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EC number: 224-548-7 | CAS number: 4404-43-7
- 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
Carcinogenicity
Administrative data
Description of key information
Oral NOAEL: 542 mg/kg bw/day (chronic; rat)
Dermal chronic mouse: the test substance does not contribute to carcinogenicity induced by UV-irradiation
Key value for chemical safety assessment
Carcinogenicity: via oral route
Link to relevant study records
- Endpoint:
- carcinogenicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- From November 1973 to November 1975.
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Test procedures cannot be subsumed under testing guideline, nevertheless are well documented and scientifically acceptable.
- Reason / purpose for cross-reference:
- reference to same study
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
- GLP compliance:
- no
- Remarks:
- Pre GLP:
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Dtrainn: Winstar II.
- Source: Winkelmann, Borchen, Germany.
- Age at study initiation: 28 - 32 days.
- Weight at study initiation: 54 g male and 53 g female, average at the start.
- Housing: individually, in Macrolon cages (Type 2).
- Diet: ad libitum, weekly fresh Altromin R-powder feed.
- Water: ad libitum, tap water.
ENVIRONMENTAL CONDITIONS
- Temperature: 23 ± 1 °C - Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Details on exposure:
- DIET PREPARATION
Mixing appropriate amounts with: Altromin R-Pulverfutter (Altromin GmbH, Lage/Lippe, Germany). - Duration of treatment / exposure:
- 24 months.
- Frequency of treatment:
- Daily.
- Remarks:
- Doses / Concentrations:
0, 100, 1000, 10000 ppm
Basis:
nominal conc. - No. of animals per sex per dose:
- 50 males and 50 females per dose.
- Control animals:
- yes, plain diet
- Observations and examinations performed and frequency:
- DETAILED CLINICAL OBSERVATIONS
The experimental animals were inspected daily and occurring changes and symptoms recorded.
BODY WEIGHT
The body weight of the animals was determined weekly up to the 27th week; after that, the weight determination was carried out at intervals of 14 days.
FOOD CONSUMPTION AND COMPOUND INTAKE
The weekly feed consumption was determined by reweighing.
HAEMATOLOGY
The blood tests included: Erythrocyte and leukocyte count, platelet count, reticulocyte hemoglobin content, haematocrit , MCH, MCV, thromboplastin time.
CLINICAL CHEMISTRY
Clinical laboratory investigations were conducted in 5 male and 5 female rats in each dose at 1, 3, 6 and male 12 months; at the end of the experiment, the analysis were conducted to 10 male and 10 female rats.
Parameters: Alkaline phosphatase (ALP), glutamic-oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), glutam-dehydrogenases (GIDH), creatinin, urea, blood glucose, cholesterin, bilirubin, protein.
To test the liver function following enzymes in heparin plasma were determined: Alkaline phosphatase, glutamic-oxaloacetic transaminase and glutamic pyruvic transaminase.
URINALYSIS
Semiquantitative: glucose, ketone bodies, bilirubin, urobilinogen.
Quantitative: proteins. - Sacrifice and pathology:
- SACRIFICE
At the end of the experiment all survivors animals were anesthetized with ether and killed by exanguination.
GROSS PATHOLOGY
The rats dead during the experiment and the rats sacrified at the end were dissected and examined macroscopically.
The weights of the following organs were determined: thyroid, heart, lungs, liver, spleen, kidneys, adrenal glands, testes and ovaries.
HISTOPATHOLOGY
The following organs were fixed in Bouin solution: Aorta, eyes, intestine (duodenum, jejunum, ileum, colon), femur, brain, bladder, heart, testis, pituitary gland, liver, lung, lymph nodes, stomach, spleen, epididymis, adrenal glands, sciatic nerve, kidney, esophagus, parotid gland , ovaries, pancreas, prostate, seminal vesicles, thyroid, skeletal muscle, sternum, trachea, and uterus, as well as all changes macroscopically found.
From the fixed organs or organ approximately samples of 5 g were prepared and stained with Hamalaun-eosin.
