Registration Dossier
Registration Dossier
Data platform availability banner - registered substances factsheets
Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.
The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.
Diss Factsheets
Use of this information is subject to copyright laws and may require the permission of the owner of the information, as described in the ECHA Legal Notice.
EC number: 700-503-1 | CAS number: 101238-01-1
- 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
The substance is tolerated better by feed dosing than by gavage application. This is most likely due to the highly irritating properties resulting in more severe local effects that have a more pronounced effect upon gavage dosing. In the 90-day feeding study, local inflammation of the caecum was observed at the highest dose group of 10000 ppm for males and females and body weight was affected for males only. The NOAEL for 90-day feed exposure was identified as 2500 ppm (ca 170 - 193 mg/kg bw).
Key value for chemical safety assessment
Repeated dose toxicity: via oral route - systemic effects
Link to relevant study records
- Endpoint:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 2013-2014
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: GLP and guideline conform study with well characterised material
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
- Species:
- rat
- Strain:
- other: Crl:WI(Han)
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services GmbH, Sulzfeld, Germany
- Age at study initiation: 42 ± 1 days
- Weight at study initiation: 130g females and 160 g males
- Fasting period before study: no
- Housing: 5 animals per cage
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 14 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24°C
- Humidity (%): 30-70%
- Air changes (per hr):15
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: 2 July 2013 To: 11 October 2013 - Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Details on oral exposure:
- For each concentration, the test substance was weighed out and mixed with a small amount of food. Then corresponding amounts of food, depending on test group, were added to this premix in order to obtain the desired concentrations. Mixing was carried out for about 10 minutes in a laboratory mixer.
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The stability in the diet at room temperature for a period of 32 days was proven before the start of the administration period in a separate GLP study.
- Duration of treatment / exposure:
- 92 days (male animals) / 93 days (female animals).
- Frequency of treatment:
- daily
- Remarks:
- Doses / Concentrations:
500, 2500 and 10000 ppm
Basis:
actual ingested - Remarks:
- Doses / Concentrations:
32, 170 and 722 mg/kg bw (males)
Basis:
other: average calculated from food consumption - Remarks:
- Doses / Concentrations:
39, 193 and 961 mg/kg bw (females)
Basis:
other: average calculated from food consumption - No. of animals per sex per dose:
- 10
- Control animals:
- yes, plain diet
- Details on study design:
- - Dose selection rationale: based on result of the dose-range finding studies.
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: A check for moribund and dead animals was made twice daily on working day and once daily on Saturday, Sunday and public holidays. If animals were in a moribund state, they were sacrificed and dissected.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: All rats were checked daily for any abnormal clinical signs prior administration, as well as, within 2 hours and 5 hours post administration. Detailed clinical observation (DCO) was performed in all animals prior to the administration period and thereafter at weekly intervals. The findings were ranked according to the degree of severity, if applicable. The animals were transferred to a standard arena (50 × 37.5 cm with sides of 25 cm high). The following parameters were examined:
1. abnormal behavior during “handling”
2. fur
3. skin
4. posture
5. salivation
6. respiration
7. activity/arousal level
8. tremors
9. convulsions
10. abnormal movements
11. impairment of gait
12. lacrimation
13. palpebral closure
14. exophthalmos
15. feces (appearance/ consistency)
16. urine
17. pupil size
BODY WEIGHT: Yes
- Time schedule for examinations:
Body weight was determined before the start of the administration period in order to randomize the animals. During the administration period the body weight was determined on day 0 (start of the administration period) and thereafter at weekly intervals. The difference between body weight on the respective day of weighing and body weight on day 0 was calculated as body weight change.
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: At the end of the administration period, on study day 91.
- Dose groups that were examined: control and highest dose group animals
HAEMATOLOGY: Yes
- Time schedule for collection of blood: At the end of the administration period, on study day 92.
- Anaesthetic used for blood collection: Yes, isoflurane
- Animals fasted: Yes
- How many animals: 5 animals per test group and sex
- Parameters checked below were examined.
Leukocyte count
(WBC)
Erythrocyte count
(RBC)
Hemoglobin
(HGB)
Hematocrit
(HCT)
Mean corpuscular volume
(MCV)
Mean corpuscular hemoglobin
(MCH)
Mean corpuscular hemoglobin concentration
(MCHC)
Platelet count
(PLT)
Differential blood count
Reticulocytes
Prothrombin time (Hepato Quick’s test) (HQT)
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: At the end of the administration period, on study day 92.
