Registration Dossier

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Diss Factsheets

Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2018
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

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

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Version / remarks:
2016
Deviations:
no
Remarks:
No deviations ocurred that negatively impacted the integrity of the study.
GLP compliance:
yes (incl. QA statement)
Limit test:
no
Justification for study design:
Per OECD 422

Test material

Constituent 1
Chemical structure
Reference substance name:
Reaction mass of (((1,3-phenylenebis(oxy))bis(ethane-2,1-diyl))bis(oxy))bis(ethane-2,1-diyl) bis(2-methylacrylate) and (1,3-phenylenebis(oxy))bis(propane-3,1-diyl) bis(2-methylacrylate) and 3-(3-(2-(2-(methacryloyloxy)ethoxy)ethoxy)phenoxy)propyl methacrylaterate
EC Number:
944-271-1
Cas Number:
2305048-54-6
Molecular formula:
not applicable for multi-constituent.
IUPAC Name:
Reaction mass of (((1,3-phenylenebis(oxy))bis(ethane-2,1-diyl))bis(oxy))bis(ethane-2,1-diyl) bis(2-methylacrylate) and (1,3-phenylenebis(oxy))bis(propane-3,1-diyl) bis(2-methylacrylate) and 3-(3-(2-(2-(methacryloyloxy)ethoxy)ethoxy)phenoxy)propyl methacrylaterate
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source (i.e. manufacturer or supplier) and lot/batch number of test material: 3M Company, Batch 653940
- Purity, including information on contaminants, isomers, etc.: >95% targeted substances

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: At room temperature protected from light
- Stability and homogeneity of the test material in the vehicle/solvent under test conditions (e.g. in the exposure medium) and during storage: Stable under storage conditions until 31 May 2019. Analysis was performed on the dosing formulations to ensure proper homogeneity and concentration.

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing (e.g. warming, grinding): The test article was homogenized in PEG 400 prior to dosing.

FORM AS APPLIED IN THE TEST (if different from that of starting material)
Homogenized in PEG 400.

Test animals

Species:
rat
Strain:
Wistar
Details on species / strain selection:
The Wistar Han rat was chosen as the animal model for this study as it is an accepted rodent species for toxicity testing by regulatory agencies. This animal model has been proven to be susceptible to the effects of reproductive toxicants.
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany.
- Females (if applicable) nulliparous and non-pregnant: Yes
- Age at study initiation:Males: 10-12 weeks, Females: 12-14 weeks
- Weight at study initiation: Males: 278-332 g; Females: 195-237 g
- Fasting period before study: None
- Housing: On arrival and following the pretest (females only) and pre-mating period, Main animals were group housed (up to 5 animals of the same sex and same dosing group together) in polycarbonate cages (Macrolon, MIV type, height 18 cm). Recovery males and females were housed as such during the entire study period. During the mating phase, Main males and females were cohabitated on a 1:1 basis in Macrolon plastic cages (MIII type, height 18 cm). During the post-mating phase, Main males were housed in their home cage (Macrolon plastic cages, MIV type, height 18 cm) with a maximum of 5 males/cage. Main Females were individually housed in Macrolon plastic cages (MIII type, height 18 cm). During the lactation phase, Main females were housed in Macrolon plastic cages (MIII type, height 18 cm). Pups were housed with the dam, except during locomotor activity monitoring of the dams, when the pups were kept warm in their home cage using bottles filled with warm water. In order to avoid hypothermia of pups, pups were not left without their dam or a bottle filled with warm water for longer than 30-40 minutes. During locomotor activity monitoring, animals were housed individually in a Hi-temp polycarbonate cage (Ancare corp., USA; dimensions: 48.3 x 26.7 x 20.3 cm) without cageenrichment, bedding material, food and water.
- Diet (e.g. ad libitum): elleted rodent diet (SM R/M-Z) ad libitum
- Water (e.g. ad libitum): Tap water, ad libitum.
- Acclimation period: 8 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-22
- Humidity (%): 33-58%
- Air changes (per hr): at least 10
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: No data

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: See 'Remarks'
Remarks:
PEG 400
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:

VEHICLE
- Justification for use and choice of vehicle: Test article solubility and test system compatibility.
- Concentration in vehicle: Formulations were prepared to dose animals at 0 (vehicle), 100, 300, and 1000 mg/kg bw (0, 20, 60, and 200 mg/mL, respectively).
- Amount of vehicle (if gavage): 5 mL/kg.
- Lot/batch no. (if required): No data
- Purity: No data
Details on mating procedure:
- M/F ratio per cage: 1:1
- Length of cohabitation: 14 days
- Proof of pregnancy: vaginal plug or sperm in vaginal smear referred to as day 0 of pregnancy.
- After successful mating each pregnant female was caged (how): Individually
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Analyses were performed by UPLC-UV using a validated analytical procedure.

