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EC number: 233-118-8 | CAS number: 10039-54-0
- 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:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study with acceptable restrictions
Cross-reference
- Reason / purpose for cross-reference:
- other: range-finding study
Reference
- Endpoint:
- short-term repeated dose toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Acc. to guidelines, but preliminary study with technical shortcomings concerning definite dosing.
- Reason / purpose for cross-reference:
- other: main study
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- Principles of method if other than guideline:
- 28-day range-finding oral toxicity study mostly according to OECD TG 407
- GLP compliance:
- yes
- Limit test:
- no
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Karl Thomae, Biberach a.d. Riss, Germany
- Age at study initiation: 42 days
- Average weight at study initiation: males: 164.8 g; females 135.2 g
- Housing: individually, in V2A cages, type DK III (Becker & Co. Castrop-Rauxel, Germany)
- Diet: Kliba 343 Futter Ratte/Maus/Hamster "A" (Klingentalmuehle AG, Kaiseraugst, Switzerland), ad libitum
- Water: tap water, ad libitum
- Acclimation period: 6 days
ENVIRONMENTAL CONDITIONS
- Temperature: 20 - 24 °C
- Humidity: 30 - 70 %
- Air changes: fully air-conditioned rooms
- Photoperiod: 12 hrs dark / 12 hrs light - Route of administration:
- oral: drinking water
- Vehicle:
- water
- Details on oral exposure:
- In a 28-day range-finding oral toxicity study mostly according to OECD TG 407 groups of five male and five female Wistar rats received the test material in the drinking water in doses of 0, 25, 100, 400 or 1600 ppm for 4 consecutive weeks. The analytical investigation of the test substance preparations are performed at the end of the study. But, the estimation of compound consumption based on water consumption by male and female rats could not definitely be done in all dose groups because of some study restrictions. There were some technical shortcomings concerning definite calculated achieved intake of BHAS from the drinking water in the 25, 100 and 400 ppm dose groups because of the instability of the test material in water. No test substance or only minor amounts were verifiable especially for the low dose groups. Therefore, the dose is given in ppm instead of mg/kg bw. Stability tests for the test material at the highest dose of 1600 ppm in the drinking water for a storage of 4 days resulted in an average of 1437 ppm. So the average concentration of the test material in drinking water of the 1600 ppm dose group was approx. 142 mg/kg bw/d for males and 149 mg/kg bw/d for females.
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The stability of the test material was checked by photometry over a period of 4 days, but not over a time period of 10 days (as intended).
- Duration of treatment / exposure:
- 4 weeks
- Frequency of treatment:
- ad libitum
- Remarks:
- Doses / Concentrations:
0, 25, 100, 400, and 1600 ppm
Basis:
nominal in water - No. of animals per sex per dose:
- 5
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- After arrival of the animals they were acclimized for 6 days. 4 days prior to start of the exposure period the animals were divided into the treatment groups. The randomization was computer-based.
The preparation of the test material in the drinking water was conducted twice weekly. The test material was mixed with the water and then subsequently stirred for 10 minutes to ensure homogenization. The bottling was conducted with a partially automatized dosage apparatus (Fortuna Optifix). - Observations and examinations performed and frequency:
- - The animals were inspected twice daily for mortality/moribundity (monday to friday) and once daily on saturday, sunday and on public holidays.
- Feed consumption, drinking water consumption and body weight were determined once a week. The average feed consumption (in mg/kg bw/day) was calculated for the high-dose group (1600 ppm) only.
- The state of health was checked each day, and when the animals were weighed, they were additionally inspected and palpated. Approx. 14 days after study inititation and at the end of the study, a swim-test was conducted with the high-dose animals as well as with the controls. The swim test was conducted in a 200 l tank (80 cm x 54 cm x 50 cm) which was 50 % filled with water at 25 °C. The animals were set into the middle of the tank and the time period was documented from setting the animals into the water until the beginning of swimming-movements. For a good comparison, one animal of the high dose group was simultaneously inserted into the water with an animal of the control group. Approx. 30 sec. after insertion the animals were taken out of the water and their fur was dried, possible observations were noted.
- Urine was collected for urinalyses on day 23 after the beginning of administration.