In addition kidney sections were subjected by these rats of the Periodic Acid Schiff (PAS) reaction. The decalcification of the bones was performed in Ethylanadinitrilotetraacetic acid tetrasodium salt (EDTA). - Statistics:
- Were calculated: Arithmetic group means, standard deviation s, upper and lower confidence limits on the confidence level α = 95% and 1-α = 99%.
The values of the collective test the investigated doses were compared with the control group with the significance test, U-test according to Mann, Whitney and Wilcoxon on the significance level of α = 5 % and α = 1 %.
The mortality rates were compared using Fisher's exact de-tests on the significance level of α = 5 % and α = 1 % with the control group. - Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- dosed and control goups showed a temporarily low but significant weight depression
- Food consumption and compound intake (if feeding study):
- no effects observed
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- no effects observed
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Description (incidence and severity):
- no treatment-related histomorphological alterations
- Histopathological findings: neoplastic:
- no effects observed
- Description (incidence and severity):
- no treatment-related histomorphological alterations
- Details on results:
- CLINICAL SIGNS AND MORTALITY
During the experimental period no differences in appearance and behaviour between treated groups and control were noted. Furthermore no differences in the vividness and coat condition were observed.
Mortality of the dosed groups is comparable to that recorded into the control group.
BODY WEIGHT AND WEIGHT GAIN
The rats of the dosed groups at 100, 1000 and 10000 ppm as well as the rats of the control group, showed a temporarily low but significant weight depression. No significant difference between dosed and control groups has been found.
FOOD CONSUMPTION AND COMPOUND INTAKE
No difference from the control group were recorded in food and drink consumption in all dosed groups.
CLINICAL CHEMESTRY
At 1 month from the start of the test no significant difference between dosed groups and control were recorded. The treated rats did not differ significantly and in dose-dependent manner at 5, 6, and 12 months test period and at end of test from the control animals.
At 24 months the haemoglobine count in the male dosed goups at 1000 and 10000 ppm resulted higher than in the control ( P < 0.01 and P < 0.05, respectively).
At the end of the experiment the values of alkaline phosphatase (ALP) in the male dosed goups at 1000 and 10000 ppm was higher than in the control ( P < 0.05 and P < 0.01, respectively) and the protein contents (GPT) resulted higer in the female groups dosed at 1000 and 10000 ppm (both P < 0.01), than in the control.
Blood sugar and cholesterol levels were determined to not lying in the pathological range in the dose groups up to 10000 ppm.
URINALYSIS
In all of the investigated rats, glucose, ketone bodies or bilirubin found in the urine, protein and blood-positive urine findings were present in approximately the same abundance.
Urobilinogen content and pH-value of the treated animals did not differ significantly from that of control animals.
The examination of the sediment revealed no treatment-related effect.
At three months after beginning the test creatinine conted resulted in all the females dosed groups significantly and dose-dependent higher than in the control group. Significant and dose-dependent lower protein contents are also recorded at 12 months in the female animals after doses of 100, 1000 and 10000 ppm at end of test.
ORGAN WEIGHTS
In comparison to the control group significantly different organ weights were recorded.
In comparison to the values of the control group, the liver weights of the male rats were not significantly increased up to the administered dose of 10000 ppm.
The kidney weights of female animals doses at 1000 and 10000 increased respect to the control group.
The remaining organ weight differences are distributed low and independent of dose.
GROSS PATHOLOGY
_RATS DEAD during the experiment: no pathological changes which could be attributed to treatment were found in all the animals.
_RATS KILLED at the end of the experiment: no evidence of specific injury in the experimental groups to 10000 ppm.
HISTOPATHOLOGY
In summary, it was found that all the investigated organ exhibited no treatment-related histomorphological alterations.
HISTOPATHOLOGY - Neoplastic
In the In the male rats were observed adenomas, essentially benign tumors, of the pituitary gland, mammary and thyroidhe endocrine system; of the thyroid adenoma and pheochromocytoma and adenoma of the Hodeninterstitiums and in female rats in all groups at approximately the same frequency. The malignant neoplasms of various types are distributed randomly on all experimental groups. Type and location of all observed tumors are fir the rat strain used typical. - Relevance of carcinogenic effects / potential:
- Non carcinogen
- Dose descriptor:
- NOAEL
- Effect level:
- 542
- Based on:
- test mat.
