Registration Dossier

Administrative data

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Effects on fertility

Description of key information

Combined repeated dose toxicity study with reproduction/developmental toxicity screening (OECD 422):


NOAEL for reproductive performance of male/ female rats: 1000 mg/kg bw/day

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From 4 June 2019 to 15 November 2019
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Version / remarks:
29 July 2016
Qualifier:
according to
Guideline:
other: OPPTS 870.3650 Combined Repeated Dose Toxicity with the Reproduction/Developmental Toxicity Screening Test
Version / remarks:
July 2000
GLP compliance:
yes (incl. certificate)
Limit test:
no
Specific details on test material used for the study:
The test solution contains NaOH due to the production method.
Species:
rat
Strain:
Wistar
Details on species / strain selection:
Han:Wistar of Wistar origin
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Toxi-Coop Zrt. 1103 Budapest, Cserkesz u. 90 Hungary
- Females nulliparous and non-pregnant: yes
- Age at study initiation: Males: 83-92 days; Females: 75-83 days
- Weight at study initiation: Males: 348-421 g; Females: 210-259 g
- Housing: Type III polypropylene/polycarbonate
Before mating: 2 animals of the same sex /cage.
Mating: 1 male and 1 female /cage.
Mated females: individually.
Males after mating: 2 animals /cage.
- Diet: Commercial ssniff® SM R/M-Z+H complete diet for rats and mice - breeding and maintenance and ssniff® SSNIFF rat/Souris Elevage E, 10 mm autoclavable complete feed for rats, ad libitum
- Water: Ad libitum
- Acclimation period: 20 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3°C
- Humidity (%): 30-70 %
- Air changes (per hr): Above 10 air-exchanges/hour by a central air-condition system
- Photoperiod (hrs dark / hrs light): 12 hours dark/12 hours light

IN-LIFE DATES: From 26 June 2019 to 21 August 2019
Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS
VEHICLE:
- Concentration in vehicle: The test substance was formulated in the vehicle in concentrations of 30, 90 and 200 mg/mL.
- Amount of vehicle (if gavage): The dose volume was 5 mL/kg bw.
Details on mating procedure:
M/F ratio per cage: 1:1
- Length of cohabitation: 1-4 days
- Proof of pregnancy: Vaginal smears were prepared daily and examined for the presence of vaginal plug or sperm. Presence of vaginal plug or sperm in the vaginal smear was considered as evidence of copulation (day 0 of pregnancy as defined by OECD 422)
- After successful mating each pregnant female was caged individually.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Analytical control of dosing formulations (control of concentration) was performed three times during the study. Five aliquots of 5 mL of each formulation and five aliquots of control substance (vehicle) were taken and analyzed. The samples were stored at 2 - 8°C until analysis. Concentration of the test item in the dosing formulations varied between the range of 97.3 % and 105 % in comparison to the nominal values.
Duration of treatment / exposure:
Dosing of both sexes began after acclimatization and two weeks before mating and was continued up to and including the day before the necropsy.
Male animals were dosed for 44 days (14 days pre-mating and 1-4 days mating, plus 26-29 days of post-mating period); and were sacrificed on Day 44.
Females were dosed for 14 days pre-mating, through 1-4 days mating period and throughout pregnancy and at least up to and including day 13 post-partum or the day before sacrifice on Days 51 or 56.
Frequency of treatment:
Once daily
Dose / conc.:
0 mg/kg bw/day (nominal)
Remarks:
Control
Dose / conc.:
150 mg/kg bw/day (nominal)
Dose / conc.:
450 mg/kg bw/day (nominal)
Dose / conc.:
1 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
12
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: See supporting study: 14-Day Oral Gavage Dose Range Finding Study with EP1-Na (Danafloat 123) in Rats, Toxi-Coop Zrt., 2019
Positive control:
No
Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS:
- Time schedule: Twice daily.

