale: Data from a pilot two week repeated dose oral study
- Positive control:
- No.
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Daily
BODY WEIGHT: Yes
- Time schedule for examinations: Twice weekly
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data
FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No
- Time schedule for examinations:
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Weekly
- Dose groups that were examined:
HAEMATOLOGY: Yes
- Time schedule for collection of blood: At termination
- Anaesthetic used for blood collection: No
- Animals fasted: Yes
- How many animals: All
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: At termination
- Animals fasted: Yes
- How many animals: All
URINALYSIS: Yes
- Time schedule for collection of urine: Overnight before termination
- Metabolism cages used for collection of urine: No
- Animals fasted: Yes
NEUROBEHAVIOURAL EXAMINATION: No
- Time schedule for examinations:
- Dose groups that were examined:
- Battery of functions tested: sensory activity / grip strength / motor activity / other: - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes - Statistics:
- Tests applied included; parametric ANOVA with Dunnetts post-hoc test, non parametric Kruskal-Wallis and Mann-Whitney U test, Bartletts test for equal variances, Students t test and Dixons test for rejection of outlying values
- Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not examined
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- effects observed, treatment-related
- Urinalysis findings:
- no effects observed
- Behaviour (functional findings):
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- no effects observed
- Details on results:
- CLINICAL SIGNS AND MORTALITY
One animal was sacrificed on Day 0 and one animal was found dead on Day 9, a result of probable misdosing.
Stained fur was observed in high dose animals, scabbed skin occurred in one control male and high dose female displayed sneezing and abnormal respiratory sounds.
BODY WEIGHT AND WEIGHT GAIN
No statistically significant differences were observed in mean bodyweights or body weight gains.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
A statistically significant increase in food consumption was observed in low dose males compared with controls.
FOOD EFFICIENCY
No statistically significant differences were observed in food efficiency.
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study)
Not recorded
OPHTHALMOSCOPIC EXAMINATION
Not recorded
HAEMATOLOGY
Male mean cell haemoglobin concentrations were significantly decreased compared with the controls at all dose levels. However, these were not considered to be biologically significant, as there was no dose response trend. A statistically significant increase in partial thromboplastin time was observed in mid and top dose males compared with controls. Prothrombin time was significantly increased in the mid and high dose females during the treatment period, and was significantly reduced in males in the recovery group. This were within normal limits and therefore not considered to be biologically significant. A statistically significant increase in the reticulocyte count was observed in treated males in the recovery group, however, was not considered to be biologically significant.
CLINICAL CHEMISTRY
A statistically significant decrease in serum cholesterol was observed in high dose males and females and persisted in females into the recovery period. This was considered to be treatment related.
Statistically significant increases were observed in alanine aminotransferase, lactic dehydrogenase, aspartate aminotransferase, sodium, phosphorus and triglycerides, as well as decreases in albumin and chloride.There was no dose related trend with these changes, therefore they are not considered to be treatment related.
URINALYSIS
A statistically significant increase in specific gravity was observed in low dose males. Urine volume was significantly reduced in treated males in the recovery group. This was not considered to be biologically significant.
NEUROBEHAVIOUR
Not recorded
ORGAN WEIGHTS
No statistically significant differences were observed.
GROSS PATHOLOGY
No substance related macroscopic changes were observed.
HISTOPATHOLOGY: NON-NEOPLASTIC
No substance related microscopic changes were observed.
HISTOPATHOLOGY: NEOPLASTIC (if applicable)
Not recorded
HISTORICAL CONTROL DATA (if applicable)
Not recorded - Dose descriptor:
- NOAEL
- Effect level:
- 500 mg/kg bw/day (actual dose received)
- Sex:
- male/female
- Basis for effect level:
- other: Mean serum cholesterol levels were significantly reduced in the 1000 mg/kg males and females at termination of dosing. This was still significantly reduced in 1000 mg/kg females at the end of the 14 day recovery period.
- Critical effects observed:
- not specified
- Conclusions:
- A NOAEL of 500 mg/kg bw/day was identified in this study.
- Executive summary:
- In a
subchronic toxicity study calcium sulphonate was
administered to 12 rats/sex in the control and top dose and 6
rats/sex in the low and mid dose
via gavage at dose levels of 0, 100, 500 or 1000 mg/kg bw/day.
A decrease in serum cholesterol levels occurred in the top dose group. The LOAEL is 1000 mg/kg bw/day, based on a decrease in serum cholesterol at the top dose. The NOAEL is 500 mg/kg bw/day.
This subchronic toxicity study in the rat is acceptable and satisfies the guideline requirement for a subchronic oral study (OPPTS 870.3100; OECD 408) in rats.
Reference
Table 1: Average body weights and body weight gains during xx days of treatment
Dose rate (ppm) |
Body Weights (g)
|
Total Weight Gain |
|||||
Week 0 |
Week 1 |
Week 2 |
Week 3 |
Week 4 |
g |
% of control |
|
Male |
|||||||
0 |
195 |
243 |
286 |
323 |
352 |
157 |
181 |
100 |
196 |
245 |
298 |
340 |
374 |
175 |
191 |
500 |
200 |
245 |
289 |
329 |
362 |
162 |
181 |
1000 |
193 |
240 |
283 |
315 |
346 |
154 |
179 |
Female |
|||||||
0 |
155 |
175 |
194 |
213 |
223 |
67 |
144 |
100 |
156 |
174 |
194 |
215 |
228 |
72 |
146 |
500 |
154 |
175 |
190 |
212 |
221 |
67 |
144 |
1000 |
155 |
174 |
195 |
212 |
224 |
69 |
145 |
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- NOAEL
- 500 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rat
Repeated dose toxicity: inhalation - systemic effects
Link to relevant study records
- Endpoint:
- sub-chronic toxicity: inhalation
- Type of information:
- migrated information: read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Study period:
- 1986
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Study conducted to OECD guidelines and to GLP, and therefore meets the criteria for Klimisch code 1.
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River
- Age at study initiation: males, 6 weeks; females, 7 weeks
- Weight at study initiation: males, 205-232g; females 156-186g
- Housing: suspended wire mesh cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 2 weeks
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-26°C
- Humidity (%): 20-76%
- Photoperiod (hrs dark / hrs light): 12 hours light/dark cycle - Route of administration:
- inhalation: aerosol
- Type of inhalation exposure:
- whole body
- Vehicle:
- other: unchanged (no vehicle)
- Remarks on MMAD:
- MMAD / GSD: MMAD 3.3-3.7 µm
GSD 2.0-2.1 µm - Details on inhalation exposure:
- GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus:Glass and stainless steel exposure chambers
- System of generating particulates/aerosols:
- Temperature, humidity, pressure in air chamber: 21-26°C, 20-76%
- Air flow rate: 210-215 pm
- Air change rate: 4.8/minute
- Method of particle size determination: Delron DCI-6 cascade impactor
TEST ATMOSPHERE
- Samples taken from breathing zone: yes - Analytical verification of doses or concentrations:
- no
- Details on analytical verification of doses or concentrations:
- Concentration measured by gravimetric analysis.