The following parameters were determined semiquantitatively in urine using test stripes and a reflection photometer (Clini-Tek, Ames, Frankfurt, Germany):
- pH
- total protein
- glucose
- ketones
- bilirubin
- blood
- nitrite
- urobilinogen
The sediment analysis was conducted by microscopy.
- Blood samples were taken for clinicochemical and hematological examinations 7, 28 and 30 days after the beginning of administration. Blood was taken in the morning out of non-fasted animals.
The following clinico-chemical/hematological parameters were determined:
Hematological examinations:
The following parameters were determined in blood using a particle counter:
- leukocytes
- erythrocytes
- hemoglobin
- hematocrit
- mean corpuscular volume
- mean corpuscular hemoglobin
- mean corpuscular hemoglobin concentration
- platelets
- Heinz-bodies
- methaemoglobin
The data obtained were transferred to a computer. The differential blood count was evaluated visually. The data were transferred to the computer.
Clotting analyses:
The clotting analyses were carried out using a ball coagulometer and the results transferred off-line to the computer.
The following parameter was determined:
- thromboplastin time (Hepato Quick's test)
Clinicochemical examinations:
An automatic analyzer was used to examine the clinicochemical parameters. The values obtained were transferred to a computer.
The following parameters were determined:
Enzymes
- glutamate-pyruvate transaminase
- glutamate-oxalacetate transaminase
- alkaline phosphatase
- lactate dehydrogenase
- plasma-cholinesterase
Blood chemistry:
- sodium
- potassium
- chloride
- inorganic phosphate
- calcium
- urea
- creatinine
- glucose
- total bilirubin
- total protein
- albumin
- globulins
- triglycerides
- cholesterol
Liver homogenate:
- gamma-glutamyl transferase
- GSH
- hormones (trijodthyronine and thyroxine) - Sacrifice and pathology:
- At the end of the administration period, all animals were sacrificed by decapitation after they had been anesthetized by CO2 and were assessed by gross pathology.
Subsequently, a histopathological examination was carried out.
The weight of the animals as well as the weights of liver, kidneys, adrenal glands, testes, brain and spleen from all animals sacrificed at scheduled dates was determined.
Subsequently the following organs or tissues were fixed in 4 % formaldehyde solution:
brain, thyroid, kidneys, spleen, adrenal glands, heart, testes, peripheral nerve, sternum with medulla, spinal cord, all macroscopic changes and target organs.
After the organs had been fixed, processing, the examination by light microscopy and the evaluation of findings was performed in all animals of the control and the high dose groups. Additionally, the spleen, liver and kidneys were examined fom all animals of the 100 ppm and 400 ppm dose group. - Statistics:
- Means and standard deviations were calculated.
Statistical analyses were conducted by using the Dunnett´s- test and the ANOVA analysis, the William´s test or the t-test.
- Details on results:
- No deaths occurred during the study. Food intake of BHAS-treated rats was similar to that of the controls. At 1600 ppm, rats of both sexes showed decreased water consumption, cyanosis and discoloration (yellow-red) of the urine in the last treatment week. The relevant study results of hematology, clinical biochemistry, organ weight assessment, necropsy and microscopy from males and females receiving 1600, 400 and 100 ppm are summarized in the following.