- Animals fasted: Yes
- How many animals: 5 per sex and dose
- Parameters checked below were examined.
Alanine aminotransferase
(ALT)
Aspartate aminotransferase
(AST)
Alkaline phosphatase
(ALP)
g-Glutamyltransferase
(GGT)
Sodium
(NA)
Potassium
(K)
Chloride
(CL)
Inorganic phosphate
(INP)
Calcium
(CA)
Urea
(UREA)
Creatinine
(CREA)
Glucose
(GLUC)
Total bilirubin
(TBIL)
Total protein
(TPROT)
Albumin
(ALB)
Globulins
(GLOB)
Triglycerides
(TRIG)
Cholesterol
(CHOL)
Magnesium
(MG)
Bile acids
(TBA)
URINALYSIS: Yes
- Time schedule for collection of urine: study day 85
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes (For urinalysis the individual animals were transferred to metabolism cages
(withdrawal of food and water) and urine was collected overnight.)
- Parameters checked below were examined.
pH
Protein
Glucose
Ketones
Urobilinogen
Bilirubin
Blood
Specific gravity
Sediment
Color, turbidity
Volume
NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: days 86 - 91
- Dose groups that were examined: all
- Battery of functions tested: sensory activity / grip strength / motor activity / (FOB) - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
The following weights were determined in all animals sacrificed on schedule:
1. Anesthetized animals
2. Adrenal glands
3. Brain
4. Epididymides
5. Heart
6. Kidneys
7. Liver
8. Ovaries
9. Spleen
10. Testes
11. Thymus
12. Thyroid glands
13. Uterus with cervix
HISTOPATHOLOGY: Yes (see table) - Statistics:
- Blood parameters For parameters with bidirectional changes:
Non-parametric one-way analysis using KRUSKAL-WALLIS test. If the resulting p-value was equal or less than 0.05, a pairwise comparison of each dose group with the control group was performed using WILCOXON-test (two-sided) for the hypothesis of equal medians
For parameters with unidirectional changes:
Pairwise comparison of each dose group with the control group using the WILCOXON-test (one-sided) with Bonferroni-Holm adjustment for the hypothesis of equal medians * for p < 0.05
** for p < 0.01 SIEGEL, S. (1956):
Non-parametric statistics for the behavioural sciences.
McGraw-Hill New York Holm (1979): A Simple Sequentially Rejective Multiple Test Procedure. Scand. J. Statist. 6, 65-70
Urinalysis parameters (except pH, urine volume, specific gravity, color and turbidity Pairwise comparison of each dose group with the control group using the WILCOXON-test (one-sided) for the hypothesis of equal medians * for p < 0.05
** for p < 0.01 SIEGEL, S. (1956):
Non-parametric statistics for the behavioural sciences.
McGraw-Hill New York
Urine pH, volume, specific gravity, color and turbidity Non-parametric one-way analysis using KRUSKAL-WALLIS test. If the resulting p-value was equal or less than 0.05, a pairwise comparison of each dose group with the control group was performed using WILCOXON-test (two-sided) for the hypothesis of equal medians. Urine color and turbidity are not evaluated statistically. * for p < 0.05
** for p < 0.01 SIEGEL, S. (1956):
Non-parametric statistics for the behavioural sciences.
McGraw-Hill New York
Weight parameters Non-parametric one-way analysis using KRUSKAL-WALLIS test (two-sided). If the resulting p-value was equal or less than 0.05, a pairwise comparison of each dose group with the control group was performed using WILCOXON-test (two-sided) for the equal medians * for p ≤ 0.05
** for p ≤-0.01 HETTMANNSPERGER, T.P. (1984): Statistical Inference based on Ranks, John W - Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Palpable mass in abdomen was observed in male animal Nos. 32 and 37 as well as in female animal Nos. 71, 72, 73 and 77 of test group 3 (10000 ppm) during the last third of the administration period for a limited time.
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- Palpable mass in abdomen was observed in male animal Nos. 32 and 37 as well as in female animal Nos. 71, 72, 73 and 77 of test group 3 (10000 ppm) during the last third of the administration period for a limited time.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- reduced at 2500 and 10000 ppm for males (see figure)
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- no effects observed
- Water consumption and compound intake (if drinking water study):
- no effects observed
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- hemoglobin and hematocrit values were slightly increased in rats of both sexes of test group 3 (10000 ppm).