Duplicate sets of samples (approximately 500 mg) for each sampling time point were sent to the analytical laboratory. Concentration results were considered acceptable if mean sample concentration results were within or equal to ± 10% for solutions of target concentration.

Duplicate sets of samples (approximately 500 mg) for each sampling time point were sent to the analytical laboratory. Homogeneity results were considered acceptable if the coefficient of variation (CV) of concentrations was ≤ 10%.

Stability analyses performed previously in conjunction with the method development and validation study (Test Facility Study No. 519511) demonstrated that the test item is stable in the vehicle when prepared and stored under the same conditions at concentrations bracketing those used in the present study. Stability data have been retained in the study records for Test Facility Study No. 519511
Duration of treatment / exposure:
The test item and vehicle were administered to the appropriate animals by once daily oral gavage 7 days a week for a minimum of 28 days. Main males and Recovery males were treated for 29 days, including a minimum of 14 days prior to mating and during the mating period for Main males. For both Main and Recovery males treatment ended one day before scheduled necropsy of Main males. Main females were treated for 50 - 55 days, i.e. 14 days prior to mating (with the objective to cover at least two complete estrous cycles), the variable time to conception, the duration of pregnancy and at least 14 - 16 days after delivery, up to and including the day before scheduled necropsy. Recovery females were treated during the same period as Main females, until at least the first scheduled necropsy of
Main females.
Frequency of treatment:
Daily
Details on study schedule:
Screening-level reproductive and developmental study with a combined 28 day repeated dose study.
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (nominal)
Remarks:
Group 1 - Vehicle - PEG 400
Dose / conc.:
100 mg/kg bw/day (nominal)
Remarks:
Group 2
Dose / conc.:
300 mg/kg bw/day (nominal)
Remarks:
Group 3
Dose / conc.:
1 000 mg/kg bw/day (nominal)
Remarks:
Group 4
No. of animals per sex per dose:
10 per sex per dose in the main groups and 5 per sex per dose in the recovery group (vehicle group and 1000 mg/kg/day group).
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: A range-finding study was conducted to select doses.
- Rationale for animal assignment (if not random): Random
- Fasting period before blood sampling for clinical biochemistry: 24 hours.
:
Positive control:
None

Examinations

Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Clinical observations were performed once daily, beginning prior to the first administration of the test item and lasting throughout the dosing and recovery periods up to the day prior to necropsy

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Clinical observations were performed once daily, beginning prior to the first administration of the test item and lasting throughout the dosing and recovery periods up to the day prior to necropsy

BODY WEIGHT: Yes
- Time schedule for examinations: Animals were weighed individually on the first day of treatment (prior to dosing), and weekly thereafter. Mated Main females were weighed on Days 0, 4, 7, 11, 14, 17, and 20 post-coitum and during lactation on PND 1, 4, 7, and 13
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Food consumption was quantitatively measured weekly, except for Main males and Main females which were housed together for mating and for Main females without evidence of
mating. Food consumption of mated Main females was measured on Days 0, 4, 7, 11, 14, 17, and 20 post-coitum and during lactation on PND 1, 4, 7, and 13.

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study):
- Time schedule for examinations:Subjective appraisal was maintained during the study, but no quantitative investigation was introduced as no effect was suspected

Oestrous cyclicity (parental animals):
Estrous cycles were evaluated by examining the vaginal cytology of samples obtained by vaginal lavage.
Daily vaginal lavage was performed for all females (Main and Recovery) during 14 days prior to treatment (pretest period) and the first 14 days of treatment. For Main females, daily vaginal lavage was continued during mating until evidence of copulation was observed.
On the day of necropsy, a vaginal lavage was also taken from Main females to determine the stage of estrus. This was done for all females, except for females that had to be euthanized in extremis or died spontaneously.
Sperm parameters (parental animals):
Parameters examined in F0 male parental generations:
Spermatogenic profile via stage aware evaluation of the testes.
Litter observations:
STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: Yes
To reduce variability among the litters, on PND 4 eight pups from each litter of equal sex distribution (if possible) were selected. Blood samples were collected from two of the surplus pups (if possible from one male and one female pup). Selective elimination of pups, e.g. based upon body weight or AGD, was not done. Whenever the number of male or female pups prevents having four of each sex per litter, partial adjustment (for example, five males and three females) was acceptable.

PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities, anogenital distance (AGD), pup weight on the day of AGD, presence of nipples/areolae in male pups.

GROSS EXAMINATION OF DEAD PUPS:
Pups that died before scheduled termination were examined externally and sexed (both externally and internally).
Pups found dead during the weekend were fixed in identified containers containing 70% ethanol as they were not necropsied on the same day. The stomach of pups not surviving to the scheduled necropsy date was examined for the presence of milk, if possible. If possible, defects or cause of death were evaluated.

ASSESSMENT OF DEVELOPMENTAL NEUROTOXICITY: None, screening study.

ASSESSMENT OF DEVELOPMENTAL IMMUNOTOXICITY: None, screening study.
Postmortem examinations (parental animals):
SACRIFICE
- Male animals: Main Males: All surviving animals following completion of the mating period (a minimum of 29 days of administration). Recovery Males: After the recovery period of at least 14 days, which is at least 14 days after the scheduled necropsy of the Main males.
- Maternal animals: Mean Females: PND 14-16. Recovery Females: 14 days after the first scheduled necropsy of Main females.

GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.

HISTOPATHOLOGY / ORGAN WEIGHTS
Organ weights recorded for the following:

Brain
Heart
Cervix
Kidney
Epididymis
Liver
Ovaries
coagulation gland
Parathyroid gland
Prostate gland
Seminal vesicle
Thryoid gland
Ovaries
Spleen
Testes
Thymus
Uterus

Tissue collected and histopathology performed on the following:

Animal identification
Artery, aorta
Body cavity, nasopharynx
Bone marrow
Bone, femur
Bone, sternum
Brain (seven levels)
Cervix
Epididymisa
Esophagus
Eyea
Gland, adrenal
Gland, coagulation
Gland, harderiana
Gland, lacrimal
Gland, mammary
Gland, parathyroidc
Gland, pituitary
Gland, prostate
Gland, salivary
Gland, seminal vesicle
Gland, thyroid
Gross lesions/masses
Gut-associated lymphoid tissue
Heart
Kidney
Large intestine, cecum
Large intestine, colon
Large intestine, rectum
Larynx
Liverd
Lung
Lymph node (mandibular and mesenteric site)
Muscle, skeletal
Nerve, optica
Nerve, sciatic
Ovaries
Pancreas
Skin
Small intestine, duodenum
Small intestine, ileum
Small intestine, jejunum
Spinal cord
Spleen
Stomach
Testesa
Thymus
Tongue
Trachea
Urinary bladder
Uterus
Vagina



Postmortem examinations (offspring):
SACRIFICE
On PND 4, the surplus pups (> 8 pups per litter) were euthanized by decapitation. From two surplus pups per litter, blood was collected, if possible. All remaining pups were euthanized on PND 14-16. Sex was determined both externally and internally. Descriptions of all external abnormalities were recorded. Particular attention was paid to the external reproductive genitals to examine signs of altered development. In addition, blood was collected from two pups per litter, and the thyroid from two pups per litter (one male and one female pup) was preserved in 10% buffered formalin. The pups selected for blood sampling were the same pups as selected for thyroid preservation.

GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.

HISTOPATHOLOGY / ORGAN WEIGTHS
As this was a screening study, gross necropsy was performed. No histopathology was conducted with F1 animal tissues.
Statistics:
All statistical tests were conducted at the 5% significance level. All pairwise comparisons were conducted using two sided tests and were reported at the 1% and 5% levels. Numerical data collected on scheduled occasions for the listed variables were analyzed as indicated according to sex and occasion. Descriptive statistics number, mean and standard deviation (or %CV or SE when deemed appropriate) were reported whenever possible. Inferential statistics were performed according to the matrix below when possible, but excluded semi-quantitative data, and any group with less than 3 observations.

Parametric:
Datasets with at least 3 groups (the designated control group and 2 other groups) were compared using Dunnett-test (many-to-one-t-test).

Non-Parametric:
Datasets with at least 3 groups was compared using a Steel-test (many-to-one rank test). The motor activity data set was compared using an overall Kruskal-Wallis. The Wilcoxon Rank-Sum test was applied to compare the treated groups to the control group.