1600 ppm:
- blood (m/f): ↓ RBC, ↓ HB, ↓ HCT, ↓ MCHC, ↑ MCH, ↑ MCV, ↑ RET, ↑ Heinz bodies, ↑ methaemoglobin, morphological changes of RBC: anisocytosis, poikilocytosis, and polychromasia (m/f), ↑ WBC (m/f), ↑ Neut (m/f), ↑ Eos (m/f), ↑ Lymph (m/f), ↑ Mono (m/f), ↓ PLT (m/f), ↑ bilirubin (m/f), ↓ AP (m/f), ↓ glucose (f), ↓ Ca (m), ↑ P (m), ↑ bilirubin in urine (f)
- spleen (m/f): ↑ weight (abs/rel), splenomegaly, hemosiderin deposits, extramedullary hematopoiesis
- liver: hemosiderin deposits in Kupffer cells (m/f), extramedullary hematopoiesis and erythrophagocytosis (m/f), single megacaryocytes in intrasinosidial space (m/f), iron pigment deposition in hepatocytes (f)
- kidney: ↑ weight, abs/rel (m), tubular hemosiderosis (m/f), iron-negative pigment deposition in proximal tubulus (m/f)
- bone marrow (m): reticuloid hypeplasia, necrosis
400 ppm:
- blood: ↓ RBC (m), ↓ HCT (m), ↓ HB (m/f), ↑ MCV (f), ↑ RET (m/f), ↑ Heinz bodies (m/f), morphological changes of RBC: anisocytosis, micro- and macrocytosis (m), polychromatophily (m/f), ↑ Neut (m), ↓ bilirubin (f),
- spleen (m/f): splenomegaly; extramedullary hematopoiesis
- liver (m/f): extramedullary hematopoiesis
100 ppm: :
- blood (m): anisocytosis, polychromatophily
- spleen (m): splenomegaly
footnote:
↑: statistically significant increase compared with controls;
↓: statistically significant decrease compared with controls;
m: male; f: female;
RBC: Erythrocyte count; HB: Haemoglobin; HCT: Hematocrit; MCV: Mean corpuscular volume; MCH: Mean corpuscular haemoglobin; MCHC: Mean corpuscular haemoglobin concentration; WBC: Leukocyte count; PLT: Platelet count; RET: Reticulocyte count; Neut: Neutrophiles; Lymph: Lymphocytes; Mono: Monocytes; Eos: Eosinophiles; AP: Alkaline phosphatase; Ca: Calcium; P: Inorganic phosphorus; - Dose descriptor:
- NOAEL
- Effect level:
- 25 ppm
- Sex:
- male
- Dose descriptor:
- NOAEL
- Effect level:
- 100 ppm
- Sex:
- female
- Critical effects observed:
- not specified
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 989
- Report date:
- 1989
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
- Deviations:
- yes
- Remarks:
- ; no recovery period
- Principles of method if other than guideline:
- similar/equivalent to OECD TG 408, but without recovery period.
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- Bis(hydroxylammonium) sulphate
- EC Number:
- 233-118-8
- EC Name:
- Bis(hydroxylammonium) sulphate
- Cas Number:
- 10039-54-0
- Molecular formula:
- H3NO.1/2H2O4S
- IUPAC Name:
- bis(hydroxyammonium) sulfate
- Details on test material:
- - Name of test material (as cited in study report): Hydroxylammoniumsulfat (HAS)
- Analytical purity: >= 99 %
- Lot/batch No.: 84/389
- Stability under test conditions: was ensured during the study period
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Dr. Karl Thomae GmbH, Biberach a.d. Riss, Germany
- Age at study initiation: 42 days
- Average weight at study initiation: males ca. 117 g; females ca. 136 g
- Housing: individually in V2A wire mesh cages, type DK III (Becker & Co. Castrop-Rauxel, Germany)
- Diet: Kliba-Haltungsdiaet Ratte/Maus/Hamster 343 Mehl (Klingentalmuehle AG, Kaiseraugst, Switzerland), ad libitum
- Water: Milli-Q-Reinstwasser, ad libitum
- Acclimation period: 7 days
ENVIRONMENTAL CONDITIONS
- Temperature: 20 - 24 °C
- Humidity: 30 - 70 %
- Air changes: fully air-conditioned rooms
- Photoperiod: 12 hrs dark / 12 hrs light
Administration / exposure
- Route of administration:
- oral: drinking water
- Vehicle:
- other: Mili-Q extra pure water
- Details on oral exposure:
- In a subchronic oral toxicity study similar to OECD TG 408 (but without recovery period), Hydroxylammonium sulfate was administered to 60 Wistar rats (30 males and 30 females ) via the drinking water (in Milli-Q extra pure water) for 90 consecutive days. For comparison, one group of untreated animals (10 males and 10 females) was used as control.
The doses in the drinking water were 10 ppm (test group 1), 50 ppm (test group 2) and 250 ppm (test group 3). The doses administered corresponded to a mean daily test substance intake of approx. 0.9, 4 and 21 mg/kg body weight. The average daily food intake in mg/kg bw was calculated for each animal at the time intervals when the water consumption was determined. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- For homogeneity and concentration control analyses, each samples of all concentrations were drawn at the start of the study, after 6 weeks and towards at the end of the administration period after 12 weeks of the study.
