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EC number: 260-976-0 | CAS number: 57834-33-0
- 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
Eversorb EP4 (2, 10 or 50 mg/kg/day) was given orally by gavage once daily to male rats for 28 days and female rats for 40 to 61 days, depending on the time of copulation and gestation. Eversorb EP4 did not affect clinical observations, body weight, food consumption, male and female rats’ reproductive performance such as gonadal function, mating behavior, conception, development of the conceptus, and parturition and offspring parameters including litter weight, AGD and nipple retention. The no observed adverse effect level of Eversorb EP4 in rat’s reproductive performance was 50 mg/kg/day.
Link to relevant study records
- Endpoint:
- one-generation reproductive toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 25 July 2017 - 23 March 2018
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
- GLP compliance:
- yes (incl. QA statement)
- Species:
- rat
- Strain:
- other: Crl:CD(SD)
- Details on species / strain selection:
- Crl:CD (SD) rats (47 males and 50 females) used in this study were purchased from
BioLASCO Taiwan Co., Ltd., Taipei, Taiwan. A total of 46 males and 46 females were
selected for the study. Animals were approximately 12 weeks of age and weighed 406 to
505 g (males) and 243 to 295 g (females) at dosing and mated at an age of 14 weeks.
Animals were identified by an ear-notch and a cage tag. The rat was chosen since it is
an appropriate rodent experimental species for reproduction/developmental toxicity
studies with documented susceptibility to a wide range of toxic substances. - Sex:
- male/female
- Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on exposure:
- The oral route was selected since it is the proposed exposure route to human. Dose formulations were stirred during the dosing session for drawing into dosing syringe
. All animals received vehicle or test article formulation via oral gavage once daily from pre-mating, mating, gestation (female only, Deviation 4) until 12 days after delivery (female only). The dosing period for males was 28 days and for females was 40-61 days, depending on the time of copulation and gestation. - Details on mating procedure:
- There was a 12-day pre-exposure period from A12. A 2-week per-mating period followed a 14-day mating period. In mating period, all animals were copulated at
a ratio of 1:1. The female was placed with the same male until pregnancy occurred. When pairing was unsuccessful in a continued 6 days, re-mating of females with proven males of the same group was conducted.
The gestation period was 21 to 23 days. Males were sacrificed after a dosing period of four weeks (D29). Maternal females with pups were sacrificed on P13. Presumed pregnant but non-delivering females were sacrificed on G25, and one non-copulated female was sacrificed on D54. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The samples were analyzed using the method entitled “Validation of a Method for the Determination of Eversorb EP4 in Dose Formulation by HPLC-UV”, which
was validated at QPS Taiwan. The details of the assay procedure and validation data are listed and summarized in the assay validation report (QPS Taiwan T653-1601).
Eversorb EP4 was obtained from Everlight Chemical Industrial Corporation and was subsequently used to prepare standard solutions and check standard (CS) solutions for this study.
All sample results were reported from analysis runs that met the acceptability criteria of QPS’ standard operating procedures. - Duration of treatment / exposure:
- The dosing period for males was 28 days and for females was 40-61 days, depending on the time of copulation and gestation.
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Remarks:
- group 1
- Dose / conc.:
- 2 mg/kg bw/day (nominal)
- Remarks:
- group 2
- Dose / conc.:
- 10 mg/kg bw/day (nominal)
- Remarks:
- group 3
- Dose / conc.:
- 50 mg/kg bw/day (nominal)
- Remarks:
- group 4
- No. of animals per sex per dose:
- 12 males/ 12 females
- Control animals:
- yes
- Details on study design:
- The high dose (50 mg/kg/day) was determined based on the results of previous studies (QPS Taiwan Study No.: T65316003-RP and T65316001-GN).
The mid (10 mg/kg/day) and low (2 mg/kg/day) doses represent a fifth decrements from the high dose and are included to better define the dose-response of test article effects and assure that a nonseverely toxic dose is identified with the extension to repeated dosing.
T65316003-RP is the reproduction screen study. Doese are 1000, 300, 100 and 0 mg/kg/day. The impact at 100 mg/kg/day was significant. Therefore, the highest dose was determined at 50 mg/kg/day. - Clinical signs:
- no effects observed
- Description (incidence and severity):
- No test article-related death or clinical signs was observed in males and females during the study period.
