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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
Developmental toxicity / teratogenicity
Administrative data
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 27. Apr 1993 - 24. May 1993
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: GLP guideline study (OECD 414)
Cross-reference
- Reason / purpose for cross-reference:
- other: Range-finding study
Reference
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Only limited (range finding) study with the gravidity period reduced (up to day 16 only).
- Reason / purpose for cross-reference:
- other: Main study
- Principles of method if other than guideline:
- Range finding study in which 0, 5, 15 and 30 mg hydroxylammoniumsulfate/kg body weight/day were administered by gavage to pregnant rats during organogenesis.
- GLP compliance:
- not specified
- Species:
- rat
- Strain:
- Wistar
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Dr. K. Thomae GmbH, Biberach/Riss
- Age at study initiation: 10-15 weeks
- Weight at study initiation: ca. 200-300 g
- Housing: single housing in mesh wire cages type DK III, EBECO, Becker &Co., Castrop-Rauxel
- Diet (e.g. ad libitum): ad libitum (Kliba diet "Ratte-Maus A Haltung GLP 343", Klingentalmühle AG, CH-4303 Kaiseraugst)
- Water (e.g. ad libitum): tap water ad libitum
- Acclimation period: at least 5 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 30-70
- Air changes (per hr): not specified
- Photoperiod (hrs dark / hrs light): 12/12
- Route of administration:
- oral: gavage
- Vehicle:
- water
- Remarks:
- Milli-Q-purified water
- Analytical verification of doses or concentrations:
- yes
- Remarks:
- after end of experiment all concentrations were analytically verified, stability of test substance in vehicle was demonstrated before the start of the experiment.
- Details on analytical verification of doses or concentrations:
- after end of experiment all concentrations were analytically verified, stability of test substance in vehicle was demonstrated before the start of the experiment.
- Details on mating procedure:
- - Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: not specified
- Length of cohabitation: 4PM until 7.30 AM of the following day
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy - Duration of treatment / exposure:
- day 6 - 15 p.c.
- Frequency of treatment:
- daily
- Duration of test:
- 11 days
- Remarks:
- Doses / Concentrations:
5, 15, 30 mg/kg bw/d (ca. 2, 6.1, and 12.3 mg base/kg bw/d)
Basis:
nominal conc. - No. of animals per sex per dose:
- 9 or 10 pregnant rats were applied per dose.
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: Based on data available from repeated dose toxicity studies and the results observed (see IUCLID section 7.5)
- Rationale for animal assignment (if not random): random
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: At least once per day, if symptoms were observed several observations per day
DETAILED CLINICAL OBSERVATIONS: No data
BODY WEIGHT: Yes
- Time schedule for examinations: days 0, 1, 3, 6, 8, 10, 13, 15 and 16 post coitum
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 16
- Hematology: Leukocytes, Erythrocytes, Hemoglobin, Hematocrit, MCV, Hemoglobin content per erythrocyte, MCH, thrombocytes, differential hematology, reticulocytes, Heinz bodies
- Hemoglobin status: total hemoglobin, oxihemoglobin, carboxihemoglobin, methemoglobin, oxygen content, oxygen saturation, reduced hemoglobin, oxygen capacity
- coagulation: Hepato Quick test
- enzymes: Alanin aminotransferase, aspartate aminotransferase, alkalic phosphatase, gamma glutamyltransferase
- clinical chemistry: sodium, potassium, chloride, phosphate, calcium, urea, creatinin, glucose, total bilirubin, total protein, albumin, globulins, triglycerides, cholesterol, magnesium
- Gross pathology: liver weight, kidney weight, spleen weight, unopened uterus weight, number of corpora lutea, number of implantations early resoptions, situation of implants in uterus - Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes. The number of resorptions was determined (not further specified).