DETAILED CLINICAL OBSERVATIONS:
- Time schedule: General clinical observations were made on parental animals once a day, after the administration.
Detailed examinations were made weekly, prior to and during the mating and until necropsy. Detailed clinical observations were made on all animals outside the home cage in a standard arena once prior to the first exposure and once weekly thereafter. Observations were performed on the skin, fur, eyes and mucous membranes, autonomic activity (lachrymation, piloerection, pupil size, respiratory pattern, occurrence of secretions and excretions), circulatory and central nervous system, somatomotor activity and behavior pattern, changes in gait, posture and response to handling. Special attention was directed towards the observation of tremors, convulsions, salivation, diarrhea, lethargy, sleep and coma.
Sensory reactivity to different type of stimuli (e.g. auditory, visual and proprioceptive), assessment of grip strength and motor activity were conducted on five male and five female animals randomly selected from each group during the last exposure week. General physical condition and behavior of animals were tested.

BODY WEIGHT:
- Time schedule for examinations:
Parental males were weighed on the first day of dosing (Day 0) and weekly thereafter and on the day of the necropsy.
Parental females were weighed on the first day of dosing (Day 0) then weekly, on gestation days 0, 7, 14 and 21 and on days 0 (within 24 hours after parturition), 4 and 13 post-partum. Body weight of the female animals was additionally weighed on gestational day 10 in order to give accurate treatment volumes, but these data were not evaluated statistically. Body weight was measured on the day of necropsy for female animals subjected to organ weighing (selected for further examinations).

FOOD CONSUMPTION:
The food consumption was determined weekly during the treatment period except mating phase (pre-mating days 0, 7, 13 and post-mating days 20, 27, 34 and 41 for male animals, pre-mating days 0, 7, 13, gestation days 0, 7, 14 and 21, lactation days 0, 4 and 13 for female animals).

CLINICAL PATHOLOGY:
Clinical pathology examinations including hematology and clinical chemistry were conducted in five male and five female animals randomly selected from each group one day after the last treatment (i.e. on the day of necropsy). Animals were food deprived for approximately 16 hours (overnight) prior to blood collection.

HEMATOLOGY:
Parameters checked in Table 1 were examined.

BLOOD COAGULATION:
Parameters examined: Activated partial Thromboplastin Time (APTT), Prothrombin Time (PT)

CLINICAL CHEMISTRY:
Parameters checked in Table 2 were examined.

DETERMINATION OF SERUM THYROID HORMONE:
Blood samples for determination of serum levels of thyroid hormones (FT4 and TSH) were collected from animals as follows:
- from 2-8 pups per litter on post-natal day 4 (if it was feasible; samples were pooled by litter)
- from all dams and from 6-7 pups per litter on post-partum/post-natal day 13;
- from all parent male animals at termination on Day 44.
Oestrous cyclicity (parental animals):
Estrous cycle was monitored by examining vaginal smears daily before the treatment for two weeks and for two weeks from the beginning of the treatment period and during the mating period until evidence of copulation. Vaginal smears were prepared on the day of the necropsy for each female animal.
Sperm parameters (parental animals):
Parameters examined in all male animals:
Weight of testis, epidymides and prostate and seminal vesicles with coagulating glands weight as a whole.
Litter observations:
STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: yes
Each litter was adjusted to 4 pups/sex/litter if feasible.

PARAMETERS EXAMINED
The following parameters were examined: Number and gender of pups, stillbirths, live births, runts (pups that are significantly smaller than normal pups), and the presence of gross abnormalities. Litters were weighed on day 0, 4 and 13 post-natal. Any abnormal behavior of the offspring was recorded. The anogenital distance of each pup was determined on post-natal day 4. The number of nipples/areolae in male pups was counted on post-natal day 13.

GROSS EXAMINATION OF DEAD PUPS:
Dead or stillborn offspring were subjected to necropsy by macroscopic examination on the day when they were found dead.
Postmortem examinations (parental animals):
SACRIFICE
- Male animals: All male animals were sacrificed on Day 44
- Maternal animals: Dams selected for toxicology examination were sacrificed on Day 51; dams remained on Day 56 and non-pregnant female animal on Day 44.