- Duration of treatment / exposure:
- 6 hours per day for 28 days.
- Frequency of treatment:
- 5 days per week.
- Remarks:
- Doses / Concentrations:
49.5, 156, 260 mg/m3
Basis:
analytical conc. - No. of animals per sex per dose:
- 5
- Control animals:
- yes, concurrent no treatment
- Positive control:
- None.
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice daily
BODY WEIGHT: Yes
- Time schedule for examinations: weekly
FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No
FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No
WATER CONSUMPTION: No
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: Yes
- Time schedule for collection of blood: Prior to terminal sacrifice
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: All animals
- Parameters examined: Haemoglobin concentration, haematocrit, erythrocyte count, platelet count, clotting time, total and differential leukocyte count
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Prior to terminal sacrifice
- Animals fasted: No data
- How many animals: All animals
URINALYSIS: Yes
- Time schedule for collection of urine: Prior to terminal sacrifice
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
NEUROBEHAVIOURAL EXAMINATION: No - Sacrifice and pathology:
- gross pathology on all animals
GROSS PATHOLOGY: Yes (see table)
HISTOPATHOLOGY: Yes (see table) - Statistics:
- ANOVA with Dunnets test
Regression analysis
Krusal-Walis and Dunns summed rank test
Jonsheere's test for monotonic trend - 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):
- not specified
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not specified
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- not specified
- Behaviour (functional findings):
- not specified
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Histopathological findings: neoplastic:
- no effects observed
- Details on results:
CLINICAL SIGNS AND MORTALITY
No mortality occurred during the test.
BODY WEIGHT AND WEIGHT GAIN
Bodyweight gain was decreased in treated animals, although this was not statistically significant.
FOOD CONSUMPTION
Not measured
FOOD EFFICIENCY
Not measured
WATER CONSUMPTION
Not measured
OPHTHALMOSCOPIC EXAMINATION
Not measured
HAEMATOLOGY
Statistically significant differences were observed in females. Specifically; increased haematocrit in the low dose group.
CLINICAL CHEMISTRY
Statistically significant differences were observed in females. Specifically; increased creatine phospholinase in the mid and top dose groups and sodium in the top dose group.
NEUROBEHAVIOUR
Not measured
ORGAN WEIGHTS
Statistically significant increased lung weights and lung to body weight ratios were observed in a dose dependant manner in the mid and top dose groups.
GROSS PATHOLOGY
Gross lesions were sporadic and were not considered to be caused by the test article.
HISTOPATHOLOGY: NON-NEOPLASTIC
A higher incidence of accumulations of intraalveolar macrophages and hyperplasia/hypertrophy of bronchiole epithelium was seen in the lungs of the treated animals. These were dose related at the mid and top dose levels.
- Dose descriptor:
- NOAEL
- Effect level:
- 49.5 mg/m³ air (analytical)
- Sex:
- male/female
- Basis for effect level:
- other: Statistically significant dose related increase in lung weight and relative lung weights with corresponding accumulations of intraalveolar macrophages and hyperplasia/hypertrophy of the bronchiole epithelium.
- Critical effects observed:
- not specified
- Conclusions:
- A NOAEL of 49.5 mg/m³ was identified for males and females, based on increased lung weight and microscopic changes of the lung.
- Executive summary:
In a subacute inhalation toxicity study, a petroleum derived calcium salt was administered to 5 Sprague-Dawley rats/sex/concentration by whole body exposure at concentrations of 0, 49.5, 156 or 260 mg/m³ for 6 hours per day, 5 days/week for a total of 28 days.
Statistically significant, dose related increases in lung weights occurred in the mid and top dose groups, with corresponding increases in intraalveolar macrophages and hyperplasia/hypertrophy of bronchiole epithelium. The LOAEL is 156 mg/m³, based on effects in the lung. The NOAEL is 49.5 mg/m³.
This subchronic toxicity study in the rat is acceptable and satisfies the guideline requirement (OECD 412) for a subchronic inhalation study in the rat.
Reference
Table 1: Average body weights and body weight gains during 28 days of treatment
Analytical concentration (mg/L) |
Body Weights (g) |
Total Weight Gain |
|||||
Week 0 |
Week 1 |
Week 2 |
Week 3 |
Week 4 |
g |
% of control |
|
Male |
|||||||
0 |
217 |
249 |
295 |
336 |
369 |
152 |
|
LCT |
216 |
248 |
294 |
331 |
359 |
143 |
94 |
MCT |
215 |
247 |
302 |
346 |
384 |
169 |
111 |
HCT |
215 |
243 |
285 |
319 |
347 |
132 |
87 |
Female |
|||||||
0 |
171 |
185 |
206 |
223 |
239 |
68 |
|
LCT |
169 |
185 |
205 |
220 |
232 |
63 |
93 |
MCT |
168 |
181 |
203 |
219 |
229 |
61 |
90 |
HCT |
172 |
186 |
205 |
223 |
238 |
66 |
97 |
Table 2 Selected haematology, clinical chemistry and pathology findings
Doses (unit) |
0 |
50 |
150 |
250 |
0 |
50 |
150 |
250 |
male |
female |
|||||||
Number of animals/group |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