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: yes
- Number of implantations: yes
- Number of early resorptions: yes
- Number of late resorptions: No data - Fetal examinations:
- - External examinations: Yes: all per litter
- Soft tissue examinations: No
- Skeletal examinations: No
- Head examinations: No
- Fetal weights were determined - Statistics:
- Dunnett test (food consumption, body weights, body weight changes, corrected body weight change, clinical chemistry and hematology, organ weights, placenta weights and fetus weights, corpora lutea, impantations, pre- and post-implantation loss, resorptions, living fetuses
Fisher's exact test: conception rate, mortality rate (maternal), fetal findings - 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
- Haematological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Increased white blood cells were observed in the two highest dose groups which are correlating with an increase in polymorphonuclear neutrophils and lymphocytes in these two treatment groups and with an increase in monocytes and monoblasts in the highest dose group.
Red blood cells, hemoglobin and hematocrit were statistically significantly decreased in the mid- and high-dose groups. Mean corpuscular volume (MCV) was statistically significantly increased in all dose groups and mean corpuscular hemoglobin (MCV) was increased in test groups
2 and 3 (15 mg/kg body weight and 30 mg/kg body weight).
In the differential blood count of the animals given 15 mg/kg body weight and 30 mg/kg body weight increased polychromasia, anisocytosis, makrocytosis, normoblasts and Howell-Jolly bodies were detected. Furthermore, a dose-dependent, statistically significant increase in
reticulocytes was seen in all treatment groups and an extreme increase in Heinz bodies was observed in the mid- and high-dose.
All changes in the red blood picture are signs of a severe anemia with Heinz body-formation caused by the test substance. The findings observed in the white blood picture are also treatment-related and might be a consequence of the anemic process. - Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Statistically significantly increased total bilirubin concentrations were found in the serum of the intermediate and high-dose rats (15 or 30 mg/kg body weight/day). The increase in bilirubin is due to an increased rate of hemoglobin degradation as the result of the accelerated destruction of red blood cells in the anemic process.
The other clinicochemical examinations revealed no treatment-related changes. - Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- Absoiute and relative spleen weights were distinctly increased and the spleens were considerably enlarged in the intermediate (15 mg/kg body weight/day) and the high dose group (30 mg/kg body weight/day). Furthermore, slightly, but statistically insignificantly increased spleen weights were also noted for the low dose rats (5 mg/kg body weight/day). These findings are attributed to the test substance administration and are a consequence of the hemolytic anemia.
The weights of the gravid uteri were not influenced by the administration of the test substance. - Gross pathological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- A spontaneous necropsy finding (hydrometra) occurred in one control dam, which did not become pregnant.
- Other effects:
- effects observed, treatment-related
- Description (incidence and severity):
- Hemoglobin status:
Statistically significantly decreased values for total hemoglobin, oxygen content and oxygen capacity were found in the peripheral blood of the animals of test groups 2 and 3 (15 mg/kg body weight and 30 mg/kg body weight).
Moreover, reduced oxyhemoglobin and oxygen saturation and increased deoxygenated hemoglobin were detected in the highest dose group.
The changes seen in the hemoglobin status are substance related, too. They are caused by a disturbance of the oxygen supply which is associated with the anemic process. - Pre- and post-implantation loss:
- no effects observed
- Total litter losses by resorption:
- no effects observed
- Early or late resorptions:
- no effects observed
- Changes in number of pregnant:
- no effects observed
- Description (incidence and severity):
- The conception rate varied between 90% (control group and test group 2) and 100% (test group 1 and 3).
- Details on maternal toxic effects:
- There were no substance-related and/or statistically significant differences between the groups in conception rate, the mean number of corpora lutea and implantation sites or in the values calculated for the pre- and postimplantation losses, the number of resorptions and viable fetuses. The differences evident are considered to be incidental and within the normal range of deviations for animals of this strain and age.
- Dose descriptor:
- NOAEL
- Remarks on result:
- not determinable
- Remarks:
- no NOAEL identified
- Abnormalities:
- effects observed, treatment-related
- Localisation:
- other: blood
- Description (incidence and severity):
- mid and high dose:
- increase in white blood cells, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), polymorphonuclear neutrophils, lymphocytes, monocytes, monoblasts, polychromasia, anisocytosis, makrocytosis, normoblasts, Howell-Jolly bodies, reticulocytes, Heinz bodies, deoxygenated hemoglobin and total bilirubin
- decrease in red blood cells, hemoglobin, hematocrit, oxyhemoglobin, oxygen content, oxygen saturation and oxygen capacity
- statistically significantly increased absolute and relative spleen weights with considerably enlargement of the spleen
==> severe hemolytic anemia with considerable enlargement of the spleen.
