Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

No information on toxicity for reproduction and development was located for hydrogen peroxide- urea (1:1) but since the substance dissolves upon contact with water and breaks down to hydrogen peroxide and urea, information for these substances may be read across to the target substance. Existing information for hydrogen peroxide and urea indicates that there is no undue hazard for this endpoint for either source substance.

Effect on fertility: via oral route
Endpoint conclusion:
no study available
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Hydrogen peroxide- urea (1:1)

No information on toxicity for reproduction and development was located but since the substance dissolves upon contact with water and breaks down to hydrogen peroxide and urea, information for these substances may be read across to the target substance.

Hydrogen peroxide

Regarding hydrogen peroxide it is noted that existing data from old, non-guideline do not indicate undue effects on reproduction and development parameters in mice, rats and rabbits. These studies were summarised in the EU Risk Assessment Report (ECB, 2003) and it is stated in the conclusions that it was consented at the Technical Meeting level to derogate reproduction toxicity screening. “The decision was reached on the presumption that conventional study protocols (e.g. administration in drinking water) were unlikely to show specific embryonal or foetal effects firstly, because it is doubtful whether hydrogen peroxide (as opposed to its degradation products oxygen and water) would reach the foetus and secondly, because local effects in the mother, possibly causing nutritional disturbances and general toxicity, are expected.” (ECB, 2003). Therefore, new animal studies for hydrogen peroxide are not required and technically not feasible.

Urea

According to REACH Annex VIII point 8.7.1 the study does not need to be conducted as pre-natal developmental toxicity studies are available.

 

Conclusions

Existing information for hydrogen peroxide and urea indicates that there is no undue hazard for this endpoint for either source substance. Hydrogen peroxide is the most relevant breakdown product and a new animal study with hydrogen peroxide –urea (1:1) is not needed. The reason is that hydrogen peroxide would determine the toxicity whereas that of urea is negligible, as evidenced by the results of existing studies for the substance. It was, however, consented in the EU at Technical Meeting level that reproduction toxicity studies for hydrogen peroxide are derogated on two grounds. Firstly, it was doubted that hydrogen peroxide would reach the foetus, and secondly because local effects in the mother, possibly causing nutritional disturbances and general toxicity, were expected. This applies also to hydrogen peroxide –urea (1:1) because this substance liberates hydrogen peroxide upon contact with water.

Effects on developmental toxicity

Description of key information

No information on toxicity for reproduction and development was located for hydrogen peroxide- urea (1:1) but since the substance dissolves upon contact with water and breaks down to hydrogen peroxide and urea, information for these substances may be read across to the target substance. Existing information for hydrogen peroxide and urea indicates that there is no undue hazard for this endpoint for either source substance.

Link to relevant study records

Referenceopen allclose all

Endpoint:
developmental toxicity
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
Clinical signs:
not specified
Mortality:
no mortality observed
Body weight and weight changes:
not specified
Gross pathological findings:
no effects observed
Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
no statistically significant difference between vehicle control and urea-treated rats regarding percent fetal resorptions (2.4 vs. 0%)
Total litter losses by resorption:
no effects observed
Early or late resorptions:
not specified
Dead fetuses:
no effects observed
Description (incidence and severity):
no statistically significant difference between vehicle control and urea-treated rats regarding number of live fetuses (13.3 ± 0.8 vs. 13.8 ± 2.2)
Changes in pregnancy duration:
not examined
Description (incidence and severity):
dams sacrificed before parturition
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not examined
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.DescriptionIncidenceAndSeverityEffectsOnPregnancyDuration): dams sacrificed before parturition
Changes in number of pregnant:
not examined
Description (incidence and severity):
only pregnant rats (or mice) were used
Key result
Dose descriptor:
NOAEL
Effect level:
2 000 mg/kg bw (total dose)
Based on:
act. ingr.
Basis for effect level:
other: no maternal toxicity noted
Remarks on result:
other: result ist for urea; one single dose was administered
Key result
Abnormalities:
no effects observed
Fetal body weight changes:
no effects observed
Description (incidence and severity):
no statistically significant difference between fetuses from vehicle control and urea-treated rats: fetal body weight (3,671 ± 197 mg vs. 3,626 ± 104 mg)
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.DescriptionIncidenceAndSeverityFetalPupBodyWeightChanges): no statistically significant difference between fetuses from vehicle control and urea-treated rats: fetal body weight (3,671 ± 197 mg vs. 3,626 ± 104 mg)
Reduction in number of live offspring:
no effects observed
Description (incidence and severity):
no statistically significant difference between fetuses from vehicle control and urea-treated rats: number of live fetuses (13.3 ± 0.8 vs. 13.8 ± 2.2),
Changes in sex ratio:
not specified
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
not examined
External malformations:
no effects observed
Description (incidence and severity):
no statistically significant difference between fetuses from vehicle control and urea-treated rats: percent fetuses malformed (0 vs. 1.8%)
Skeletal malformations:
not specified
Visceral malformations:
not specified
Key result
Dose descriptor:
NOAEL
Effect level:
2 000 mg/kg bw (total dose)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: no adverse effect noted
Remarks on result:
other: result is for urea; one single dose administered
Key result
Abnormalities:
no effects observed
Key result
Developmental effects observed:
no