Haematology(day x) |
|
|
|
|
|
|
|
|
- RBC (TERA/L) |
6.62 |
6.89 |
6.66 |
6.52 |
6.60 |
6.90 |
6.59 |
6.70 |
- MCV (FL) |
- |
- |
- |
- |
- |
- |
- |
- |
- HCT (L/L) |
46 |
47 |
46 |
43 |
46 |
48 |
47 |
44 |
- HGB (MMOL/L) |
16.1 |
16.7 |
16.1 |
15.5 |
15.5 |
16.6 |
16.1 |
15.5 |
- WBC (GIGA/L) |
13.9 |
13.7 |
12.9 |
10.5 |
9.0 |
12.8 |
11.5 |
13.8 |
Blood chemistry(day x) |
|
|
|
|
|
|
|
|
- sodium (MMOL/L) |
146 |
146 |
147 |
146 |
145 |
143 |
144 |
141 |
- potassium (MMOL/L) |
4.4 |
4.4 |
4.5 |
4.3 |
4.3 |
4.3 |
4.3 |
4.3 |
- chloride (MMOL/L) |
101 |
102 |
102 |
102 |
102 |
102 |
102 |
101 |
- gobulin (G/L) |
2.2 |
2.3 |
2.4 |
2.0 |
2.1 |
2.1 |
2.1 |
2.0 |
- cholesterol (MMOL/L) |
56 |
53 |
63 |
55 |
59 |
75 |
60 |
69 |
- triglyceride (MMOL/L) |
45 |
39 |
54 |
35 |
30 |
24 |
25 |
25 |
Pathology |
|
|
|
|
|
|
|
|
Accumulation of intraalveolar macrophages |
3 |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
Bronchiolar epithelium: hyperplasia/hypertrophy |
3 |
4 |
5 |
5 |
4 |
5 |
5 |
5 |
Table 3: Absolute and relative organ weights
|
Males |
Females |
|||||||
DAILY DOSE |
0 |
50 |
150 |
250 |
0 |
50 |
150 |
250 |
|
NUMBER OF ANIMALS |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
|
BODY WEIGHT (g)a |
335 |
323 |
346 |
313 |
213 |
204 |
204 |
208 |
|
BRAIN |
|
|
|
|
|
|
|
|
|
Absolute Weighta |
g |
1.976 |
1.939 |
2.032 |
1.943 |
1.900 |
1.876 |
1.856 |
1.830 |
Per Body Weighta |
% |
5.93 |
6.03 |
5.90 |
6.21 |
8.96 |
9.20 |
9.12 |
8.84 |
ADRENALS |
|
|
|
|
|
|
|
|
|
Absolute Weighta |
g |
0.051 |
0.052 |
0.054 |
0.054 |
0.068 |
0.069 |
0.070 |
0.060 |
Per Body Weighta |
% |
1.52 |
1.63 |
1.56 |
1.71 |
3.21 |
3.37 |
3.44 |
2.90 |
Per Brain Weighta |
% |
|
|
|
|
|
|
|
|
HEART |
|
|
|
|
|
|
|
|
|
Absolute Weighta |
g |
1.220 |
1.173 |
1.179 |
1.122 |
0.803 |
0.801 |
0.753 |
0.793 |
Per Body Weighta |
% |
3.64 |
3.65 |
3.41 |
3.59 |
3.79 |
3.92 |
3.70 |
3.82 |
Per Brain Weighta |
% |
|
|
|
|
|
|
|
|
KIDNEYS |
|
|
|
|
|
|
|
|
|
Absolute Weighta |
g |
2.592 |
2.779 |
3.054 |
2.704 |
1.745 |
1.696 |
1.694 |
1.883 |
Per Body Weighta |
% |
7.79 |
8.61 |
8.81 |
8.61 |
8.16 |
8.32 |
8.29 |
9.05 |
Per Brain Weighta |
% |
|
|
|
|
|
|
|
|
LIVER |
|
|
|
|
|
|
|
|
|
Absolute Weighta |
g |
10.775 |
10.306 |
11.470 |
9.999 |
7.020 |
6.464 |
6.789 |
7.357 |
Per Body Weighta |
% |
3.22 |
3.20 |
3.31 |
3.18 |
3.30 |
3.17 |
3.33 |
3.53 |
Per Brain Weighta |
% |
|
|
|
|
|
|
|
|
SPLEEN |
|
|
|
|
|
|
|
|
|
Absolute Weighta |
g |
0.670 |
0.569 |
0.652 |
0.594 |
0.426 |
0.441 |
0.471 |
0.484 |
Per Body Weighta |
% |
2.00 |
1.77 |
1.88 |
1.89 |
2.01 |
2.17 |
2.30 |
2.34 |
Per Brain Weighta |
% |
|
|
|
|
|
|
|
|
TESTES |
|
|
|
|
n.a.b |
n.a.b |
n.a.b |
n.a.b |
|
Absolute Weighta |
g |
3.187 |
3.072 |
2.796 |
3.135 |
n.a.b |
n.a.b |
n.a.b |
n.a.b |
Per Body Weighta |
% |
9.54 |
9.54 |
8.16 |
10.02 |
n.a.b |
n.a.b |
n.a.b |
n.a.b |
Per Brain Weighta |
% |
|
|
|
|
n.a.b |
n.a.b |
n.a.b |
n.a.b |
LUNGS |
|
|
|
|
|
|
|
|
|
Absolute Weighta |
g |
1.306 |
1.302 |
1.515 |
1.537 |
1.051 |
1.127 |
1.138 |
1.338 |
Per Body Weighta |
% |
3.91 |
4.05 |
4.39 |
4.91 |
4.93 |
5.52 |
5.59 |
6.46 |
Per Brain Weighta |
% |
|
|
|
|
|
|
|
|
OVARIES |
n.a.b |
n.a.b |
n.a.b |
n.a.b |
0.0921 |
0.0768 |
0.0943 |
0.0742 |
|
Absolute Weighta |
g |
n.a.b |
n.a.b |
n.a.b |
n.a.b |
4.34 |
3.77 |
4.62 |
3.56 |
Per Body Weighta |
% |
n.a.b |
n.a.b |
n.a.b |
n.a.b |
|
|
|
|
Per Brain Weighta |
% |
n.a.b |
n.a.b |
n.a.b |
n.a.b |
|
|
|
|
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- NOAEC
- 881.58 mg/m³
- Study duration:
- subacute
- Species:
- rat
Repeated dose toxicity: inhalation - local effects
Link to relevant study records
- Endpoint:
- sub-chronic toxicity: inhalation
- Type of information:
- migrated information: read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Study period:
- 1986
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Study conducted to OECD guidelines and to GLP, and therefore meets the criteria for Klimisch code 1.
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River
- Age at study initiation: males, 6 weeks; females, 7 weeks
- Weight at study initiation: males, 205-232g; females 156-186g
- Housing: suspended wire mesh cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 2 weeks
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-26°C
- Humidity (%): 20-76%
- Photoperiod (hrs dark / hrs light): 12 hours light/dark cycle - Route of administration:
- inhalation: aerosol
- Type of inhalation exposure:
- whole body
- Vehicle:
- other: unchanged (no vehicle)
- Remarks on MMAD:
- MMAD / GSD: MMAD 3.3-3.7 µm
GSD 2.0-2.1 µm - Details on inhalation exposure:
- GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus:Glass and stainless steel exposure chambers
- System of generating particulates/aerosols:
- Temperature, humidity, pressure in air chamber: 21-26°C, 20-76%
- Air flow rate: 210-215 pm
- Air change rate: 4.8/minute
- Method of particle size determination: Delron DCI-6 cascade impactor
TEST ATMOSPHERE
- Samples taken from breathing zone: yes - Analytical verification of doses or concentrations:
- no
- Details on analytical verification of doses or concentrations:
- Concentration measured by gravimetric analysis.
