Sodium O,O-diethyl dithiophosphate

Endpoint summary

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

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

Guideline:

other: OPPTS 870.3650 Combined Repeated Dose Toxicity with the Reproduction/Developmental Toxicity Screening Test

Version / remarks:

July 2000

GLP compliance:

yes (incl. QA statement)

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 or test system 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

Quality of whole database:

high quality

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:

Please refer to Read Across Statement attached in Section 13

Reason / purpose for cross-reference:

read-across source

Species:

rat

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:

behaviour (functional findings)

body weight and weight gain

changes in number of pregnant

changes in pregnancy duration

clinical signs

dead fetuses

early or late resorptions

effects on pregnancy duration

food consumption and compound intake

gross pathology

mortality

number of abortions

pre and post implantation loss

total litter losses by resorption

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:

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.

Executive summary:

The test was performed according to the OECD guideline 414 under GLP compliance. Wistar starin rat was tested with test item at dose levels of 60, 300, and 800 mg/ kg body weight/ day administered on gestation days 5 to 19. 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.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

800 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

high quality

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 according to Regulation (EC) No 1272/2008.