Incidence:
An overall Fisher’s exact test was used to compare all groups at the 5% significance level. The above pairwise comparisons were conducted using Fisher’s exact test whenever the overall test is significant.
Reproductive indices:
The following reproductive and developmental indices were recorded/calculated:

Mating (5)
Precoital time
Fertility index (%)
Gestation index (%)
Duratrion of gestation
Offspring viability indices:
The following offspring viability indices were recorded/calculated:

Post-implantation survival index (%)
Live birth index (%)
Percentage live males at First Litter Check (%)
Percentage live females at First Litter Check (%)
Viability index (%)
Lactation index (%)

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
no effects observed
Description (incidence and severity):
No clinical signs of toxicity were noted during the observation period.
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, non-treatment-related
Description (incidence):
No treatment-related mortality occurred during the study period. Early deaths that did occur included Control (2 animals) and treated group (1 Group 2, 2 Group 3, 1 Group 4) males and females. Deaths were secondary to intubation accidents or bleeding of the animals.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Body weights and body weight gain were not considered to have been affected by treatment.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
Food consumption before or after allowance for body weight was not considered to have been affected by treatment.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Description (incidence and severity):
No eye-related findings were noted during functional tests.
Haematological findings:
no effects observed
Description (incidence and severity):
Haematological parameters of treated rats were not considered to be affected by treatment.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
Clinical chemistry parameters of treated rats were not considered to be affected by treatment.
Endocrine findings:
effects observed, non-treatment-related
Description (incidence and severity):
T4 hormone was reduced in the 1000 mg/kg dose group adult males. This reduction
was not considered adverse as this change was considered relatively slight (within the
normal variation) without a clear dose-related trend (10, 10 and 17% lower than
controls at 100, 300 and 1000 mg/kg, respectively), and occurred in the absence of
treatment-related thyroid weight or histopathological changes.
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Description (incidence and severity):
No statistically-significant changes were noted in functional tests.
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
There were no test item-related microscopic observations.
Histopathological findings: neoplastic:
no effects observed
Description (incidence and severity):
There were no test item-related microscopic observations.

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Description (incidence and severity):
Length and regularity of the estrous cycle were not considered to have been affected by treatment
Reproductive function: sperm measures:
no effects observed
Description (incidence and severity):
Spermatogenic profiling (i.e. stage aware evaluation) did not reveal treatement-related changes.
Reproductive performance:
no effects observed
Description (incidence and severity):
No treatment-related changes were noted in any of the reproductive parameters investigated in this study (i.e. mating and fertility indices, precoital time, and number of implantations, estrous cycle, spermatogenic profiling (i.e. stage aware evaluation), and histopathological examination of reproductive organs).

Details on results (P0)

No adverse parental effects were observed up to the highest dose level tested (1000 mg/kg).
Females at 1000 mg/kg had a non-adverse lower mean motor activity (total movements)
compared to control mean at the end of treatment. This mean was not statistically significant,
and remained with the range considered normal for rats of this age and strain. Additionally,
since means between the control and 1000 mg/kg group the end of the recovery phase were
similar, and there were no other indicators of neurobehavioural deficits (eg. at
histopathological assessment), this variation was not considered to be adverse.
Non-mated females at 1000 mg/kg had a higher white blood cell, lymphocyte and platelet
count. These changes were not recorded for mated females at this dose. These changes may
have been related to treatment and their occurrence influenced by pregnancy status. However,
they were not considered adverse since means of these parameters remained within the
normal range, and occurred in the absence of any correlating histopathological changes.
No treatment-related changes were noted in any of the parental parameters investigated
in this study (i.e. clinical appearance, body weight, food consumption, haematological
investigations, macroscopic examination, organ weights, and microscopic examination).
T4 hormone was reduced in the 1000 mg/kg dose group adult males. This reduction
was not considered adverse as this change was considered relatively slight (within the
normal variation) without a clear dose-related trend (10, 10 and 17% lower than
controls at 100, 300 and 1000 mg/kg, respectively), and occurred in the absence of
treatment-related thyroid weight or histopathological changes.

Effect levels (P0)

Key result
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: See 'Remarks'

Target system / organ toxicity (P0)

Key result
Critical effects observed:
no

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Description (incidence and severity):
No treatment-related changes were noted in clinical signs.
Dermal irritation (if dermal study):
not examined
Mortality / viability:
no mortality observed
Description (incidence and severity):
No treatment-related changes in survival rates were obsered.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Body weights of pups were not considered to be affected by treatment.
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:
no effects observed
Description (incidence and severity):
Serum T4 levels in male and female PND 14-16 pups were not considered to be affected by
treatment.
Urinalysis findings:
not examined
Sexual maturation:
not examined
Anogenital distance (AGD):
no effects observed
Description (incidence and severity):
Treatment up to 1000 mg/kg/day had no effect on the anogenital distance normalized for
body weight. Absolute anogenital distance was not statistically significantly different to
control mean.
Nipple retention in male pups:
no effects observed
Description (incidence and severity):
Treatment up to 1000 mg/kg/day had no effect on areola/nipple retention. For none of the
examined male pups nipples were observed at PND 13
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Description (incidence and severity):
No macroscopic findings were noted among pups that were considered to be
related to treatment
Histopathological findings:
not examined