- Duration of treatment / exposure:
- 6 hours per day for 28 days.
- Frequency of treatment:
- 5 days per week.
- Remarks:
- Doses / Concentrations:
49.5, 156, 260 mg/m3
Basis:
analytical conc. - No. of animals per sex per dose:
- 5
- Control animals:
- yes, concurrent no treatment
- Positive control:
- None.
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice daily
BODY WEIGHT: Yes
- Time schedule for examinations: weekly
FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No
FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No
WATER CONSUMPTION: No
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: Yes
- Time schedule for collection of blood: Prior to terminal sacrifice
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: All animals
- Parameters examined: Haemoglobin concentration, haematocrit, erythrocyte count, platelet count, clotting time, total and differential leukocyte count
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Prior to terminal sacrifice
- Animals fasted: No data
- How many animals: All animals
URINALYSIS: Yes
- Time schedule for collection of urine: Prior to terminal sacrifice
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
NEUROBEHAVIOURAL EXAMINATION: No - Sacrifice and pathology:
- gross pathology on all animals
GROSS PATHOLOGY: Yes (see table)
HISTOPATHOLOGY: Yes (see table) - Statistics:
- ANOVA with Dunnets test
Regression analysis
Krusal-Walis and Dunns summed rank test
Jonsheere's test for monotonic trend - 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):
- not specified
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not specified
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- not specified
- Behaviour (functional findings):
- not specified
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Histopathological findings: neoplastic:
- no effects observed
- Details on results:
CLINICAL SIGNS AND MORTALITY
No mortality occurred during the test.
BODY WEIGHT AND WEIGHT GAIN
Bodyweight gain was decreased in treated animals, although this was not statistically significant.
FOOD CONSUMPTION
Not measured
FOOD EFFICIENCY
Not measured
WATER CONSUMPTION
Not measured
OPHTHALMOSCOPIC EXAMINATION
Not measured
HAEMATOLOGY
Statistically significant differences were observed in females. Specifically; increased haematocrit in the low dose group.
CLINICAL CHEMISTRY
Statistically significant differences were observed in females. Specifically; increased creatine phospholinase in the mid and top dose groups and sodium in the top dose group.
NEUROBEHAVIOUR
Not measured
ORGAN WEIGHTS
Statistically significant increased lung weights and lung to body weight ratios were observed in a dose dependant manner in the mid and top dose groups.
GROSS PATHOLOGY
Gross lesions were sporadic and were not considered to be caused by the test article.
HISTOPATHOLOGY: NON-NEOPLASTIC
A higher incidence of accumulations of intraalveolar macrophages and hyperplasia/hypertrophy of bronchiole epithelium was seen in the lungs of the treated animals. These were dose related at the mid and top dose levels.
- Dose descriptor:
- NOAEL
- Effect level:
- 49.5 mg/m³ air (analytical)
- Sex:
- male/female
- Basis for effect level:
- other: Statistically significant dose related increase in lung weight and relative lung weights with corresponding accumulations of intraalveolar macrophages and hyperplasia/hypertrophy of the bronchiole epithelium.
- Critical effects observed:
- not specified
- Conclusions:
- A NOAEL of 49.5 mg/m³ was identified for males and females, based on increased lung weight and microscopic changes of the lung.
- Executive summary:
In a subacute inhalation toxicity study, a petroleum derived calcium salt was administered to 5 Sprague-Dawley rats/sex/concentration by whole body exposure at concentrations of 0, 49.5, 156 or 260 mg/m³ for 6 hours per day, 5 days/week for a total of 28 days.
Statistically significant, dose related increases in lung weights occurred in the mid and top dose groups, with corresponding increases in intraalveolar macrophages and hyperplasia/hypertrophy of bronchiole epithelium. The LOAEL is 156 mg/m³, based on effects in the lung. The NOAEL is 49.5 mg/m³.
This subchronic toxicity study in the rat is acceptable and satisfies the guideline requirement (OECD 412) for a subchronic inhalation study in the rat.
Reference
Table 1: Average body weights and body weight gains during 28 days of treatment
Analytical concentration (mg/L) |
Body Weights (g) |
Total Weight Gain |
|||||
Week 0 |
Week 1 |
Week 2 |
Week 3 |
Week 4 |
g |
% of control |
|
Male |
|||||||
0 |
217 |
249 |
