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Diss Factsheets

Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
16 October 2017 - 14 March 2018
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2018

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
GLP compliance:
yes (incl. QA statement)
Limit test:
no

Test material

Constituent 1
Reference substance name:
1,2,4-tris[(oxiran-2-yl)methyl] benzene-1,2,4-tricarboxylate; 1,4-bis[(oxiran-2-yl)methyl] benzene-1,4-dicarboxylate
EC Number:
940-592-6
Molecular formula:
-
IUPAC Name:
1,2,4-tris[(oxiran-2-yl)methyl] benzene-1,2,4-tricarboxylate; 1,4-bis[(oxiran-2-yl)methyl] benzene-1,4-dicarboxylate

Test animals

Species:
rat
Strain:
Crj: CD(SD)
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Reputable global supplier
- Age at study initiation: Approximately 72 days old.
- Weight at study initiation: 229 to 293 g.


- Fasting period before study: none
- Housing: Solid bottom cages contained softwood based bark-free fiber bedding, which was changed at appropriate intervals each week.
- Diet (e.g. ad libitum): SDS VRF1 Certified pelleted diet. Non-restricted.
- Water (e.g. ad libitum): Non-restricted.
- Acclimation period: Six days before commencement of pairing

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24ºC
- Humidity (%): 40-70%
- Air changes (per hr): Filtered fresh air which was passed to atmosphere and not recirculated.
- Photoperiod (hrs dark / hrs light): Artificial lighting, 12 hours light : 12 hours dark.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
propylene glycol
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: The required amount of test item was ground in a mortar using a pestle to a fine powder and mixed with a small amount of the vehicle to form a paste. Any agglomerates were broken down. Further amounts of vehicle were gradually added and mixed to produce a smooth, pourable suspension. The suspension was transferred to a measuring cylinder which had been wetted with vehicle, the mortar was rinsed with vehicle and this was added to the measuring cylinder. Vehicle was added to achieve the final volume and the suspension was transferred to a beaker and mixed using a high shear homogenizer. The suspension was transferred to the final containers, via syringe whilst magnetically stirring.
A series of formulations at the required concentrations were prepared by dilution of individual weighings of the test item.

VEHICLE - Propylene glycol
- Justification for use and choice of vehicle (if other than water): n/a
- Concentration in vehicle: n/a
- Amount of vehicle (if gavage): 2.5 mL/kg
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The analytical procedure was successfully validated with respect to specificity of chromatographic analysis, limit of detection and quantification, linearity of detector response, repeatability, method accuracy and precision.
The homogeneity and stability was confirmed for Araldite PT 910 in propylene glycol formulations at nominal concentrations of 1 mg/mL and 400 mg/mL during distribution between the bottles, during magnetic stirring for 2 hours, ambient temperature storage (15 to 25ºC) for 1 day and refrigerated storage (2 to 8ºC) for up to 15 days.
The mean concentrations of Araldite PT 910 in test formulations analyzed for the study were within +10/-15% of nominal concentrations, confirming accurate formulation. The difference between the samples remained within 2%, confirming precise analysis.
Details on mating procedure:
- Impregnation procedure: cohoused

- M/F ratio per cage: 1:1 with identified stock males
- Daily checks for evidence of mating: Ejected copulation plugs in cage tray and vaginal smears were checked for the presence of sperm.
- Day 0 of gestation: When positive evidence of mating was detected.
A colony of stud males was maintained specifically for the purpose of mating; these animals were not part of the study and were maintained as stock animals.
Duration of treatment / exposure:
19 days
Frequency of treatment:
once daily
Duration of test:
19 days
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day
Remarks:
Control
Dose / conc.:
20 mg/kg bw/day
Remarks:
Group 2
Dose / conc.:
60 mg/kg bw/day
Remarks:
Group 3
Dose / conc.:
200 mg/kg bw/day
Remarks:
Group 4
No. of animals per sex per dose:
20 females
Control animals:
yes, concurrent no treatment
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: The dose levels were selected based on the effects of a preliminary embryo-fetal study at this laboratory (Envigo study number WB30PP) which investigated dose levels of 50, 100 or 200 mg/kg/day.
- Rationale for animal assignment (if not random): random