GROSS NECROPSY
- Gross necropsy was performed on all parental animals and consisted of external and internal examinations including the cranial, thoracic and abdominal cavities. Special attention was paid to the organs of the reproductive system.

HISTOPATHOLOGY / ORGAN WEIGHTS
At the time of termination, body weight, brain weight, weight of the testes, epididymides and prostate and seminal vesicles with coagulating glands as a whole of all male adult animals were determined. In addition, for five males and females randomly selected from each group, adrenal glands, brain, heart, kidneys, liver, spleen and thymus were weighed.
The ovaries, uterus with cervix, vagina, testes, epididymides (total and cauda), prostate, and seminal vesicles with coagulating glands, and all organs showing macroscopic lesions of all adult animals were preserved. Thyroid gland was preserved from all adult males and females and from one male and one female pup per litter. Tissues and organs (see Table 3) were collected from 5 male and five female animals randomly selected from each group.

Detailed histological examination was performed on the ovaries, uterus with cervix, vagina, testes, epididymides, prostate and seminal vesicles with coagulating gland in all animals of control and high dose groups – including non-pregnant female and its mating partner – with special emphasis on stages of spermatogenesis in the male gonads and histopathology of interstitial testicular cell structure and on the ovaries covering the follicular, luteal, and interstitial compartments of the ovary, as well as the epithelial capsule and ovarian stroma.
Full histopathology examinations were performed on the preserved organs and tissues of the randomly selected animals in the control and high dose (1000 mg/kg bw/day) groups and in dead female animals at 450 mg/kg bw/day.
Additionally, organs and tissues were processed and evaluated histologically on the basis of necropsy observations.
Postmortem examinations (offspring):
On the day of birth, pups found dead were subjected to a lung flotation test to differentiate pups died intrauterine (stillborn; negative lung flotation test) from pups died after the birth (dead pups; positive lung flotation test).
Offspring were sacrificed on Day 13 or shortly thereafter and carefully examined for gross abnormalities. All organs showing macroscopic lesions were preserved and evaluated histologically.
Statistics:
The statistical evaluation was performed with the statistical program package SPSS PC+4.0. The homogeneity of variance between groups was checked by Bartlett’s homogeneity of variance test. Where no significant heterogeneity was detected a one-way analysis of variance (ANOVA) was carried out. If the obtained result was significant Duncan Multiple Range test was used to access the significance of inter-group differences. Getting significant result at Bartlett’s test, the Kruskal-Wallis analysis of variance was used and the inter-group comparisons were performed using Mann-Whitney U-test. Chi2 test was performed if feasible.
Frequency of toxic response, pathological and histopathological findings by sex and dose was calculated.
Reproductive indices:
Male and female mating and fertility index, female gestation index
Offspring viability indices:
Survival index
Clinical signs:
no effects observed
Mortality:
mortality observed, non-treatment-related
Description (incidence):
There was no test item related mortality at any dose level.
One dam at 450 mg/kg bw/day (1/12), was found dead on post-partum (lactation) day 5. There were no preceding clinical signs for this animal. Based on findings at necropsy and histological evaluation, the cause of death was judged to be individual disease and not related to the treatment as no death occurred at the higher (1000 mg/kg bw/day) dose level.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Slightly reduced mean body weight gain in male and female animals at 1000 mg/kg bw/day resulted in minor changes in the mean body weight (≥ - 7 % relative to control) therefore was considered to have little or no toxicological relevance.
Food consumption and compound intake (if feeding study):
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Squamous cell hyperplasia in the non-grandular part of the stomach was observed in some female animals at 450 and 1000 mg/kg bw/day (4/4 and 6/6 respectively)
Reproductive function: oestrous cycle:
no effects observed
Reproductive performance:
no effects observed
Key result
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: Systemic toxicity
Key result
Dose descriptor:
NOAEC
Effect level:
30 other: mg/mL (administered to animals of 150 mg/kg bw/day group)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: Stomach irritation
Key result
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
reproductive performance
Critical effects observed:
not specified
Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Anogenital distance (AGD):
no effects observed
Nipple retention in male pups:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings:
no effects observed
Other effects:
no effects observed
Description (incidence and severity):
The thyroid hormone (free T4 and TSH) levels were not affected by the test item in offspring sampled on post-natal day 13.
Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: General health parameters
Reproductive effects observed:
no
Conclusions:
Under the conditions of the present study, EP1-Na administered at 150, 450 or 1000 mg/kg bw/day by oral gavage did not adversely influence the reproductive performance (gonad function, mating behavior, conception, parturition) or gave any indication to cause endocrine effects in parental male and female Han:WIST rats as far as investigated in this study.
There were no signs of systemic toxicity in male or female animals at 150, 450 or 1000 mg/kg bw/day. In the female animals at 450 and 1000 mg/kg bw/day, squamous cell hyperplasia in the non-glandular part of the stomach referred to the local effect of the test item. Besides of this local tissue irritation no other histological findings were noted.
The development of the F1 offspring was not impaired from birth to post-natal day 13 as far as investigated in this study after repeated oral administration of dams at 150, 450 or 1000 mg/kg bw/day.

