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EC number: 416-600-4 | CAS number: -
- 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
![](https://poisoncentres.echa.europa.eu/o/diss-blank-theme/images/factsheets/A-REACH/factsheet/print_toxicological-information.png)
Developmental toxicity / teratogenicity
Administrative data
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 2009-04-01 to 2009-05-27
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 009
- Report date:
- 2009
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Version / remarks:
- 22 January 2001
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- other: OECD Guidance no. 43 on Mammalian Reproductive Toxicity Testing and Assessment; 24th July 2008
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- -
- EC Number:
- 416-600-4
- EC Name:
- -
- Cas Number:
- 77703-56-1
- Molecular formula:
- C23H32N4O2
- IUPAC Name:
- 3-butyl-1-[4-({4-[(butylcarbamoyl)amino]phenyl}methyl)phenyl]urea
Constituent 1
- Specific details on test material used for the study:
- Analytical purity: > 99.4 %
Lot/batch No.: HAT-ISO 05-12-06
Test animals
- Species:
- rabbit
- Strain:
- New Zealand White
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Sándor Ferenc (formerly TETRABBIT Kft.) 2173 Kartal, Császár út 135, Hungary;
- Age at study initiation: young adult rabbits; approximately 4 month;
- Weight at study initiation: mean weight 3547 - 4227 g;
- Fasting period before study: Not stated;
- Housing: individually in AAALAC approved metal wire rabbit cages;
- Diet: PURINA Base - Lap gr. diet for rabbits; Supplier: AGRIBRANDS Europe Hungary PLC, H-5300 Karcag, Madarasi
- Water: Tap water for human consumption; via automatic water system ad libitum;
- Acclimation period: at least 5 days;
ENVIRONMENTAL CONDITIONS
- Temperature: 17.3 - 21.65 °C;
- Humidity: 32 - 98.79 % R.H.
- Air changes: not stated;
- Photoperiod: 12 hours light/12 hours dark; from 6:00 a.m. to 6:00 p.m.;
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on exposure:
- The test item was administered to pregnant female rabbits daily by oral gavage on a 7 days/week basis, at similar times in the morning, from GD 6 to GD 27 (one day prior to caesarean section and necropsy examination). Prior to the insemination procedure, the animals were acclimatised for at least 5 days (see also dosing scheme). Control animals were treated concurrently with the vehicle only.
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Analytical verification was made by HPLC Analysis and detection on a DAD-Detector at 250 nm wavelength;
- Details on mating procedure:
- The female rabbits were artificially inseminated. The day of insemination was regarded as Day 0 of gestation (GD 0). Synchronisation of the oestrus cycle of the does was performed 48 hours prior to insemination by administration of PMSG (gonadotropin) hormone (40 IU/female, sc). The insemination procedure was performed by the breeder at LAB Research Ltd. in batches (staggered; see detailed schedule in Appendix 7). Each female was inseminated with diluted sperm containing at least 2 million spermatozoa. Simultaneously with the artificial insemination, the does’ ovulation was provoked with 1 ml buserelin-based compound (0.2 mL/animal, i.m.) (see Details of Other Materials section). The sperm originated from New Zealand White male rabbits from the same source as the females. Females were randomly assigned to dose groups on the basis of their body weight on the day of insemination.
- Duration of treatment / exposure:
- The test item was administered to pregnant female rabbits daily by oral gavage on a 7 days/week basis, at similar times in the morning, from GD 6 to GD 27 (one day prior to caesarean section and necropsy examination). Prior to the insemination procedure, the animals were acclimatised for at least 5 days (see also dosing scheme). Control animals were treated concurrently with the vehicle only.
- Frequency of treatment:
- The test item was administered to pregnant female rabbits daily by oral gavage on a 7 days/week basis, at similar times in the morning, from GD 6 to GD 27 (one day prior to caesarean section and necropsy examination).