The analysis of the amount of the test material in the drinking water was determined by photometry. - Duration of treatment / exposure:
- 3 months
- Frequency of treatment:
- ad libitum
Doses / concentrations
- Remarks:
- Doses / Concentrations:
0, 10, 50, 250 ppm, corresponding to approx. 0.9, 4 and 21 mg/kg bw/day
Basis:
nominal in water
- No. of animals per sex per dose:
- 10 animals per sex per dose
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- The preparation of the test material in the drinking water was conducted twice weekly (on tuesdays and fridays). The test material was mixed with the water and then subsequently stirred for 10 minutes to ensure homogenization. The bottling was conducted with a fully automatized dosage apparatus (Fortuna Optimat MP).
Examinations
- Observations and examinations performed and frequency:
- - The animals were inspected twice daily for mortality/moribundity (monday to friday) and once daily on saturday, sunday and on public holidays.
- Feed consumption, drinking water consumption and body weight were determined once a week.
- The state of health was checked each day, and when the animals were weighed, they were additionally inspected and palpated.
- Before the beginning of test substance administration and toward the end of the study, ophthalmological examinations were carried out in the animals of the control and 250 ppm groups.
- Urine was collected for urinalyses 29 and 78 days after the beginning of administration.
The following parameters were determined semiquantitatively in urine using test stripes and a reflection photometer (Clini-Tek, Ames, Frankfurt, Germany):
- pH
- total protein
- glucose
- ketones
- bilirubin
- blood
- nitrite
- urobilinogen
The sediment analysis was conducted by microscopy.
- Blood samples were taken for clinicochemical and hematological examinations 36 and 85 days after the beginning of administration. Blood was taken in the morning out of non-fasted animals.
The following clinico-chemical/hematological parameters were determined:
Hematological examinations:
The following parameters were determined in blood using a particle counter (S Plus model, by Coulter, Krefeld, Germany):
- leukocytes
- erythrocytes
- hemoglobin
- hematocrit
- mean corpuscular volume
- mean corpuscular hemoglobin
- mean corpuscular hemoglobin concentration
- platelets
- Heinz-bodies
- methaemoglobin
The data obtained were transferred to a computer (VAX 11/780; supplied by DEC, Munich, FRG). The differential blood count was evaluated visually. The data were transferred to the computer.
Clotting analyses:
The clotting analyses were carried out using a ball coagulometer (KC 10 model, by Amelung, Lemgo, Germany) and the results transferred off-line to the computer.
The following parameter was determined:
- thromboplastin time (Hepato Quick's test)
Clinicochemical examinations:
An automatic analyzer (Hitachi 737; by Boehringer, Mannheim, Germany) was used to examine the clinicochemical parameters. The values obtained were transferred to a computer (VAX 11/780; by DEC, Munich, Germany).
The following parameters were determined:
Enzymes
- alanine aminotransferase
- aspartate aminotransferase
- alkaline phosphatase
Blood chemistry:
- sodium
- potassium
- chloride
- inorganic phosphate
- calcium
- urea
- creatinine
- glucose
- total bilirubin
- total protein
- albumin
- globulins
- triglycerides
- cholesterol - Sacrifice and pathology:
- At the end of the 3-month administration period, after a fasting period, all animals were sacrificed by decapitation after they had been anesthetized by CO2 and were assessed by gross pathology.
Subsequently, a histopathological examination was carried out.
The weight of the animals as well as the weights of liver, kidneys, adrenal glands, testes, brain and spleen from all animals sacrificed at scheduled dates was determined.
Subsequently the following organs or tissues were fixed in 4 % formaldehyde solution:
brain, pituitary gland, thyroid, thymus, trachea, lungs, heart, aorta, liver, spleen, kidneys, adrenal glands, pancreas, testes/ovaries, uterus, oesophagus, stomach, duodenum, jejunum, ileum, cecum, colon, rectum, bladder, mesenterial lymph nodes, peripheral nerve, sternum with medulla, all macroscopic changes.
After the organs had been fixed, processing, the examination by light microscopy and the evaluation of findings was performed in all animals of the control and the high dose groups. Additionally, the lung, liver and kidneys were examined fom all animals of any dose group.
In the liver, spleen of all dose groups as well as in the kidneys of high dose and control groups an iron analysis was also conducted. - Statistics:
- For food consumption, water consumption, body weights, organ weights and substance consumption, as well as for clinico-chemical and haematological parameters means and standard deviations were calculated. Statistical analyses were conducted for body weight as well as for clinico-chemical and haematological parameters by using the Dunnett´s- test and the ANOVA analysis.
