Registration Dossier

Administrative data

Description of key information

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP study according to internationally accepted protocol. No deviations.
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPP 81-1 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Taconic Farms, Germantown, New York
- Age at study initiation: no data
- Weight at study initiation: 211 +/- 4.7 g (males), 224 +/- 4.9 g (females)
- Fasting period before study: overnight
- Housing: individually, stainless steel suspended rat cages
- Diet (e.g. ad libitum): Purina Laboratory Rodent Chow 5001, ad libitum
- Water (e.g. ad libitum): tap water, ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°F): 66-76°F
- Humidity (%): 24-59%
- Photoperiod (hrs dark / hrs light): 12h fluorescent light, 12h dark
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 25%
- Lot/batch no. (if required): 65084-BAB

DOSE VOLUME APPLIED: 4.1-4.6 mL of corn oil suspension, depending on body weight

TEST MATERIAL ADMINISTRATION
The test material was introduced directly into the stomach by means of a straight, 13 gauge stainless steel dosing needle.
Doses:
5000 mg/kg bw
No. of animals per sex per dose:
5 males, 5 females
Control animals:
not specified
Details on study design:
STUDY DESIGN
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: day 0, 7 and 14
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight

DATA INTERPRETATION
FMC internal guidelines for acute oral toxicity:
LD50 value (mg/kg bw) Toxicity rating
> 5000 Practically non-toxic
500-5000 Slightly toxic
50.0-500 Moderately toxic
<= 50.0 Highly toxic
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Based on:
test mat.
Mortality:
No deaths occurred during the observation period.
Clinical signs:
Abdominogenital staining and diarrhea were noted in several rats shortly after dosing. All rats recovered by day 2 and remained healthy throughout the study.
Body weight:
Male body weights:
Day 0: 211 +/- 4.7
Day 7: 271 +/- 9.3
Day 14: 310 +/- 12.0

Female body weights:
Day 0: 224 +/- 4.9
Day 7: 243 +/- 8.1
Day 14: 256 +/- 9.7
Gross pathology:
There were no gross internal lesions observed in any animal at necropsy.
Interpretation of results:
practically nontoxic
Remarks:
Migrated information Criteria used for interpretation of results: other: FMC internal guidelines
Conclusions:
Under the conditions of this study, the test material is classified as practically non-toxic to both male and female rats.
Executive summary:

5 Male and 5 female Sprague-Dawley rats were orally dosed with Calcium peroxide as a 25% (w/v) suspension in corn oil at a dosage level of 5000 mg/kg bw. Observations for toxicity were conducted at 0.5, 1, 2, 3, 4 and 6 hours on the day of dosing and twice daily thereafter for 13 days. A gross necropsy was performed on all animals.

No deaths occurred during the study. Abdominogenital staining and diarrhea were noted in several rats shortly after dosing. All rats recovered by day 2 and remained healthy throughout the study. There were no gross internal lesions observed in any animal at necropsy.

