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REACH

2-Oxazolidinone, 3-ethenyl-5-methyl-

EC number: 809-852-5 | CAS number: 3395-98-0

Life Cycle description
Uses advised against

Toxicological information

Endpoint summary

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

NOAEL: 150 mg/kg bw/d

Link to relevant study records

Reference

Endpoint:: screening for reproductive / developmental toxicity
Type of information:: experimental study
Adequacy of study:: supporting study
Study period:: 21 Jul 2015 - 10 Jun 2016
Reliability:: 1 (reliable without restriction)
Rationale for reliability incl. deficiencies:: guideline study
Reason / purpose for cross-reference:: reference to same study
Remarks:: see also chapter 7.5.1
Reason / purpose for cross-reference:: reference to same study
Remarks:: see also chapter 7.8.2
Qualifier:: according to guideline
Guideline:: OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Version / remarks:: 22 mar 1996
Deviations:: no
Qualifier:: according to guideline
Guideline:: other: EPA OPPTS 870.3650: Combined Repeated Dose Toxicity Study With the Reproduction/Developmental Toxicity Screening Test
Version / remarks:: Jul 2000
Deviations:: no
GLP compliance:: yes
Limit test:: no
Specific details on test material used for the study:: SOURCE OF TEST MATERIAL
- Test substanc No.: 14/0031-3
- Cas No.: 3395-98-0
- Source and lot/batch No.of test material: DEIMLIB-00070
- Expiration date of the lot/batch: 26 Jan 2017
- Purity: assumed 99.5%

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: room temperature
- Stability under test conditions: The stability of the test substance under storage conditions over the test period was guaranteed by the sponsor, and
the sponsor holds this responsibility.
- Solubility and stability of the test substance in the solvent/vehicle:
- Reactivity of the test substance with the solvent/vehicle of the cell culture medium:

OTHER SPECIFICS:
- Physical state/appearance; liquid, colorless, clear
Species:: rat
Strain:: Wistar
Sex:: male/female
Details on test animals or test system and environmental conditions:: TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services Germany GmbH
- Age at study initiation: 10-11 weels
- Housing: During the study period, the rats were housed individually in polycarbonate cages type III
(floor area of about 800 cm²) with the following exceptions:
• During overnight matings, male and female mating partners were housed together in
polycarbonate cages type III.
• Dams and their litters were housed together until PND 4 (end of lactation).
• For motor activity (MA) measurements the animals were housed individually in polycarbonate cages supplied by TECNIPLAST, Hohenpeißenberg, Germany with
wire covers from Ehret, Emmendingen, Germany (floor area of about 800 cm2) and small amounts of bedding material
- Diet (e.g. ad libitum): ground The food used was ground Kliba maintenance diet mouse-rat “GLP”, meal, supplied by Provimi Kliba SA, Kaiseraugst, Switzerland.
- Water: ad libitum
- Acclimation period: 6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24°C
- Humidity (%): 30 - 70%
- Air changes (per hr): 15 per hour
- Photoperiod (hrs dark / hrs light): 12 hours (12 hours light from 06.00- 18.00h, 12 hours dark from 18.00-06.00h
Route of administration:: oral: gavage
Vehicle:: corn oil
Details on exposure:: PREPARATION OF DOSING SOLUTIONS:
5-Methyl-3-vinyloxazolidin-2-on was applied as solutions. To prepare this solution, the appropriate amount of test substance was weighed out depending on the desired concentration. Then, corn oil was filled up to the desired volume, subsequently mixed with a magnetic stirrer. The test substance preparations were produced at least once a week and were stored at room temperature. The administration volume was 4 mL/kg body weight