295 |
336 |
369 |
152 |
|
LCT |
216 |
248 |
294 |
331 |
359 |
143 |
94 |
MCT |
215 |
247 |
302 |
346 |
384 |
169 |
111 |
HCT |
215 |
243 |
285 |
319 |
347 |
132 |
87 |
Female |
|||||||
0 |
171 |
185 |
206 |
223 |
239 |
68 |
|
LCT |
169 |
185 |
205 |
220 |
232 |
63 |
93 |
MCT |
168 |
181 |
203 |
219 |
229 |
61 |
90 |
HCT |
172 |
186 |
205 |
223 |
238 |
66 |
97 |
Table 2 Selected haematology, clinical chemistry and pathology findings
Doses (unit) |
0 |
50 |
150 |
250 |
0 |
50 |
150 |
250 |
male |
female |
|||||||
Number of animals/group |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
Haematology(day x) |
|
|
|
|
|
|
|
|
- RBC (TERA/L) |
6.62 |
6.89 |
6.66 |
6.52 |
6.60 |
6.90 |
6.59 |
6.70 |
- MCV (FL) |
- |
- |
- |
- |
- |
- |
- |
- |
- HCT (L/L) |
46 |
47 |
46 |
43 |
46 |
48 |
47 |
44 |
- HGB (MMOL/L) |
16.1 |
16.7 |
16.1 |
15.5 |
15.5 |
16.6 |
16.1 |
15.5 |
- WBC (GIGA/L) |
13.9 |
13.7 |
12.9 |
10.5 |
9.0 |
12.8 |
11.5 |
13.8 |
Blood chemistry(day x) |
|
|
|
|
|
|
|
|
- sodium (MMOL/L) |
146 |
146 |
147 |
146 |
145 |
143 |
144 |
141 |
- potassium (MMOL/L) |
4.4 |
4.4 |
4.5 |
4.3 |
4.3 |
4.3 |
4.3 |
4.3 |
- chloride (MMOL/L) |
101 |
102 |
102 |
102 |
102 |
102 |
102 |
101 |
- gobulin (G/L) |
2.2 |
2.3 |
2.4 |
2.0 |
2.1 |
2.1 |
2.1 |
2.0 |
- cholesterol (MMOL/L) |
56 |
53 |
63 |
55 |
59 |
75 |
60 |
69 |
- triglyceride (MMOL/L) |
45 |
39 |
54 |
35 |
30 |
24 |
25 |
25 |
Pathology |
|
|
|
|
|
|
|
|
Accumulation of intraalveolar macrophages |
3 |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
Bronchiolar epithelium: hyperplasia/hypertrophy |
3 |
4 |
5 |
5 |
4 |
5 |
5 |
5 |
Table 3: Absolute and relative organ weights
|
Males |
Females |
|||||||
DAILY DOSE |
0 |
50 |
150 |
250 |
0 |
50 |
150 |
250 |
|
NUMBER OF ANIMALS |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
|
BODY WEIGHT (g)a |
335 |
323 |
346 |
313 |
213 |
204 |
204 |
208 |
|
BRAIN |
|
|
|
|
|
|
|
|
|
Absolute Weighta |
g |
1.976 |
1.939 |
2.032 |
1.943 |
1.900 |
1.876 |
1.856 |
1.830 |
Per Body Weighta |
% |
5.93 |
6.03 |
5.90 |
6.21 |
8.96 |
9.20 |
9.12 |
8.84 |
ADRENALS |
|
|
|
|
|
|
|
|
|
Absolute Weighta |
g |
0.051 |
0.052 |
0.054 |
0.054 |
0.068 |
0.069 |
0.070 |
0.060 |
Per Body Weighta |
% |
1.52 |
1.63 |
1.56 |
1.71 |
3.21 |
3.37 |
3.44 |
2.90 |
Per Brain Weighta |
% |
|
|
|
|
|
|
|
|
HEART |
|
|
|
|
|
|
|
|
|
Absolute Weighta |
g |
1.220 |
1.173 |
1.179 |
1.122 |
0.803 |
0.801 |
0.753 |
0.793 |
Per Body Weighta |
% |
3.64 |
3.65 |
3.41 |
3.59 |
3.79 |
3.92 |
3.70 |
3.82 |
Per Brain Weighta |
% |
|
|
|
|
|
|
|
|
KIDNEYS |
|
|
|
|
|
|
|
|
|
Absolute Weighta |
g |
2.592 |
2.779 |
3.054 |
2.704 |
1.745 |
1.696 |
1.694 |
1.883 |
Per Body Weighta |
% |
7.79 |
8.61 |
8.81 |
8.61 |
8.16 |
8.32 |
8.29 |
9.05 |
Per Brain Weighta |
% |
|
|
|
|
|
|
|
|
LIVER |
|
|
|
|
|
|
|
|
|
Absolute Weighta |
g |
10.775 |
10.306 |
11.470 |
9.999 |
7.020 |
6.464 |
6.789 |
7.357 |
Per Body Weighta |
% |
3.22 |
3.20 |
3.31 |
3.18 |
3.30 |
3.17 |
3.33 |
3.53 |
Per Brain Weighta |
% |
|
|
|
|
|
|
|
|
SPLEEN |
|
|
|
|
|
|
|
|
|
Absolute Weighta |
g |
0.670 |
0.569 |
0.652 |
0.594 |
0.426 |
0.441 |
0.471 |
0.484 |
Per Body Weighta |
% |
2.00 |
1.77 |
1.88 |
1.89 |
2.01 |
2.17 |
2.30 |
2.34 |
Per Brain Weighta |
% |
|
|
|
|
|
|
|
|
TESTES |
|
|
|
|
n.a.b |
n.a.b |
n.a.b |
n.a.b |
|
Absolute Weighta |
g |
3.187 |
3.072 |
2.796 |
3.135 |
n.a.b |
n.a.b |
n.a.b |
n.a.b |
Per Body Weighta |
% |
9.54 |
9.54 |
8.16 |
10.02 |
n.a.b |
n.a.b |
n.a.b |
n.a.b |
Per Brain Weighta |
% |
|
|
|
|
n.a.b |
n.a.b |
n.a.b |
n.a.b |
LUNGS |
|
|
|
|
|
|
|
|
|
Absolute Weighta |
g |
1.306 |
1.302 |
1.515 |
1.537 |
1.051 |
1.127 |
1.138 |
1.338 |
Per Body Weighta |
% |
3.91 |
4.05 |
4.39 |
4.91 |
4.93 |
5.52 |
5.59 |
6.46 |
Per Brain Weighta |
% |
|
|
|
|
|
|
|
|
OVARIES |
n.a.b |
n.a.b |
n.a.b |
n.a.b |
0.0921 |
0.0768 |
0.0943 |
0.0742 |
|
Absolute Weighta |
g |
n.a.b |
n.a.b |
n.a.b |
n.a.b |
4.34 |
3.77 |
4.62 |
3.56 |
Per Body Weighta |
% |
n.a.b |
n.a.b |
n.a.b |
n.a.b |
|
|
|
|
Per Brain Weighta |
% |
n.a.b |
n.a.b |
n.a.b |
n.a.b |
|
|
|
|
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- NOAEC
- 881.58 mg/m³
- Study duration:
- subacute
- Species:
- rat
Repeated dose toxicity: dermal - systemic effects
Link to relevant study records
- Endpoint:
- short-term repeated dose toxicity: dermal
- Type of information:
- migrated information: read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- supporting study
- Study period:
- 1981
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: The study was not conducted to recognised guidelines, nor to GLP. The study report was unclear in places.