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- mortality observed, non-treatment-related
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- The test article did not have effect on body weight and body weight gain.
- Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- no effects observed
- Description (incidence and severity):
- The test article did not have effect in food consumption.
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Immunological findings:
- no effects observed
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- no effects observed
- Description (incidence and severity):
- There were no statistically significantly differences in T4 concentration determinate on D29 (male adult), P4 (pup), P13 (pup and maternal rat) between control and treated
groups. - Reproductive function: oestrous cycle:
- no effects observed
- Description (incidence and severity):
- The estrus cycles of all animals during 15 consecutive days of premating period. The sequence of the stages was: proestrus, estrus, metestrus and diestrus.
It was normal to observe extra diestrus and estrus stages. The estrus was cycling when the proestrus was followed by the estrus. A 4–5 day cycle was observed in almost all animals. Some animals showed 1 or 2 cycles during pre-mating, which included one control animal (ID# 0007), two animals of Group 2 (IDs# 0021 and 0023), three animals of Group 3 (IDs# 0024, 0029 and 0033) and three animals of Group 4 (ID# 0040, 0041, and 0045). Except for ID# 0007, other animals mentioned above were mated in 2–5 days (see section 5.6). There were no statistically significant differences in the number of estrus cycles between control and treated groups. The intergroup difference may be due to discrepancies caused by different examiners.
Overall, the test article did not have an effect of the estrus cycle. - Reproductive function: sperm measures:
- not examined
- Reproductive performance:
- no effects observed
- Description (incidence and severity):
- In males, a positive indication of mating was obtained for 11 of 12, 10 of 11, 10 of 11 and 12 of 12 animals in Groups 1 to 4, resulting in a mating index of 92%, 91%, 91% and 100%, respectively, indicating that the test article did not have an effect in male mating behavior.
In females, 4-5 day cycles were observed in almost animals during the pre-mating period. Some animals showed a 3-day cycle, which included one in the control (ID#
0008), two in Group 2 (IDs# 0017 and 0019), two in Group 3 (IDs# 0027 and 0030) and one in Group 4 (ID# 0039). One Group 2 animal (ID# 0022) showed an 8-day cycle. One animal in Groups 2 and 4 (IDs# 0023 and 0045) showed no cycling.
A positive indication of mating was obtained for 11 of 12, 11 of 11, 10 of 10, 12 of 12 animals in Groups 1 to 4. The mating index was 92%, 100%, 100% and 100% for
Group 1 to 4, respectively. There was one animal (ID# 0017) in Group 2 that showed a pre-coital interval of longer than 5 days. In this female, the mating with the first male failed but the copulation with another male was successful. In Groups 1, 2 and 4, one animal with positive indications of mating was later found not to be pregnant (IDs# 0002, 0023 and 0041). All Group 3 animals were found to be pregnant. Thus, the fertility index was 91%, 91%, 100% and 92% in the control, low, mid and high dose group, respectively, indicating that the test article did not have an effect in female fertility. The average length of gestation was 22 days without dose-dependency. - Dose descriptor:
- NOAEL
- Effect level:
- 50 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No effects seen at 50 mg/kg bw/day
- Critical effects observed:
- no
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- No externally abnormal pups were observed at birth in the control and treated groups. At birth, 49.3% to 57.0% of pups were male and on P4, 50.3% to 56.9% pups were
male. The highest male pup rate at birth and on P4 was 57.0% and 56.9%, respectively and observed in Group 3. There was no dose-dependency in gender distribution. - Dermal irritation (if dermal study):
- not examined
- Mortality / viability:
- mortality observed, non-treatment-related
- Description (incidence and severity):
- There were 1, 5 and 5 dead pups observed at birth in Groups 1, 3 and 4, respectively. The incidence of dams with dead pups at birth was 10%, 0%, 40% and 27% in Group 1, 2, 3 and 4, respectively. The dead pup incidence in Group 4 was slightly higher than in the control group. However, the number of stillborns per litter was 0.45 (5 stillborns divided by 11 litters), which was still within the historical data range. In this case, the slightly higher stillborn rate was not considered to be test article-related in absence of a dose-dependency. On P4, a decreased number of live pups was observed in all groups. The 4-day survival index was 99.3%, 98.7%, 96.6% and 99.4% in Groups 1 to 4, respectively, showing no dose-dependency.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- There were no statistically significant differences in litter weight gain on P4 and P13 between control and treated groups. The weight gain between P0 and P4 relative to
