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Administrative data

Description of key information

Based on a study according to OECD Guideline 423 in rats the oral LD50 of the test item was determined to be > 2000 mg/kg bw.

As hydrogen peroxide determines the toxicity of the target substance, the estimated dermal LD50 for hydrogen peroxide (source substance) is used to derive an estimate of the dermal LD50 value for the target substance. The dermal LD50 of the target substance was derived to be 13800 mg/kg.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Reference:
Composition 0
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Version / remarks:
2001-12-17
Deviations:
no
GLP compliance:
yes
Test type:
acute toxic class method
Test material information:
Composition 1
Specific details on test material used for the study:
Supplier: Degussa
CAS number: 124-43-6
Name in teh study report: carbamide-peroxide
Purity: not specified
Batch number: 073590600
Species:
rat
Strain:
Crj: CD(SD)
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland, D-97633 Sulzfeld, Germany
- Females nulliparous and non-pregnant: yes
- Age at study initiation: approx. 8 weeks at the time of administration
- Weight at study initiation: Group 1: 188 ± 8.1 g; Group 2: 178.3 ± 3.2 g
- Fasting period before study: yes, overnight
- Housing:
- Diet: ad libitum, starting at 3 hours after dosing
- Water: tap water ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): average 22.1 °C
- Humidity (%): average 66.1 %
- Air changes (per hr): 12
- Photoperiod (hrs dark / hrs light): 12 /12

Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 2000 mg/10 mL
- Amount of vehicle (if gavage): 10 mL/kg bw
- Justification for choice of vehicle: water is the preferred vehicle according to the OECD TG 423; test substance is water soluble


MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg bw


CLASS METHOD
- Rationale for the selection of the starting dose: aqcute toxicity expected to be low
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
6
Control animals:
no
Statistics:
calculation of means ± SD
Key result
Sex:
female
Dose descriptor:
LD0
Effect level:
2 000 mg/kg bw
Based on:
test mat.
Mortality:
none (0/6 animals)
Clinical signs:
yes, shortly after administration and lasting up tp 6 hours. Fully reversible. Signs of reduced well-being encompasses unspecific alterations, like sedation, apathy, piloerection, hunched posture or closed eyes, in síngle or multiple occurrence.
Body weight:
Animals of both groups gained body weight at 7 or 14 days post treatment.
Gross pathology:
No necropsy findings at termination 14 days after treatment.
Interpretation of results:
GHS criteria not met
Conclusions:
The LD50 value is > 2000 mg/kg bw
Executive summary:

The acute oral toxicity of hydrogen peroxide-urea (carbamide peroxide) was determined in the female rat, according to the OECD TG 423 and under GLP conditions. Animals (two groups of 3 rats each) received the test material by oral gavage at 2000 mg/kg bw. Clinical signs were seen during the first 6 hours after dosing. The animals gained body weight after 7 and 14 days post treatment. No mortalities occurred, and there were no necropsy findings at termination on day 14 post treatment. Hence, the oral LD50 is > 2000 mg/kg bw in the rat.

This study is considered to be valid and suitable for assessment.

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Reference:
Composition 0
Qualifier:
no guideline followed
Principles of method if other than guideline:
- Principle of test: examination of esophagus, stomach, liver, kidneys at 1 and 24 hours following a single gavage dose of hydrogen peroxide, or a tooth-bleaching agent, to female rats (3 per dose group).
- Short description of test conditions:
doses: 0 (control), 5, 15, and 50 mg hydrogen peroxide /kg bw
tooth-bleaching agent: 150 and 500 mg/kg bw, corresponding to 15 and 50 mg hydrogen peroxide/kg bw
- Parameters analysed / observed:
GLP compliance:
not specified
Test type:
other: no determination of the LD50 but examination of short-term effects on the esophagus, stomach, liver, and kidneys
Limit test:
no
Test material information:
Composition 1
Specific details on test material used for the study:
Name of test material in the report: carbamide peroxide
CAS numer: 124-43-6
Supplier: Sigma Chemical Company, St. Louis, MO, USA
Purity: not specified
Species:
rat
Strain:
Wistar Kyoto (WKY)
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Wiga, Sulzfeld, Germany
- Females (if applicable) nulliparous and non-pregnant: not specified
- Age at study initiation: not speified
- Weight at study initiation: 225-275 g
- Fasting period before study: overnight
- Housing:
- Diet: Norwegian Standard diet ad libitum, starting at 4 h after treatment
- Water: ad libitum
- Acclimation period: not specified

