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EC number: 211-402-2 | CAS number: 643-79-8
- 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
Endpoint summary
Administrative data
Key value for chemical safety assessment
Effects on fertility
Description of key information
In accordance with Annex VIII of REACH Regulation 1907/2006, column 2, information requirement 8.7.1, it is not necessary to conduct a reproductive toxicity study as data is available from a pre-natal developmental toxicity study (see IUCLID section 7.8.2).
Link to relevant study records
- Endpoint:
- screening for reproductive / developmental toxicity
- Data waiving:
- study scientifically not necessary / other information available
- Justification for data waiving:
- the study does not need to be conducted because a pre-natal developmental toxicity study is available
Reference
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
Effects on developmental toxicity
Link to relevant study records
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1988-07-07 to 1989-07-06
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Qualifier:
- according to guideline
- Guideline:
- EPA OPP 83-3 (Prenatal Developmental Toxicity Study)
- Version / remarks:
- Guideline Subdivision F, Series 83-3 (a)
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
- Specific details on test material used for the study:
- - Name of the test material in the report: Cidex
- Batch No.: P07298
- Appearance: yellow granular material
- Purity: 99.0%
- Storage conditions: stored under refrigeration
TREATMENT OF TEST MATERIAL PRIOR TO TESTING
For each dose level, the test item was ground into a powder with a mortar and pestle. The desired amount was weighed on a balance and transferred to a pre-calibrated beaker. A small amount of vehicle was added and mixed into a paste. Additional vehicle was added to achieve the desired volume and mixed with a Tekmar Tissumizer for 15-20 minutes until in solution. The solution was transferred to amber jars under refrigeration. Solutions of each concentration were prepared weekly, stored under refrigeration and removed from the refrigerator approx. 1 hour prior to dosing. Reserve samples of each batch were taken and retained at room temperature. - Species:
- rat
- Strain:
- other: Crl:CD BR
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories, Inc., Raleigh, North Carolina
- Age at study initiation: ca. 8-10 weeks
- Weight at study initiation: 230 - 310 g
- Housing: The rats were housed individually in hanging stainless steel cages prior to initiation of breeding. During breeding, one male and one female were housed per cage. All mated females were housed individually in hanging stainless steel cages.
- Diet (e.g. ad libitum): ad libitum, purina certified rodent chow #5002
- Water (e.g. ad libitum): ad libitum, tap water
- Acclimation period: 2 weeks
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 - 27 °C (72 - 82 °F)
- Humidity (%): 27 - 57%
- Photoperiod (hrs dark / hrs light): 12 / 12 - Route of administration:
- oral: gavage
- Vehicle:
- water
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
For each dose level, the test item was ground into a powder with a mortar and pestle. The desired amount was weighed on a (mg) balance and transferred to a pre-calibrated beaker. A small amount of vehicle was added and mixed into a paste. Additional vehicle was added to achieve the desired volume and mixed with a Tekmar Tissumizer for 15-20 minutes until in solution. The solution was transferred to amber jars for dosing. Solutions of each concentration were prepared weekly, stored under refrigeration, and removed from the refrigerator approximately 1 hour prior to dosing. Reserve samples of each batch were taken and retained at room temperature. The appropriate test solution or the vehicle alone were administered via oral intubation at a constant volume of 10 mL/kg bw/day beginning on Day 6 of gestation and continuing through gestation Day 15. The dosages were based on the individual animal body weights on Day 6 of gestation.
VEHICLE
- Amount of vehicle (if gavage): 10 mL/kg/day
- Lot/batch no. (if required): 1028901 - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Reserve samples of the test and control articles (5 g and 10 mL respectively) were taken at initiation and retained under refrigeration (test article) and at room temperature (control article). Stability of ortho-phthalaldehyde has been demonstrated for 28 days under refrigeration by the Sponsor. Routine analyses for concentration were conducted on each dose level at weeks 1, 2, and 3. Analyses were performed by gas chromatography.
- Details on mating procedure:
- During the mating period, one female was paired with one male until mating was confirmed. Daily examinations were performed to detect the presence of sperm (vaginal lavage) or a retained copulatory plug. The day pf observation of sperm or of a plug was designated as Day 0 of gestation. Following breeding, the confirmed-mated females were individually identified by a tail tattoo and cagetag with a unique animal number.