VEHICLE
- Justification for use and choice of vehicle (if other than water):
- Concentration in vehicle: 0.375, 1.250 3.750 g/100ml
- Amount of vehicle (if gavage): 4 ml/kg bw
Details on mating procedure:: - M/F ratio per cage: 1:1
- Length of cohabitation: overnight, for a maximum of 2 weeks.
- The animals were paired by placing the female in the cage of the male mating partner from
about 16.00 h until 06.30 - 09.00 h of the following morning. Deviations from the specified
times were possible on weekends and public holidays and were reported in the raw data. A
vaginal smear was prepared after each mating and examined for the presence of sperm. If
sperm was detected, pairing of the animals was discontinued. The day on which sperm was
detected was denoted gestation day (GD) 0 and the following day "GD 1".
Analytical verification of doses or concentrations:: yes
Details on analytical verification of doses or concentrations:: The analyses of the test substance preparations were carried out at the Analytical Chemistry Laboratory of Experimental Toxicology and Ecology of BASF SE, Ludwigshafen, Germany.
The stability of 5-Methyl-3-vinyloxazolidin-2-on in corn oil over a period of 7 days at room temperature was proven before the start of the study.
Samples of the test substance preparations were sent to the analytical laboratory for verification of the concentrations. The samples taken for the concentration control analyses
were also used to verify the homogeneity of the samples of the low- and high-concentrations. Three samples (one from the top, middle and bottom) were taken from the preparation
vessels with the magnetic stirrer running. Of each sample, one additional reserve sample was retained. Details of the sampling schedule were recorded with the raw data.
Duration of treatment / exposure:: Males:
- 14 days premating
- up to 14 days mating
- sacrifice minimum 4 days after littering
The exposure duration was at least 30 days

Females:
-14 days premating
- up to 14 days mating
- gestation about 22 days
- sacrifice minimum 4 days after littering
The exposure duration was at least 52 days
Frequency of treatment:: daily
Remarks:: Doses/Concentrations:
0, 15, 50, 150 mg/kg bw/day
No. of animals per sex per dose:: 10 males/10 females
Control animals:: yes, concurrent vehicle
Parental animals: Observations and examinations:: CAGE SIDE OBSERVATIONS: Yes
A cageside examination was conducted once daily for any signs of morbidity, pertinent behavioral changes and signs of overt toxicity before the administration. Furthermore, all animals were checked for any abnormal clinically signs within 2 hours and within 5 hours after the administration. Abnormalities and changes were documented daily for each affected animal. If signs occurred the animals were examined several times daily.
The littering and lactation behavior of the dams was generally evaluated in the mornings in combination with the daily clinical inspection of the dams. Only particular findings (e.g. inability to deliver) were documented on an individual dam basis. On weekdays (except Saturdays, Sundays and public holidays) the parturition behavior of the dams was inspected in the afternoons in addition to the evaluations in the mornings.
The day of littering was considered the 24-hour period from about 15.00 h of one day until about 15.00 h of the following day.

DETAILED CLINICAL OBSERVATIONS: Yes
Detailed clinical observations (DCO) were performed in all animals prior to the administration period and thereafter at weekly intervals. The findings were ranked according to the degree
of severity, if applicable. The animals were transferred to a standard arena (50 × 37.5 cm with sides of 25 cm high).

BODY WEIGHT: Yes
Body weight was determined before the start of the administration period in order to randomize the animals. During the administration period body weight was determined on
study day 0 (start of the administration period) and thereafter once a week at the same time of the day (in the morning).The body weight change of the animals was calculated from
these results.
The following exceptions are notable for the female animals:
• During the mating period the parental females were weighed on the day of positive evidence of sperm (GD 0) and on GD 7, 14 and 20.
• Females with litter were weighed on the day of parturition (PND 0) and on PND 4.
• Females without a litter and without positive evidence of sperm in the vaginal smear or
waiting for necropsy were weighed weekly. These body weight data were solely used for the calculations of the dose volume.

FOOD CONSUMPTION:
Generally, food consumption was determined once a week for male and female parental animals, with the following exceptions:
• Food consumption was not determined during the mating period (male and female F0 animals).
• Food consumption of the F0 females with evidence of sperm was determined on GD 0 - 7, 7 - 14 and 14 - 20.
• Food consumption of F0 females, which gave birth to a litter was determined for PND 1 - 4.
Food consumption was not determined in females without positive evidence of sperm (during the mating period of dams) and females without litter (during the lactation period of
dams) and in males after the premating period.

WATER CONSUMPTION
Drinking water consumption was monitored by daily visual inspection of the water bottles for any changes in volume.

