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EC number: 204-701-4 | CAS number: 124-43-6
- 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 read across results indicate that the repeated dose toxicity of hydrogen peroxide – urea (1:1) relies on the toxicity of the breakdown product, hydrogen peroxide, as this is the case for acute toxicity. The lower NOAEL value for male mice (26 mg/kg bw/day) is taken for the calculation of a NOAEL for the target substance (71.8 mg hydrogen peroxide - urea (1:1)/kg bw/d) and derivation of DNEL values.
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:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- weight of evidence
- Justification for type of information:
- ANALOGUE APPROACH JUSTIFICATION
Please refer to the attached read across justification in section 13. - Reason / purpose for cross-reference:
- read-across source
- Clinical signs:
- not specified
- Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- ne male mouse died in the control group (the cause of death was undetermined), and one male mouse in the 3000 ppm group died on study day 43 (no histopathological findings).
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Body weights were significantly reduced only in male and female animals receiving 3000 ppm.
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- Dose-related reductions in both food and water consumption were observed in female animals receiving 300 ppm and greater, while among the males consistent reductions were observed at the top dose level.
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- effects observed, treatment-related
- Description (incidence and severity):
- Dose-related reductions in both food and water consumption were observed in female animals receiving 300 ppm and greater, while among the males consistent reductions were observed at the top dose level
- Ophthalmological findings:
- not specified
- Haematological findings:
- not specified
- Clinical biochemistry findings:
- not specified
- Urinalysis findings:
- not specified
- Organ weight findings including organ / body weight ratios:
- not specified
- Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Hydrogen peroxide related changes were observed only in the duodenum at terminal sacrifice in the 1000 and 3000 ppm groups of males and females, and in a single 300 ppm group male. Although the general architecture of the affected duodenum was normal, there was an increase in cross sectional diameter and a larger mucosal area with broader, more substantial villi when compared to those of control mice. The change was assessed as mucosal hyperplasia because of the increase in mucosal thickness and size of the villi.
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Mucosal hyperplasia in the duodenum in animals at 1000 or 3000 ppm, and in one male at 300 ppm
- Histopathological findings: neoplastic:
- no effects observed
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 100 ppm
- Based on:
- act. ingr.
- Sex:
- male/female
- Basis for effect level:
- food consumption and compound intake
- gross pathology
- histopathology: non-neoplastic
- water consumption and compound intake
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 26 mg/kg bw/day (actual dose received)
- Based on:
- act. ingr.
- Sex:
- male
- Basis for effect level:
- body weight and weight gain
- food consumption and compound intake
- gross pathology
- histopathology: non-neoplastic
- water consumption and compound intake
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 37 mg/kg bw/day (actual dose received)
- Based on:
- act. ingr.
- Sex:
- female
- Basis for effect level:
- body weight and weight gain
- food consumption and compound intake
- water consumption and compound intake
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 300 mg/L drinking water
- System:
- gastrointestinal tract
- Organ:
- duodenum
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- yes
Reference
Results are for the source substance hydrogen peroxide. Read across to the target substance can be made taking the molecular weights into account which results in a factor of 2.76. Resulting NOAEL values for the target substance:
male mice: 71.8 mg/kg bw /day
female mice: 102.1 mg/kg bw /day
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- NOAEL
- 71.8 mg/kg bw/day
- Study duration:
- subchronic
- Species:
- mouse
- Quality of whole database:
- Source substance data suffiicient for read across and assessment. NOAEL derivation based on data from H2O2 (worst case).
- System:
- gastrointestinal tract
- Organ:
- duodenum
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
Link to relevant study records
- Endpoint:
- sub-chronic toxicity: dermal
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Justification for type of information:
- ANALOGUE APPROACH JUSTIFICATION
Please refer to the attached read across justification in section 13. - Reason / purpose for cross-reference:
- read-across source
- Clinical signs:
- no effects observed
- Dermal irritation:
- no effects observed
- Description (incidence and severity):
- No erythema, scab and other irritative response were noted at the application site in any of the experimental groups including the control group of the 4-week and the 25-week-study
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- no effects observed
- Water consumption and compound intake (if drinking water study):
- no effects observed
- Ophthalmological findings:
- not examined
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- no effects observed
- Behaviour (functional findings):
- no effects observed
- Immunological findings:
- no effects observed
- Description (incidence and severity):
- no change in the albumin /globulin ratio in either study
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Neuropathological findings:
- no effects observed
- Description (incidence and severity):
- behaviour was unchanged in all treated groups
- Histopathological findings: non-neoplastic:
- no effects observed
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 338.4 mg/kg bw/day
- Based on:
- test mat.
- Remarks:
- hydroegn peroxide- urea (1:1)
- Sex:
- male/female
- Basis for effect level:
- other: no adverse effects noted
- Remarks on result:
- other:
- Remarks:
- calculated for the target substance from the NOAEL for urea (source), taking into account molecular weights
- Key result
- Critical effects observed:
- no
Reference
The NOAEL for the target substance (338.4 mg/kg bw and day) was calculated from the NOAEL value for urea (source; 216 mg/kg bw and day), taking into account molecular weights of 94 for the target substance and 60 for the source substance.