ENVIRONMENTAL CONDITIONS
- Temperature (°C): not specified
- Humidity (%): not specified
- Air changes (per hr): not specified
- Photoperiod (hrs dark / hrs light): 12/12 automatically controleld

:
Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 1.5 to 15 mg/mL (0.15 to 1.5% w/w)
- Amount of vehicle: 3 to 6 mL/kg bw
- Justification for choice of vehicle:

MAXIMUM DOSE VOLUME APPLIED:
6 mL/kg bw



Doses:
Hydrogen peroxide: 0, 5, 15, 50 mg/kg bw
No. of animals per sex per dose:
3
Control animals:
yes
Details on study design:
- Duration of observation period following administration: 1 hour
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, histopathology: stomach, liver, kidneys
Statistics:
not needed
Key result
Dose descriptor:
other: mild gastric mucosa lesions
Effect level:
15 mg/kg bw
Based on:
test mat.
Mortality:
none
Clinical signs:
Impaired mobility in one rat dosed with 50 mg hydrogen peroxide-urea/kg bw (and in two rats dosed with the tooth-bleaching agent at 500 mg/kg bw)
Gross pathology:
All organs unchanged compared with controls

Number of animals with gastric mucosa lesions (rated as present or not present)

Test material

Dose

[mg/kg bw]

1 h

24 h

Control

0

0/3

0/3

Hydrogen peroxide-urea

5

n.d

0/3

15

3/3

2/3

50

3/3

2/3

Opalescence®

(tooth-bleaching agent)

150

3/3

3/3

500

2/3

3/3

 

Interpretation of results:
study cannot be used for classification
Conclusions:
Overall, reversible local irritation of the gastric mucosa was seen within 1 hour after oral dosing of 15 and 50 mg hydrogen peroxide-urea (1:1)/kg bw whereas no effects were seen in the liver or kidneys.
Executive summary:

Female rats (Wistar Kyoto, 3 per dose group) received either 0, 5, 15, or 50 mg hydrogen peroxide-urea (1:1)/ kg bw, or a tooth-bleaching agent at 150 and 500 mg/kg bw (which corresponds to 15 and 50 mg hydrogen peroxide-urea (1:1)/kg bw, respectively) in water by oral gavage. The animals were sacrificed at 1 hour and 24 hours after dosing and necropsied. Stomach, liver and kidney specimen were subjected to histopathological examinations.

No effects were seen in the liver and the kidneys. Gastric ulceration was seen in all groups receiving test material at 1 hour after dosing. Healing was seen in groups receiving hydrogen peroxide-urea (1:1) within 24 hours, i.e. the effect was absent in the low dose group at 5 mg/kg bw and was diminished in the animals at 15 and 50 mg hydrogen peroxide-urea (1:1)/kg bw. No healing was seen in animals dosed with the consumer product, most probably because the viscous material prolonged the contact to the mucous membrane.

Overall, reversible local irritation of the gastric mucosa was seen within 1 hour after oral dosing of 15 and 50 mg hydrogen peroxide-urea (1:1)/kg bw whereas no effects were seen in the liver or kidneys (Dahl and Becher, 1995).