- Duration of treatment / exposure:
- between gestation day 6 and 15
- Frequency of treatment:
- daily between gestation day 6 and 15
- Duration of test:
- 20 days
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Remarks:
- Control (Group 1)
- Dose / conc.:
- 10 mg/kg bw/day (nominal)
- Remarks:
- Low dose (Group 2)
- Dose / conc.:
- 20 mg/kg bw/day (nominal)
- Remarks:
- Mid dose (Group 3)
- Dose / conc.:
- 40 mg/kg bw/day (nominal)
- Remarks:
- High dose (Group 4)
- No. of animals per sex per dose:
- 25 mated female rats
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: A rationale for the selection of doses was not reported
- Rationale for animal assignment (if not random): Mated females were assigned in an unbiased manner to the control and treatment groups ensuring that the mean body weights were comparable to each other. - Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: All animals were observed twice daily for mortality and moribundity. Cageside observations for obvious indications of a toxic effect were conducted daily. Throughout the treatment period, cageside observations were performed approximately 1 hour following dosing.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Detailed clinical observations were performed at each weighing interval prior to dosing
BODY WEIGHT: Yes
- Time schedule for examinations: Individual body weights were recorded on gestation days 0, 6, 8, 12, 16 and 20.
FOOD CONSUMPTION: Yes
- Time schedule for examinations: Food consumption was measured on gestation days 0, 6, 8, 12, 16 and 20.
WATER CONSUMPTION: Yes
- Time schedule for examinations: Water consumption was measured on gestation days 0, 3, 6, 8, 10, 12, 14, 16, 18 and 20.
POST-MORTEM EXAMINATIONS: Yes
- On day 20 all females were weighed, sacrificed by carbon dioxide inhalation and exsanguination and examined grossly for abnormalities of the thoracic, abdominal, and pelvic viscera. The uterus from each gravid female was excised, weighed, and examined for the number and placement of implantation sites, live and dead fetuses, early and late resorptions, and any abnormalities of the uterus or embryonic sac. The ovaries were examined for the number of corpora lutea. - Ovaries and uterine content:
- The uterus from each gravid female was excised, weighed, and examined for the number and placement of implantation sites, live and dead fetuses, early and late resorptions, and any abnormalities of the uterus or embryonic sac. The ovaries were examined for the number of corpora lutea.
- Fetal examinations:
- Each fetus was sexed, weighed, examined for external abnormalities, identified with a tag, and sacrificed via intraperitoneal injection of sodium pentobarbital. Approximately one-half of all the fetuses from each litter were randomly selected and processed for visceral examination by the Wilson technique for assessing soft tissue development. The remaining fetuses were eviscerated and processed for skeletal examination using the Alizarin Red S staining method. Findings were judged to be variations or malformations. Malformations are developmental deviations which are gross structural changes, are incompatible with life, or may affect the quality of life. Variations are structural deviations which are thought to have no effect on body conformity or the well-being of the animal. They include delays in development and common variations in rib counts. All fetuses were retained in either Bouin´s fixative or glycerin with thymol added as preservative.
- Statistics:
- The mean maternal body weight (gestation Days 0, 6, 8, 12, 16, and 20), body weight change and food consumption (gestation Days 0-6, 6-8, 8-12, 12-16, 16-20, and 0-20), water consumption (gestation Days 0-3, 3-6, 6-8, 8-10, 10-12, 12-14, 14-16, 16-18, 18-20, and 0-20), gravid uterine weight, carcass weight, and net body weight change values (from Day 0) for the pregnant animals of the control group were compared statistically to the compound-treated groups by one-way ANOVA. When variances of untransformed data were heterogeneous, analyses were performed on rank-transformed data. Criterion for significance of group comparisons was at the 5.0% two-tailed probability level. The percent of male and female, live fetuses per litter, total, early, and late resorptions per litter, preimplantation loss, and postimplantation loss were also analyzed. Mean live fetal weights (male, female, and combined) were analyzed by one-way ANCOVA analysis of covariance techniques. The total number of fetuses in each litter was used as the covariate.
The incidence (fetal and litter) of unossified vertebral centrum, less than four caudal vertebrae ossified, 5th, 6th, and other sternebrae unossified, 5th, 6th, and other sternebrae incomplete ossification, and wavy/bent rib(s) were statistically analyzed using the Cochran-Armitage test for linear trend followed by the Fisher-Irwin exact test. In cases of significant trend criterion for significance of group comparisons was at the 5.0% one-tailed probability level. Statistical significance was designated throughout the text of this report by the term, significant. - Indices:
- The percent of male and female, live fetuses per litter, total, early and late resorptions per litter, pre-implantation loss and post-implantation loss.
- Historical control data:
- No historical control data was reported.
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Treatment-related clinical observations noted during and after the treatment period in a dose-related pattern included wheezing (0, 10, 15, and 18 animals in groups 1-4, respectively), labored respiration (0, 1, 2, and 7 animals in groups 1-4, respectively), and few or no feces (0, 3, 13, and 18 animals in groups 1-4, respectively). Treatment-related cage side observations included hypoactivity, red dust around nose (predominantly in group 4), excessive salivation, labored respiration, wheezing, and few or no faeces (groups 3 and 4).
