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EC number: 207-313-3 | CAS number: 461-72-3
- 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
Developmental toxicity / teratogenicity
Administrative data
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Study period:
- 1981
- Reliability:
- 3 (not reliable)
- Rationale for reliability incl. deficiencies:
- significant methodological deficiencies
- Remarks:
- The doses exceeded the upper limit stated in the OECD TG 414. Materials and method section is incomplete and in parts not comprehensive. Maternal effects were not specified. Main focus of this publication is the comparison of the teratogenic potential within a group of hydantoin derivatives, not a valid study of the substance hydantoin.
Data source
Reference
- Reference Type:
- publication
- Title:
- Unnamed
- Year:
- 1 982
Materials and methods
Test guideline
- Qualifier:
- no guideline followed
- Version / remarks:
- No guideline is stated in the publication.
- Principles of method if other than guideline:
- CD-1 dams were treated ip with the drugs on Days 8, 9, and 10 or Days 11, 12, and 13 of gestation (plug-positive day = Day 1). The drugs were administered as a suspension in methylcellulose (0.5%, w/v, 1 ml / 100 g body wt), with control animals receiving vehicle alone. Dams were killed by cervical dislocation on Day 18 and uterine contents were examined (Brown et al., 1979). Each live fetus was weighed and examined for gross and visceral abnormalities (Staples, 1974). Fetal heads were fixed and examined by the method of Wilson (1965) and skeletons were stained and examined by the method of Staples and Schnell (1964).
The doses utilized in the teratogenicity study were selected following evaluation of the adult lethality. The highest dose was within the 95% confidence limits of the calculated LD01, and a geometric progression of lower doses was utilized until no significant teratogenic or embryolethal effects were observed. - GLP compliance:
- not specified
- Limit test:
- no
Test material
- Reference substance name:
- Hydantoin
- EC Number:
- 207-313-3
- EC Name:
- Hydantoin
- Cas Number:
- 461-72-3
- Molecular formula:
- C3H4N2O2
- IUPAC Name:
- hydantoin
- Test material form:
- not specified
Constituent 1
- Specific details on test material used for the study:
- Material was greater than 98% pure, as determined by GLC, TLC, and NMR techniques.
Test animals
- Species:
- mouse
- Strain:
- CD-1
Administration / exposure
- Route of administration:
- intraperitoneal
- Vehicle:
- other: methylcellulose (suspension, 0.5%, w/v, 1 mL/100 g body wt)
- Analytical verification of doses or concentrations:
- not specified
- Details on analytical verification of doses or concentrations:
- The doses utilized in the teratogenicity study were selected following evaluation of the adult lethality (from the acute toxicity study). The highest dose was within the 95% confidence limits of the calculated LD01, and a geometric progression of lower doses was utilized until no significant teratogenic or embryolethal effects were observed.
- Details on mating procedure:
- Not specified
- Duration of treatment / exposure:
- 6 days: Days 8, 9, and 10 or Days 11, 12, and 13 of gestation (plug-positive day = Day 1)
- Frequency of treatment:
- Daily on 3 consecutive days
- Duration of test:
- 18 days
Doses / concentrationsopen allclose all
- Dose / conc.:
- 20 other: mmol/kg
- Remarks:
- equivalent to 2001.54 mg/kg bw/day
- Dose / conc.:
- 30 other: mmol/kg
- Remarks:
- equivalent to 3002.31 mg/kg bw/day
- Dose / conc.:
- 40 other: mmol/kg
- Remarks:
- equivalent to 4003.08 mg/kg bw/day
- No. of animals per sex per dose:
- Treatment on Days 8, 9 and 10 of pregnancy:
Treated: Pregnant:
Control: 208 Control: 192
20 mmol/kg: 21 20 mmol/kg: 18
30 mmol/kg: 28 30 mmol/kg: 27
40 mmol/kg: 10 40 mmol/kg: 10
Treatment on Days 11, 12 and 13 of pregnancy:
Treated: Pregnant:
Control: 135 Control: 134
30 mmol/kg: 15 30 mmol/kg: 14
40 mmol/kg: 19 40 mmol/kg: 17 - Control animals:
- yes, concurrent vehicle
Examinations
- Maternal examinations:
- Not specified
- Ovaries and uterine content:
- Number of conceptuses: number/litter, resorptions and dead, live, malformed;
percentage embryo mortality/litter, percentage malformations/litter - Fetal examinations:
- Fetal weight/litter, number of affected fetuses: external abnormalities (cleft palate, exen-cephaly, open eyes, others), visceral abnormalities (cardiovascular, others), skeletal abnormalities (ribs or vertebrae, others)
- Statistics:
- Fetal weights, embryo mortality, and malformation percentages are reported as mean values/litter +/- SE, with statistical comparisons to control parameters by the Mann-Whitney U test (Siegel, 1956). Dose-response relationships for adult lethality, teratogenicity, embryolethality, and combined teratogenicity and embryonic death were examined by probit analysis, using an SAS program (SAS, 1979).