Based on these observations the No Observed Adverse Effect Levels (NOAEL) were determined as follows:
NOAEL for systemic toxicity of male/ female rats: 1000 mg/kg bw/day
NOAEC (stomach irritation, female rats): 30 mg/mL (administered to animals of 150 mg/kg bw/day group)
NOAEL for reproductive performance of male/ female rats: 1000 mg/kg bw/day
NOAEL for F1 Offspring: 1000 mg/kg bw/day

Remark: The test substance as produced and marketed contains NaOH due to the production method.
Executive summary:

The toxicity of the substance was assessed in a Combined Dose Toxicity Study with the Reproductive/Developmental Screening Test according to OECD 422 (adopted 29 July 2016). Doses of 0 (control), 150, 450 and 1000 mg/kg bw/day was administered by gavage to 12 Wistar rats/sex/dose. Male rats were dosed daily for 44 days starting 14 days before mating up to the day before necroscopy. Female rats were dosed daily for 51 or 56 days starting 14 days before mating up to lactation day 13 or 17, the day before necroscopy.


 


The test item did not adversely influence the reproductive performance (gonad function, mating behavior, conception, parturition) or gave any indication to cause endocrine effects in parental male and female Han:WIST rats as far as investigated in this study.
There were no signs of systemic toxicity in male or female animals at 150, 450 or 1000 mg/kg bw/day. In the female animals at 450 and 1000 mg/kg bw/day, squamous cell hyperplasia in the non-glandular part of the stomach referred to the local effect of the test item. Besides of this local tissue irritation no other histological findings were noted.
The development of the F1 offspring was not impaired from birth to post-natal day 13 as far as investigated in this study after repeated oral administration of dams at 150, 450 or 1000 mg/kg bw/day.


 


Based on these observations the No Observed Adverse Effect Levels (NOAEL) were determined as follows:
NOAEL for systemic toxicity of male/ female rats: 1000 mg/kg bw/day
NOAEC (stomach irritation, female rats): 30 mg/mL (administered to animals of 150 mg/kg bw/day group)
NOAEL for reproductive performance of male/ female rats: 1000 mg/kg bw/day
NOAEL for F1 Offspring: 1000 mg/kg bw/day


 


Remark: The test substance as produced and marketed contains NaOH due to the production method.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

The available data indicate that the test substance is not toxic to the reproduction system.