Results are for urea, adminstered to rats and mice (data not shown); can be read across to the target substance

Endpoint:
developmental toxicity
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
Clinical signs:
not specified
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Number of abortions:
not specified
Pre- and post-implantation loss:
not specified
Total litter losses by resorption:
not specified
Early or late resorptions:
not specified
Dead fetuses:
not specified
Changes in pregnancy duration:
not specified
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not specified
Changes in number of pregnant:
not specified
Details on maternal toxic effects:
no maternal toxicity noted
Key result
Dose descriptor:
NOAEL
Effect level:
50 000 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Basis for effect level:
other: no adverse effect noted
Remarks on result:
other: no maternal toxicity
Abnormalities:
not specified
Fetal body weight changes:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): not examined
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
not specified
Other effects:
no effects observed
Description (incidence and severity):
There was no effect on pup kidney weight. Dry weights, reported as a percentage of the fresh weights, were 14.4 ± 2.54% (≈1.12 g) for the test group compared with 14.7 ± 1.96% (≈1.18 g) for the control group.
Key result
Dose descriptor:
NOAEL
Effect level:
50 000 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: no adverse effects noted
Remarks on result:
other: no effect on pup weight or kidney development
Key result
Abnormalities:
not specified
Key result
Developmental effects observed:
no

Results are for urea (source substance), may be read across to the target substance

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

Hydrogen peroxide- urea (1:1)

No information on toxicity for reproduction and development was located but since the substance dissolves upon contact with water and breaks down to hydrogen peroxide and urea, information for these substances may be read across to the target substance.

Hydrogen peroxide

Regarding hydrogen peroxide it is noted that existing data from old, non-guideline do not indicate undue effects on reproduction and development parameters in mice, rats and rabbits. These studies were summarised in the EU Risk Assessment Report (ECB, 2003) and it is stated in the conclusions that it was consented at the Technical Meeting level to derogate reproduction toxicity screening. “The decision was reached on the presumption that conventional study protocols (e.g. administration in drinking water) were unlikely to show specific embryonal or foetal effects firstly, because it is doubtful whether hydrogen peroxide (as opposed to its degradation products oxygen and water) would reach the foetus and secondly, because local effects in the mother, possibly causing nutritional disturbances and general toxicity, are expected.” (ECB, 2003).Therefore, new animal studies for hydrogen peroxide are not required and technically not feasible.

Urea

Two studies on developmental toxicity using rats and mice indicate low toxicity for this endpoint. These studies are not compliant with current test guidelines, but can be used in a weight of evidence approach.

In the first study, Seipelt et al. (1969) examined whether high urea doses during pregnancy had an effect on kidney weight. Pregnant albino Wistar rats were divided into test and vehicle control groups (six/group). No additional information on mating procedure was provided. The test group was dosed by gavage with urea for 14 days starting 6 days after the last oestrus. Urea was dissolved in water and administered in two doses totalling 50 g/kg-day. No maternal toxicity was reported. Within 48 hours of birth, pups were sacrificed by decapitation and kidneys removed and weighed; the right kidney was then dried at 105 ºC and weighed. No maternal toxicity was reported. Dams of the test group delivered 39 pups, compared to 34 pups in the control group. Hence, litter size was comparable across the groups. The pup fresh and dry kidney weight was not affected (Seipelt et al., 1969). It is concluded that even an excessive dose of urea (50,000 mg/kg bw/day), administered to pregnant rats for 14 days by oral gavage, did not cause maternal or foetal toxicity, or affect development of the foetal kidneys. Hence, the administered dose represents the LOAEL in this study (ECB, 2003).