Endpoint:
acute toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Justification for type of information:
ANALOGUE APPROACH JUSTIFICATION
Please refer to the attached read across justification in section 13.
Reason / purpose:
read-across source
Related information:
Composition 1
Test material information:
Composition 1
Key result
Sex:
male
Dose descriptor:
LD50
Effect level:
14 300 mg/kg bw
Based on:
test mat.
Remarks on result:
other: LD50 was 14.3 (12.9-15.9 ) g urea/kg bw
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
15 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: LD50 was 15.0 (13.4-16.8) g urea/kg bw

The oral LD50 for the source substance urea was 14,300 mg/kg bw in the male and 15,000 mg/kg in the female rat. Taking into account molecular weights, the lower value of 14,300 mg urea/kg bw corresponds to 22,408 mg of the target substance, hydrogen peroxide (1:1) / kg bw.

Endpoint:
acute toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Justification for type of information:
ANALOGUE APPROACH JUSTIFICATION
Please refer to the attached read across justification in section 13.
Reason / purpose:
read-across source
Related information:
Composition 1
Test material information:
Composition 1
Key result
Sex:
male
Dose descriptor:
LD50
Effect level:
11 500 mg/kg bw
Based on:
test mat.
Remarks on result:
other: LD50 was 11.5 (10.6-12.5) g urea/kg bw
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
13 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other:
Remarks:
LD50 was 13.0 (11.0-15.4) g urea/kg bw

The oral LD50 for the source substance urea was 11,500 mg/kg bw in the male and 13,000 mg/kg in the female mouse. Taking into account molecular weights, the lower value of 11,500 mg urea/kg bw corresponds to 20,724 mg of the target substance, hydrogen peroxide (1:1) / kg bw.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
2 000 mg/kg bw
Quality of whole database:
Key study, Reliability 1. Guideline study under GLP conditions. Test substance: hydrogen peroxide - urea (1:1)

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: dermal
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:
read-across source
Related information:
Composition 1
Test material information:
Composition 1
Key result
Sex:
not specified
Dose descriptor:
LD0
Effect level:
700 mg/kg bw
Based on:
act. ingr.
Remarks on result:
other: result for the source substance: 2000 mg/kg bw of a 35% hydrogen peroxide solution

2000 mg/kg of a 35% solution corresponds to 700 mg H2O2 /kg bw.

Taking the molecular weights of the source substance (H2O2) and of the target substance into consideration, the LD0 for H2O2 (700 mg/kg bw) corresponds to 1935 mg of the target substance/kg bw.

Endpoint:
acute toxicity: dermal
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:
read-across source
Related information:
Composition 1
Test material information:
Composition 1
Key result
Sex:
male
Dose descriptor:
LD50
Effect level:
9 200 mg/kg bw
Based on:
test mat.
Endpoint:
acute toxicity: dermal
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:
read-across source
Related information:
Composition 1
Test material information:
Composition 1
Key result
Sex:
not specified
Dose descriptor:
LD0
Effect level:
700 mg/kg bw
Based on:
act. ingr.
Remarks on result:
other: 2000 mg/kg bw of a 35% hydrogen peroxide solution

The study is considered to be valid and suitable for assessment. The toxicity of hydrogen peroxide largely depends on its concentration; this is discussed in the endpoint summary. For the read across to hydrogen peroxide - urea (1:1), the result for the 35% solution can be adopted. This is explained in the endpoint summary.

700 mg of the active ingredient/kg bw corresponds to 1935 mg of the target substance, hydrogen peroxide – urea (1:1), per kg bw .

Endpoint:
acute toxicity: dermal
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:
read-across source
Related information:
Composition 1
Test material information:
Composition 1
Sex:
not specified
Dose descriptor:
LD0
Effect level:
1 400
Based on:
test mat.
Remarks on result:
other: 10% H2O2; signs of systemic toxicity
Sex:
not specified
Dose descriptor:
LD50
Effect level:
> 8 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: 28% H2O2; "some animals were killed"

Results most probably refer to the respective hydrogen peroxide solutions, i.e. no deaths were seen at 140 mg/kg bw of the active ingredient, whereas the LD50was >2240 mg active ingredient /kg bw with the 28% hydrogen peroxide solution.

