Registration Dossier

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:
2019

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
Version / remarks:
2016
Deviations:
no
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
liquid: viscous
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 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.