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EC number: 908-343-6 | CAS number: -
Table 1: Results of analysis of stock solution (35 % hydrogen peroxide), dose solutions (100, 300, 1000 and 3000 ppm), and mean hydrogen peroxide consumption.
Stability of refrigerated 35 % test material
Range of % of target concentration in dose solutions
Hydrogen peroxide consumption (mg/kg/day) based on water consumption and nominal conc.
Time point of sampling
Total % hydrogen peroxide
% change from initial analysis
Target concentration (ppm)
Initial range, % of target
26 ± 6.0
37 ± 10.0
76 ± 17.1
103 ± 25.5
239 ± 56.4
328 ± 81.4
547 ± 95.3
785 ± 194.3
NA: not applicable
Table 2: Development of body weights, food and water consumption throughout the study
Body weight [g/animal]
Mean food consumption [g/animal/week]
Mean water consumption [g/animal/week]
-- Indicates a decrease in comparison with controls
Table 3: Results of clinical chemistry (blood samples)
Table 4: Incidence of histopathological findings
number of animals examined
- mucosal hyperplasia
A 90-day oral, subchronic toxicity study with a 35 % aqueous solution of hydrogen peroxide dissolved in drinking water to produce concentrations ranging from 100 to 3000 ppm was performed with C57BL/6NCrlBR mice under GLP conditions and in essential accordance with OECD Guideline No. 408. C57BL/6NCRlBR mice were chosen due to their particular sensitivity to hydrogen peroxide because of a deficient detoxification pathway. The strain can therefore be regarded as a very sensitive animal model for this particular substance. Groups of 15 males and 15 females received different doses of hydrogen peroxide dissolved in their drinking water. After the 90 -day exposure duration, 10 animals/sex of each dose group were sacrificed, while the remaining five animals/sex were submitted to a six week recovery period. No treatment-related mortality or clinical signs were noted throughout the study. No other treatment-related effects were observed at the 100 ppm dose level. At 300 ppm, the consumption of food and water was reduced. Tissue slides indicated an increase in the cross sectional diameter and wall thickness of the duodenum. Subsequent microscopic evaluations revealed mild mucosal hyperplasia in eight of nine males and ten of ten females receiving 3000 ppm and in seven of ten males and eight of ten females receiving 1000 ppm. Minimal mucosal hyperplasia was noted in one of ten males but in none of the females receiving 300 ppm. No other areas of the gastrointestinal tract were affected. Microscopically, no evidence of cellular atypia or architectural disruptions nor any other indications of neoplastic changes were observed; therefore, the treatment-related mucosal hyperplasia noted in the study was not considered as neoplastic lesion.
Based on dose-related reductions in food and water consumption and the observation of duodenal mucosal hyperplasia the lowest observed effect level in the study was 300 ppm and the no observed effect level (NOEL) was 100 ppm (26 and 37 mg/kg/day for males and females, respectively). Clinical pathologic effects (decreased total protein and globulin blood levels) were limited to the 3000 ppm level. All effects noted during the treatment period were reversible; animals sacrificed following the recovery period were considered biologically normal.