- Duration of test:
- The test item was administered to pregnant female rabbits daily by oral gavage on a 7 days/week basis, at similar times in the morning, from GD 6 to GD 27
Doses / concentrationsopen allclose all
- Dose / conc.:
- 100 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 350 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 1 000 mg/kg bw/day (actual dose received)
- No. of animals per sex per dose:
- 24 females per dose
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- The test item was administered to pregnant female rabbits daily by oral gavage on a 7 days/week basis, at similar times in the morning, from GD 6 to GD 27 (one day prior to caesarean section and necropsy examination). Prior to the insemination procedure, the animals were acclimatised for at least 5 days (see also dosing scheme). Control animals were treated concurrently with the vehicle only.
Examinations
- Maternal examinations:
- Animals were inspected for signs of morbidity and mortality twice daily (at the beginning and end of each day).
- Ovaries and uterine content:
- The ovaries and uterus were removed and the pregnancy status ascertained. The uterus including the cervix were weighed and examined for early and late embryonic or foetal deaths and for the number of live foetuses. Where no implantation sites were evident but corpora lutea were present, the uterus was
stretched and held in front of a light source to identify properly the implantation sites. Uteri that appeared non-gravid were further examined to confirm the non-pregnant status by Salewski staining. The corrected body weight was calculated (body weight on gestation day 28 – weight of the gravid uterus). - Fetal examinations:
- The live foetuses were identified, weighed individually, and the litter mean was calculated. The crown-rump length of foetuses was measured (accuracy 1 mm) and the litter mean was calculated. All foetuses were externally and viscerally examined, and sex determined. The heads from approximately half of each litter were removed and processed for evaluation of soft tissue alterations (including eyes, brain, nasal passages and tongue), using fixation in Sanomiya mixture for Wilson-sections. After fixation the heads were examined by Wilson's free-hand razor blade method. Then all foetuses were prepared for skeletal examination. The skeletons were examined after double staining with acetic alcian blue + KOH-alizarin red S staining (cartilage and bone staining). All abnormalities (external, soft tissue and skeletal malformations, and variations) found during the foetal examinations were recorded.
- Statistics:
- The statistical evaluation of data was performed with the program package SPSS PC+4.0. The homogeneity of variance between groups was checked by Bartlett`s homogeneity of variance test. Where no significant heterogeneity was detected, a one-way analysis of variance (ANOVA) was made. If the obtained result was significant, Duncan Multiple Range test was used to access the significance of inter-group differences. Getting significant result, inter-group comparisons were performed using Kruskal-Wallis and Mann-Whitney U-test.
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- no effects observed
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- no effects observed
- Ophthalmological findings:
- not examined
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- no effects observed
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- no effects observed
Maternal developmental toxicity
- Number of abortions:
- no effects observed
- Pre- and post-implantation loss:
- no effects observed
- Total litter losses by resorption:
- no effects observed
- Early or late resorptions:
- no effects observed
- Dead fetuses:
- no effects observed
- Changes in pregnancy duration:
- not examined
- Changes in number of pregnant:
- not examined
- Other effects:
- no effects observed
- Details on maternal toxic effects:
- Maternal toxic effects: no effects observed
Details on maternal toxic effects:
There were no test-item related clinical signs noted following administration of HAT-ISO to pregnant does from GD 6 to 27, by daily oral gavage, at dose levels up to and including 1000 mg/kg bw/day HAT-ISO, at a dose volume of 2 mL/kg bw.
Effect levels (maternal animals)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day
- Basis for effect level:
- other: no effects observed at highest dose tested
Maternal abnormalities
- Key result
- Abnormalities:
- no effects observed
Results (fetuses)
- Fetal body weight changes:
- no effects observed
- Reduction in number of live offspring:
- no effects observed
- Changes in sex ratio:
- no effects observed
- Changes in litter size and weights:
- no effects observed
- Changes in postnatal survival:
- not examined
- External malformations:
- no effects observed
- Skeletal malformations:
- no effects observed
- Visceral malformations:
- no effects observed
- Other effects:
- no effects observed
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects: no effects observed
Details on embryotoxic / teratogenic effects:
No test-item related effects were noted in the number of dead/viable foetuses, or their sex distribution. The sex ratios were similar in the control and treated groups. The litter mean values of foetal weight and crown-rump length were similar in the foetuses from the treated and control does. There were no abnormalities considered toxicologically significant and/or possibly ascribed to HAT-ISO administration at external, visceral or skeletal foetal examinations.