- Qualifier:
- no guideline followed
- Deviations:
- yes
- Remarks:
- only two treatment doeses were included (guidleine reccomends 3) Elizerabethan collars were used to prevent ingestion. The test site was not covered with a gauze patch
- GLP compliance:
- no
- Limit test:
- no
- Species:
- rabbit
- Strain:
- New Zealand White
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: HARE Rabbits for Research
- Weight at study initiation: males, 1.6-2.8kg; females, 1.6-2.5kg
- Housing: Individually in stainless steel cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 14 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 10-24°C
- Humidity (%): 17-65%
- Photoperiod (hrs dark / hrs light): 12 hour light/dark cycle - Type of coverage:
- open
- Vehicle:
- other: mineral oil
- Details on exposure:
- TEST SITE
- Area of exposure: 6.5 x 5 cm
- Surface area: 25%
- Time intervals for shavings or clipplings: Monday and Thursday of each week
REMOVAL OF TEST SUBSTANCE
- Washing (if done): Wiping with paper towels
- Time after start of exposure: 6 hours
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2 ml/kg
USE OF RESTRAINERS FOR PREVENTING INGESTION: yes - Analytical verification of doses or concentrations:
- no
- Duration of treatment / exposure:
- 6 hours
- Frequency of treatment:
- 5 times per week
- Remarks:
- Doses / Concentrations:
0, 25, 100 %
Basis:
other: w/v in primol 205 - No. of animals per sex per dose:
- 15
- Control animals:
- yes, concurrent vehicle
- Positive control:
- none
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Weekly
DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: Daily
BODY WEIGHT: Yes
- Time schedule for examinations: Weekly
FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No
FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No
WATER CONSUMPTION: No
- Time schedule for examinations:
OPHTHALMOSCOPIC EXAMINATION: No
- Time schedule for examinations:
- Dose groups that were examined:
HAEMATOLOGY: Yes
- Time schedule for collection of blood: Termination
- Anaesthetic used for blood collection: No data
- Animals fasted: Yes
- How many animals: Termination 10/sex/group
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood:
- Animals fasted: Yes
- How many animals:Termination: 10/sex/group
URINALYSIS: No
- Time schedule for collection of urine:
- Metabolism cages used for collection of urine: Yes / No / No data
- Animals fasted: Yes / No / No data
- Parameters checked in table [No.?] were examined.
NEUROBEHAVIOURAL EXAMINATION: No
- Time schedule for examinations:
- Dose groups that were examined:
- Battery of functions tested: sensory activity / grip strength / motor activity / other: - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes - Statistics:
- ANOVA with Dunnett's test
Regression analysis
Kruskal-Walis and Dunn's summed rank test
Joncheere's test for monotonic trend - Clinical signs:
- effects observed, treatment-related
- Dermal irritation:
- effects observed, treatment-related
- Mortality:
- mortality observed, treatment-related
- Body weight and weight changes:
- no effects observed
- 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
- Clinical biochemistry findings:
- effects observed, treatment-related
- Urinalysis findings:
- not specified
- Behaviour (functional findings):
- not specified
- 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 AND MORTALITY
There were a number of mortalities in the study, One control and four high dose animals died or were sacrificed early in the study. One control female was sacrificed during the recovery phase. Two high dose males were sacrificed moribund during the treatment period. one high dose male was found dead during recovery. One high dose female was sacrificed during recovery. Cause of death was not established.
Alopecia was observed throughout the study in treated animals. In addition there were numerous incidences of erythema, oedema, atonia, desquamation, fissuring and exfoliation in treated animals but without dose response. These findings decreased in recovery phase.
BODY WEIGHT AND WEIGHT GAIN
Mean body weights were slightly reduced in treated groups but evaluation is confounded by the small number of animals.
FOOD CONSUMPTION
Not recorded
FOOD EFFICIENCY
Not recorded
WATER CONSUMPTION
Not recorded
OPHTHALMOSCOPIC EXAMINATION
Not recorded
HAEMATOLOGY
The mean total leukocyte count of low and high dose females was lower at termination of treatment. Mean haemaglobin and haemocrit values and mean erythrocyte counts were also reduced.
CLINICAL CHEMISTRY
Decreases in total protein and globulin levels occurred.
URINALYSIS
Not recorded
NEUROBEHAVIOUR
Not recorded
ORGAN WEIGHTS
Absolute and relative weights of testes and epididymis were decreased in low and high dose males, together with increases in mean and absolute liver weights.
GROSS PATHOLOGY
Discolouration of the liver was observed in males and females. Testes were small.
HISTOPATHOLOGY: NON-NEOPLASTIC
Microscopic examination revealed treatment related morphological changes in the skin, testes, epididymis and possibly liver.
HISTOPATHOLOGY: NEOPLASTIC (if applicable)
Not recorded
HISTORICAL CONTROL DATA (if applicable)
Not recorded - Dose descriptor:
- NOAEL
- Basis for effect level:
- other: Effects were observed at the lowest dose tested, therefore a NOAEL cannot be identified from this study.
- Remarks on result:
- not determinable
- Remarks:
- no NOAEL identified
- Dose descriptor:
- LOAEL
- Effect level:
- < 250 mg/kg bw/day
- Sex:
- male/female
- Basis for effect level:
- other: Effects observed at the lowest dose, therefore an arbitary LOAEL has been identified.
- Critical effects observed:
- not specified
- Conclusions:
- Toxicity occurred at all doses tested, therefore a NOAEL has not been identified. an arbitary LOAEL of 250 mg/kg bw has been identified, based on effects at the lowest dose.
- Executive summary:
In a repeat-dose dermal toxicity study, an alkaryl magnesium salt derivative was applied to the shaved skin of 15white rabbits/sex/dose at dose levels of 0, 25 and 100%, 6 hours/day for 5 days/week during a 28-day period.
A NOAEL cannot be identified from this study, as effects were observed at the lowest dose.
This dermal toxicity study in the rabbit is acceptable.
Reference
Table 1: Incidence of selected pathologies
Parameter |
n=10/sex |
Dose level |
|||||
Control |
25 |
100 |
Recovery control |
Recovery 25 |
Recovery 100 |
||
Small testis |
M |
0/10 |
3/10 |
6/13 |
0/5 |
0/5 |
1/3 |
Table 2: Absolute and relative organ weights
|
Males |
Females |
|||||||
DAILY DOSE |
0 |
25 |
100 |
0 |
25 |
100 |
|
||
NUMBER OF ANIMALS |
10 |
10 |
10 |
10 |
10 |
10 |
|
||
BODY WEIGHT (g)a |
- |
- |
- |
- |
- |
- |
|
||
LIVER |
|
|
|
|
|
|
|
||
Absolute Weighta |
g |
70.850 |
74.006 |
92.314 |
73.677 |
82.772 |
90.501 |
|
|
Per Body Weighta |
% |
2.93 |
3.11 |
3.83 |
2.72 |
3.05 |
3.95 |
|
|
TESTES |
|
|
|
n.a.b |
n.a.b |
n.a.b |
|
||
Absolute Weighta |
g |
3.047 |
2.421 |
1.997 |
n.a.b |
n.a.b |
n.a.b |
|
|
Per Body Weighta |
% |
12.49 |
10.16 |
7.76 |
n.a.b |
n.a.b |
n.a.b |
|
|
aGroup means at the end of terminal necropsy are shown.
bn.a. = not applicable
* p<0.05, ** p<0.01
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- NOAEL
- 1 000 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rabbit
Repeated dose toxicity: dermal - local effects
Link to relevant study records
- Endpoint:
- short-term repeated dose toxicity: dermal
- Type of information:
- migrated information: read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- supporting study
- Study period:
- 1981
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: The study was not conducted to recognised guidelines, nor to GLP. The study report was unclear in places.