Effects on developmental toxicity

Description of key information

Prenatal developmental toxicity study (OECD 414, read-across from structural analogue):


NOAEL for maternal toxicity and embryo-fetal developmental toxicity, rats: 800 mg/kg bw/d

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
A detailed justification of the used read across for the different endpoints can be found in the document “Justification of read across from CAS No 53378-51-1 IBP1-Na (source) to CAS No 3338-24-7, EP1-Na (target)” attached in “Point 13 Assessment reports”.
Reason / purpose:
read-across source
Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
The observation of moving the bedding started with the onset of treatment in MD and HD group animals. Few animals of LD group also showed moving the bedding from GD 12. This behavior was seen immediately post dose administration, was transient and is considered to be a local and non-specific reaction.
Abnormal breathing was observed in 1 of 24 females of MD group and 4 of 24 females of HD group; alopecia was observed in 3 of 29 females of LD group and 1 of 24 females of HD group; crust formation was observed in 1 of 24 females of HD group; piloerection was observed in 4 of 24 females of HD group; salivation was observed in 2 of 29 females of LD group, 1 of 24 females of MD group and 1 of 24 females of HD group. The clinical signs alopecia and salivation in test item treated groups did not show dose dependency and occurred sporadically in single animals. The abnormal breathing was transient, occurred sporadically and was limited to 4 of 24 animals. Therefore, these clinical findings were not considered to be adverse or treatment-related.
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
There were no effects on body weight and body weight gain in test-item treated groups compared to the controls. HD animals showed statistically significantly lower weight gain or body weight loss between GD 5-8 however all animals recovered quickly and between GD 8-11 there was a higher weight gain in the HD group compared to the corresponding control. These changes were transient and are not considered to be an adverse effect of test-item treatment.
There were no statistically significant differences in the mean terminal body weights and mean adjusted maternal body weights in test-item treated groups compared to the corresponding control group.
Food consumption and compound intake (if feeding study):
effects observed, non-treatment-related
Description (incidence and severity):
There was no adverse effects on food consumption during the treatment period in test-item treated groups compared to the control. There was statistically significantly lower food consumption between GD 5-8 in the HD group compared to the corresponding control however all animals recovered quickly and showed food consumption values similar to controls from GD 8 and onwards. This transient change was not considered to be an adverse effect of test-item treatment.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
There were no adverse macroscopic findings in test-item treated group animals. In the LD group there were observations of a cyst on the ovary (1 of 29 females), extra growth in fat tissue (1 of 29 females), and fluid filled and distended uterus (2 of 29 females). In the MD group there was one observation of a fluid filled ovary (1 of 24 females). These findings occurred in a limited number of females and without dose dependency. Therefore, these findings are not considered to be related to test-item treatment.
Neuropathological findings:
no effects observed
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
not specified
Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
effects observed, non-treatment-related
Description (incidence and severity):
There were no effects of test-item treatment on prenatal parameters including the number of corpora lutea, number of implantation sites, number of live fetuses and number of resorptions (early and late), number of male and female fetuses, sex ratio and percent pre- and post-implantation losses. Statistically significantly higher mean resorptions (early and total) occurred in the MD group (1.45) compared to the control group (0.48). This finding was not dose dependent and therefore, is not assumed to be related to test-item treatment
Early or late resorptions:
effects observed, non-treatment-related
Description (incidence and severity):
There were no effects of test-item treatment on prenatal parameters including the number of corpora lutea, number of implantation sites, number of live fetuses and number of resorptions (early and late), number of male and female fetuses, sex ratio and percent pre- and post-implantation losses. Statistically significantly higher mean resorptions (early and total) occurred in the MD group (1.45) compared to the control group (0.48). This finding was not dose dependent and therefore, is not assumed to be related to test-item treatment
Dead fetuses:
effects observed, non-treatment-related
Description (incidence and severity):
The finding of 8 dead fetuses in female no. 79 of the HD group was an isolated incidence and is not considered to be a treatment-related effect. The adjusted body weight of this animals was significantly lower compared to the other animals in the group, and the food consumption was reduced from gd 17-20 during which period the animal lost weight
Changes in pregnancy duration:
no effects observed
Changes in number of pregnant:
no effects observed
Other effects:
not specified
Key result
Dose descriptor:
NOAEL
Effect level:
800 mg/kg bw/day (nominal)
Based on:
act. ingr.
Basis for effect level:
clinical signs
mortality
body weight and weight gain
food consumption and compound intake
behaviour (functional findings)
gross pathology
number of abortions
pre and post implantation loss
total litter losses by resorption
effects on pregnancy duration
early or late resorptions
dead fetuses
changes in pregnancy duration
changes in number of pregnant
Key result
Abnormalities:
no effects observed
Fetal body weight changes:
no effects observed
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
no effects observed
External malformations:
no effects observed
Skeletal malformations:
effects observed, non-treatment-related
Description (incidence and severity):
There were slightly higher incidences of incomplete ossification of supraoccipital bones in MD (30%) and HD (35%) compared to control (23.81%); and slightly higher incidences of full 14th rib (right sided) in MD (10%) and HD (10%) group compared to control (4.76%). In addition, in the HD group there was a higher incidence of misshapen 6th sternebrum (10% in HD and 0% in control); a higher incidence of extra ossification sites at vertebral lumbar arch(es) (10% in HD group and 0% in control); a higher incidence of unossified forelimb metacarpals (63.16% in HD group (and 28.57% in control); a higher incidence of pelvic caudal bone (Bilateral) shift (25% in HD and 19.05% in control) a higher incidence of cervical 7th rudimentary rib (bilateral) (15% in HD (and 4.76% in control); and a higher incidence of cervical 7th rudimentary rib (left) (15% in HD group and 9.52% in control).
Higher incidences of cervical 7th rudimentary rib (right) were noted in LD (14.29%) and HD (10%) groups compared to control (4.76%).
The incidences of all of these observations in the test-item treated groups were without statistical significance, without dose dependency and/or were within the historical control data range, except for the misshapen 6th sternebrum in HD group, for which the incidence was outside the historical control data range (0% to 4.55%). The misshapened sternebrae is a malformation, but considering that only 3 of 112 fetuses were affected, and in the complete absence of any other indication of treatment-related fetal effects within the group, the finding was not considered to be related to the test item, but rather a coincidental finding.
Visceral malformations:
effects observed, non-treatment-related
Description (incidence and severity):
There were a range of visceral observations in control and test item treated groups. Most of the observations were noted in single animals and none occurred at statistically significantly higher incidences in test- item treated groups when compared to the corresponding control group. There were higher litter incidences of dilated ureter (bilateral) in MD (30%) and HD (30%) groups compared to control (23.81%) without statistical significance and these were within the historical control data range (see Appendix 4). Therefore, this finding was not an adverse effect of test-item treatment
Other effects:
not specified
Key result
Dose descriptor:
NOAEL
Effect level:
800 mg/kg bw/day (nominal)
Based on:
act. ingr.
Sex:
not specified
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
changes in postnatal survival
external malformations
skeletal malformations
visceral malformations
Key result
Abnormalities:
no effects observed
Localisation:
external: cranium
external: ear
external: eye
external: face
external: limb
external: paw
external: tail
external: trunk
external: anogenital distance
external: anus
external: genital tubercle
external: large intestine
external: thorax
external: umbilicus
external: pelvic region
skeletal: skull
skeletal: skull, fontanelles
skeletal: skull sutures
skeletal: clavicle
skeletal: scapule
skeletal: forelimb
skeletal: sternum
skeletal: rib
skeletal: supernumerary rib
skeletal: vertebra
skeletal: pelvic girdle
skeletal: hindlimb
visceral/soft tissue: integumentary
visceral/soft tissue: gastrointestinal tract
visceral/soft tissue: hepatobiliary
visceral/soft tissue: urinary
visceral/soft tissue: cardiovascular
visceral/soft tissue: heamatopoietic
visceral/soft tissue: immune system
visceral/soft tissue: musculoskeletal system
visceral/soft tissue: nervous system
visceral/soft tissue: central nervous system
visceral/soft tissue: peripheral nervous system
visceral/soft tissue: somatic nervous system
visceral/soft tissue: autonomic nervous system
visceral/soft tissue: endocrine system
visceral/soft tissue: respiratory system
visceral/soft tissue: male reproductive system
visceral/soft tissue: female reproductive system
visceral/soft tissue: eye
visceral/soft tissue: ear
other:
Key result
Developmental effects observed:
no
Conclusions:
On the basis of this prenatal developmental toxicity study in Wistar pregnant female rats with IBP1-Na at dose levels of 60, 300, and 800 mg/ kg body weight/ day administered on gestation days 5 to 19, the following conclusions can be made:
There were no observed effects on maternal animals of test-item treated groups compared to the corresponding control group. There were no treatment-related adverse effects on embryo-fetal development. Thus, the NOAEL for the maternal toxicity and embryo-fetal developmental toxicity is 800 mg/ kg body weight/ day.