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Animals were inspected visually at least twice daily for evidence of ill-health or reaction to treatment. Cages were inspected daily for evidence of animal ill-health amongst the occupant(s). Any deviation from normal was recorded at the time in respect of nature and severity, date and time of onset, duration and progress of the observed condition, as appropriate. During the acclimatization period, observations of the animals and their cages were recorded at least once per day.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: A detailed physical examination was performed on each animal on Days 0, 5, 12, 18 and 20 after mating to monitor general health.

BODY WEIGHT: Yes
- Time schedule for examinations: The weight of each adult was recorded on Days 0-20 after mating.

FOOD CONSUMPTION: Yes
- The weight of food supplied to each adult, that remaining and an estimate of any spilled was recorded for the periods Days 0, 1-2, 3-5, 6-9, 10-13, 14-17 and 18-19 after mating inclusive.

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice: Animals were killed on Day 20 after mating
- All adult animals were subject to a detailed necropsy. After a review of the history of each animal, a full macroscopic examination of the tissues was performed. All external features and orifices were examined visually. Any abnormality in the appearance or size of any organ and tissue (external and cut surface) was recorded and the required tissue samples preserved in appropriate fixative.

OTHER:
Reproductive Assessment
The following were recorded for all animals:
Uterus - Gravid uterine weight (including cervix and ovaries).
For each ovary/uterine horn - Number of: Corpora lutea, Implantation sites, Resorption sites (classified as early or late), and Fetuses (live and dead).
Apparently non pregnant animals - The number of uterine implantation sites were checked after staining with ammonium sulphide.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other: Fetuses, live and dead
Fetal examinations:
- External examinations: Yes - all viable fetuses and placentae
- Soft tissue examinations: Yes - all viable fetuses and placentae
- Skeletal examinations: Yes - all viable fetuses and placentae
- Head examinations: No
Statistics:
- Bartlett's test
- Williams’ test
- Dunnett's test
- Kruskal-Wallis’ test
- Wilcoxon rank sum tests
- Shirley's test
- Steel's test
- Fisher’s exact tests
Indices:
Litter size and survival indices.
Historical control data:
Available from this laboratory

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):
not examined
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:
not examined
Gross pathological findings:
no effects observed
Description (incidence and severity):
There were no test-material related macroscopic abnormalities detected in the adult females at scheduled termination on Day 20 of gestation.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
no effects observed
Description (incidence and severity):
There was no effect of treatment on the numbers of implantations, resorptions (classified as early or late), live young, sex ratio or pre- and post-implantation loss.
Details on results:
There were no deaths on this study.
There were no signs seen at physical examinations or at post-dose observation considered related to treatment with Araldite PT 910.

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:
no effects observed
Changes in number of pregnant:
no effects observed
Other effects:
not examined
Details on maternal toxic effects:
There was no effect of treatment on the numbers of implantations, resorptions (classified as early or late), live young, sex ratio or pre- and post-implantation loss.

Effect levels (maternal animals)

Key result
Dose descriptor:
NOEL
Effect level:
ca. 60 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
body weight and weight gain
changes in number of pregnant
changes in pregnancy duration
clinical signs
dead fetuses
early or late resorptions
effects on pregnancy duration
food consumption and compound intake
gross pathology
mortality
number of abortions
pre and post implantation loss
total litter losses by resorption

Maternal abnormalities

Key result
Abnormalities:
no effects observed
Localisation:
not specified

Results (fetuses)