Effect levels (fetuses)
- Key result
- Dose descriptor:
- NOEL
- Effect level:
- 1 000 mg/kg bw/day
- Basis for effect level:
- other: no effects observed at highest dose tested
Fetal abnormalities
- Key result
- Abnormalities:
- no effects observed
Overall developmental toxicity
- Key result
- Developmental effects observed:
- no
Any other information on results incl. tables
No mortality or test-item related clinical signs occurred during the study.
HAT-ISO administered to artificially-inseminated New Zealand White female rabbits by oral gavage at dose levels of 100, 350, and 1000 mg/kg bw/day in corn oil from GD 6 to 27, led to dose and time-dependent increases in does’ food consumption, correlated with higher body weights and/or body weight gain at 1000 mg/kg bw/day. In the absence of any maternal or developmental toxicity, these changes were not considered an adverse effect of the test item in the conditions of this study.
There were no test item related effects on any of the maternal reproductive parameters examined during the study. The number of corpora lutea and implantation sites was similar in the treated groups compared to control animals. There were no differences between the treated and control animals regarding the pre-implantation loss, early and late embryonic death, postimplantation loss, or total intrauterine mortality; the mean values and/or percentile were comparable, or lower in the HAT-ISO treated animals, with no statistically significant variations compared to the animals administered vehicle control (corn oil) only. No macroscopic findings or treatment-related changes in the gravid uterine weight were recorded in the treated pregnant does surviving to termination when compared to the controls. The placenta was normal in all the does examined.
As necropsy followed by histopathology evaluation of the females with macroscopic findings, no macroscopic or microscopic findings recorded were ascribed to HAT-ISO administration. One low dose doe administered 100 mg/kg bw/day (1/24, female 2523) aborted and was necropsied on GD27; based on the isolated incidence and in the absence of similar findings in this group, or at higher dose levels, abortion in this animal was considered spontaneous and not related to treatment.
No test-item related effects were noted in the number of dead/viable foetuses, or their sex distribution. The sex ratios were similar in the control and treated groups. The litter mean values of foetal weight and crown-rump length were similar in the foetuses from the treated and control does. There were no abnormalities considered toxicologically significant and/or possibly ascribed to HAT-ISO administration at external, visceral or skeletal foetal examinations.
In conclusion, under the conditions of this study, the no-observed-effect-level values are:
NOAEL maternal toxicity: 1000 mg/kg bw/day
NOAEL developmental toxicity: 1000 mg/kg bw/day
NOEL teratogenicity: 1000 mg/kg bw/day
Applicant's summary and conclusion
- Conclusions:
- HAT-ISO was tested for Developmental Toxicity / Teratology in rabbits by oral gavage during the gestation period. No mortality or test-item related clinical signs occurred during the study. The no-observed effect levels are:
NOAEL maternal toxicity: 1000 mg/kg bw/day;
NOAEL developmental toxicity: 1000 mg/kg bw/day;
NOEL teratogenicity: 1000 mg/kg bw/day.
No classification and labelling is necessary according to Regulation 1271/2008/EEC (CLP). - Executive summary:
A Prenatal Developmental Toxicity/Teratology Study was performed in the rabbit according to OECD 414 and the draft OECD guidance document 43. The objective of this study was to assess the effects of HAT-ISO on pregnant females and developing conceptuses when administered to artificially inseminated, assumed pregnant New Zealand White rabbits. Test substance was administered daily by oral gavage at dose levels of 100, 350, and 1000 mg/kg bw/day.
No mortality or test-item related clinical signs occurred during the study.
Under the conditions of this study, the no-observed-effect-level values are:
NOAEL maternal toxicity: 1000 mg/kg bw/day;
NOAEL developmental toxicity: 1000 mg/kg bw/day;
NOEL teratogenicity: 1000 mg/kg bw/day.
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.
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