HEAMATOLOGY
In the morning blood was taken from the retro-bulbar venous plexus from fasted animals.The animals were anaesthetized using isoflurane. The blood sampling procedure and
subsequent analysis of blood and serum samples were carried out in a randomizedsequence. For urinalysis the individual animals were transferred to metabolism cages
(withdrawal of food and water) and urine was collected overnight. Urine samples wereevaluated in a randomized sequence
The assays of blood and serum parameters were performed under internal laboratory qualitycontrol conditions with reference controls to assure reliable test results
The following examinations were carried out in the first 5 surviving parental males and the first 5 surviving females with litter (in order of delivery) per group.
Leukocyte count (WBC), Erythrocyte count (RBC), Hemoglobin (HGB), Hematocrit (HCT), Mean corpuscular volume (MCV), Mean corpuscular hemoglobin (MCH)
Mean corpuscular hemoglobin concentration (MCHC), Platelet count (PLT), Differential blood, Reticulocytes (RET)

CLINICAL CHEMISTRY
Alanine aminotransferase; Aspartate aminotransferase; Alkaline phosphatase; γ-Glutamyltransferase
Sodium, Potassium, Chloride, Inorganic phosphate, Calcium, Urea, Creatine, Glucose, Total bilirubin, Total protein, Albumin, Globlulins, Triglycerides, Cholesterol, Bile acids,

URINALYSIS
pH, Protein, Glucose, Ketones, Urobilnogen, Bilirubin, Blood, Specific gravity, Sediment, Color turbitdity; Volume

FUNCTIONAL OBSERVATION BATTERY
A functional observational battery was performed in the first five surviving male animals per test group and the first five surviving females with litter (in order of delivery) of all test groups
at the end of the administration period starting in the morning. The FOB started with passive observations without disturbing the animals, followed by removal from the home cage, open
field observations in a standard arena and sensorimotor tests as well as reflex tests. The findings were ranked according to the degree of severity, if applicable. The observations were performed at random.

HOME CAGE OBSERVATIONS.
The animals were observed in their closed home cages; during this period any disturbing activities (touching the cage or rack, noise) were avoided during these examinations in order
not to influence the behavior of the animals.

MOTOR ACTIVITY ASSESSMENT
Motor activity (MA) was also measured in the early afternoon onwards on the same day as the FOB was performed in the first five parental males and the first five surviving females
with litter (in order of delivery) per group. The examinations were performed using the TSE Labmaster System supplied by TSE Systems GmbH, Bad Homburg, Germany. For this
purpose, the animals were placed in new clean polycarbonate cages with a small amount of bedding for the duration of the measurement. Eighteen beams were allocated per cage. The
numbers of beam interrupts was counted over 12 intervals of 5 minutes per interval. The sequence in which the animals were placed in the cages was selected at random. On account of the time needed to place the animals in the cages, the starting time was "staggered" for each animal. The measurement period began when the 1st beam was interrupted and finished exactly 1 hour later. No food or water was offered to the animals during these measurements and the measurement room was darkened after the transfer of the last animal. The program required a file name for the measured data to be stored. This
name consisted of the reference number and a serial number.
Litter observations:: Pup number and status at delivery
All pups delivered from the F0 parents (F1 litter) were examined as soon as possible on the day of birth to determine the total number of pups, the sex and the number of liveborn and
stillborn pups in each litter. At the same time, the pups were also being examined for macroscopically evident changes. Pups, which died before this initial examination, were
defined as stillborn pups.

Pup viability/mortality
In general, a check was made for any dead or moribund pups twice daily on workdays (once in the morning and once in the afternoon) or as a rule, only in the morning on Saturdays, Sundays or
public holidays. The number and percentage of dead pups on the day of birth (PND 0) and of pups dying between PND 1 - 4 (lactation period) were determined. Pups which died accidentally or were sacrificed due to
maternal death were not included in these calculations. The number of live pups/litter was calculated on the day after birth, and on lactation day 4. The viability index was calculated
according to the following formula:
Viablity index(%)=(number of live pups on day 4 after birth/number of live pups on the day of birth)x100

Sex ratio
On the day of birth (PND 0) the sex of the pups was determined by observing the distance between the anus and the base of the genital tubercle; normally, the anogenital distance is considerably
greater in male than in female pups. The sex of the pups was finally confirmed at necropsy. The sex ratio was calculated at day 0 and day 4 after birth according to the following formula:
Sex ratio = (number of live male or female pups on day 0/4 / number of live male and female pups on day 0/4)x100

Pup clinical observations
The live pups were examined daily for clinical symptoms (including gross-morphological findings) during the clinical inspection of the dams.