Table 1: Results of the clinical chemistry haematology
Control group 1 (0 ppm)
Control group 2 (0 ppm)A
Mean cell volume (fl)
Mean cell haemoglobin (pg)
Total protein (g/L)
Red blood cell count (10e12/L)
A) 25 ppm group is compared to control group 2 since animals were treated simultaneously. *p <0.05, **p <0.01 (student's t-test, two-sided)
Table 2: Microscopic findings
Control (0 ppm)
Necrosis and inflammation (sqamous epithelium, anterior region of nasal cavity)
3/5 males, 2/5 females
Necrosis and inflammation (sqamous epithelium, anterior regions of nasal cavity)
4/5 males, 4/5 females
Mononuclear cell infiltration
Increase in perivascular neurophil infiltration
2/5 males, 1/5 females
1/5 males, 2/5 females
A repeated dose inhalation toxicity study was performed with male and female Alpk:APfSD (Wistar-derived) rats exposed to hydrogen peroxide vapours for 6 hours per day, 5 days per week for a period of 28 days at concentrations of 2.03, 10.3 or 23.3 ppm. The study was carried out under GLP conditions and in accordance with OECD Guideline No. 412. Treatment of a group exposed initially to 58.1 ppm and subsequently to 27.3 ppm was terminated before schedule due to the toxicity of the test material. Clinical observations were consistent with the material being a respiratory tract irritant (reddened noses, stains around the nose, abnormal respiratory noise) and in general the time to onset, incidence and severity of clinical signs increased with exposure concentration and repeated exposure. Males exposed to 23.3 ppm hydrogen peroxide showed lower food consumption and body weight gain compared to controls. Minimal changes in albumin and total protein blood levels were found in males and females exposed to 23.3 ppm. Histopathological, treatment-related changes were seen in the anterior-most regions of the nasal cavity lined with squamous epithelium, where minimal to slight necrosis (with associated inflammation) and rhinitis were seen in animals exposed to 10.3 and 23.3 ppm hydrogen peroxide. Inflammation and epithelial erosion in the larynx and increased perivascular neutrophil infiltration in the lungs were considered unlikely to be related to treatment in the absence of a clear dose response relationship. The no observed effect level (NOEL) for the study was considered to be 2.03 ppm hydrogen peroxide (corresponding to 2.9 mg/m3).
In order to be systemically available, a chemical needs to be absorbed, either via the oral, inhalatory or dermal route. Dissolution of solids is generally assumed to be a prerequisite for absorption. As the reaction mass of calcium carbonate and calcium dihydroxide and calcium peroxide is a solid inorganic multi-constituent substance, this means that Ca2+, OH- and hydrogen peroxide are the species to be taken into account when assessing its toxicity.
Oral repeated dose toxicity
* Ca2 +: A comprehensive evaluation of all available human data on prolonged oral exposure to various calcium compounds is published in “Opinion of the Scientific Committee on Food on the Tolerable Upper Intake Level of Calcium” dd 4 April 2003. In this document, a tolerable upper intake level (UL) of 2500 mg of calcium per day for calcium intake from all sources is proposed for adults, which corresponds to a dose of approximately 36 mg calcium/kg bw/day taking into account an average body weight of 70 kg/person.
The Tolerable Upper Intake Level (UL) derived by the SCF is considered as sufficient and adequate for risk characterisation. In conclusion, the conduct of any further repeated-dose toxicity studies in animals would not contribute any new information and is therefore not considered to be required.
* H2O2: A key study is available that assesses the repeated oral exposure to hydrogen peroxide. In this oral toxicity study (Freeman 1997) 35 % hydrogen peroxide was applied to mice via the drinking water for 90 days. Reduced food and water consumption were seen at ≥ 300 ppm. Body weight was reduced in mice receiving 3000 ppm during most of treatment period in male animals. Further signs of treatment indicated the duodenum as target organ with local mucosal hyperplasia at ≥ 1000 ppm (corresponding to 239 and 328 mg/kg bw/d for males and females, respectively). Mucosal hyperplasia in the duodenum was not found in any dose group after recovery. The no observed adverse effect level (NOAEL) was 100 ppm (26 mg/kg bw/day in males and 37 mg/kg bw/day in females).
* OH-: When administered via the oral route, the hydroxide ions will be neutralised in the GI tract. No further assessment is therefore deemed required.