- Clinical biochemistry findings:
- effects observed, treatment-related
- Urinalysis findings:
- no effects observed
- Behaviour (functional findings):
- no effects observed
- 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
- Description (incidence and severity):
- caecum at 10000 ppm
- Histopathological findings: neoplastic:
- not examined
- Details on results:
- With regard to clinical examinations, signs of general systemic toxicity in Wistar rats of either sex were observed in test group 3 (10000 ppm) indicated by decreased mean body weight values below the historical control data. In addition, masses in the abdomen were palpable in several animals during the last third of the treatment period. A clear reason for the occurrence of this finding could not be evaluated.
No signs of toxicological relevance were observed for male and female animals in test groups 1 and 2 (500 and 2500 ppm).
Regarding clinical pathology in rats of both sexes of test group 3 (10000 ppm), higher hemoglobin and hematocrit values were due to hemoconcentration in these individuals. Higher albumin levels in males of the mentioned test group were also due to this effect. No hint of a renal dysfunction as cause of hemoconcentration could be found. The reason for isolated higher calcium levels in males and females of test group 3 (10000 ppm) and lower urea levels in males of this test group could not be elucidated.
Regarding pathology, the cecum was the target organ. In the cecum of three males and three females of test group 3 (10000 ppm) slight inflammatory cell infiltrates and edema were present, which was interpreted to be an inflammation of the cecum. This inflammation was regarded to be tre tment related and adverse.
Furthermore, a body weight decrease in male animals of test group 3 (10000 ppm) was observed. This was also regarded to be test substance-related and adverse. Whether or not there was a relation between the cecum findings and the body weight could not be determined. All other findings occurred either individually or were biologically equally distributed over control and treatment groups. They were considered to be incidental or spontaneous in origin and without any relation to treatment.
During numerous time intervals, food consumption in male animals of test group 1-3 (500, 2500 and 10000 ppm) was lower when compared to the control group. As no dose-response relationship occurred the changes were assessed to be incidental and not related to treatment.
In female animals, mean food consumption in female animals of test group 3 (10000 ppm) was higher during the entire study period. The higher values were caused by the animals of cage No. 16, most likely related to spilling of food out of the tray. The values of cage No. 15 were within the range typical for animals of this strain and age. Therefore, the effect was assessed as being incidental and without toxicological relevance.
Specifically. three males (Nos. 31, 32 and 39) and three females (Nos. 72, 73 and 75) of test group 3 (10000 ppm) revealed a slight infiltration of the mucosa of mixed cells (granulocytes, macrophages and lymphocytes). The same animals also showed a submucosal edema, with occasionally inflammatory cells of the mucosa infiltrating the edematous submucosa. This finding was regarded to be an inflammation of the cecum and treatment related.
Other: No test substance-related effects on estrous cycle length and the number of cycles were obtained. Concerning motility of the sperms and incidence of abnormal sperms in the cauda epididymidis as well as sperm head counts in the testis and in the cauda epididymidis no treatment-related effects were observed. - Dose descriptor:
- NOEL
- Effect level:
- 500 ppm
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- other: Dose-dependent reduction in body weight gain at higher doses.
- Dose descriptor:
- NOAEL
- Effect level:
- 2 500 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: local inflammation of the caecum at 10000 mg/kg bw
- Critical effects observed:
- not specified
- Conclusions:
- The substance caused a local inflammation of the caecum at the highest dose group of 10000 ppm as shown by histopathology. Body weight gain was affected in males only. The NOAEL for 90-day feed exposure was identified as 2500 ppm (ca 170 - 193 mg/kg bw).