Taking the molecular weights into consideration, 2240 mg of the active ingredient correspond to 6182 mg of the target substance/kg bw in the mouse.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
13 800 mg/kg bw
Quality of whole database:
read across suitable for assessement

Additional information

Acute oral toxicity

The acute oral toxicity of hydrogen peroxide-urea (1:1) (carbamide peroxide) was determined in the female rat, according to the OECD TG 423 and under GLP conditions. Animals (two groups of 3 rats each) received the test material by oral gavage at 2000 mg/kg bw. Clinical signs were seen during the first 6 hours after dosing. The animals gained body weight after 7 and 14 days post treatment. No mortalities occurred, and there were no necropsy findings at termination on day 14 post treatment. Hence, the oral LD50 is > 2000 mg/kg bw in the rat.

 

Acute inhalation toxicity

No study was located. Information is waived because inhalation is not considered to be a likely route of exposure, taking into account the physico-chemical properties (solid crystals; vapour pressure) of hydrogen peroxide - urea (1:1).

 

Acute dermal toxicity

Hydrogen peroxide - urea (1:1) is present as solid crystals at ambient temperature, and as such it is not dermally absorbed and does not cause systemic effects, and no acute dermal studies have been located. However, it dissolves in water and decomposes to hydrogen peroxide and urea. Under certain use conditions this could lead to absorption of hydrogen peroxide or urea. It is therefore reasonable to use data on these breakdown products for assessment.

Hydrogen peroxide governs the acute toxicity of the target substance, Hydrogen peroxide - urea (1:1). H2O2 is a moderate reactive oxygen species that may react at the point of contact and cause skin irritation or corrosion depending on the concentration, but which is also absorbed through the skin and may distribute with the blood stream to other sites where it is either enzymatically decomposed by catalase and glutathione peroxidase, or it oxidises cellular molecules (e.g. thiol groups), or decomposes to give rise of the highly reactive hydroxyl radical which reacts with any material including DNA at the site of generation. In this context it should also be noted that the degradation by catalase leads to the formation of water and oxygen according to the equation

2 H2O2 2 H2O + O2 (enzyme: catalase).

About 100 mL of oxygen are liberated by 1 mL of a 30% solution of H2O2, with bubble formation, local lesions and embolism as one of the acute toxic principles following uptake via either route of exposure.

Only skin reactions (eschar, exfoliation) but no mortality were seen in 10 rabbits receiving 2000 mg/kg bw of a 35% hydrogen peroxide solution under an occlusive dressing for 24 hours, Therefore, the LD0 value was 700 mg hydrogen peroxide/kg bw in this study. The LD50 value for hydrogen peroxide in rats or rabbits was in the range of > 5000 mg/kg bw in modern studies, as can be seen from data in published assessments (see table below). According to the assessments from ECB (2003) and SCCP (2007), the older dermal study results have to be interpreted with caution because the technical conditions are generally poorly described.

 

Overview and discussion of data contained in assessments

Dermal toxicity data are reported in several assessments. A compilation of the available data on acute dermal toxicity of hydrogen peroxide is presented in the table below.

 

Assessment

H2O2

[%]

Dose

[mg/kg bw]

Result

[mg/kg bw]

Primary reference

 

 

 

(based on

test material)

(LD0or LD50, based on active ingredient, H2O2)

 

ECB (2003)

DFG (2006)

NICNAS (2018)

90

700 – 5000

LD50, rabbit: 700

(mortality: 6/12 animals)

LD50, rat: 5000

630

 

 

 

4500

Hrubetz et al. (1951)

ECB (2003)

DFG (2006)

NICNAS (2018)

70

6500, 13000

LD0, rabbit: 6500

LD50, rabbit: 9200

4550

 

6440

FMC (1979b)

ECB (2003)

NICNAS (2018)

35

2000

Rabbit: no mortality

LD0: 2000

700

FMC (1983b)

ECB (2003)

28

Up to

> 8000

Mouse: “some mortality” at > 8000

2240

Liarskii et al. (1983)

10

1400

Mouse: no mortality

LD0: 1400

140

SCCP (2007)

 

 

LD50, rabbit: 630

Not assignable

FDA (1983)

 

 

LD50, rat: 700 - 7500

Not assignable

 

The data from Hrubetz et al. (1951) suggest the rabbit is more sensitive than the rat. However, the LD50value obtained in modern studies with rabbits (9200 mg/kg bw) was comparably high as the values reported for the rat. On the basis of these findings it is concluded that the dermal LD50 is > 5000 mg/kg bw for both the rat and the rabbit, with no need for classification for acute dermal toxicity according to the regulation (EC) 1272/2008.