The NOAEL of the reaction mass of calcium peroxide, calcium hydroxide and calcium carbonate was calculated from the NOAEL available for hydrogen peroxide (26 mg/kg bw/d) by taking into account the composition of the reaction mass:
According to the applicable chemical reaction, the amount of hydrogen peroxicde formed is equimolar to the amount of calcium peroxide present in the reaction mass. As the concentration of calcium peroxide in the reaction mass is ca. 75%, 100 mg of the reaction mass contains 75 mg of calcium peroxide, which corresponds to 1.04 mmol of calcium peroxide. Therefore, 1.04 mmol (= 35.36 mg) of hydrogen peroxide is formed upon dissolution of 100 mg of calcium peroxide. As a consequence, the NOAEL for the reaction mass of calcium peroxide, calcium hydroxide and calcium carbonate was calculated to be 100*26/35.36 = 73.53 mg/kg bw/d.
Inhalatory repeated dose toxicity
* Ca2+and OH-: An adopted Recommendation from the Scientific Committee on Occupational Exposure Limits (SCOEL) for calcium oxide (CaO) and calcium dihydroxide (Ca(OH)2) is in place, setting a short-term exposure limit (STEL) of 4 mg/m³ respirable dust, and a 8 -h TWA of 1 mg/m³ respirable dust which is considered protective against long-term exposure to calcium oxide and calcium dihydroxide. In particular, two ethically approved human volunteer studies taken into account by SCOEL indicate chemosensory feel and local irritation of mucous membranes in the respiratory tract being the primary effect upon inhalation exposure of alkaline mineral materials due to a pH shift.
Following the criteria of Annex XI, point 1.1.2 of Regulation No 1907/2006, the SCOEL recommendation is considered as adequate for purpose of classification and labelling and for the risk assessment.
* H2O2: A key study is available that assesses the repeated inhalatory exposure to hydrogen peroxide. In this 28 -days inhalation study in the rat (Kilgour 2002), local effects appeared in the nose with necrosis and inflammation at ≥10 ppm followed by respiratory irritation and reduced body weight gain in higher exposure concentrations. The no observed adverse effect level (NOAEL) was 2.9 mg/m³ (2.03 ppm).
The NOAEC of the reaction mass of calcium peroxide, calcium hydroxide and calcium carbonate was calculated from the NOAEC available for hydrogen peroxide (2.9 mg/m3) by taking into account the composition of the reaction mass:
According to the applicable chemical reaction, the amount of hydrogen peroxide formed is equimolar to the amount of calcium peroxide present in the reaction mass. As the concentration of calcium peroxide in the reaction mass is ca. 75%, 100 mg of the reaction mass contains 75 mg of calcium peroxide, which corresponds to 1.04 mmol of calcium peroxide. Therefore, 1.04 mmol (= 35.36 mg) of hydrogen peroxide is formed upon dissolution of 100 mg of calcium peroxide. As a consequence, the NOAEC for the reaction mass of calcium peroxide, calcium hydroxide and calcium carbonate was calculated to be 100*2.9/35.36 = 8.20 mg/m3.
Dermal repeated dose toxicity
In the REACH registration dossiers for hydrogen peroxide and calcium hydroxide, elaborate documentation is available that confirms that both these substances have a low bioavailability through the skin. As a consequence, assessment of the repeated dose toxicity for the dermal exposure route is not considered to be required as systemic effects following dermal exposure are not expected due to the low absorption rate of the substance. Furthermore, calcium hydroxide is neutralized in the blood while hydrogen peroxide is degraded in the blood, and therefore, the substance is not expected to be systemically available.
In accordance to EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008, classification is not necessary for repeated dose toxicity based on the available test results for the read-across substances hydrogen peroxide and calcium hydroxide. The dose at which the transient effects of mucosal hyperplasia in the duodenum was observed (239 mg/kg bw/d, which corresponds to 100*239/35.36 = 675 mg/kg bw/d of the reaction mass of calcium carbonate and calcium dihydroxide and calcium peroxid) is outside the classification criteria.
Furthermore, for the inhalatory route a STOT-RE is not required as repeated dose testing of both read-across substances (calcium dihydroxide and hydrogen peroxide) did not show any systemic effects. Both substances only exhibited local irritancy.
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.
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