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Diss Factsheets

Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
August - September 2019
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Justification for type of information:
The test was initiated based on a request for information in a final ECHA decision (CCH-D-2114376213-53-01/F).

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2020

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Version / remarks:
25 June 2018
Deviations:
no
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Reaction products of 4,4'-isopropylidenediphenol, ethoxylated and methacrylic acid
EC Number:
935-411-2
Cas Number:
not available
Molecular formula:
C23H24O4 (C2H4O)n
IUPAC Name:
Reaction products of 4,4'-isopropylidenediphenol, ethoxylated and methacrylic acid
Test material form:
liquid

Test animals

Species:
rat
Strain:
Sprague-Dawley
Remarks:
RjHan:SD (CD®), SPF
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Janvier, le Genest-Saint-Isle, France
- Age at study initiation: 10-11 weeks
- Weight at study initiation: 242g to 342g
- Fasting period before study: No
- Housing: Individual housing in polycarbonate cages with stainless steel lids and containing autoclaved sawdust. Each cage contained nylabone and rat hut for environmental enrichment.
- Diet: Free access to SSNIFF rat/mouse pelleted maintenance diet (SSNIFF Spezialdiäten GmbH, Soest, Germany)
- Water: Free access to bottles containing tap water (filtered with a 0.22 µm filter)
- Acclimation period: 4 or 5 days

CONTAMINANT ANALYSES
The batches of diet and sawdust were analyzed by the Suppliers for composition and contaminant levels. Bacterial and chemical analyses of water are performed regularly by external laboratories. These analyses include the detection of possible contaminants (pesticides and heavy metals). No contaminants were present in the diet, drinking water or sawdust at levels which could be expected to interfere with, or prejudice, the outcome of the study.

ENVIRONMENTAL CONDITIONS (SET CONDITIONS)
- Temperature (°C): 22 ± 2
- Humidity (%): 50 ± 20
- Air changes (per hr): about 8 to 15 cycles/hour of filtered, non-recycled air
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 12 August 2019 To: 05 September 2019

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
The formulations were prepared according to Citoxlab France/Study No. 46148 AHS (homogeneity testing) describing the preparation procedure for a range of concentrations covering the lowest and highest used in this study. The formulations were freshly prepared on the days of treatment. The dose formulations were maintained under delivery conditions (at room temperature and protected from light) throughout the administration procedure. They were stirred for at least 15 minutes before administration and were maintained under continuous magnetic stirring throughout the dosing procedure. The test item dose formulations were administered within 4 hours after the end of their preparation.

A constant dosage volume of 5 mL/kg bw/day was used (concentrations 0, 20, 60 and 200 mg/mL).
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The dose formulation analyses were done using a validated method (HPLC/UV).
Determination of test item concentrations in dose formulations was done twice in the study (Day 5 and Day 20 p.c.).
Acceptance criterion: Measured concentration = nominal concentration ± 10%
Details on mating procedure:
Females were mated at the breeder's facilities. The day of confirmed mating (detection of a vaginal plug) was designated as Day 0 p.c.
Duration of treatment / exposure:
16 days (from Day 5 to Day 20 post-coitum (p.c.) inclusive)
Frequency of treatment:
Once daily
Duration of test:
females were sacrificed Day 21 post-coitum
Doses / concentrationsopen allclose all
Dose / conc.:
100 mg/kg bw/day (actual dose received)
Remarks:
Low dose group
Dose / conc.:
300 mg/kg bw/day (actual dose received)
Remarks:
Mid dose group
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
Remarks:
High dose group
No. of animals per sex per dose:
24
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale:
The dose levels were selected on the basis of the results of a previous OECD 422 study (Citoxlab France/Study No. 46151 RSR), in which the test item was administered by gavage at 100, 300 or 1000 mg/kg bw/day to male and female rats from 2 weeks before mating, through mating and, for females, through gestation until Day 13 post-partum (p.p.). The No Observed Adverse Effect Level (NOAEL) for parental toxicity and the No Observed Effect Level (NOEL) for reproductive performance were established at 1000 mg/kg bw/day due to the absence of adverse effects at this high dose. The NOEL for toxic effects on progeny was considered to be 100 mg/kg/ bwday based on the retention of areola in male pups at 300 and 1000 mg/kg bw/day.