- Sex:
- male/female
- Remarks on result:
- other: Effect type: carcinogenicity (migrated information)
- Dose descriptor:
- NOAEL
- Effect level:
- 779
- Based on:
- test mat.
- Sex:
- male/female
- Remarks on result:
- other: Effect type: carcinogenicity (migrated information)
- Conclusions:
- NOAEL: 779 mg/kg bw/day (actual dose received) (female)
NOAEL: 542 mg/kg bw/day (actual dose received) (male) - Executive summary:
Method
The 50 male and 50 female rats received the test substance, administered for 2 years in the following concentrations with the feed: 0 (control), 100, 1000, 10000 ppm.
ResultsAppearance, behaviour, feed intake, body weights and mortality were not influenced in male and female animals of doses up to and including 10000 ppm. The animals in the dose groups to 10000 ppm did not show during the entire experimental period any treatment-related symptoms. The growth of the rats was not affected until the dose of 10000 ppm. The haematological investigations performed during and at the end of the test showed no dose of injuries. The clinical chemical analysis, sections and histopathological examinations revealed no evidence for treatment-related damage to the liver. Urinalysis, urea and creatinine concentrations in serum as well as macroscopic and histopathological organ findings did not indicate any influence.NOAEL: 779 mg/kg bw/day (actual dose received) (female) NOAEL: 542 mg/kg bw/day (actual dose received) (male)
Reference
Number of tumors
0 ppm | 100 ppm | 1000 ppm | 10000 ppm | |||||
male | female | male | female | male | female | male | female | |
N. of total tumors | 29 | 18 | 16 | 31 | 23 | 15 | 16 | 16 |
N. of malign tumors | 1 | 2 | 1 | 4 | 3 | 2 | 3 | 2 |
Food and active ingredient intake
Dosis [ppm] | mean food intake | mean active ingredient intake | ||
kg/animal | g/animal/day | g/kg bw | mg/kg bw /day | |
male |
||||
0 | 14.85 | 20.21 | - | - |
100 | 15.82 | 21.52 | 3.92 | 5.33 |
1000 | 15.62 | 21.25 | 39.75 | 54.08 |
10000 | 15.28 | 20.79 | 398.96 | 542.80 |
female |
||||
0 | 13.25 | 18.03 | - | - |
100 | 13.48 | 18.33 | 5.74 | 7.80 |
1000 | 13.40 | 18.23 | 58.78 | 79.97 |
10000 | 13.40 | 18.24 | 572.84 | 779.37 |
Mortality
Dose ppm |
N. dead / N rat Male |
% | N. dead / N rat Female |
% |
1 year |
||||
0 | 1/50 | 2.0 | 1/50 | 2.0 |
100 | 1/50 | 2.0 | 0/50 | 0.0 |
1000 | 1/50 | 2.0 | 0/50 | 0.0 |
10000 | 0/50 | 0.0 | 0/50 | 0.0 |
2 years |
||||
0 | 6/50 | 12.0 | 9/50 | 18.0 |
100 | 16/50 | 32.0* | 8/50 | 16.0 |
1000 | 11/50 | 22.0 | 6/50 | 12.0 |
10000 | 6/50 | 16.2 | 8/50 | 16.0 |
* significance P < 0.05
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 542 mg/kg bw/day
- Study duration:
- chronic
- Species:
- rat
Carcinogenicity: via inhalation route
Endpoint conclusion
- Endpoint conclusion:
- no study available
Carcinogenicity: via dermal route
Link to relevant study records
- Endpoint:
- carcinogenicity: dermal
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Test procedures cannot be subsumed under testing guideline, nevertheless are well documented and scientifically acceptable.