Pup body weight data
The pups were weighed on the day after birth (PND 1) and on PND 4. Pups' body weight change was calculated from these results. The individual weights were always determined at about the same time
of the day (in the morning). In the summary tables pup body weights and pup body weight change are listed for males, females and males + females.
“Runts” were defined on the basis of the body weights on PND 1. "Runts" are pups that weigh less than 75% of the mean weight of the respective control pups.
Postmortem examinations (parental animals):: Necropsy
All parental animals were sacrificed by decapitation under isoflurane anesthesia. The exsanguinated animals were necropsied and assessed by gross pathology, special attention
being given to the reproductive organs. One female animal of the control group (No. 109) which died spontaneously after blood sampling, was necropsied and assessed by gross
pathology as soon as possible.

Organ weights
The following weights were determined in all animals sacrificed on schedule:
Anesthetized animals, epididymides, Testes
The following weights were determined in 5 animals/sex and test group (females with litters, same animals as used for clinical pathology examinations):
Adrenal glands, Brain, Heart, Kidneys, Liver, Spleen, Thymus

Histopathology
All gross lesions , Adrenal cortex ,Adrenal medulla, Bone marrow (femur), Brain,Cecum, Cervix, Coagulating glands, Colon, Duodenum, Epididymides, Heart, leum, Jejunum, Kidneys, Liver, Lung,
Lymph nodes, Ovaries, Oviducts, Peyers patches, Prostate, Rectum, Sciatic nerve, Seminal vesicles, spinal cord, Spleen, Stomach, Testes, Thymus , Thyroid glands, Trachea, Urinary bladder, Uterus, Vagina.
Postmortem examinations (offspring):: All pups with scheduled sacrifice on PND 4 were sacrificed under isoflurane anesthesia with CO2. All pups were examined externally and eviscerated; their organs were assessed
macroscopically. All stillborn pups and all pups that died before PND 4 were examined externally, eviscerated and their organs were assessed macroscopically.
All pups without notable findings or abnormalities were discarded after their macroscopic evaluation. Animals with notable findings or abnormalities were evaluated on a case-bycase
basis, depending on the type of finding noted.
Statistics:: Food consumption (parental animals), body weight and body weight change (parental animals and pups; for the pup weights, the litter means were used), gestation days: DUNNETT test (two-sided)
Male and female mating indices, male and female fertility indices, gestation index (females with liveborn pups), females delivering,females with stillborn pups, females with all stillborn pups, female pregnant: FISHER'S EXACT test (onesided)
Mating days until day 0 pc,%postimplantation loss, pups stillborn, %perinatal loss: WILCOXON test (one-sided+) with BONFERRONI-HOLM adjustment
Implantation sites, pups delivered, pups liveborn, live pups day x, viability Index:WILCOXON test (one-sided+) with BONFERRONI-HOLM adjustment
% live male day x, %live female day x: WILCOXON test (two-sided)
Rearing, grip strength of forelimbs and hindlimbs, landing foot-splay test, motor activity: WILCOXON test (two-sided)
Reproductive indices:: Reproductive indices
Male mating index
Male mating index (%) = (number of males with confirmed mating*/number of males placed with females) x 100
* defined by a female with vaginal sperm or with implants in utero
Male fertility index
Male fertility index (%) = (number of males proving their fertility*/number of males placed with females)x100
* defined by a female with implants in utero
Female mating index
Female mating index (%) = (number of females mated*/number of females placed with males) x 100
* defined as the number of females with vaginal sperm or with implants in utero
Female fertility index
Female fertility index (%) = (number of females pregnant*/number of females mated**) x 100
* defined as the number of females with implants in utero
** defined as the number of females with vaginal sperm or with implants in utero
Gestation index
Gestation index (%) = (number of females with live pups on the day of birth/number of females pregnant*) x 100
* defined as the number of females with implants in utero
Live birth index
Live birth index (%) = (number of liveborn pups at birth/total number of pups born) x 100
Offspring viability indices:: Pup viability/mortality
In general, a check was made for any dead or moribund pups twice daily on workdays (once in the morning and once in the afternoon) or as a rule, only in the morning on Saturdays, Sundays or public
holidays.
The number and percentage of dead pups on the day of birth (PND 0) and of pups dying between PND 1´- 4 (lactation period) were determined. Pups which died accidentally or were sacrificed due to maternal
death were not included in these calculations. The number of live pups/litter was calculated on the day after birth, and on lactation day 4. The viability index was calculated according to the following formula:
Viability index (%) = (number of live pups on day 4 after birth/number of live pups on the day of birth) x 100
Dose descriptor:: NOAEL
Effect level:: 150 mg/kg bw/day
Based on:: test mat.
Sex:: male/female
Remarks on result:: other: no reproductive effects were noted
Dose descriptor:: NOAEL
Generation:: F1
Effect level:: 150 mg/kg bw/day
Based on:: test mat.
Sex:: male/female
Remarks on result:: other: no developmental effects were noted
Reproductive effects observed:: not specified