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- In groups 1-4, there were 0, 0, 5, and 11 animals found dead during the study, respectively. All of the animals found dead were pregnant with the exception of one group 4 female. All other females survived to cesarean section on gestation day 20.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Body weight in high-dose dams was significantly below controls on GD 8, 12, 16 and 20. All treated animals experienced significantly lower weight gain than controls during GD 6-8. For the dosing period as well as for the entire gestational period (GD 0-20), weight gain in mid and high dose animals was significantly below controls. Corrected weight gain was also significantly below controls in mid and high dose groups.
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- The mean maternal food consumption values for gestation days 6-8, 8-12, and 0-20 were significantly lower for groups 3 and 4 when compared to the respective control values. All other treatment group values were similar to their respective control values.
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- effects observed, non-treatment-related
- Description (incidence and severity):
- The mean maternal water consumption value for gestation days 6-8 was significantly lower for group 4 when compared to the respective control value. All other treatment group values were similar to their respective control values.
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Description (incidence and severity):
- Gravid uterine weights were similar for all groups.
- Gross pathological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- In animals that survived to study termination, gross findings were noted in two dams from the low-dose group. One had a pale spleen, and the other had a dilated renal pelvis. In mid and high dose animals that died during the study, the following findings were noted: dark lungs, mottled liver, foci on liver, distended stomach and/or intestine, depressions in stomach and a dark stomach.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- not examined
- Number of abortions:
- no effects observed
- Description (incidence and severity):
- No abortions were observed.
- Pre- and post-implantation loss:
- no effects observed
- Description (incidence and severity):
- Preimplantation loss values were similar in all groups and not indicative of a treatment-related effect.
- Total litter losses by resorption:
- not specified
- Early or late resorptions:
- no effects observed
- Description (incidence and severity):
- The mean percent early resorptions were statistically similar in all groups. No late resorptions were observed.
- Dead fetuses:
- no effects observed
- Description (incidence and severity):
- No dead foetuses were observed.
- Changes in pregnancy duration:
- not specified
- Changes in number of pregnant:
- effects observed, non-treatment-related
- Description (incidence and severity):
- In each of the control and high dose group, two females were not pregant (23/25 pregnant).
- Other effects:
- not specified
- Dose descriptor:
- LOEL
- Effect level:
- 10 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Basis for effect level:
- body weight and weight gain
- clinical signs
- food consumption and compound intake
- mortality
- Remarks on result:
- other: No NOEL could be determined
- Abnormalities:
- no effects observed
- Fetal body weight changes:
- not examined
- Reduction in number of live offspring:
- not examined
- Changes in sex ratio:
- no effects observed
- Description (incidence and severity):
- No test item-related effects were noted for sex ratio.
- Changes in litter size and weights:
- effects observed, treatment-related
- Description (incidence and severity):
- Mean fetal weights were lower in the high dose group. When using covariate adjusted fetal weights in the statistical analysis, the decrease was significant
- Changes in postnatal survival:
- not examined
- External malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- A flap of skin (near the junction of the thoracic and abdominal cavities) was noted in one group 3 foetus. This was classified as a variation. One malformation of partial twinning (fused forelimbs and hindlimbs) was noted in group 1. There were no external observations noted in groups 2 and 4.
- Skeletal malformations:
- effects observed, treatment-related
- Description (incidence and severity):
- There was a significant positive trend and significantly higher foetal/litter incidences in group 4 of several indicators of a delay in ossification of the developing fetuses. Among these was a significant positive in both the foetal and litter incidences of less than four caudal vertebrae ossified (group 4 foetal incidence was significantly higher than the respective control incidences). There was a significant positive trend in both the fetal and litter incidences of 6th sternebra unossified, other sternebra(e) unossified, and other sternebra(e) incomplete ossification (group 4 foetal and litter incidences were significantly higher than the respective control incidences). There was a significant positive trend in the fetal incidence of 5th sternebra unossified (the fetal incidence in group 3 was significantly lower and the foetal incidence in group 4 was significantly higher than the control incidence). There was a significant positive trend in the foetal incidence of wavy/bent rib(s) (group 4 fetal incidence was significantly higher than the control incidence). There were no fetuses with this finding in either groups 2 or 3. A vertebral anomaly with an associated rib anomaly noted in group 2 was classified as a malformation.
- Visceral malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Variations noted included dilatation of the lateral and third ventricles of the brain, dilated ureters, and liver and renal pelvic cavitation. Variations noted did not appear in a dose-related pattern. One malformation of partial twinning was noted in group 1.