Developmental neurotoxicity (F1)

Behaviour (functional findings):
not examined

Developmental immunotoxicity (F1)

Developmental immunotoxicity:
not examined

Details on results (F1)

No treatment-related changes were noted in any of the other developmental parameters
investigated in this study (i.e. gestation, viability and lactation indices, duration of
gestation, parturition, sex ratio, maternal care and early postnatal pup development
consisting of mortality, clinical signs, body weight, areola/nipple retention (PND 13
males), anogenital distance, T4 thyroid hormone levels (PND 13-15) and macroscopy.

Effect levels (F1)

Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: See 'Remarks'

Target system / organ toxicity (F1)

Key result
Critical effects observed:
no

Overall reproductive toxicity

Key result
Reproductive effects observed:
no

Applicant's summary and conclusion

Conclusions:
Based on the results of the study, the No Observed Adverse Effect Level (NOAEL) for systemic toxicity, reproductive performance, fertility, and developmental effects was 1,000 mg/kg-day DiBrORMA.
Executive summary:

A combined repeated-dose toxicity study with reproductive/developmental screening test was conducted with DiBrORMA according to OECD 422 (2016). The study was conducted in compliance with OECD GLP. DiBrORMA was administered by daily oral gavage to male and female Wistar Han rats at dose levels of 0 (control), 100, 300, and 1,000 mg/kg, followed by a 14-day treatment-free recovery period. Main males (10/group) and recovery males (5 in the control and 1,000 mg/kg-day group) were both exposed to DiBrORMA for 29 days. Main females (10/group) were exposed to DiBrORMA for 41-55 days, while recovery females (5 in the control and 1,000 mg/kg-day group) were exposed for 44 days. The following organs and tissues were examined: bone marrow, bone (femur and sternum), brain, cervix, epididymis, eye, adrenal gland, mammary gland, parathyroid gland, pituitary gland, prostate, seminal vesicles, thyroid gland, gross lesions, gut-associated lymphoid tissue, heart, kidney, small and large intestines (duodenum, jejunum, ileum, cecum, colon, and rectum), liver, lung, lymph node, skeletal muscle, sciatic nerve, ovaries, pancreas, spinal cord, spleen, stomach, testes, thymus, trachea, urinary bladder, uterus, and vagina. Two animals in the control group and four animals in the treatment groups (1 from 100 mg/kg-day, 2 from 300 mg/kg-day, and 1 from 1,000 mg/kg-day) died. These deaths were determined to be secondary to intubation accidents or bleeding of the animals (non-treatment-related). Overall, no adverse parental effects were observed up to the highest dose level tested (1,000 mg/kg). Females in the 1,000 mg/kg-day group had a lower mean motor activity (total movements) compared to control mean at the end of treatment. This variation was not considered to be adverse since the mean was not statistically significant and remained within the range considered normal for rats of this age and strain. Additionally, there were no other indicators of neurobehavioral deficits (e.g. at histopathological assessment). Non-mated females in the 1,000 mg/kg-day group had a higher white blood cell, lymphocyte, and platelet count. However, these changes were not considered adverse since the means of these parameters remained within the normal range and occurred in the absence of any correlating histopathological changes. T4 hormone was reduced in adult males in the 1,000 mg/kg-day group. However, this reduction was not considered adverse as this change was considered relatively slight (within the normal variation) without a clear dose-related trend (10, 10 and 17% lower than controls at 100, 300, and 1,000 mg/kg, respectively), and occurred in the absence of treatment-related thyroid weight or histopathological changes. No treatment-related changes were noted in any of the reproductive parameters (i.e. mating and fertility indices, precoital time, number of implantations, estrous cycle, spermatogenic profiling, and histopathological examination of reproductive organs) or developmental parameters (i.e. gestation, viability and lactation indices, duration of gestation, parturition, sex ratio, maternal care and early postnatal pup development consisting of mortality, clinical signs, body weight, areola/nipple retention (PND 13 males), anogenital distance, T4 thyroid hormone levels (PND 13-15) and macroscopy) investigated in this study. Based on these findings, the No Observed Adverse Effect Level (NOAEL) for systemic toxicity, reproductive performance, fertility, and developmental effects was 1,000 mg/kg-day DiBrORMA.