- Qualifier:
- no guideline followed
- Deviations:
- yes
- Remarks:
- only two treatment doeses were included (guidleine reccomends 3) Elizerabethan collars were used to prevent ingestion. The test site was not covered with a gauze patch
- GLP compliance:
- no
- Limit test:
- no
- Species:
- rabbit
- Strain:
- New Zealand White
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: HARE Rabbits for Research
- Weight at study initiation: males, 1.6-2.8kg; females, 1.6-2.5kg
- Housing: Individually in stainless steel cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 14 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 10-24°C
- Humidity (%): 17-65%
- Photoperiod (hrs dark / hrs light): 12 hour light/dark cycle - Type of coverage:
- open
- Vehicle:
- other: mineral oil
- Details on exposure:
- TEST SITE
- Area of exposure: 6.5 x 5 cm
- Surface area: 25%
- Time intervals for shavings or clipplings: Monday and Thursday of each week
REMOVAL OF TEST SUBSTANCE
- Washing (if done): Wiping with paper towels
- Time after start of exposure: 6 hours
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2 ml/kg
USE OF RESTRAINERS FOR PREVENTING INGESTION: yes - Analytical verification of doses or concentrations:
- no
- Duration of treatment / exposure:
- 6 hours
- Frequency of treatment:
- 5 times per week
- Remarks:
- Doses / Concentrations:
0, 25, 100 %
Basis:
other: w/v in primol 205 - No. of animals per sex per dose:
- 15
- Control animals:
- yes, concurrent vehicle
- Positive control:
- none
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Weekly
DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: Daily
BODY WEIGHT: Yes
- Time schedule for examinations: Weekly
FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No
FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No
WATER CONSUMPTION: No
- Time schedule for examinations:
OPHTHALMOSCOPIC EXAMINATION: No
- Time schedule for examinations:
- Dose groups that were examined:
HAEMATOLOGY: Yes
- Time schedule for collection of blood: Termination
- Anaesthetic used for blood collection: No data
- Animals fasted: Yes
- How many animals: Termination 10/sex/group
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood:
- Animals fasted: Yes
- How many animals:Termination: 10/sex/group
URINALYSIS: No
- Time schedule for collection of urine:
- Metabolism cages used for collection of urine: Yes / No / No data
- Animals fasted: Yes / No / No data
- Parameters checked in table [No.?] were examined.
NEUROBEHAVIOURAL EXAMINATION: No
- Time schedule for examinations:
- Dose groups that were examined:
- Battery of functions tested: sensory activity / grip strength / motor activity / other: - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes - Statistics:
- ANOVA with Dunnett's test
Regression analysis
Kruskal-Walis and Dunn's summed rank test
Joncheere's test for monotonic trend - Clinical signs:
- effects observed, treatment-related
- Dermal irritation:
- effects observed, treatment-related
- Mortality:
- mortality observed, treatment-related
- Body weight and weight changes:
- no effects observed
- 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
- Clinical biochemistry findings:
- effects observed, treatment-related
- Urinalysis findings:
- not specified
- Behaviour (functional findings):
- not specified
- 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 AND MORTALITY
There were a number of mortalities in the study, One control and four high dose animals died or were sacrificed early in the study. One control female was sacrificed during the recovery phase. Two high dose males were sacrificed moribund during the treatment period. one high dose male was found dead during recovery. One high dose female was sacrificed during recovery. Cause of death was not established.
Alopecia was observed throughout the study in treated animals. In addition there were numerous incidences of erythema, oedema, atonia, desquamation, fissuring and exfoliation in treated animals but without dose response. These findings decreased in recovery phase.
BODY WEIGHT AND WEIGHT GAIN
Mean body weights were slightly reduced in treated groups but evaluation is confounded by the small number of animals.
FOOD CONSUMPTION
Not recorded
FOOD EFFICIENCY
Not recorded
WATER CONSUMPTION
Not recorded
OPHTHALMOSCOPIC EXAMINATION
Not recorded
HAEMATOLOGY
The mean total leukocyte count of low and high dose females was lower at termination of treatment. Mean haemaglobin and haemocrit values and mean erythrocyte counts were also reduced.
CLINICAL CHEMISTRY
Decreases in total protein and globulin levels occurred.
URINALYSIS
Not recorded
NEUROBEHAVIOUR
Not recorded
ORGAN WEIGHTS
Absolute and relative weights of testes and epididymis were decreased in low and high dose males, together with increases in mean and absolute liver weights.
GROSS PATHOLOGY
Discolouration of the liver was observed in males and females. Testes were small.
HISTOPATHOLOGY: NON-NEOPLASTIC
Microscopic examination revealed treatment related morphological changes in the skin, testes, epididymis and possibly liver.
HISTOPATHOLOGY: NEOPLASTIC (if applicable)
Not recorded
HISTORICAL CONTROL DATA (if applicable)
Not recorded - Dose descriptor:
- NOAEL
- Basis for effect level:
- other: Effects were observed at the lowest dose tested, therefore a NOAEL cannot be identified from this study.
- Remarks on result:
- not determinable
- Remarks:
- no NOAEL identified
- Dose descriptor:
- LOAEL
- Effect level:
- < 250 mg/kg bw/day
- Sex:
- male/female
- Basis for effect level:
- other: Effects observed at the lowest dose, therefore an arbitary LOAEL has been identified.
- Critical effects observed:
- not specified
- Conclusions:
- Toxicity occurred at all doses tested, therefore a NOAEL has not been identified. an arbitary LOAEL of 250 mg/kg bw has been identified, based on effects at the lowest dose.
- Executive summary:
In a repeat-dose dermal toxicity study, an alkaryl magnesium salt derivative was applied to the shaved skin of 15white rabbits/sex/dose at dose levels of 0, 25 and 100%, 6 hours/day for 5 days/week during a 28-day period.
A NOAEL cannot be identified from this study, as effects were observed at the lowest dose.
This dermal toxicity study in the rabbit is acceptable.