- Other effects:
- not examined
- Key result
- Dose descriptor:
- NOEL
- Effect level:
- 20 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: see "Remarks on result"
- Remarks on result:
- other: No adverse effects observed
- Dose descriptor:
- LOEL
- Effect level:
- 40 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: variations oberserved in the skeletal examination: wavy ribs
- Key result
- Abnormalities:
- effects observed, treatment-related
- Localisation:
- other: delay of ossicifaction and wavy ribs in the high dose group foetuses
- Key result
- Developmental effects observed:
- yes
- Lowest effective dose / conc.:
- 40 mg/kg bw/day (nominal)
- Treatment related:
- yes
- Relation to maternal toxicity:
- developmental effects as a secondary non-specific consequence of maternal toxicity effects
- Dose response relationship:
- yes
- Relevant for humans:
- no
- Conclusions:
- In a prenatal developmental toxicity study the test item was prepared using water as vehicle and orally administered to 25 female Wistar rats/dose group at dose levels of 0, 10, 20 and 40 mg/kg bw/day from days 6 through 15 of gestation. Based on the results, the maternal NOEL could not be determined and the maternal LOEL was 10 mg/kg bw/day. The NOEL for foetal toxicity is considered to be 20 mg/kg bw/day.
- Executive summary:
In a prenatal developmental toxicity study (performed in accordance with EPA OPP 83-3) the test item was prepared using water as vehicle and administered orally to 25 female Wistar rats/dose group at dose levels of 0, 10, 20 and 40 mg/kg bw/day from days 6 through 15 of gestation. On gestation day 20 the animals were sacrificed and examined. Maternal toxicity was observed in all treated groups as evidenced by increased mortality (mid and high dose), increased incidence of clinical signs of toxicity (all treated groups), and reduced weight gain and food consumption (mid- and high-dose). In addition, a slight reduction in weight gain was observed in low-dose animals during gestation 6–8. In the mid and high dose animals that die during the study, findings including dark lungs, mottled liver, foci on liver, distended stomach and/or intestine, dark stomach or depressions in stomach were noted. Foetal weights were slightly but not statistically reduced in foetuses from high dose dams. In foetuses from high dose dams, covariant adjusted body weights were significantly below controls. In the high dose group, litter/foetal incidences of less than four caudal vertebrae ossified, 5th/6th/or other sternebrae unossified and way/bent ribs were significantly increased above controls.
Based on the results, no NOEL could be determined for maternal toxicity. The LOEL was considered to be 10 mg/kg bw/day. For developmental toxicity the NOEL and LOEL were considered to be 40 mg/kg bw/day, respectively.
The prenatal developmental toxicity study in the rat is classified as acceptable and satisfies the guideline requirement for a developmental toxicity study (EPA Guideline 83-3) in the rat.
Reference
Effect on developmental toxicity: via oral route
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- NOAEL
- 20 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rat
- Quality of whole database:
- GLP guideline study
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
In a prenatal developmental toxicity study performed in accordance with EPA OPP 83 -3, the test item was prepared using water as vehicle and administered orally to 25 female Wistar rats/dose group at dose levels of 0, 10, 20 and 40 mg/kg bw/day from days 6 through 15 of gestation. On gestation day 20 the animals were sacrificed and examined. Maternal toxicity was observed in all treated groups as evidenced by increased mortality (mid and high dose), increased incidence of clinical signs of toxicity (all treated groups), and reduced weight gain and food consumption (mid- and high-dose). In addition, a slight reduction in weight gain was observed in low-dose animals during gestation 6-8. In the mid and high dose animals that dies during the study, findings including dark lungs, mottled liver, foci on liver, distended stomach and/or intestine, dark stomach or depressions in stomach were noted. Fetal weights were slightly but not statistically reduced in fetuses from high dose dams. In fetuses from high dose dams, covariant adjusted body weights were significantly below controls. In the high dose group, litter/fetal incidences of less than four caudal vertebrae ossified, 5th/6th/or other sternebrae unossified and way/bent ribs were significantly increased above controls. Observed foetal effects at 40 mg/kg bw/day were considered to be secondary to maternal toxicity (see also CLP Regulation 1272/2008, paragraph 3.7.2.4.2)
Based on the results, no NOEL could be determined for maternal toxicity. The LOEL for maternal toxicity was considered to be 10 mg/kg bw/day. For developmental toxicity the NOEL and LOEL were considered to be 40 mg/kg bw/day, respectively.
Justification for classification or non-classification
As only minor developmental changes were observed (reduction of foetal body weight, unossification of sternebrae and way/bent ribs) in the high dose group together with maternal toxicity, classification for reproductive toxicity is not warranted.
Additional information
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.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.