Remark: The test substance as produced and marketed contains NaOH due to the production method.

Due to the similarity of the target substance, EP1-Na, and the source substance, IBP1-Na, the result of this study is assessed to be adequate in order to fulfil the requirements of REACH. The read-across approach is further described in the document “Justification of read across from CAS No 53378-51-1 IBP1-Na (source) to CAS No 3338-24-7, EP1-Na (target)” attached in “Point 13 Assessment reports”.
Executive summary:

The source substance was investigated to assess possible effects on pregnant female Wistar rats and embryo-fetal development consequent to repeated exposure of the test item according to OECD Guideline 414 (adopted 22 Janaury 2001). Doses of 0 (control), 60, 300 and 800 mg/kg bw/day were administered orally by gavage to pregnant female rats daily on gestation days 5 to 19 (23 sperm positive females in control group, 29 sperm positive females in low dose group, 24 sperm positive female rats in each of medium dose and high dose groups).


 


There were no mortalities in the control and test-item treated groups. No adverse clinical symptoms related to treatment with the test item were noted during the study. Body weight, body weight gain and food consumption were not affected in test-item treated groups compared to the control. No adverse macroscopic findings were noted during necrospopy in the animals from the test-item treated groups.


 


There were no effects of test-item treatment on prenatal parameters including number of corpora lutea, number of implantation sites, number of live fetuses and number of resorptions (early and late), number of male and female fetuses, sex ratio and percent pre- and post-implantation losses. There were no effects on uterus weight. Fetal deaths (8 fetuses) occurred in a single female of the high dosis group; as an isolated incidence this was considered incidental. In two litters from other high dose females, a total of three fetuses were found with a misshapen 6th sternebrum. In the absence of any other indications of test item related fetal effects, this finding was considered incidental.


 


There were no effects of test-item treatment on litter weight parameters including mean fetus weight, total litter weight, male litter weight or female litter weight. There were no statistically significantly different litter weight values in test-item treated groups compared to corresponding control groups. There were comparable numbers of fetuses in both (left and right) uterine horns of control and test-item treated groups. There was a range of fetal anomalies observed at external, visceral, craniofacial and skeletal examination in the fetuses of the test- item treated groups and control group. None of these anomalies occurred at statistically significantly higher incidence in test item treated groups compared to controls and therefore, were not considered treatment-related.


On the basis of this prenatal developmental toxicity study, the following conclusions can be made:
There were no observed effects on maternal animals of test-item treated groups compared to the corresponding control group. There were no treatment-related adverse effects on embryo-fetal development. Thus, the NOAEL for the maternal toxicity and embryo-fetal developmental toxicity is 800 mg/ kg body weight/ day.


 


Remark: The test substance as produced and marketed contains NaOH due to the production method.


 


Due to the similarity of the target substance, EP1-Na, and the source substance, IBP1-Na, the result of this study is assessed to be adequate in order to fulfil the requirements of REACH. The read-across approach is further described in the document “Justification of read across from CAS No 53378-51-1 IBP1-Na (source) to CAS No 3338-24-7, EP1-Na (target)” attached in “Point 13 Assessment reports”.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
800 mg/kg bw/day
Species:
rat
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

The available data indicate that the test substance is not developmentally toxic.

Justification for classification or non-classification

Based on the available information, EP1-Na is not required to be classified for reproductive/developmental toxicity.