Under the conditions of this study, the test material is classified as practically non-toxic to both male and female rats. The LD50 is judged to be > 5000 mg/kg to both male and female animals.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: The study was carried out in compliance with GLP and US-EPA Vol 50 (§798.1150) Guideline, which is equivalent to OECD Guideline No. 403.
Qualifier:
according to
Guideline:
other: US-EPA Vol 50 (§798.1150)
GLP compliance:
yes
Test type:
standard acute method
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc. Raleigh, North Carolina
- Age at study initiation: 8-9 weeks;
- Weight at study initiation: males: 262 - 277 g; females 217 – 257 g
- Fasting period before study:
- Housing: Doubly in suspended, stainless steel, wire mash cages during acclimation and non-exposure period; individually in 100 litre Plexiglass exposure chambers during exposure
- Diet (e.g. ad libitum): Purina Rodent Laboratory Chow Brand Animal Diet #5001 ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: All animals were acclimated for 11 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-25 °C; 25 °C (during exposure)
- Humidity (%): 17-60 % (40-44 % during exposure)
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
inhalation
Type of inhalation exposure:
whole body
Vehicle:
other: no data
Details on inhalation exposure:
The atmosphere was generated by bubbling air flow through a reservoir containing 1000 ml of 50% hydrogen peroxide. Particle size distribution measurements showed a particulate level of 0.020 mg/m3, which was comparable to background air levels thus indicating no appreciable aerosol formation.
Analytical verification of test atmosphere concentrations:
yes
Remarks:
Samples for colorimetric determination of vapours of hydrogen peroxide (50 %) were withdrawn once per hour
Duration of exposure:
4 h
Concentrations:
Nominal concentration: 7.7 [mg/L]
Analytical concentration: 0.17 [mg/L] (maximum attainable vapour)
No. of animals per sex per dose:
5 rats
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Necropsy of survivors performed: yes/no
- Other examinations performed: clinical signs, body weight,organ weights, histopathology
Statistics:
no data
Preliminary study:
none
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 170 mg/m³ air
Exp. duration:
4 h
Mortality:
No deaths occurred.
Clinical signs:
Observations noted during exposure included decreased activity and eye closure. Signs exhibited by animals upon removal from the chamber and during the two-hour post-exposure observation period on Day 1 included nasal discharge, excessive salivation and anogenital staining. During Test Week 1, test animals exhibited a few continuing responses such as dried red nasal discharge and dried red material on fur. During Test Week 2, animals exhibited some but not complete recovery from these signs.
Body weight:
Body weight at day 2 was slightly less than pre-test value. Recovery of weight occurred thereafter and all animals were in excess of their pre-exposure body weight by termination of the study.
Gross pathology:
No effects considered treatment-related were found. Lung weights were comparable to historical values
Other findings:
no other findings

none

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Classification according to Directive 2001/59/EC (adaptation of 67/548/EEC) is not necessary since at the maximum technical attainable vapour concentration of 0.17 mg/L no deaths occurred.
Executive summary:

The acute inhalation toxicity of hydrogen peroxide (50 %) aerosols was tested in male and female Sprague-Dawley rats according to US EPA Guideline Vol 50 (§798.1150). Animals received a single 4 -hour whole-body exposure to the maximum attainable aerosol concentration of 170 mg/m3. All tested animals survived the exposure and subsequent 14 -day post-exposure observation period. Signs of treatment were minimal during the exposure but a few responses such as nasal discharge were noted during the whole 14 -day observation period. A minimal, transient adverse effect upon body weight was produced by treatment. Otherwise, body weight gain was considered unremarkable. Gross post mortem observations and lung weights were considered unremarkable. No LD50 value for acute inhalation toxicity could be established and the LD50 value must be greater than the attainable aerosol concentration of hydrogen peroxide of 170 mg/m3.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: The study was carried out according to US EPA Guidelines for acute dermal toxicity study (PB82-232984, August 1982) and in compliance with GLP.
Qualifier:
according to
Guideline:
other: US EPA Toxic Substance Health Effects Test Guidelines (PB82-232984, 1982)
Principles of method if other than guideline:
US EPA Toxic Substance Health Effects Test Guidelines (PB82-232984, 1982) Acute dermal toxicity study
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Davidson's Mill Farm, Jamesburg, New Jersey
- Age at study initiation: Young adult
- Weight at study initiation: Males weighed between 2.1 to 2.45 kg, females weighed between 2.03 to 2.49 kg
- Fasting period before study: no data
- Housing: Individually in suspended, stainless steel, wire mash cages
- Diet (e.g. ad libitum): Purina Laboratory Rabbit Chow 5321 ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 8 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 70 to 74 °F
- Humidity (%): 42 to 69 %
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12/12
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
A pretest was conducted. On the day prior to test material administration, the trunks of ten rabbits were clipped free of hair with an electric clipper. The clipped exposure sites extended from the scapulae to the pelvic girdle and encompassed approximately 20 % of the animal's body surface. Doses corresponding to a dosage level of 2000 mg/kg were individually calculated based on the body weight of each animal on the day of dosing. A 4x4 inch gauze pad was positioned on the intact test site and held in place with hypoallergenic tape. The test site was then occluded with impervious plastic sheeting for 24 hours. The test material was introduced under the gauze pad using a dosing needle and a syringe. Each animal was fitted with an everted plastic Elizabethan collar to prevent disturbance of the test site and possible ingestion of the test material. The animals were dosed approximately 3 hours after initiation of the light cycle.
Duration of exposure:
24h
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
The animals were observed for mortality and clinical signs (local irritation excluded) at 0.5, 1, 2, 3, 4 and 6 hours on the day of dosing and twice daily thereafter for 13 days; on day 14 the animals were observed once. A description on the local irritation was recorded on day 1, 4, 7 and 14 of the study. Body weights were taken on the day of dosing and again on day 7 and 14. Rabbits were killed on day 14 of the study and submitted to gross necropsy.
Statistics:
No statistics were applied.
Preliminary study:
none
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Mortality:
There were no deaths.
Clinical signs:
Nasal discharge in one rabbit and lacrimation in another rabbit were observed on day 4 and 5 of the study, respectively.
Body weight:
Seven rabbits gained weight and three rabbits lost weight in the course of the study (see Table 1).
Gross pathology:
There were no gross internal lesions observed in any animal at necropsy.
Other findings:
Erythema, oedema and blanching of the test sites were observed in all rabbits 24 hours after administration. By day 4 of the study, all rabbits had necrosis which developed into eschar on day 7. At termination of the study, eschar and exfoliation were present in all rabbits.