x2 tests were utilized to determine the goodness of fit of the observed data to the probit model. Probability values (p) are computed from standard distribution of x2 with k - 2 degrees of freedom (k = number of doses used). When little heterogeneity was observed (p > 0.10) confidence limits were computed using a t value of 1.98 (probability 0.05, co df). When probability from the x2 test was less than 0.10, the heterogeneity factor, h, was introduced (h = x2/(k - 2), Finney, 1971a).
Variances and covariances were multiplied by this factor, and we computed confidence limits using the t value at probability 0.05, k - 2 df. This procedure has the effect of widening considerably the computed confidence limits when heterogeneity is observed (Finney, 1971a).
The relative teratogenic index was calculated at LD01/tD05 as discussed elsewhere (Fabro et al., 1982).
Tests for parallelism between dose-response curves were performed by a computer program based upon the method of Finney (1971a).
The linear free energy related (LFER), or physiochemical, approach to quantitative structure-activity relationships (QSAR) was taken in the analysis of structure-toxicity variations. - Indices:
- Not specified
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- not specified
- Dermal irritation (if dermal study):
- not specified
- Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- In the group treated with 40 mmol hydantoin/kg on days 11, 12 and 13, two dams died before day 18. No other mortalities occurred after hydantoin exposure.
- Body weight and weight changes:
- not specified
- Food consumption and compound intake (if feeding study):
- not specified
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not specified
- Haematological findings:
- not specified
- Clinical biochemistry findings:
- not specified
- Urinalysis findings:
- not specified
- Behaviour (functional findings):
- not specified
- Immunological findings:
- not specified
- Organ weight findings including organ / body weight ratios:
- not specified
- Gross pathological findings:
- not specified
- Neuropathological findings:
- not specified
- Histopathological findings: non-neoplastic:
- not specified
- Histopathological findings: neoplastic:
- not specified
- Other effects:
- not specified
Maternal developmental toxicity
- Number of abortions:
- not specified
- Pre- and post-implantation loss:
- not specified
- Total litter losses by resorption:
- effects observed, treatment-related
- Description (incidence and severity):
- Treatment on Days 8, 9 and 10 of pregnancy:
Resorptions and dead (number of litters):
Control: 243 (125)
20 mmol/kg: 16 (11)
30 mmol/kg: 30 (18)
40 mmol/kg: 8 (7)
Treatment on Days 11, 12 and 13 of pregnancy:
Resorptions and dead (number of litters):
Control: 192 (92)
30 mmol/kg: 21 (11)
40 mmol/kg: 52 (13) - Early or late resorptions:
- not specified
- Dead fetuses:
- no effects observed
- Description (incidence and severity):
- Treatment on Days 8, 9 and 10 of pregnancy:
Live (number of litters):
Control: 2143 (192)
20 mmol/kg: 215 (18)
30 mmol/kg: 318 (27)
40 mmol/kg: 109 (9)
Treatment on Days 11, 12 and 13 of pregnancy:
Live (number of litters):
Control: 1473 (134)
30 mmol/kg: 163 (14)
40 mmol/kg: 142 (16) - 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:
- no effects observed
- Description (incidence and severity):
- Treatment on Days 8, 9 and 10 of pregnancy:
Treated: Pregnant:
Control: 208 Control: 192
20 mmol/kg: 21 20 mmol/kg: 18
30 mmol/kg: 28 30 mmol/kg: 27
40 mmol/kg: 10 40 mmol/kg: 10
Treatment on Days 11, 12 and 13 of pregnancy:
Treated: Pregnant:
Control: 135 Control: 134
30 mmol/kg: 15 30 mmol/kg: 14
40 mmol/kg: 19 40 mmol/kg: 17 - Other effects:
- not specified
Results (fetuses)
- Fetal body weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Treatment on Days 8, 9 and 10 of pregnancy:
Fetal weight / litter:
Control: 0.97 +/- 0.01
20 mmol/kg: 0.89 +/- 0.01**
30 mmol/kg: 0.92 +/- 0.02*
40 mmol/kg: 0.83 +/- 0.02**
Treatment on Days 11, 12 and 13 of pregnancy:
Fetal weight / litter:
Control: 0.98 +/- 0.01
30 mmol/kg: 0.95 +/- 0.03*
40 mmol/kg: 0.87 +/- 0.02**
*,** Significantly different from control values, p < 0.05 and p > 0.01, respectively; Mann-Whitney U test
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): not specified - Reduction in number of live offspring:
- effects observed, treatment-related
- Description (incidence and severity):
- Treatment on Days 8, 9 and 10 of pregnancy:
Percentage embryo mortality/litter:
Control: 10.4 +/- 0.7
20 mmol/kg: 6.9 +/- 1.7
30 mmol/kg: 8.3 +/- 1.5
40 mmol/kg: 15.4 +/- 9.5
Treatment on Days 11, 12 and 13 of pregnancy:
Percentage embryo mortality/litter:
Control: 11.5 +/- 1.1
30 mmol/kg: 13.3 +/- 3.6
40 mmol/kg: 25.6 +/- 6.5**
** Significantly different from control values, p > 0.01; Mann-Whitney U test - Changes in sex ratio:
- not specified
- Changes in litter size and weights:
- no effects observed
- Description (incidence and severity):
- Treatment on Days 8, 9 and 10 of pregnancy:
Number of conceptuses per litter:
Control: 12.4 +/- 0.2
20 mmol/kg: 12.8 +/- 0.5
30 mmol/kg: 12.9 +/- 0.5
40 mmol/kg: 11.7 +/- 1.3
Treatment on Days 11, 12 and 13 of pregnancy:
Number of conceptuses per litter:
Control: 12.4 +/- 0.2
30 mmol/kg: 13.1 +/- 0.9
40 mmol/kg: 11.4 +/- 0.9 - Changes in postnatal survival:
- not specified
- External malformations:
- effects observed, treatment-related
- Description (incidence and severity):
- Treatment on Days 8, 9 and 10 of pregnancy (numbers (number of litters)):
Malfomed: Percentage malformations/litter: Cleft palate: Exencephaly: Open eyes: Others:
Control: 24 (23) Control: 1.2 +/- 0.2 7 (7) 5 (5) 0 2 (2)
20 mmol/kg: 1 (1) 20 mmol/kg: 0.4 +/- 0.4' 0 1 (1) 0 0
30 mmol/kg: 22 (8) 30 mmol/kg: 6.4 +/- 1.7** 1 (1) 4 (3) 2 (2) 1 (1)
40 mmol/kg: 8 (4) 40 mmol/kg: 8.1 +/- 3.8** 1 (1) 4 (2) 4 (2) 0
Treatment on Days 11, 12 and 13 of pregnancy:
Malfomed: Percentage malformations/litter: Cleft palate: Exencephaly: Open eyes: Others:
Control: 12 (10) Control: 1.1 +/- 0.3 8 (8) 2 (2) 2 (2) 2 (2)
30 mmol/kg: 0 (0) 30 mmol/kg: 0 0 0 0 0
40 mmol/kg: 9 (6) 40 mmol/kg: 5.2 +/- 2.0** 5 (5) 0 0 3 (3)
' Significant dose response, p < 0.05; Jonckheere´s test
** Significantly different from control values, p > 0.01; Mann-Whitney U test - Skeletal malformations:
- no effects observed
- Description (incidence and severity):
- Treatment on Days 8, 9 and 10 of pregnancy (numbers (number of litters)):
Cardiovascular: Others:
Control: 1 (1) 0
20 mmol/kg 0 0
30 mmol/kg 0 0
40 mmol/kg 0 0