In a second study, Teramoto et al. (1981) examined the developmental toxicity of urea compounds in pregnant Wistar rats (n=4) and pregnant ICR mice (n=10) that received a single oral dose of urea at 2000 mg/kg bw on gestational day 12 (rats) or GD 10 (mice). Rats were sacrificed on GD 20 (mice: GD 18). The number of implants and live and dead foetuses were counted. Living foetuses from each litter were divided into two groups after being weighed individually and examined for gross abnormalities. Foetuses from the right uterine horn were processed for skeletal examination and those from the left horn were processed for visceral examination. For statistical comparisons, the litter was considered the experimental unit. No maternal toxicity was noted in rats or mice. There were no statistical differences between the vehicle control and the urea-treated rats based on the mean ± SD for number of implants (13.7 + 1.0 vs.13.8 ± 2.2), number of live foetuses (13.3 ± 0.8 vs. 13.8 ± 2.2), percent foetal resorptions (2.4 vs. 0%), foetal body weight (3,671 ± 197 mg vs. 3,626 ± 104 mg), or percent foetuses malformed (0 vs. 1.8%). These endpoints also were unaffected in mice treated with urea (data not shown). Thus, no maternal or developmental toxicity was noted in pregnant rats or mice receiving a single oral dose of 2000 mg/kg bw (EPA, 2011).

The two developmental studies above are not equivalent with a GLP guideline study, however, new animal studies are, not deemed to be necessary as justified below. Urea is of low toxicological activity. No evidence of toxicity was seen in any of the tests available up to 2000 mg/kg bw; no developmental toxicity was seen in pregnant rats and mice up to 2000 mg/kg bw (single dose) or pregnant rats at 50,000 mg/kg bw/day (repeat dose, 14 days). Further, no effects on the reproduction organs were noted in cancer bioassays using male and female rats and mice which were treated for 12 months (oral feeding studies; approximate dose levels for the various groups were 0, 379, 757, or 3,786 mg/kg-day for male F344 rats; 0, 419, 838, or 4,191 mg/kg- day for F344 females; 0, 644, 1,288, or 6,442 mg/kg-day for male C57BL/6 mice; and 0, 655, 1,311, or 6,553 mg/kg-day for C57BL/6 females (Fleischmann et al., 1980; summarised In the EPA assessment, EPA, 2011; assessment attached in section 13). Urea is a normal intermediary metabolite that humans produce and excrete in large quantities (25-50 g/day, i.e. approx. 500 mg/kg bw/day) under normal conditions without any adverse effect on fertility or reproduction. Toxicokinetic information indicates that additional exogenous urea is rapidly excreted via urine, i.e. urea plasma levels are constantly controlled. Small amounts of additional exogenous urea is therefore not considered to cause adverse effects on reproduction. On this basis, animal studies are not considered to be justified.

 

Conclusions

Existing information for hydrogen peroxide and urea indicates that there is no undue hazard for this endpoint for either source substance. Hydrogen peroxide is the most relevant breakdown product and a new animal study with hydrogen peroxide –urea (1:1) is not needed. The reason is that hydrogen peroxide would determine the toxicity whereas that of urea is negligible, as evidenced by the results of existing studies for the substance. It was, however, consented in the EU at Technical Meeting level that reproduction toxicity studies for hydrogen peroxide are derogated on two grounds. Firstly, it was doubted that hydrogen peroxide would reach the foetus, and secondly because local effects in the mother, possibly causing nutritional disturbances and general toxicity, were expected. This applies also to hydrogen peroxide –urea (1:1) because this substance liberates hydrogen peroxide upon contact with water.

 

Mode of Action Analysis / Human Relevance Framework

Hydrogen peroxide - urea (1:1) dissolves in water and breaks down to hydrogen peroxide and urea. The toxicity of urea is negligible. Hydrogen peroxide is corrosive at high concentrations, irritating at low concentrations. It determines the toxicity of the target substance. The concentration of exogenous hydrogen peroxide is strictly controlled by glutathione peroxidase, catalase, or antioxidants. It is therefore doubted that hydrogen peroxide does reach the foetus. Based on this, and because local maternal effects are expected, it was concluded at Technical Meeting level hat hydrogen peroxide is of low relevance and animal studies are not feasible. This applies also to hydrogen peroxide –urea (1:1) because this substance liberates hydrogen peroxide upon contact with water.

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 toxicity to reproduction under Regulation (EC) No 1272/2008, as amended for the tenth time in Regulation (EC) No 2017/776.