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Diss Factsheets
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EC number: 202-987-5 | CAS number: 101-90-6
- 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
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Toxicity to reproduction
Administrative data
- Endpoint:
- screening for reproductive / developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 10 April 2018 - (no data as audited draft report)
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Justification for type of information:
- On 12th April 2019, Emerald submitted the Lead Registration for this substance under the DCG (Directors’ Contact Group) issue 10 as communicated to ECHA in communication INC000000227877. However, some of the screening studies for the substance were still ongoing with the CRO, and since then they have experienced further unforeseen delay in finalizing the report.
ECHA has since provided a deadline to submit the complete information as an update by the technical completeness check deadline of 30 May 2019 (Communication number: SUB-C-2114468593-38-02/F).
Unfortunately, the CRO has encountered an extended delay for the OECD 421 - Reproduction/Developmental Toxicity Screening Test in the Rat by Oral Gavage study.
In the 'Attached Justification' section as well as in section 13 of the dossier, you can find an explanatory letter from the CRO to confirm this situation and explaining therefore that the current deadline of 30th May 2019 could unfortunately not be fully met. The letter additionally includes predicted final report dates for these studies.
With regards to that, we would like to confirm that a spontaneous dossier update will be conducted as soon as data will become available.
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 019
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
- Version / remarks:
- 2016
- Deviations:
- no
- GLP compliance:
- yes
Test material
- Reference substance name:
- m-bis(2,3-epoxypropoxy)benzene
- EC Number:
- 202-987-5
- EC Name:
- m-bis(2,3-epoxypropoxy)benzene
- Cas Number:
- 101-90-6
- Molecular formula:
- C12H14O4
- IUPAC Name:
- 2-({3-[(oxiran-2-yl)methoxy]phenoxy}methyl)oxirane
- Test material form:
- liquid: viscous
Constituent 1
- Specific details on test material used for the study:
- SOURCE OF TEST MATERIAL
- Source: CVC Thermoset Specialties, 844 N. Lenola Road, Moorestown, New Jersey 08057
- Lot/batch No.of test material: 53715080
- Expiration Date: 5 August 2019, when stored at ambient temperature
- Storage Conditions: Room temperature (15 to 25 °C)
- Purity: 100%
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories, Raleigh, North Carolina 27610
- Age at study initiation: 11 weeks males and 13 weeks female
- Weight at study initiation: Males:395 - 494 grams, Females: 27 - 315 grams
- Housing: Suspended, solid bottom cages with cellulose-based contact bedding
- Diet: ad libitum (Teklad Global 18% Protein Rodent Diet (Certified), 2018C, Envigo, Madison, Wisconsin)
- Water: ad libitum (Potable water from the public supply)
- Acclimation period: 5 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 26
- Humidity (%): 30 - 70
- Photoperiod (hrs dark / hrs light): 12/ 12
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on exposure:
- VEHICLE
- Justification for use and choice of vehicle (if other than water):
- Dose (mg/kg/day): 0, 45, 90 and 180
- Concentrations in vehicle (mg/mL): 0, 9, 18 and 36
- Volume Dose (mL/ kg): 5
- Lot/batch no. (if required):
- Storage conditions: Room temperature, dry, protected from light
- Lot numbers: 2HB0068, 2GK0223
- Purity: 100%
- Expiration dates: 31 January 2019, 31 October 2018
- Fresh formulations were prepared once weekly and were stored refrigerated (2 to 8 °C) when not in use - Details on mating procedure:
- - M/F ratio per cage: 1:1
- Length of cohabitation: Until evidence of mating was seen or until 14 consecutive days of cohabitation had elapsed.
- Proof of pregnancy: vaginal plug or sperm in the vaginal smear
- After 14 days of unsuccessful pairing replacement of first male by another male with proven fertility.
- Further matings after two unsuccessful attempts: no - Analytical verification of doses or concentrations:
- yes
- Duration of treatment / exposure:
- F0 males was 2 weeks pre-cohabitation, during cohabitation (up to 3 weeks) and continuing during post-cohabitation until the day prior to termination (approximately 35 days).