Treatment on Days 11, 12 and 13 of pregnancy:
Cardiovascular: Others:
Control: 1 (1) 0
20 mmol/kg 0 0
30 mmol/kg 3 (2) 0
40 mmol/kg 0 0 - Visceral malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Treatment on Days 8, 9 and 10 of pregnancy (numbers (number of litters)):
Ribs or vertebrae: Others:
Control: 9 (8) 0
20 mmol/kg 0 0
30 mmol/kg 12 (8) 2 (2)
40 mmol/kg 3 (2) 1 (1)
Treatment on Days 11, 12 and 13 of pregnancy:
Ribs or vertebrae: Others:
Control: 0 0
20 mmol/kg 0 0
30 mmol/kg 0 0
40 mmol/kg 0 0 - Other effects:
- not specified
- Details on embryotoxic / teratogenic effects:
- The incidence of malformed fetuses from vehicle-treated dams was 1.2% per litter for Days 8, 9, and 10 and 1.1% per litter for Days 11, 12, and 13.
Hydantoin induced significantly elevated incidences of malformed fetuses per litter with both treatment schedules. The incidence of malformations was higher following treatment on Days 8,9, and 10 than on Days 11, 12 and 13. There was a significant dose response (p < 0.05, Johnckheere’s test) on Days 8, 9, and 10. The incidence of malformations (Days 8, 9, and 10, LD01 dose) was as follows: 8.1% per litter. Following treatment on Days 8, 9, and 10, the most common defects were of the skeletal system. Fused or branched ribs were the most frequent skeletal abnormality for each compound, with fused or branched vertebral arches the next most common. A variety of other defects of the ribs, arches, and centra were also observed. Hydantoin induced cleft palate and exencephaly, which was accompanied by open eyes in most cases. The abnormalities induced by hydantoin treatment on Days 11, 12, and 13 was different from those profiles observed following earlier treatment. Cleft palate was the most common defect, plus low levels of exencephaly (with open eyes) and cardiovascular malformations. Hydantoin also caused intrauterine growth retardation, as shown by the dose-related reduction in mean fetal weight/litter. The effect on fetal weight was more marked with treatment on Days 8, 9, and 10, compared to Days 11, 12, and 13.
Any other information on results incl. tables
The relative teratogenic index gives an estimate of the relationship between general toxicity and specific developmental toxicity by calculating the ratio between adult toxicity (LD01) and teratogenicity (tD05). Thus, a compound with an RTI of 1 induces a significant incidence (5%) of malformation only at the minimally lethal dose while an RTI of 2 indicates effects at half the minimal lethal dose, etc. In this study, the compounds can be ranked as follows, in increasing order of relative teratogenic hazard: mephenytoin,
~0.9; hydantoin, 1.27; ethotoin, 1.39; phenytoin, 1.66; and phenacemide, 3.32.
Applicant's summary and conclusion
- Conclusions:
- The teratogenic potential of Hydantoin was investigated in pregnant CD-1 mice after animals were treated intraperitoneally on Days 8, 9, and 10 or Days 11, 12, and 13 of gestation. Hydantoin showed a teratogenic potential, however, the doses were well above the recommendation of the OECD TG 414 and maternal effects were not specified. Based on the available information, a classification of Hydantoin as teratogen is not justified.
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