The individual parameters of the urinalysis were checked for statistical significance by using the chi square test.
Results and discussion
Results of examinations
- Details on results:
- Regarding mortality, general appearance and behaviour of the animals there was no difference between treated and untreated animals. No toxicologically relevant differences in mean feed consumption per animal/d or per kg bw/d as well as body weight and body weight development were detected in male and female rats. The following findings were obtained and assessed as substance-induced.
At 250 ppm, rats of both sexes showed dark coloration of the urine. This is considered to be due to the substance-related effects on the blood. The hematological examination revealed indications of an increased destruction of red blood cells.
At 250 ppm in both sexes and at 50 ppm in females there was a reduction of the erythrocytes and haemoglobin values. In addition there were an increase of the MCH values in both sexes at 250 ppm and in females at 50 ppm, furthermore reduced values of hematocrit in females and of the MCHC in males at 250 ppm. In males receiving 50 ppm, decreased counts of red blood cells and decreased values of haemoglobin were also apparent during the treatment period, although these did not attain statistical significance. These findings are considered to be related also to an increased decay of erythrocytes. The increase of the MCV, and reticulocyte counts at 250 ppm in males and females were assessed as sign of compensate increased erythropoiesis. As a consequence of an increased leaving of juvenile erythrocytes out of the bone marrow a reinforced polychromasia was seen dose-dependent at 250 and 50 ppm in both sexes. At 50 ppm, a slight increase of reticulocytes in male and female rats was noted, and moreover in females a marginal increase of the MCV values. Furthermore, an increase of bilirubin concentration in both sexes at 250 ppm was observed. In males and females receiving 50 ppm, increased values of bilirubin were also apparent during the treatment period, although these did not attain statistical significance. This finding appears to be due to the increased decay of erythrocytes. The elevated methaemoglobin concentration and the reinforced evidence of Heinz bodies in both sexes at 250 ppm are indicative for methaemoglobinemia. Increased absolute and relative spleen weights were seen at 250 ppm in male and female rats. Increase of relative liver weights were noted only in males. In males and females receiving 50 ppm, increased absolute and relative adrenal weights were noted.
Histopathological findings representing secondary effects to the anemia included increased hemosiderin deposits in the spleen and liver of both males and females given 250 ppm. At 50 ppm, moderate increased hemosiderin deposits in the spleen were revealed in both sexes. In addition, sinus dilatation together with congestion of the spleen were observed dosedependent in both sexes at 50 and 250 ppm. 10 ppm did not alter the blood parameters in rats of both sexes.