Table 1: Mean body weights of test animals in the male and female dose groups

Gender

Mean body weights ± S.D. (kg)

Days after administration

0

7

14

Male

2.3 ± 0.15

2.12 ± 0.17

2.47 ± 0.21

Female

2.3 ± 0.2

1.93 ± 0.12

2.25 ± 0.28

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
No classification for dermal toxicity is necessary for hydrogen peroxide (35%) according to Directive 2001/59/EC (adaptation of 67/548/EEC) or according to Regulation (EC) 1272/2008.
Executive summary:

The acute dermal toxicity of a 35 % aqueous solution of hydrogen peroxide was tested according to US EPA Guidelines (PB82 -232984, August 1982) and under GLP conditions. Male and female young adult New Zealand White rabbits received a single dose of 2000 mg/kg the test material under occlusion. Animals were prevented from manipulating the test site by the application of Elizabethan collars. Occlusion remained for 24 hours. After removal of the occlusion, animals were observed for 14 days. None of the animals died so that the dermal LD50 value was greater than 2000 mg/kg. All animals showed local skin irritation exhibiting erythema, oedema and blanching of the test sites after 24 hours and eschar and exfoliation at termination of the study. No gross internal lesions were found at necropsy at termination of the study.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Additional information

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 systemic toxicity.

Acute oral toxicity

A reliable and well-documented acute oral toxicity limit test is available that assessed the effects upon administration of 5000 mg/kg bw calcium peroxide to Sprague-Dawley rats. The study was performed according to GLP and internationally accepted protocols. No deaths occurred during the 14 observation period of the study and no gross internal lesions were observed at necropsy. Transient clinical observations included diarrhea and abdominogenital staining.

As a consequence it was concluded that the LD50 of the test substance is > 5000 mg/kg bw and the substance is practically non-toxic to both male and female rats.

Acute inhalation toxicity

No reliable experimental data are available that assess the acute inhalation toxicity of the reaction mass of calcium carbonate and calcium dihydroxide and calciumperoxide. Nevertheless,the information available for the read-across substances is considered to be sufficient for the purpose of the chemical safety assessment and for the classification and labelling.