Reference
Table 1: Incidence of selected pathologies
Parameter |
n=10/sex |
Dose level |
|||||
Control |
25 |
100 |
Recovery control |
Recovery 25 |
Recovery 100 |
||
Small testis |
M |
0/10 |
3/10 |
6/13 |
0/5 |
0/5 |
1/3 |
Table 2: Absolute and relative organ weights
|
Males |
Females |
|||||||
DAILY DOSE |
0 |
25 |
100 |
0 |
25 |
100 |
|
||
NUMBER OF ANIMALS |
10 |
10 |
10 |
10 |
10 |
10 |
|
||
BODY WEIGHT (g)a |
- |
- |
- |
- |
- |
- |
|
||
LIVER |
|
|
|
|
|
|
|
||
Absolute Weighta |
g |
70.850 |
74.006 |
92.314 |
73.677 |
82.772 |
90.501 |
|
|
Per Body Weighta |
% |
2.93 |
3.11 |
3.83 |
2.72 |
3.05 |
3.95 |
|
|
TESTES |
|
|
|
n.a.b |
n.a.b |
n.a.b |
|
||
Absolute Weighta |
g |
3.047 |
2.421 |
1.997 |
n.a.b |
n.a.b |
n.a.b |
|
|
Per Body Weighta |
% |
12.49 |
10.16 |
7.76 |
n.a.b |
n.a.b |
n.a.b |
|
|
aGroup means at the end of terminal necropsy are shown.
bn.a. = not applicable
* p<0.05, ** p<0.01
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- NOAEL
- 5.13 mg/cm²
- Species:
- other: Human voluntary and laboratory species
Additional information
The repeat dose toxicity has been determined by subacute 28-day oral toxicity studies by oral, dermal and
inhalation exposure. Based on the data available, the substance may have the potential for haemotological
effects with a reduction in cholesterol observed in one of the studies by oral exposure.
Effects observed in the repeat dose inhalation toxicity study available demonstrated enlarged lungs in high and
intermediate dose animals which are likely to be physical effects due to the inhalation of mineral oil [Test
material: Product as manufactured in mineral oil solvent further diluted in mineral oil (65/35)] and not
necessarily a direct toxicological effect of the registered substance. The data are therefore considered unsuitable
for determination of the intrinsic hazard of the substance as effects due to the registered substance may well be
masked by the effects due to inhalation of mineral oil mist. For example, Occupation Exposure Limits (OELs)
expressed for human exposure in the work place are typically 5 mg/m³. Considering a typical intraspecies
assessment factor of 10 the results demonstrate good correlation to the anticipated effect level for mineral oil
mist.
In view of this it is considered justifiable, for the purposes of assessing DNELs, to extrapolate inhalation hazard
from the oral exposure data available.
Oral-to-inhalation extrapolation was based on the following conditions:
(1) the available repeated dose toxicity study on EC 274-263-7 was reliable;
(2) the critical effect for the oral exposure were systemic, i.e., decreased serum cholesterol levels;
(3) the considered systemic toxic effects was independent of the route of exposure;
(4) the chemical is relatively soluble in body fluid.
RtR extrapolation may require corrections for difference in absorptions between oral (starting route) and the
inhalation (extrapolation route) (Dethloff, L. Z. 1993; Gerrity T. R., 1990; Sharrat M. 1988). Rennen et al. ran a
critical assessment on oral-to-inhalation route extrapolation for 215 substances with various physicochemical
properties. In this study, they compared the experimentally established NOAEL for inhalation study to the
values predicted from oral toxicity study by RtR extrapolation using various absorption assumptions, such as
100% oral and 100% inhalation; 100% oral and 75% inhalation; 50% oral and 100% inhalation. And they
demonstrated that when using systemic effect as criterion and under assuming equal absorption, 55% of the predication were regarded as “safe extrapolation”, whereas 45% as underestimation of the level of toxicity via
inhalation route. Based on this study, it is feasible to assume that equal absorption for this substance. Correcting
from oral to inhalation route of exposure was based on REACH guidance R8, and the mathematic formula was
described in DNEL derivations.
Furthermore, one dermal repeat dose study exists noting effects which resulted in the Study Director being
unable to assign a NOAEL. Due consideration of these data has been taken, but the results are considered not
representative of the toxicological effects of the substance since the observations have not been repeated in the
remaining study with dermal exposure, nor following exposure by oral and inhalation routes which are generally
considered to represent greater systemic exposure routes. Furthermore, effects to the testes of male rats were not
been observed in the reproductive toxicity study. In consequence, although data are not available to adequately
determine the cause of these effects, the fact that no similar observations have been found in any other study
undertaken is considered adequate justification to regard these data as not representative of the toxicological
profile of the registered substance.
Notwithstanding these effects, no further effects were observed in the studies and each study achieved a
NOAEL. The data are therefore considered adequate to assess the toxicological profile of the substance and for
the purposes of classification.
The following information is taken into account for any hazard / risk assessment:
The toxicity of the substance has been assessed by the repeated exposure over a period of 28-days by the three
routes of exposure, oral, dermal and inhalation. Effects observed by oral exposure demonstrate a reduction in
serum cholesterol at the highest tested dose. Furthermore, the results obtained by inhalation exposure are
considered unsuitable for determination of the intrinsic hazard of the substance by inhalation due to the high
proportion of mineral oil in the test sample [Test material: Product as manufactured in mineral oil solvent
further diluted in mineral oil (65/35) ].
Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
A NOAEL of 500 mg/kg bw/day was identified in this study.
Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
The test article elicted a range of effects in the lung; accumulation of intraalveolar macrophages, hyperplasia/hypertophy of the bronchiole epithelium. While these effects were also seen in control animals, there was a dose response in mid and high dose treated animals which was considered treatment related. A NOAEL of 49.5 mg/m³ was identified.
Justification for selection of repeated dose toxicity inhalation - local effects endpoint:
The test article elicted a range of effects in the lung; accumulation of intraalveolar macrophages, hyperplasia/hypertophy of the bronchiole epithelium. While these effects were also seen in control animals, there was a dose response in mid and high dose treated animals which was considered treatment related. A NOAEL of 49.5 mg/m³ was identified.
Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:
Toxicity occurred at all doses tested, therefore a NOAEL has not been identified. an arbitary LOAEL of 250 mg/kg bw has been identified, based on effects at the lowest dose.
Justification for classification or non-classification
Based on the NOAEL values available from these repeat dose toxicity data, the substance is considered to be not
classified under CLP for these repeat dose toxicity endpoints.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.