low dose shows marginal indications of these effects with increased MCV and reticulocytes as well as marginally increased absolute and relative spleen weights. - Fetal body weight changes:
- no effects observed
- External malformations:
- no effects observed
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:no effects
Details on embryotoxic / teratogenic effects:
Gross macroscopic examination of fetuses revealed no teratogenic effects. - Dose descriptor:
- NOAEL
- Remarks on result:
- not determinable due to absence of adverse toxic effects
- Abnormalities:
- no effects observed
- Developmental effects observed:
- no
Clinical chemistry and hematology:
30 mg/kg body weight:
Increase in white blood cells, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), polymorphonuclear neutrophils, lymphocytes, monocytes, monoblasts, polychromasia, anisocytosis, makrocytosis, normoblasts, Howell-Jolly bodies, reticulocytes, Heinz bodies, deoxygenated hemoglobin and total bilirubin.
Decrease in red blood cells, hemoglobin, hematocrit, oxyhemoglobin, oxygen content, oxygen saturation and oxygen capacity.
15 mg/kg body weight:
Increase in white blood cells, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), polymorphonuclear neutrophils, lymphocytes, polychromasia,
anisocytosis, makrocytosis, normoblasts, Howell-Jolly bodies, reticulocytes, Heinzbodies and total bilirubin.
Decrease in red blood cells, hemoglobin, hematocrit, oxygen content and oxygen capacity.
5 mg/kg body weight:
Increase in mean corpuscular volume (MCV) and reticulocytes.
Spleen weights:
Spleen weights | ||||||||
Dose | absolute [g] | relative [% final body weight] |
||||||
0 mg/kg bw/day | 0.72 (100%) | 0.245 (100%) | ||||||
5 mg/kg bw/day | 0.82 (114%) | 0.270 (110%) | ||||||
15 mg/kg bw/day | 1.36** (189%) | 0.437** (178%) | ||||||
30mg/kg bw/day | 1.74** (242%) | 0.566** (231%) |
**: p<0.01
From the results of this preliminary study it was obvious, that hydroxylammoniumsulfate caused clear signs of maternal toxicity at 15 and 30 mg/kg body weight in the form of a severe hemolytic anemia with a considerable enlargement of the spleen. Marginal indications of these effects occurred already at the lowest dose, 5 mg/kg body weight/day.
Due to the stage of development of the implants on the day of study termination the examination of the uterus content was very limited. Taking this into consideration, no adverse effects on the fetuses occurred.
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 994
- Report date:
- 1994
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- GLP compliance:
- yes
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): Hydroxylammoniumsulfate (solid salt)
- Physical state: solid, crystals/white
- Analytical purity: > 98.4%
- Lot/batch No.: continuous production of April 4, 1991
- Storage condition of test material: refrigerator, dry
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Karl THOMAE, Biberach an der Riss, Germany
- Age at study initiation: 76 99 days
- Weight at study initiation: 248 g (average)
- Housing: singly in type DK III stainless steel wire mesh cages (floor area about 800 cm2) .
- Diet: ground Kliba 343 feed rat/mouse/hamster supplied by KLINGENTALMUEHLE AG, Switzerland, ad libitum
- Water: tap water quality from water bottles, ad libitum
- Acclimation period: at least 5 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24°C
- Humidity (%): 30 - 70 %
- Photoperiod: 12 hrs dark / 12 hrs light
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- other: Milli-Q-water
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Analyses of the test substance:
Analytical determinations of the purity of the test substance itself were carried out before the beginning of the study (method: potentiographic titration). The stability of the test substance was proven by reanalysis. - Details on mating procedure:
- - Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1/1-4
- Length of cohabitation: from about 16.00 hours to about 7.30 hours on the following day.
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy - Duration of treatment / exposure:
- day 6 - 15 p.c.