A reliable acute inhalation toxicity study is available for hydrogen peroxide in which male and female Sprague-Dawley rats received a single 4 -hour whole-body exposure to a 50% aqueous solution of hydrogen peroxide at the maximum attainable aerosol concentration of 170 mg/m3. All tested animals survived the exposure and subsequent 14 -day post-exposure observation period. Signs of treatment were minimal during the exposure but a few responses such as nasal discharge were noted during the whole 14 -day observation period. It was as a consequence concluded that the LC50 value must be greater than the attainable aerosol concentration of hydrogen peroxide of 170 mg/m3.

Acute dermal toxicity

No reliable experimental data are available that assess the acute dermal toxicity of the reaction mass of calcium carbonate and calcium dihydroxide and calciumperoxide. Nevertheless, the information available for the read-across substances is considered to be sufficient for the purpose of the chemical safety assessment and for the classification and labelling.

For calcium dihydroxide a key study assessing the acute dermal toxicity according to the OECD 402 guideline is available (Kietzmann, 1994). In this study 5 male and 5 female New Zealand White rabbits were exposed to 2500 mg of calcium dihydroxide under semiocclusive coverage for a period of 24 hours. The test substance was moistened in order to ensure good contact with the skin. No deaths occurred during the 14d observation period following dosing, but skin irritation effects were observed at the contact site. The LD50 was thus found to be > 2500 mg/kg bw.

 

The reliable study assigned as the key study in the REACH registration dossier for hydrogen peroxide dates from 1983 (Geiger 1983). It is carried out according to GLP and US EPA guidelines. In this experiment, male and female New Zealand White rabbits were exposed to a 35% aqueous hydrogen peroxide solution under occlusive coverage during 24 hours. The applied dose was 2000 mg/kg bw. No deaths occurred during the 14d observation period, but skin irritation effects were observed at the contact site. The LD50 was thus found to be > 2000 mg/kg bw.

 

Based on the available experimental data for hydrogen peroxide and calcium dihydroxide it can thus reasonably be assumed that the reaction mass of calcium carbonate and calcium dihydroxide and calcium peroxide will have an LD50 > 2000 mg/kg bw.


Justification for selection of acute toxicity – oral endpoint
Well-documented GLP study according to internationally accepted guideline.

Justification for selection of acute toxicity – inhalation endpoint
Well-documented GLP study according to internationally accepted guideline. Test substance: hydrogen peroxide.

Justification for selection of acute toxicity – dermal endpoint
Well-documented GLP study according to internationally accepted guideline. Test substance: hydrogen peroxide.

Justification for classification or non-classification

In accordance to EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008, classification is not necessary for acute toxicity for the oral and dermal routes based on the available test results for the reaction mass of calcium carbonate and calcium dihydroxide and calcium peroxide and/or information avaialble on the read-across substances hydrogen peroxide and calcium hydroxide. The selected dose descriptor values (oral LD50 > 5000 mg/kg bw; dermal LD50 > 2000 mg/kg bw and inhalation STEL 4 mg/m3) are outside the classification criteria.

For the inhalatory route, no adverse effects were observed at the maximum attainable aerosol concentration generated from a 50% aqueous solution of hydrogen peroxide. Therefore, in the hydrogen peroxide registration dossier it is concluded that classifying for acute toxicity via inhalation is not required for mixtures containing < 50% hydrogen peroxide. Accordingly, as the maximum concentration of hydrogen peroxide that can be formed from the reaction mass of calcium carbonate and calcium dihydroxide and calcium peroxide is < 50%, classification for acute toxicity via inhalation is not required.

The effects of respiratory irritation observed upon exposure to both hydrogen peroxide as well as calcium dihydroxide lead to a STOT-SE Cat. 3 classification for both substances. Therefore, a STOT-SE Cat. 3 with the respiratory tract as affected organ is also adopted for the reaction mass of calcium carbonate and calcium dihydroxide and calcium peroxide.