Effect on fertility: via oral route

Endpoint conclusion:: no adverse effect observed
Dose descriptor:: NOAEL
: 150 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

In a combined repeated dose toxicity study with the reproduction/developmental toxicity sreening test according to OECD 422 (BASF SE, 2016), 5-Methyl-3-vinyloxazolidin-2-one was administered orally via gavage to groups of 10 male and 10 female Wistar rats (F0 animals) at dose levels of 0 mg/kg body weight/day (mg/kg bw/d; test group 0), 15 mg/kg bw/d (test group 1), 50 mg/kg bw/d (test group 2) and 150 mg/kg bw/d (test group 3). Corn oil served as vehicle. The duration of treatment covered a 2-week pre-mating and mating period in both sexes, approximately 1 week post-mating in males, and the entire gestation period as well as 4 days of lactation followed by an additional treatment until one day before sacrifice.

The parents' and the pups' state of health was checked each day, and parental animals were examined for their mating and reproductive performances. F0 animals were mated 13 days after the beginning of treatment to produce a litter (F1 generation pups). As soon as sperm was detected in the vaginal smear, mating was discontinued. F0 animals were examined for their reproductive performance including determinations of the number of implantations and the calculation of the postimplantation loss in all F0 females. A detailed clinical observation (DCO) was performed in all animals before initial test substance administration and, as a rule, thereafter at weekly intervals. Food consumption of the F0 parents was determined regularly once weekly, males during 2 weeks of premating and females before and after the mating period, as well as in dams during gestation (days 0 - 7, 7 - 14, 14 - 20) and lactation (days 1 - 4). In general, the body weights of F0 animals were determined once a week. However, during gestation and lactation, F0 females were weighed on gestation days (GD) 0, 7, 14 and 20, and on postnatal days (PND) 0 and 4. The pups were sexed and examined for macroscopically evident changes on PND 0. They were weighed on PND 1 and on PND 4 and their viability was recorded. At necropsy on PND 4, all pups were sacrificed under isoflurane anesthesia with CO2 and examined macroscopically for external and visceral findings at necropsy. Clinicochemical and hematological examinations as well as urinalyses were performed in 5 animals per sex and group towards the end of the administration period. Towards the end of the administration period a functional observational battery was performed and motor activity was measured in 5 animals per sex and test group. All F0 parental animals were sacrificed by decapitation under isoflurane anesthesia and were assessed by gross pathology. Weights of selected organs were recorded and a histopathological examination was performed.

Under the conditions of this Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test, the oral administration by gavage of 5-Methyl-3-vinyloxazolidin-2-on to Wistar rats revealed signs of general systemic toxicity at 150 mg/kg bw/d manifested in alterations of the body weight of male animals and alterations of blood cell counts in female parental animals. Thus, the no observed adverse effect level (NOAEL) for general systemic toxicity was 50 mg/kg bw/d in both sexes of parental animals. The no observed adverse effect level (NOAEL) for reproductive performance and fertility was 150 mg/kg bw/d in male and female Wistar rats. The NOAEL for developmental toxicity in the F1 progeny was 150 mg/kg bw/d.

Effects on developmental toxicity

Description of key information

oral (OECD 414) rat: NOAEL maternal: 15 mg/kg bw/day; NOAEL prenatal toxicity 150mg/kg bw/d