- Frequency of treatment:
- 10x by gavage
- Duration of test:
- 20 days
Doses / concentrations
- Remarks:
- Doses / Concentrations:
1, 3, 10, 20 mg/kg bw/d
Basis:
actual ingested
- No. of animals per sex per dose:
- 25 (females)
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale:
Dose selection: In a pre-study it became obvious that HAS caused clear signs of maternal toxicity at 30 and 15 mg/kg bw/day (hemolytic anemia).
Therefore, 20 mg was chosen as the upper dose.
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: at least once a day
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: The animals were examined for clinical symptoms at least once a day, or more often when clinical signs of toxicity were elicited.
BODY WEIGHT: Yes
- Time schedule for examinations: All animals were weighed on days 0, 1, 3, 6, 8, 10, 13, 15, 17 and 20 p.c.
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 20
- Organs examined: gross pathology, weight of spleen was recorded.
- Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Furthermore, calculations of conception rate and preand postimplantation losses were carried out. - Fetal examinations:
- - External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: No data - Statistics:
- The DUNNETT-Test was used for a simultaneous comparison of several dose groups with the control. The hypothesis of equal means was tested. This test was performed two-sided and was used for the statistical evaluation of the following parameters: Food consumption, body weight, body weight change, corrected body weight gain (net maternal body weight change), weight of the uterus before it was opened, spleen weights (absolute and relative), number of corpora lutea, number of implantations, number of resorptions and number of live fetuses; proportion of preimplantation loss, postimplantation loss, resorptions and live fetuses in each litter; litter mean fetal body weight and litter mean placental weight.
FISHER's Exact Test was used for a pairwise comparison of each dose group with the control for the hypothesis of equal proportions. This test was performed one-sided and was used for female mortality, females pregnant at terminal sacrifice and the number of litters with fetal findings.
The WILCOXON-Test was used for a comparison of each dose group with the control for the hypothesis of equal medians. This test was performed one-sided and was used for the proportion of fetuses with malformations, variations, retardations and/or unclassified observations in each litter.
Results and discussion
Results: maternal animals
Maternal developmental toxicity
- Details on maternal toxic effects:
- Maternal toxic effects:yes
Details on maternal toxic effects:
Absolute and relative spleen weights were statistically significantly higher in the 10 and 20 mg/kg bw groups than in the control group. In the 10 mg/kg bw group the spleen weights were approx. 60% higher than the respective control values, whereas the spleen weights of the high dose group dams were nearly twice as high as in the control group. The increased spleen weights are well known substance induced effects. At the lower dose levels (1 or 3 mg/kg body weight) absolute and relative spleen weights were similar to the control weights.
At necropsy the enlargement of the spleens of all dams of test groups 10 and 20 mg/kg body weight/day is in-line with the distinct increases in absolute and relative spleen weights in these groups.
Effect levels (maternal animals)
- Dose descriptor:
- NOAEL
- Effect level:
- 3 mg/kg bw/day
- Basis for effect level:
- other: maternal toxicity
Results (fetuses)
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:no effects
Details on embryotoxic / teratogenic effects:
All signs of embryo-/ fetotoxicity and substance-related teratogenicity, malformations recorded, appeared without a clear dose-response relationship, can be found in a similar frequency in the historical control data and/or the differences between the groups are without biological relevance.
Effect levels (fetuses)
- Dose descriptor:
- NOAEL
- Effect level:
- >= 20 mg/kg bw/day
- Basis for effect level:
- other: teratogenicity
Fetal abnormalities
- Abnormalities:
- not specified
Overall developmental toxicity
- Developmental effects observed:
- not specified
Any other information on results incl. tables
In the dams an enlargement of the spleens and a dose related statistically significant increase in absolute and relative spleen weights was revealed at dosages of 10 and 20 mg/kg bw/day. No substance-related effects on dams were reported for the lower dose groups. There were no substance-related differences between the groups in conception rate, the mean number of corpora lutea and implantation sites or in the values calculated for the pre- and the postimplantation losses, the number of resorptions and of viable foetuses. Mean fetal body weight of the dosed groups did not differ from that of the control. Examination of foetuses did not reveal any signs for substance related abnormalities.
From this study a NOAEL for maternal toxicity of 3 mg/kg bw/d and a NOAEL for embryo-/fetotoxicity of 20 mg/kg bw/d can be derived.
Applicant's summary and conclusion
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