 

Urea

The acute dermal NOAEL for the target substance was calculated from the subchronic NOAEL value for urea in rats, taking into account the molecular weights of the target substance (mw 94) and of the source substance (mw 60). As no mortality or any other adverse effect was seen at the NOAEL level, 338.4 mg urea/kg bw can be taken as the dermal LD0 value.

 

As no adverse effects were seen at all it is conceivable that the LD50 value is much higher and in the range of the oral or intravenous LD50value. It is reasonable to assume that the bioavailability, dose rate, target concentrations and, hence, acute toxicity is maximal via the intravenous route of exposure. On the basis of the available data for the rat (cf. table below) the acute dermal LD50value for the rat is estimated to be > 5000 mg/kg bw. Data for the mouse support this.

 

This data basis shows that urea is of negligible toxicity in the rat or mouse, regardless of the exposure pathway. The toxicity of hydrogen peroxide is more pronounced and, therefore, determines the toxicity of the target substance, hydrogen peroxide – urea (1:1).

 

Species

Route

Exposure

period

LD0

LD50

Reference

[mg urea/kg bw]

Rat

oral

acute

 

14,300 (m)
15,000 (f)

Sato et al., 1977

 

dermal

acute

 

No data

Estimate:

>5000

Rat

intravenous

acute

 

5,400 (m)

5,300 (f)

Rat

dermal

Subacute

Subchronic

(4 and 25 weeks)

216

 

 

 

 

 

 

Mouse

oral

acute

 

11,500 (m)

13,000 (f)

Mouse

intravenous

acute

 

4,600 (m)

5,200 (f)

 

 

Conclusions

On the basis of the considerations above, the following acute toxicity dose descriptors (LD50 values) are derived and presented for comparison. The dermal LD50 for the target substance depends mainly on hydrogen peroxide because for urea the estimate for this value is very conservative, taking data for the oral and intravenous route into consideration.

Route

LD50values [mg/kg bw]

Target substance

Source substance 1

Source substance 2

Hydrogen peroxide- urea (1:1)

Hydrogen peroxide

Urea

Oral

LD50, rat > 2,000

n.a.A

LD50, rat> 14,000

LD50, mouse> 11,500

Inhalation

WaivedB

n.a.

n.a.

Dermal

No data located


Estimate

LD50, rat > 13,800

 

LD50 rat, rabbit > 5,000C

Conservative Estimate

LD50, rat > 5,000

Intravenous

No data located

No data

LD50, rat> 5,000

LD50, mouse> 4,600

A           data available but not explored because reliable data for the target substance are available
B
           relevant exposure unlikely
C
           derived from published data
n.a.
       not applicable

 

The estimate for dermal LD50value for the target substance is as follows:

 

1.     Taking molecular weights into account, H2O2corresponds for 36% of the mass of hydrogen peroxide – urea (1:1).

2.     Therefore, 13,800 mg hydrogen peroxide - urea (1:1) would liberate 5000 mg of hydrogen peroxide when dissolved in water.

3.     The solubility of hydrogen peroxide – urea (1:1) in water is 500 g/L, or 500 mg/mL. Hence, the final volume would be 27.6 mL, and the solution would be a 18% hydrogen peroxide solution.

It is obvious from this calculation that the amount of hydrogen peroxide - urea (1:1), estimated as the dermal LD50 dose, cannot be applied on the skin, and no classification for acute oral or dermal toxicity is required.

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 acute oral or acute dermal toxicity under Regulation (EC) No 1272/2008, as amended for the tenth time in Regulation (EC) No 2017/776.