F0 females was 2 weeks pre-cohabitation, cohabitation (up to 3 weeks) and during gestation and lactation continuing until LD 13 (approximately 70 days).
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Dose / conc.:
- 45 mg/kg bw/day (nominal)
- Dose / conc.:
- 90 mg/kg bw/day (nominal)
- Dose / conc.:
- 180 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- 10
- Control animals:
- yes
- Details on study design:
- Not specified
- Positive control:
- No
Examinations
- Parental animals: Observations and examinations:
- Animals were observed in their cages at least twice daily for mortality and general condition.CAGE SIDE OBSERVATIONS:
- Time schedule: Animals were observed in their cages at least twice daily for mortality and general condition
BODY WEIGHT: Yes
- F0 male rats were recorded weekly prior to treatment initiation and prior to dosing from the initiation of treatment and weekly thereafter throughout the study and at termination.
- F0 female rats were recorded weekly prior to treatment initiation and prior to dosing, from the initiation of treatment and weekly during the pre-cohabitation and cohabitation phases until mated.
- Mated female rats were weighed on GD 0, 7, 14 and 20.
- Female rats that delivered litters were weighed on LD 1, 4, 7 and 13 and at termination on LD 14.
- Female rats without evidence of mating from the second male pairing were moved into the gestation phase and upon delivery were moved into the lactation phase and weighed similarly as other females with evidence of mating.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for the male and female rats was measured (weighed) weekly prior to initiation of treatment (pretest) and during the pre-cohabitation phase.
- Food consumption was not measured during the cohabitation phase when male rats were being co-housed with female rats.
- For male rats, food consumption was measured weekly during the post-cohabitation phase.
- For female rats, gestation and lactation food consumption was measured on GDs 0-7, 7 14 and 14-20 and on LDs 1-7 and 7-14, respectively. - Oestrous cyclicity (parental animals):
- Vaginal smears were obtained daily from each F0 female pretest (to determine suitability for study) and during the pre-cohabitation and cohabitation phases until mating was confirmed and the stage of estrous was determined.
- Offspring viability indices:
- .
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- effects observed, non-treatment-related
- Description (incidence and severity):
- There were no m-bis(2,3-epoxypropoxy)benzene-related observations in the males and females that survived until scheduled termination.
Any clinical observations noted were not considered to be treatment-related due to their common occurrence in this laboratory animal species. - Dermal irritation (if dermal study):
- not specified
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- There were 14 unscheduled decedents (3 males and 11 females) over the course of this study.
Of the 11 females, 9 were euthanized due to total litter loss or failure to get pregnant.
Of the remaining 5 animals, 3 males at ≥ 90 mg/kg/day and 1 female at 45 mg/kg/day were found dead and 1 female at 90 mg/kg/day was euthanized for welfare reasons.
The cause of death/morbidity in 3 of the found dead animals was undetermined.
The remaining 2 animals dosed at 90 mg/kg/day had microscopic findings of mucosal erosion or necrosis and inflammation of the glandular or non-glandular region of the stomach that were considered to have contributed to the cause of death. - Body weight and weight changes:
- effects observed, non-treatment-related
- Description (incidence and severity):
- There was an m-bis(2,3-epoxypropoxy)benzene-related decrease in absolute mean body weight and body weight gain in males at ≥ 90 mg/kg/day over the course of this study.
By study termination, the absolute mean body weights were -8.6% and -15.4% of that of the controls at 90 and 180 mg/kg/day, respectively.
There were no m-bis(2,3-epoxypropoxy)benzene-related effects on absolute mean body weight or body weight gain in males at 45 mg/kg/day or females at any dose tested.
Any changes noted were not considered to be related to treatment due to their small magnitude, sporadic occurrence and/or lack of relation to dose. - Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- There was an m-bis(2,3-epoxypropoxy)benzene-related decrease in food consumption in males at ≥ 90 mg/kg/day and females at ≥ 45 mg/kg/day over the course of this study.
A maximal decrease of -26.1% and -31.6% was noted during the precohabitation phase (Day 7 - 14) for males and females, respectively. - 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:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- not specified
- Histopathological findings: neoplastic:
- not specified
- Other effects:
- not specified
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- no effects observed
- Description (incidence and severity):
- There were no m-bis(2,3-epoxypropoxy)benzene-related effects on estrous cycling at any dose tested. Any differences observed in the number of cycles (regular, irregular or acyclic) and/or mean cycle length were not considered to be related to treatment due to their small magnitude and/or lack of relation to dose.