10 ppm (approx. 0.9 mg/kg bw/d):
No changes were found to be attributed to the test substance administered.
50 ppm (approx. 4 mg/kg bw/d):
- Clinical signs: none specific (m/f)
- Blood: ↓ RBC (f), (↓) RBC (m), ↓ Hb (f), (↓) Hb (m), ↑ MCV (f), ↑ MCH (f), ↑ polychromasia (m/f), ↑ RET (m/f), (↑) bilirubin (m/f)
- Effects on organs:
adrenal weight ↑, abs/rel (m/f); spleen: hemosiderin deposits (m/f), sinus dilatation together with congestion (2m/2f)
250 ppm (approx. 21 mg/kg bw/d):
- Clinical signs: dark coloration of the urine (m/f)
- Blood: ↓ RBC (m/f), ↓ Hb (m/f), ↓ HCT (f), ↓ MCHC (m), ↑ MCV (m/f), ↑ MCH (m/f), ↑ RET (m/f), ↑ Heinz bodies (m/f), ↑ MetHb (m/f), ↑ polychromasia (m/f), ↑ bilirubin (m/f)
- Effects on organs:
spleen: ↑ weight, abs (m/f), ↑ weight, rel (m), hemosiderin deposits (m/f), sinus dilatation together with congestion (10m/10f);
liver: ↑ weight, rel (m), hemosiderin deposits (m/f)
↑: statistically significant increase compared with controls; (↑): increase compared with controls, no statistically significant but possibly of toxicological relevance;
↓: statistically significant decrease compared with controls;
(↓): decrease compared with controls, no statistically significant but possibly of toxicological relevance;
m: male; f: female;
RBC: Erythrocyte count; Hb: Haemoglobin; HCT: Hematocrit; MCV: Mean corpuscular volume; MCH: Mean corpuscular haemoglobin; MCHC: Mean corpuscular haemoglobin concentration; MetHb: methaemoglobin; RET: Reticulocyte count
Effect levels
open allclose all
- Dose descriptor:
- NOAEL
- Remarks:
- systemic effects
- Effect level:
- > 0.9 mg/kg bw/day (nominal)
- Sex:
- male/female
- Basis for effect level:
- other: 10 ppm: no substance related effects on blood and organs
- Dose descriptor:
- NOAEL
- Remarks:
- local effects
- Effect level:
- >= 21 mg/kg bw/day (nominal)
- Sex:
- male/female
- Basis for effect level:
- other: no substance-related effects seen
Target system / organ toxicity
- Critical effects observed:
- not specified
Any other information on results incl. tables
Table 1: Hematology data for MetHB, reticulocytes and Heinz-Bodies on day 36 and 85, respectively
Males (n = 10) |
MetHB: day 36 |
MetHB: day 85 |
reticulocytes: day 36 |
reticulocytes: day 85 |
Heinz-Bodies: day 36 |
Heinz-Bodies: day 85 |
0 ppm |
0.0 ± 0.0 |
0.1 ± 0.1 |
19 ± 4 |
20 ± 8 |
0 ± 0 |
0 ± 0 |
10 ppm |
0.0 ± 0.1 |
0.1 ± 0.2 |
17 ± 5 |
22 ± 5 |
0 ± 0 |
0 ± 0 |
50 ppm |
0.0 ± 0.1 |
0.2 ± 0.2 |
25 ± 5 |
31 ± 10 * |
0 ± 0 |
2 ± 2 |
250 ppm |
0.2 ± 0.3 |
0.6 ± 0.2 ** |
72 ± 10 ** |
76 ± 13 ** |
253 ± 64 ** |
408 ± 80 ** |
Females (n = 10) |
|
|
|
|
|
|
0 ppm |
0.0 ± 0.0 |
0.1 ± 0.2 |
14 ± 3 |
15 ± 4 |
0 ± 0 |
0 ± 0 |
10 ppm |
0.0 ± 0.0 |
0.1 ± 0.1 |
18 ± 8 |
17 ± 10 |
0 ± 0 |
0 ± 0 |
50 ppm |
0.1 ± 0.2 |
0.1 ± 0.2 |
25 ± 10 |
28 ± 9 * |
0 ± 0 |
7 ± 13 |
250 ppm |
0.3 ± 0.3 ** |
0.9 ± 0.4 ** |
79 ± 23 ** |
80 ± 15 ** |
362 ± 136 ** |
450 ± 89 ** |
Statistics: Anova + Dunnet´s tests: * = P<0.05, ** = P<0.01, two-sided (statistical unit = animal)