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: once a day before the treatment period and three times a day during the treatment period for mortality and morbidity

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once a day

BODY WEIGHT: Yes
- Time schedule for examinations: recorded on Days 2, 5, 7, 9, 12, 15, 18 and 21 p.c.

FOOD CONSUMPTION: Yes
- The quantity of food consumed by each female was recorded for the following intervals: Days 2-5, 5-7, 7-9, 9-12, 12-15, 15-18 and 18-21 p.c.

WATER CONSUMPTION: No

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 21
- Gross macroscopy
- Weight of the gravid uterus was determined
- Thyroids with parathyroids were weighed after fixation, microscopic examination was performed on the thyroids with parathyroids from all animals.
- For apparently non pregnant females, the presence of implantation scars on the uterus was checked using the ammonium sulphide staining technique.
- A gross evaluation of placentas was also undertaken. The placenta weight was recorded for each fetus and the fetal weight/placental weight ratio was calculated.

OTHER:
Blood samples were taken from all females at termination to determine the levels of the thyroid hormones (T4 and T3) and Thyroid Stimulating Hormone (TSH).
Ovaries and uterine content:
The ovaries and uterus of the females were examined to determine:
- number of corpora lutea,
- number and distribution of dead and live fetuses,
- number and distribution of early and late resorptions,
- number and distribution of uterine scars,
- number and distribution of implantation sites.

The following classification was used to record:
- uterine scar: uterine implantation without implant,
- early resorption: evidence of implant without recognizable embryo,
- late resorption: dead embryo or fetus with degenerative changes,
- dead fetus: dead fetus with no degenerative changes.
Fetal examinations:
- External examinations: Yes: all per litter
The body weight of each fetus was recorded. The sex of each fetus was determined at the time of hysterectomy by measurement of the anogenital distance (AGD) and was confirmed by internal examination of sexual organs at detailed dissection of the soft tissues or at evisceration.
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: Yes: half per litter
Statistics:
Data on body weight, food consumption and litter data were compared by one-way analysis of variances and Dunnett test (mean values being considered as normally distributed, variances being considered as homogenous) or by Fisher’s exact probability test (proportions).
Overview of the strategy used for the statistical analyses of hormone and anogenital distance data and organ weights is attached below.
Historical control data:
yes

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
No relevant clinical signs were observed during the study.
Ptyalism was noted in 19/24 females at 1000 mg/kg bw/day, starting at the earliest on Day 8 p.c. and lasted generally until the end of the treatment period. This sign, also reported in one female at 100 mg/kg bw/day and one female at 300 mg/kg bw/day, is commonly observed when a test item is administered by gavage and was not considered to represent an adverse effect.
The other clinical signs recorded in pregnant females were considered to be unrelated to the test item treatment as they were isolated findings (chromodacryorrhea in one female at 1000 mg/kg bw/day) and/or are commonly observed in pregnant females of this strain and age (brownish vaginal discharge in one female at 300 mg/kg bw/day from Day 15 p.c. and in one female at 1000 mg/kg bw/day on Day 20 p.c.).
Description (incidence and severity):
n/a
Mortality:
no mortality observed
Description (incidence):
No unscheduled deaths occurred during the study.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No effects were noted on mean body weights or mean body weight changes at any dose level.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
No effects were noted on mean food consumption at any dose level
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:
no effects observed
Description (incidence and severity):
The mean thyroid hormone levels (T3, T4 and TSH) were considered to be unaffected by the test item treatment in the absence of statistically significant changes and dose-related changes.
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):
No effects on mean gravid uterus weights, placenta weights, carcass weights or mean net body weight changes (g) were observed at any dose level. No test item-related changes in the thyroid weights were recorded.
Gross pathological findings:
no effects observed
Description (incidence and severity):
No test item-related macroscopic post-mortem findings were observed at necropsy of the dams at any dose level.
The only macroscopic observation, i.e. enlarged placenta, was not attributed to the test item treatment as it was recorded both in control and test item-treated females with the same incidence.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
No test item-related microscopic findings were observed.
Histopathological findings: neoplastic:
not examined
Details on results:
At hysterectomy on Day 21 p.c., 20/24, 24/24, 21/24 and 24/24 females were pregnant with live fetuses in the groups treated at 0, 100, 300 and 1000 mg/kg bw/day, respectively. In the control group, 4 non-pregnant females were found and two females in the mid dose group were non-pregnant. One female in the mid dose group was found with no live fetuses and uterine scars.