- GLP compliance:
- no
- Species:
- mouse
- Strain:
- other: Skh: hairless-1
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: CIBA GEIGY AG, Sisseln, Swizerland.
- Age at study initiation: about 6 weeks.
- Housing: single.
- Diet: ad libitum (once a week supplemental sunflower seeds).
- Water: ad libitum.
ENVIRONMENTAL CONDITIONS
- Temperature: 23 ± 2 °C - Route of administration:
- dermal
- Vehicle:
- other: water + 0.005 % Alkansulfonate (Emulgator K30).
- Details on exposure:
- TEST SITE
- Area of exposure: 2 x 3 cm
- Type of wrap if used: no wrap used.
REMOVAL OF TEST SUBSTANCE
- Washing : no
TEST MATERIAL
- Amount applied: 0.03 ml
- Concentration: 100 mg/l
- Constant volume or concentration used: yes.
- For solids, paste formed: no.
VEHICLE
- Justification for use and choice of vehicle: water + surfactant.
UV IRRADIATION
- Lamp used for uv-irridation: black-light lamp (Philips TL 40 W/08)
- Power: mean irridation power: 272 µW/square cm - Duration of treatment / exposure:
- 320 days
- Frequency of treatment:
- UV-irradiation: daily 4 hours.
Test substance: Mondays, Wednesdays and Fridays.
UV-irradiation started 1 hour after test substance application. - Remarks:
- Doses / Concentrations:
3 µg
Basis:
other: test material - No. of animals per sex per dose:
- 50
- Control animals:
- yes, concurrent vehicle
- Positive control:
- Historical data with 8-Methoxypsoralen.
- Observations and examinations performed and frequency:
- Skin: daily.
Body weight: every two weeks. - Histopathological findings: neoplastic:
- no effects observed
- Description (incidence and severity):
- there were no significant differences between groups
- Details on results:
- Normal body weight change in all animals.
Mortalitiy: no significant differences between groups.
Findings of erythema and necrosis was found in all groups. There were no statistically significances.
Skintumors: there were no significant differences between groups. - Relevance of carcinogenic effects / potential:
- Non carcinogen.
- Dose descriptor:
- NOAEL
- Remarks on result:
- not determinable
- Remarks:
- no NOAEL identified
- Conclusions:
- Cancerogenicity induced by UV-irradiation is not induced by the test substance.
- Executive summary:
Method
The UV irradiation was administered in rats four hours; the treatment with test susbtance was conduced three times per week (320 days) with 0.03 ml at 0.01% on an area of 2 x 3 cm. Each dose group included 50 mice.
The treatment was stopped after 320 trial days.
Results
Treatment with the test compound had no effect on tumour formation by UV irradiation.
Reference
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Study duration:
- chronic
- Species:
- rat
Justification for classification or non-classification
Additional information
50 male and 50 female rats received the test substance, administered for 2 years in the following concentrations with the feed: 0 (control), 100, 1000, 10000 ppm. Appearance, behaviour, feed intake, body weights and mortality were not influenced in male and female animals of doses up to and including 10000 ppm.The animals in the dose groups to 10000 ppmdid notshow during the entire experimental period any treatment-related symptoms. The growth of the rats was not affected until the dose of 10000 ppm. The haematological investigations performed during and at the end of the test showed no dose of injuries. The clinical chemical analysis, sections and histopathological examinations revealed no evidence for treatment-related damage to the liver. Urinalysis, urea and creatinine concentrations in serum as well as macroscopic and histopathological organ findings did not indicate any influence. NOAEL: 779 mg/kg bw/day (actual dose received) (female) NOAEL: 542 mg/kg bw/day (actual dose received) (male).
A further study was done in order to investigate whether the test substance has a carcinogenic effect onto skin under light exposure (Bayer AG, 1979).
The UV irradiation was administered in rats four hours; the treatment with test susbtance was conduced three times per week (320 days) with 0.03 ml at 0.01 % on an area of 2 x 3 cm. Each dose group included 50 mice. The treatment was stopped after 320 trial days. Treatment with the test compound had no effect on tumour formation by UV irradiation.
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