Table 2: Absolute (g) and relative (%) body weights and selected organ weights
Males (n = 10) |
body weight (abs.) (g) |
body weight (rel.) (%) |
spleen (abs.) (g) |
spleen (rel.) (%) |
liver (abs.) (g) |
liver (rel.) (%) |
adrenal glands (abs.) (g) |
adrenal gland (rel.) (%) |
0 ppm |
409.32 ± 26.35 |
100 |
0.784 ± 0.122 |
0.191 ± 0.021 |
11.998 ± 1.128 |
2.927 ± 0.126 |
0.081 ± 0.008 |
0.02 ± 0.002 |
10 ppm |
424.87 ± 42.81 |
100 |
0.837 ± 0.156 |
0.196 ± 0.026 |
13.153 ± 2.522 |
3.082 ± 0.379 |
0.091 ± 0.01 |
0.021 ± 0.002 |
50 ppm |
423.9 ± 36.25 |
100 |
0.872 ± 0.165 |
0.205 ± 0.029 |
13.261 ± 1.657 |
3.121 ± 0.151 |
0.099 ± 0.009 * |
0.024 ± 0.003 * |
250 ppm |
432.93 ± 45.6 |
100 |
1.587 ± 0.247 ** |
0.369 ± 0.066 ** |
14.236 ± 3.01 |
3.26 ± 0.373 * |
0.094 ± 0.021 |
0.022 ± 0.003 |
Females (n = 10) |
|
|
|
|
|
|
|
|
0 ppm |
235.16 ± 27.48 |
100 |
0.521 ± 0.047 |
0.223 ± 0.023 |
7.425 ± 1.004 |
3.154 ± 0.147 |
0.013 ± 0.015 |
0.048 ± 0.009 |
10 ppm |
226.16 ± 15.13 |
100 |
0.486 ± 0.066 |
0.214 ± 0.021 |
7.149 ± 0.563 |
3.163 ± 0.171 |
0.11 ± 0.008 |
0.049 ± 0.004 |
50 ppm |
237.61 ± 35.95 |
100 |
0.536 ± 0.072 |
0.227 ± 0.025 |
7.627 ± 1.111 |
3.215 ± 0.14 |
0.117 ± 0.015 |
0.05 ± 0.006 |
250 ppm |
232.35 ± 12.07 |
100 |
1.164 ± 0.307 ** |
0.499 ± 0.124 ** |
7.533 ± 0.325 |
3.247 ± 0.154 |
0.113 ± 0.011 |
0.049 ± 0.006 |
Statistics: Dunnet´s test: * = P<0.05, ** = P<0.01, two-sided (statistical unit = animal)
Table 3: Hematology data of selected parameters of control and high dose group on day 36 and 85, respectively
Day 36: |
WBC (giga/l) |
RBC (tera/l) |
HGB (mmol/l) |
HCT (l/l) |
MCV (fl) |
MCH (fmol) |
MCHC (mmol/l) |
PLT )giga/l) |
Males (n = 10) |
|
|
|
|
|
|
|
|
0 ppm |
7.06 ± 0.63 |
8.19 ± 0.36 |
9.47 ± 0.49 |
0.416 ± 0.027 |
50.72 ± 1.21 |
1.16 ± 0.02 |
22.77 ± 0.62 |
1000 ± 96 |
250 ppm |
8.18 ± 1.81 |
7.14 ± 0.51 ** |
8.72 ± 0.44 ** |
0.397 ± 0.024 |
55.56 ± 2.14 ** |
1.22 ± 0.05 ** |
22.00 ± 0.57 * |
1017 ± 110 |
Females (n = 10) |
|
|
|
|
|
|
|
|
0 ppm |
4.28 ± 0.72 |
7.88 ± 0.47 |
9.16 ± 0.38 |
0.396 ± 0.021 |
50.18 ± 1.16 |
1.16 ± 0.03 |
23.14 ± 0.58 |
1136 ± 98 |
250 ppm |
5.88 ± 1.30 |
6.61 ± 0.44 ** |
8.40 ± 0.38 ** |
0.373 ± 0.018 |
56.50 ± 2.53 ** |
1.27 ± 0.05 ** |
22.52 ± 0.53 |
1093 ± 160 |
Day 85: |
|
|
|
|
|
|
|
|
Males (n = 10) |
|
|
|
|
|
|
|
|
0 ppm |
5.87 ± 0.95 |
8.47 ± 0.54 |
9.26 ± 0.51 |
0.414 ± 0.028 |
48.84 ± 1.03 |
1.09 ± 0.03 |
22.38 ± 0.57 |
1058 ± 111 |
250 ppm |
7.31 ± 1.20 |
7.44 ± 0.44 ** |
8.69 ± 0.39 * |
0.400 ± 0.020 |
53.66 ± 1.97 ** |
1.17 ± 0.05 ** |
21.74 ± 0.35 ** |
1101 ± 171 |
Females (n = 10) |
|
|
|
|
|
|
|
|
0 ppm |
3.90 ± 1.39 |
8.39 ± 0.42 |
9.29 ± 0.51 |
0.41 ± 0.021 |
48.83 ± 1.06 |
1.11 ± 0.03 |
22.65 ± 0.52 |
1114 ± 73 |
250 ppm |
4.30 ± 0.87 |
6.49 ± 0.48 ** |
8.08 ± 0.29 ** |
0.364 ± 0.016 ** |
56.13 ± 2.00 ** |
1.25 ± 0.06 ** |
22.22 ± 0.44 |
992 ± 159 |
Statistics: Dunnet´s test: * = P<0.05, ** = P<0.01, two-sided (statistical unit = animal)
Applicant's summary and conclusion
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