Fetal body weight changes:
effects observed, treatment-related
Description (incidence and severity):
For females which received Araldite PT-910 at 200 mg/kg/day, litter weight and fetal weight (male, female and overall) was statistically significantly lower than that of the control as well as if compared to those animals which received 20 and 60 mg/kg/day.
There was no effect of treatment on placental, litter or fetal weights in animals which received Araldite PT-910 at 20 or 60 mg/kg/day.
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
effects observed, treatment-related
Description (incidence and severity):
For females which received Araldite PT-910 at 200 mg/kg/day, litter weight and fetal weight (male, female and overall) was statistically significantly lower than that of the control as well as if compared to those animals which received 20 and 60 mg/kg/day.
There was no effect of treatment on placental, litter or fetal weights in animals which received Araldite PT-910 at 20 or 60 mg/kg/day.
Changes in postnatal survival:
not specified
External malformations:
effects observed, non-treatment-related
Description (incidence and severity):
Also, at 200 mg/kg/day there was an increased incidence of variation in lens shape and delayed/incompletely ossified/unossified sacrocaudal vertebral arches compared to concurrent control and outside of HCD. These findings are indicative of a delay in fetal development and may be attributed to the very slight decrease in mean fetal bodyweight seen at this dose level. Both abnormalities are a transient stage in fetal development and would therefore not be considered adverse.
Skeletal malformations:
effects observed, non-treatment-related
Description (incidence and severity):
At 200 mg/kg/day there were 3 fetuses/litters with bent scapula(e), short/thickened humerus with associated medially thickened/kinked/incompletely ossified ribs which were just outside of litter Historical Control Data (HCD). This is a known combination of abnormalities sometimes seen in the Crl: CD(SD) strain, including control groups. At such small values this is not thought to be treatment related.
Visceral malformations:
not examined
Other effects:
not examined
Details on embryotoxic / teratogenic effects:
Mean fetal weights were slightly reduced. Embryo-fetal survival was considered unaffected by treatment, but there were a number of findings at fetal pathology examination indicative of fetuses being at a transient stage in fetal development and not considered adverse.
Therefore, the No-Observed- Effect-Level (NOEL) for maternal toxicity and for embryo-fetal toxicity was concluded to be 60 mg/kg/day.

Effect levels (fetuses)

Key result
Dose descriptor:
NOEL
Effect level:
ca. 60 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
reduction in number of live offspring
changes in sex ratio
fetal/pup body weight changes
changes in litter size and weights
external malformations
skeletal malformations

Fetal abnormalities

Key result
Abnormalities:
effects observed, non-treatment-related
Localisation:
skeletal: scapule
skeletal: rib
skeletal: vertebra
Description (incidence and severity):
There were a number of findings at fetal pathology examination in the 200 mg/kg/day group, including an increased incidence of variation in lens shape and delayed/incompletely ossified/unossified sacrocaudal vertebral arches compared to concurrent control and outside of HCD. These minor findings are indicative of a delay in fetal development and may be attributed to the very slight decrease in mean fetal bodyweight seen at this dose level. Both abnormalities are a transient stage in fetal development and would therefore not be considered adverse.

Overall developmental toxicity

Key result
Developmental effects observed:
yes
Lowest effective dose / conc.:
60 mg/kg bw/day (nominal)
Treatment related:
no
Relation to maternal toxicity:
developmental effects in the absence of maternal toxicity effects
Dose response relationship:
not specified
Relevant for humans:
yes

Any other information on results incl. tables

Results from preliminary study - Araldite PT 910: Preliminary Study for Effects on Embryo-Fetal Development in the Rat by Oral Gavage Administration (Envigo ref WB30PP)

Maternal Responses

There were no unscheduled deaths, clinical signs or signs related to dosing that were considered related to treatment with Araldite PT 910.