Reference
Males | Females | |||||||
Test group | 0 | 1 | 2 | 3 | 0 | 1 | 2 | 3 |
(ppm) | 0 | 500 | 2500 | 10000 | 0 | 500 | 2500 | 10000 |
No. of animals | 10 | 10 | 10 | 10 | 10 | 10 | 10 | 10 |
Infiltrates, mixed cell, diffuse | 0 | 0 | 0 | 3 | 0 | 0 | 0 | 3 |
Grade 2 | 3 | 3 | ||||||
Edema, submucosal | 3 | 3 | ||||||
Grade 2 | 3 | 3 |
Table 1: Histopathology findings
Male animals | Female animals | |||||
Test group | 1 | 2 | 3 | 1 | 2 | 3 |
(ppm) | 500 | 2500 | 10000 | 500 | 2500 | 10000 |
Terminal body weight | 93% | 90%* | 83%** | |||
Heart | 93% | 95% | 88%** | |||
Kidneys | 95% | 94% | 86%** | |||
Liver | 90% | 88%* | 83%** | |||
Spleen | 114%* | 123%* | 111% |
Table 2: Relevant effects on absolute organ weights and terminal body weight,*: p≤0.05, **: p≤0.01
Male animals | |||
Test group | 1 | 2 | 3 |
(ppm) | 500 | 2500 | 10000 |
Brain | 105% | 107%* | 117%** |
Epididymides | 112%* | 108% | 118%** |
Testes | 110%* | 111% | 117%** |
Table 3: Relevant effects on relative organ weights, *: p≤0.05, **: p≤0.01
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- NOAEL
- 170 mg/kg bw/day
- Study duration:
- subchronic
- Species:
- rat
- Quality of whole database:
- valid without restriction
Repeated dose toxicity: inhalation - systemic effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: inhalation - local effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: dermal - systemic effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: dermal - local effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Additional information
The substance was tested in a 14 -day range-finding study both with gavage and feed dosing since gavage dosing was needed for the developmental toxicity study and because it was suspected that higher dosages could be achieved by feed dosing. Whereas by gavage dosing, a single dose of 2000 mg/kg bw may result in mortality (BASF 2013) and 500 mg/kg bw result in drastic inital effects on body weight (BASF 2013), 90 -day feed application with 10000 ppm merely results in body weight effects and local inflammation in the caecum seen by histopathology (BASF 2014).
In all repeated-dose studies, treatment resulted in an initial dose-dependend decrease of body weight. This decrease lasts for about five days and after that body weights start increasing again. Depending on the dose, body weights then increase at a lower level in parallel to the control group or - as in the case for males in the 90 -day study, increase at a lower rate. This effect is more strongly observed for gavage than for feed dosing. Salivation after dosing for up to 10 minutes is observed in a dose-dependend manner at all dose-levels tested, including 30 mg/kg bw.
Other than the effects on body weight, the substance causes little specific organ toxicity. After subchronic exposure, the only histopatholgy findings observed was inflammation in the caecum of each 3 of ten males and females.
Regarding clinical pathology in rats of both sexes of test group 3 (10000 ppm), higher hemoglobin and hematocrit values were due to hemoconcentration in these individuals. Higher albumin levels in males of the mentioned test group were also due to this effect. No hint of a renal dysfunction as cause of hemoconcentration could be found. The reason for isolated higher calcium levels in males and females of test group 3 (10000 ppm) and lower urea levels in males of this test group could not be elucidated.
With regard to clinical examinations, signs of general systemic toxicity in Wistar rats of either sex were observed in test group 3 (10000 ppm) indicated by decreased mean body weight values below the historical control data. In addition, masses in the abdomen were palpable in several animals during the last third of the treatment period. A reason for the occurrence of this finding could not be evaluated. No signs of toxicological relevance were observed for male and female animals in test groups 1 and 2 (500 and 2500 ppm). The NOAEL for 90-day feed exposure was identified as 2500 ppm (ca 170 - 193 mg/kg bw).
As the substance is severely irritating to eyes (R41), local effects on the respiratory tract cannot be excluded. Testing is considered unjustifed due to the expected adverse effects and because an evaluation of irritating and corrosive substances showed that a generic cut-off value of 1 mg/m3 can be applied to corrosive substances (R34/R35) and one of 10 mg/m3 to irritating/highly irritating substances (R36/37/38 R41) (Messinger, Regulatory Toxicology and Pharmacology, Vol 68, pp 317 -324, 2014). As a precautionary value, the DNEL for inhalation is set at 1 mg/m3.
Repeated dose toxicity: via oral route - systemic effects (target organ) digestive: cecum
Justification for classification or non-classification
Dangerous Substance Directive (67/548/EEC)
The available studies are considered reliable and suitable for classification purposes under 67/548/EEC. No serious irreversible effects were observed at dose levels of less than 50 mg/kg bw upon subchronic exposure. As a result the substance is not considered to be classified for repeated dose toxicity under Directive 67/548/EEC, as amended for the 31st time in Directive2009/2/EG.
Classification, Labelling, and Packaging Regulation (EC) No. 1272/2008
The available experimental test data are reliable and suitable for classification purposes under Regulation 1272/2008. There were no significant toxic effects at doses of less than 100 mg/kg bw upon subchronic oral exposure in rats. As a result the substance is not classified for repeated dose toxicity under Regulation (EC) No. 1272/2008, as amended for the fifth time in Directive EC944/2013.
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.