Maternal developmental toxicity

Number of abortions:
no effects observed
Description (incidence and severity):
No effects on hysterectomy data were observed at any dose level, a table summarizing the results is included below.
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Description (incidence and severity):
The statistically lower mean number of early resorptions in females at 1000 mg/kg bw/day, when compared with controls, was considered to be not relevant due to the direction of change. The higher number of implantation scars at 300 mg/kg bw/day was considered to be unrelated to the test item treatment as this finding was due to the contribution of a single female and was not observed in the high dose group.
Dead fetuses:
no effects observed
Changes in pregnancy duration:
not examined
Changes in number of pregnant:
no effects observed

Effect levels (maternal animals)

Key result
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: No effects observed up to and including the highest dose tested (1000 mg/kg bw/day)
Remarks on result:
not determinable due to absence of adverse toxic effects

Maternal abnormalities

Key result
Abnormalities:
no effects observed

Results (fetuses)

Fetal body weight changes:
no effects observed
Description (incidence and severity):
Mean fetal body was unaffected by the test item treatment at any dose level (mean fetal weights of 5.91g, 5.87g, 5.97g and 5.85g for the fetuses in the control, low, mid and high dose, respectively). The fetal body weight/ placental weight ratio was comparable between the groups (8.26, 8.58, 8.69 and 8.26 for the control, low, mid and high dose, respectively).
Reduction in number of live offspring:
not examined
Changes in sex ratio:
no effects observed
Description (incidence and severity):
Sex ratio was unaffected by the test item treatment at any dose level (mean percentage of males of 49.5%, 49.9%, 49.5% and 44.6% for the fetuses in the control, low, mid and high dose, respectively). .
Changes in litter size and weights:
not examined
Changes in postnatal survival:
not examined
External malformations:
no effects observed
Description (incidence and severity):
No test item-related external variations or malformations were observed at any dose level. In controls, an anasarca (generalized oedema) was observed in one fetus, a finding commonly observed in this species and strain.
Skeletal malformations:
no effects observed
Description (incidence and severity):
The incidences of fetuses and litters incidences with skeletal variations and malformations are attached. No test item-related skeletal variations were observed at any dose level. When compared with controls, higher incidence of fetuses and litters with unossified or incompletely ossified bones was noted among test item-treated animals. These findings, not statistically significant, were either poorly or not dose-related or reported with a low incidence, with no effects on mean fetal body weight. A relationship to the test item treatment was therefore considered to be unlikely.

Visceral malformations:
no effects observed
Description (incidence and severity):
No visceral malformations were observed at any dose level. The incidences of fetuses and litters with soft tissues variations are attached. No test item-related visceral variations were observed at any dose level. The few findings recorded were considered to be incidental as they were noted both in control and test item-treated animals and/or are common findings in pregnant rats of this strain and age.
No test item-related skeletal cartilage effects were observed at any dose level.
No test item-related skeletal malformations were observed at any dose level. The few findings recorded were considered to be incidental as they were noted both in control and test item-treated animals and/or were noted in isolated fetuses and remained within the range of the historical data range of the test facility.
Other effects:
no effects observed

Effect levels (fetuses)

Key result
Dose descriptor:
NOEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No effects observed up to and including the highest dose tested (1000 mg/kg bw/day)
Remarks on result:
not determinable due to absence of adverse toxic effects

Fetal abnormalities

Key result
Abnormalities:
no effects observed

Overall developmental toxicity

Key result
Developmental effects observed:
no

Any other information on results incl. tables

CHEMICAL ANALYSES OF THE DOSE FORMULATIONS


The test item concentrations in the administered dose formulations analyzed on Day 5 p.c.and Day 20 p.c. remained within an acceptable range of variations (-3.3% to -0.2%) when compared to the nominal values (± 10% of the nominal concentrations).