- Reproductive function: sperm measures:
- not specified
- Reproductive performance:
- effects observed, treatment-related
- Description (incidence and severity):
- There was no m-bis(2,3-epoxypropoxy)benzene-related effect on mating at any dose tested. Specifically, 10 females per group mated. Of these 9, 9, 10, and 8 were pregnant and delivered live born pups at 0, 45, 90, and 180 mg/kg/day, respectively. There was an m-bis(2,3-epoxypropoxy)benzene-related effect on fertility at 180 mg/kg/day. Three (3) of 10 females had a total litter loss, and an additional 2 females failed to deliver by GD 25. During the necropsy, it was confirmed that these females were not pregnant. There were no m-bis(2,3-epoxypropoxy)benzene-related effects on fertility at ≤ 90 mg/kg/day.
Effect levels (P0)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- ca. 45 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- mortality
- body weight and weight gain
- food consumption and compound intake
Target system / organ toxicity (P0)
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 90 mg/kg bw/day (nominal)
- System:
- gastrointestinal tract
- Organ:
- stomach
- Treatment related:
- yes
Results: P1 (second parental generation)
General toxicity (P1)
- Gross pathological findings:
- not specified
- Histopathological findings: non-neoplastic:
- not specified
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- not specified
- Dermal irritation (if dermal study):
- not specified
- Mortality / viability:
- not specified
- Description (incidence and severity):
- There were m-bis(2,3-epoxypropoxy)benzene-related decreases on the following indices: post-implantation survival, live birth, and live litter size on PNDs 1, 4, 7 and 13 at 180 mg/kg/day. Beginning on PND 7, the viability index was -33.6% of the concurrent control value, and this reduction persisted until termination (i.e., PND 13). There were no m-bis(2,3-epoxypropoxy)benzene-related effects on the following indices: post implantation survival, live birth, and live litter size on PNDs 1, 4, 7 and 13 at ≤ 90 mg/kg/day. Any differences noted were not considered to be treatment-related due to their to their small magnitude and/or lack of relation to dose.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- There were no m-bis(2,3-epoxypropoxy)benzene-related effects on pup sex or body weight at any dose tested.
- 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
- Sexual maturation:
- not specified
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- Male and female (F1) pups at ≥ 45 mg/kg/day had higher mean thyroid gland weights, particularly relative to body weight, compared to control males.
- Gross pathological findings:
- not specified
- Histopathological findings:
- not specified
- Other effects:
- no effects observed
- Description (incidence and severity):
- There were no m-bis(2,3-epoxypropoxy)benzene-related effects on the length of gestation, total corpora lutea, number of implantations, pre-implantation loss, or average number of pups on PNDs 1, 4, 7, 11 or 13 at any dose tested. Any differences noted were not considered to be treatment-related due to their to their small magnitude and/or lack of relation to dose.
Developmental neurotoxicity (F1)
- Behaviour (functional findings):
- not specified
Developmental immunotoxicity (F1)
- Developmental immunotoxicity:
- not specified
Effect levels (F1)
- Key result
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- ca. 90 mg/kg bw/day (nominal)
- Sex:
- male/female
- Basis for effect level:
- body weight and weight gain
Target system / organ toxicity (F1)
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 45 mg/kg bw/day (nominal)
- System:
- endocrine system
- Organ:
- thyroid gland
- Treatment related:
- yes
Overall reproductive toxicity
- Key result
- Reproductive effects observed:
- yes
- Lowest effective dose / conc.:
- 90 mg/kg bw/day (nominal)
- Treatment related:
- yes
- Relation to other toxic effects:
- reproductive effects occurring together with other toxic effects, but not as a secondary non-specific consequence of other toxic effects
Applicant's summary and conclusion
- Conclusions:
- With all findings considered, the male and female systemic NOAEL was 45 mg/kg/day and the reproductive NOAEL was 90 mg/kg/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.
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.
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