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 338.4 mg/kg bw/day
- Study duration:
- subchronic
- Species:
- rat
- Quality of whole database:
- Source substance data suffiicient for read across and assessment. NOAEL derivation based only on data from urea.
Repeated dose toxicity: dermal - local effects
Link to relevant study records
- Endpoint:
- sub-chronic toxicity: dermal
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Justification for type of information:
- ANALOGUE APPROACH JUSTIFICATION
Please refer to the attached read across justification in section 13. - Reason / purpose for cross-reference:
- read-across source
- Clinical signs:
- no effects observed
- Dermal irritation:
- no effects observed
- Description (incidence and severity):
- No erythema, scab and other irritative response were noted at the application site in any of the experimental groups including the control group of the 4-week and the 25-week-study
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- no effects observed
- Water consumption and compound intake (if drinking water study):
- no effects observed
- Ophthalmological findings:
- not examined
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- no effects observed
- Behaviour (functional findings):
- no effects observed
- Immunological findings:
- no effects observed
- Description (incidence and severity):
- no change in the albumin /globulin ratio in either study
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Neuropathological findings:
- no effects observed
- Description (incidence and severity):
- behaviour was unchanged in all treated groups
- Histopathological findings: non-neoplastic:
- no effects observed
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 338.4 mg/kg bw/day
- Based on:
- test mat.
- Remarks:
- hydroegn peroxide- urea (1:1)
- Sex:
- male/female
- Basis for effect level:
- other: no adverse effects noted
- Remarks on result:
- other:
- Remarks:
- calculated for the target substance from the NOAEL for urea (source), taking into account molecular weights
- Key result
- Critical effects observed:
- no
Reference
The NOAEL for the target substance (338.4 mg/kg bw and day) was calculated from the NOAEL value for urea (source; 216 mg/kg bw and day), taking into account molecular weights of 94 for the target substance and 60 for the source substance.
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 16.92 mg/cm²
- Study duration:
- subchronic
- Species:
- rat
- Quality of whole database:
- Source substance data suffiicient for read across and assessment. NOAEL derivation based only on data from urea.
Mode of Action Analysis / Human Relevance Framework
The target substance dissolves in water and breaks down to hydrogen peroxide and urea. Toxicity is governed by hydrogen peroxide whereas oral or dermal toxicity of urea is negligible. As a metabolite of the intermediary metabolism, urea is produced and excreted mainly via urine in quantities of 25-30 g/day in humans (i.e. endogenous urea production is approx. 500 mg/kg bw/day). Excess exogenous urea is rapidly excreted even at large doses, as shown in ADME studies.
Hydrogen peroxide is also generated at in the intermediary metabolism and in the oxidative burst of immune cells. Concentrations are low and mainly enzymatically controlled (glutathione peroxidase, catalase). Hydrogen peroxide is an oxidant that may cause local irritation and corrosion at higher concentrations. External hydrogen peroxide is stable enough to be absorbed through the skin or mucous membranes and distributed with the blood stream to other sites. It is decomposed predominantly by glutathione peroxidase at low concentrations and by catalase at higher concentrations. The latter reaction leads to the formation of large amounts of oxygen (1 ml of 30% hydrogen peroxide may liberate 100 ml of oxygen [ECB, 2003; DFG, 2006]) which may cause embolism with ischaemia, local necrosis, and death. Accidental cases have been reported in the open literature.
Additional information
No repeated dose study could be located for hydrogen peroxide – urea (1:1) but since this substance readily dissolves in water and breaks down to the two components, hydrogen peroxide and urea, these can be used as source substance and data can be read across to the target substance, hydrogen peroxide – urea (1:1).
Hydrogen peroxide was subject of the EU priority substance program. The Risk Assessment Report provides detailed information on all aspects relevant for the risk assessment, including repeated dose toxicity. Of all studies addressed for this endpoint, the 90-day drinking water study using catalase-deficient male and female mice is considered to be the most reliable one.
Reportedly, the sub-chronic toxicity of hydrogen peroxide was examined in a drinking water study (FMC, 1997; dose levels: 0, 100, 300, 1000, and 3000 ppm) using catalase-deficient male and female mice (15/sex/group). At termination after 90 days, 10 animals/sex/group were sacrificed and examined (blood, body weights, gross pathology, histopathology. The latter included all gross lesions, tongue, oesophagus, stomach, duodenum, ileum, jejunum, caecum, colon, and rectum from all animals in all groups, and on all major organs including the sex organs in the high dose and control animals). The remaining 5 animals/sex/group continued on distilled water during a 6-week recovery period.