No test item was detected in the control dose formulation.

Applicant's summary and conclusion

Conclusions:
Based on the results of a prenatal developmental study, performed with Reaction products of 4,4'-isopropylidenediphenol, ethoxylated and methacrylic acid according to OECD/EC guidelines and GLP principles, the No Observed Adverse Effect Level (NOAEL) for maternal parameters was considered to be 1000 mg/kg bw/day, the No Observed Effect Level (NOEL) for embryo-fetal development was considered to be 1000 mg/kg bw/day.
Executive summary:

The objective of this study was to evaluate the potential toxic effects of the test item, Reaction products of 4,4'-isopropylidenediphenol, ethoxylated and methacrylic acid, on the pregnant female rat and on the developing organism, following daily oral administration (gavage) from Day 5 to Day 20 post-coitum (p.c.) inclusive.


Three groups of 24 time-mated female Sprague-Dawley rats received the test item, Reaction products of 4,4'-isopropylidenediphenol, ethoxylated and methacrylic acid, once daily by the oral route (gavage) at dose levels of 100, 300 or 1000 mg/kg/day from Day 5 to Day 20 p.c. inclusive. A control group of


24 time-mated females received the vehicle (corn oil), under the same experimental conditions. A constant dosage volume of 5 mL/kg/day was used. The animals were checked daily for mortality and clinical signs. Body weight and food consumption were recorded at designated intervals. At termination, thyroid hormones (TSH, T3 and T4) were determined for all females. On Day 21 p.c., the females were euthanized and a macroscopic post-mortem examination was performed. Thyroids with parathyroids were weighed and examined microscopically. Hysterectomies were performed and the numbers of corpora lutea, implantation sites, early and late resorptions, and live and dead fetuses


were recorded. Placentas were observed and weighed. The fetuses were weighed, examined for external abnormalities and sexed by internal examination of the gonads. The anogenital distance was measured. The fetuses were subjected to detailed external, soft tissue and skeletal examinations.


At hysterectomy on Day 21 p.c., 20/24, 24/24, 21/24 and 24/24 females were pregnant with live fetuses in the groups treated at 0, 100, 300 and 1000 mg/kg/day, respectively. No unscheduled deaths occurred during the study. Ptyalism was observed especially in most females at 1000 mg/kg/day. This sign, commonly noted when a test item is administered by gavage, was not considered to represent an adverse effect.


Body weight, body weight change and food consumption were unaffected by the test item treatment. At necropsy of the dams, no test item-related macroscopic findings were observed. Gravid uterus weight, carcass weight, net body weight change and gestation parameters were not impacted by the test item treatment. Thyroid hormone analysis and thyroid gland examination did not reveal any disturbances at any


dose level. No effects on the fetal body weight, placental weight, sex ratio or anogenital distance were noted at any dose level. At external, soft tissue or skeletal examination of the fetuses, no variations or malformations attributable to the test item treatment were noted.


 


The test item, Reaction products of 4,4'-isopropylidenediphenol, ethoxylated and methacrylic acid, was administered daily to time-mated female Sprague-Dawley rats by the oral route (gavage) at dose levels of 100, 300 or 1000 mg/kg/day from Day 5 to Day 20 p.c., inclusive.


Based on the results obtained in this study:


. the No Observed Adverse Effect Level (NOAEL) for maternal parameters was considered to be 1000 mg/kg/day,


. the No Observed Effect Level (NOEL) for embryo-fetal development was considered to be 1000 mg/kg/day.