weight on P0 was 61%, 56%, 49% and 59% in control and Groups 2–4, respectively, as well as between P4 and P13 relative to weight on P13 was 214%, 221%, 221% and 223%. - Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Sexual maturation:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- not examined
- Histopathological findings:
- not examined
- Other effects:
- not examined
- Dose descriptor:
- NOAEC
- Remarks:
- teratogenicity
- Generation:
- F1
- Effect level:
- 50 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: Not teratogenic effects at highest dose tested 50 mg/kg bw/day
- Critical effects observed:
- no
- Reproductive effects observed:
- no
- Conclusions:
- Eversorb EP4 (2, 10 or 50 mg/kg/day) was given orally by gavage once daily to male rats for 28 days and female rats for 40 to 61 days, depending on the time of copulation
and gestation. Eversorb EP4 did not affect clinical observations, body weight, food consumption, male and female rats’ reproductive performance such as gonadal function,
mating behavior, conception, development of the conceptus, and parturition and offspring parameters including litter weight, AGD and nipple retention. The no observed adverse effect level of Eversorb EP4 in rat’s reproductive performance was 50 mg/kg/day. - Executive summary:
The purpose of this study was to generate limited information on the effects of“Eversorb EP4” on male and female rats’ reproductive performance such as gonadalfunction, mating behavior, conception, development of the conceptus and parturition.
MethodsAnimals were assigned to four groups and received vehicle (corn oil) or Eversorb EP4(Lot 4023) at dose levels of 2, 10 and 50 mg/kg/day by oral gavage at 5 mL/kg for 28consecutive days in males and 40–61 days in females. The parent males were sacrificedafter the mating period (Day 29). Females were sacrificed on Day 54 if un-copulated, onGestation Day 25 if copulated without delivery, or reared their offspring (F1), and thensacrificed on Postnatal Day 13. The pups were sacrificed on Postnatal Day 4 or 13.
Measurements
The following parameters were monitored: adult mortality and clinical observations,adult estrus cycle, adult and litter body weights, adult food consumptions, offspringparameters including number, sex, gross abnormalities, androgen-dependentdevelopmental markers (e.g., anogenital distance [AGD] and nipple retention), adultsand pups thyroid hormones (T4) determination, adults gross necropsy (includingimplantation site examination), organ weight and microscopic examinations of collectedtissues.
Results
The dose formulations were homogeneous and target concentrations were confirmed.Test article (0.7 mg/mL) was detected in the control group on the last preparation andwas subjected to be contaminant. The dose level could be adjusted to 0–3.6 mg/kg incontrol, 2–5.8 mg/kg in Group 2 (except ID# 0017) and 10–13.7 mg/kg in Group 3.Treatment of animals with Eversorb EP4 did not induce death, abortion or prematuredelivery. One female of Group 3 delivered as a result of incorrect mating determinationon Day 40 and found dead in parturition. The animal was clinically normal during thestudy period. Pleural effusion was observed at necropsy.Clinical signs during the pre-mating, gestation and lactation period, body weights andfeed consumptions were comparable across all groups. Mating and fertility indices andestrus cycle were un-effected by treatment with Eversorb EP4. F1 pup viability, litterbody weight, sex, AGD and nipple retention were not affected by treatment withEversorb EP4. T4 concentrations in adults and pups as well as reproductive evaluationin gross or histopathology in adult male and female and external gross examination inpups were unaffected by test article treatment.
Reference
Eversorb
EP4 (2, 10 or 50 mg/kg/day) was given orally by gavage once daily to malerats
for 28 days and female rats for 40 to 61 days, depending on the time of
copulationand
gestation. Eversorb EP4 did not affect clinical observations, body
weight, foodconsumption,
male and female rats’ reproductive performance such as gonadal function,mating
behavior, conception, development of the conceptus, and parturition andoffspring
parameters including litter weight, AGD and nipple retention. The noobserved
adverse effect level of Eversorb EP4 in rat’s reproductive performance
was50
mg/kg/day.
Effect on fertility: via oral route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 50 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rat
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
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
Justification for classification or non-classification
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.