Effects during the treatment period (Days 0-90): There were no treatment-related deaths. Clear treatment-related, dose-dependent effects were noted among both females and males receiving 300, 1000 or 3000 ppm of H2O2. Body weights were significantly reduced only in male and female high-dose animals receiving 3000 ppm. Dose-related reductions in both food and water consumption were observed in female animals receiving 300 ppm and greater, while among the males consistent reductions were observed only at the top dose level. Among females 300 ppm (103 mg/kg/day) was a LOAEL based on significant reduction in water consumption. Histopathology revealed treatment-related effects only in the duodenum of males and females at 1000 and 300 ppm, and in one male at 300 ppm. Although the general architecture of the affected duodenum was normal, there was an increase in cross sectional diameter and a larger mucosal area with broader, more substantial villi when compared to those of control mice. The change was assessed as mucosal hyperplasia because of the increase in mucosal thickness and size of the villi. Mucosal hyperplasia was not found in 100 ppm group mice, neither among controls. No other histopathological changes were noted on the tongue, esophagus, stomach, duodenum, ileum, jejunum, caecum, colon, and rectum from all animals in all groups, and on all major organs including the sex organs in the high dose and control animals.
Recovery period: the most notable effect was increased water consumption observed in males that had received 3000 ppm, and among females that had received 300, 1000, or 3000 ppm. Mucosal hyperplasia was reversible, as no such lesion was seen in any dose group after the recovery period.
The NOAEL was 100 ppm (26 and 37 mg/kg bw/day) in this study for males and females, respectively, based on dose-related reductions in water and food consumption, and on the observation of duodenal mucosal hyperplasia (ECB, 2003).
Urea
The oral repeated dose toxicity of urea was examined in two 12 -month carcinogenicity screening assay. One study was performed with F344 rats and one study with C57BL/6 mice. The rodents (50/sex/group) were exposed to urea in the diet at concentrations of 4500, 9000 or 45000 ppm for 12 months. Five animals/sex/group were sacrificed at the end of the 365-day exposure period and a comprehensive list of tissues were investigated histopathologically; interim deaths were similarly investigated. All remaining animals were sacrificed after the 4-month recovery period and investigated histopathologically.
There were no signs of toxicity. Survival and bodyweights were unaffected by treatment. Gross and microscopic pathology did not reveal any treatment-related effects. The NOAEL for rats and mice was determined to be 45000 ppm.
The repeated dose dermal toxicity of urea was examined in male and female Wistar rats in a 4-week study (15 rats per dose and sex) and in a 25-week study (10 rats per dose and sex). An ointment containing urea at 0, 10, 20, and 40% was applied daily to the dorsal skin, dose levels used were 0, 56, 108, and 216 mg/kg bw and day. Examinations included observation of clinical signs and behaviour, food and water intake, body weight development, clinical chemistry, haematology, urinalysis, gross pathology, examination of organ weights, and histopathology at termination.
Several effects were seen in animals of the intermediate dose group, but there was no dose-related adverse effect or pathological change in body weights, food and water consumption, or effects on any organ, clinical chemistry, haematology or urinalysis parameters. Further, no local effects on the skin were seen at the application sites. Thus no toxicity was seen at either 4 or 25 weeks with urea doses up to and including 216 mg/kg bw and day which was the NOAEL in this study (Sato et al., 1977).
Read across
The studies above are considered to be valid and suitable for assessment. The results can be read across to hydrogen peroxide – urea (1:1), taking the molecular weights into account.
Source substance hydrogen peroxide:
Read across to the target substance can be made taking the molecular weights into account which results in a factor of 2.76.
Resulting NOAEL values for oral repeated dose toxicity for the target substance (source substance: hydrogen peroxide):
male mice: subchronic NOAELmouse,oral = 71.8 mg hydrogen peroxide – urea (1:1)/kg bw /day
female mice: subchronic NOAELmouse,oral = 102.1 mg hydrogen peroxide – urea (1:1)/kg bw /day
Resulting NOAEL values for dermal repeated dose toxicity for the target substance (source substance: urea):
The subchronic NOAELrat, dermal for urea was 216 mg/kg bw and day. Taking into account molecular weights of 94 for the target substance and 60 for the source substance, this results in a subchronic NOAELrat, dermal of 338.4 mg hydrogen peroxide – urea (1:1)/kg bw /day
Conclusions
The read across results indicate that the repeat dose toxicity of hydrogen peroxide – urea (1:1) relies on the toxicity of the breakdown product, hydrogen peroxide, as this is the case for acute toxicity. The lower value for male mice (26 mg/kg bw/day) is taken for the calculation of a NOAEL for the target substance (71.8 mg hydrogen peroxide - urea (1:1)) and derivation of DNEL values.
Justification for classification or non-classification
Classification, Labeling, and Packaging Regulation (EC) No 1272/2008
The available experimental test data are reliable and suitable for classification purposes under Regulation (EC) No 1272/2008. Based on these data the substance is not considered to be classified for repeated dose toxicity under Regulation (EC) No 1272/2008, as amended for the tenth time in Regulation (EC) No 2017/776.
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.
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