Body Weight and Gravid Uterine Weight

Females receiving Araldite PT 910 at 200 mg/kg/day showed body weight stasis from the start of treatment (Day 1 of gestation) until Day 3 of treatment (Day 4 of gestation), compared with body weight gain of 8g in the Control group. From Day 4-18 of gestation body weight gain of these females was similar to Control. From Day 18 of gestation, body weight gain of females receiving 200 mg/kg/day was lower than Control resulting in the overall body weight gain (Days 1-20 of gestation) of these females being lower than Control (79% of Control). The body weight change for these females prior to treatment (Day 0-1 of gestation) was also lower than Control. 

Body weight gain of females receiving Araldite PT 910 at 100 mg/kg/day was similar to Control from the start of treatment until Day 18 of gestation. From Day 18 of gestation body weight gain of these females was lower than Control resulting in the overall body weight gain for these females being slightly lower than Control (92% of Control).

There was no effect of treatment on body weight gain for females which received Araldite PT 910 at 50 mg/kg/day.

The gravid uterus weight and maternal weight gain adjusted for the uterine weight was lower than Control for females receiving 200 mg/kg/day.

There was no effect of treatment on the gravid uterus weight or maternal weight change adjusted for the uterine weight of females which received Araldite PT 910 at 100 or 50 mg/kg/day.

Food Consumption

Following the start of study (Day 0 of gestation) and throughout gestation, food consumption of females receiving Araldite PT 910 at 200 mg/kg/day was slightly lower than Control and when compared with the pre dose intake. The food consumption of females receiving Araldite PT 910 at 100 or 50 mg/kg/day was similar to Control throughout the study.

Macropathology

Macroscopic findings in the adult females and fetuses at necropsy on Day 20 of gestation were limited to one female in the 200 mg/kg/day group with dilated pelvis; kidney.

Reproductive Assessment

The mean corpora lutea count was lower in the treated groups compared to Control. This is not treatment related because corpora lutea formed before treatment commenced. The resultant mean number of implantations was also lower in the treated groups compared to Control and given that there was no effect of treatment on pre-implantation loss, this is likely a result of a higher corpora lutea count in controls and not an effect of treatment. There was no effect of treatment on the number of early or late resorptions or sex ratio. 

Post-implantation loss was slightly higher than Control in females receiving Araldite PT 910 at 200 or 100 mg/kg/day and the resultant mean number of live young was also lower than Control in these groups.

In females receiving Araldite PT 910 at 50 mg/kg/day the mean number of live young was lower than Control, but given that there was no effect of treatment on pre- or post‑implantation loss in this group, this is a result of a higher corpora lutea and resulting higher implantation count and number of live young in the controls.

Placental, Litter and Fetal Weights

There was no effect of treatment on placental weight.  

Amongst the litters of females receiving Araldite PT 910 at 200 mg/kg/day mean fetal and litter weights were slightly lower than Control. There was no effect of treatment on fetal or litter weight in the litters of females receiving Araldite PT 910 at 100 or 50 mg/kg/day.

Conclusion

Based on these results, the high dose level for the main OECD 414 study could be 200 mg/kg/day, aiming to induce some signs of toxicity. Possible low and intermediate dose levels could be 20 and 60 mg/kg/day to investigate the dose response of any potential toxicity observed.

Applicant's summary and conclusion

Conclusions:
In this study, treatment with Araldite PT-910 at 20 or 60 mg/kg/day was generally well tolerated.
At 200 mg/kg/day, maternal body weight performance and food consumption was lower than that of the Control after the start of treatment (early gestation) and again between Days 18-20 of gestation. The gravid uterine weight and bodyweight gain when adjusted for the weight of the gravid uterus of females which received Araldite PT-910 at 200 mg/kg/day was lower than that of the control. Mean fetal weights were slightly reduced. Embryo-fetal survival was considered unaffected by treatment, but there were a number of findings at fetal pathology examination indicative of fetuses being at a transient stage in fetal development and not considered adverse.
Therefore, the No-Observed- Effect-Level (NOEL) for maternal toxicity and for embryo-fetal toxicity was concluded to be 60 mg/kg/day.