Link to relevant study records

Reference

Endpoint:: developmental toxicity
Type of information:: experimental study
Adequacy of study:: key study
Study period:: 26 Mar 2019 - 04 Feb 2020
Reliability:: 1 (reliable without restriction)
Rationale for reliability incl. deficiencies:: guideline study
Qualifier:: according to guideline
Guideline:: OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Version / remarks:: 25 Jun 2018
Qualifier:: according to guideline
Guideline:: EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
Version / remarks:: Aug 1998
GLP compliance:: yes
Limit test:: no
Specific details on test material used for the study:: Name of test substance: 5-Methyl-3-vinyloxazolidin-2-on
Test substance No.: 14/0031-4
Batch No.: Z019-2018
CAS No.: 3395-98-0
Purity: 99.4area-%(GC,DB-1) 96.3area-%(GC,DB-WAX) 96.5 area-% (GC, CP-Sil 19S8)
Content: 95.9 g/100 g (1H-NMR)
ldentity: Confirmed
Homogeneity: Given
Expiry date: 09 Feb 2020
Storage stability: The stability of the test substance under storage
conditions over the test period was guaranteed by the
Sponsor, and the Sponsor holds this responsibility.
Storage conditions: Room temperature
Physical state/appearance: Liquid, yellow
Species:: rat
Strain:: Wistar
Details on test animals or test system and environmental conditions:: Species: rat
Strain: Crl:Wl(Han)
Source: Charles River Laboratories, Research Models and Services, Germany GmbH
Reason for species selection:
The Crl:WI(Han) strain was selected since extensive historical control data is available from
the test facility for Wistar rats. This specific strain has been proven to be sensitive to
substances with a teratogenic potential.

Sex: Female
Age at study initiation: 10-12 weeks
Weight at study initiation: 168.6 - 228.8 g.
Type of cage: Polycarbonate cages type III
No. of animals per cage: 1
Enrichment: Wooden gnawing blocks
Nesting material: Cellulose wadding was offered toward the end of gestation
Bedding: Dust-free wooden bedding

ENVIRONMENTAL CONDITIONS
Temperature 20-24°C
Relative humidity 45-65%,
15 air changes per hour
Illumination period: 12/12
Type of cage: Polycarbonate cages type III
No. of animals per cage: 1
Diet: ad libitum
Water ad libitum

Acclimatization period: From GD 0 (day of supply) to the beginning of administration (GD 6),
Route of administration:: oral: gavage
Vehicle:: corn oil
Details on exposure:: PREPARATION OF DOSING SOLUTIONS:
The test substance preparations were prepared at the beginning of the administration period
and thereafter at intervals, which took into account the period of established stability. The
preparations were kept at room temperature.
For the test substance preparations, the specific amount of test substance was weighed,
topped up with corn oil in a graduated flask and intensely mixed with a magnetic stirrer until it
was completely dissolved.

VEHICLE
- Amount of vehicle (if gavage): 4 mL/kg bw/d
Analytical verification of doses or concentrations:: yes
Details on analytical verification of doses or concentrations:: Analytical verifications of the stability of the test substance in corn oil over a period of 7 days
at room temperature had been verified prior to the start of the study in a similar batch.
All determined concentrations were in the range of 90 % - 110 % of the nominal concentration.
Details on mating procedure:: The animals were paired by the breeder (“time-mated”); the day of evidence of mating
(= detection of vaginal plug/sperm) was referred to as GD 0. The animals arrived on the same
day (GD 0) at the experimental laboratory. The following day was designated as “GD 1”. The
animals were acclimated to the laboratory conditions between start of the study (beginning of
the experimental phase) and first administration (GD 6).
Duration of treatment / exposure:: GD 6 to GD19
Frequency of treatment:: once a day
Duration of test:: On GD 20, blood samples were obtained in a randomized order from all females
by retrobulbar venous puncture. After blood sampling all surviving dams were
sacrificed and examined
The fetuses were removed from the uterus and investigated.
Dose / conc.:: 15 mg/kg bw/day
Dose / conc.:: 50 mg/kg bw/day
Dose / conc.:: 150 mg/kg bw/day
No. of animals per sex per dose:: 25
Control animals:: yes, concurrent vehicle
Maternal examinations:: CAGE SIDE OBSERVATIONS: Yes / No / No data
- A cage-side examination was conducted at least once daily before and after treatment period
(GD 0-5 and 20). During treatment period (GD 6-19) all rats were checked daily for any signs
of morbidity, pertinent behavioral changes and/or signs of overt toxicity before administration
as well as within 2 hours and between 2 and 5 hours after administration.

Mortality
A check was made twice a day on working days or once a day on Saturdays, Sundays or on
public holidays (GD 0-20).

BODY WEIGHT: Yes
- Time schedule for examinations: All animals were weighed on GD 0, 1, 3, 6, 8, 10, 13, 15, 17, 19
and 20. The body weight change of the animals was calculated based on the obtained results.
Corrected (net) body weight gain
Furthermore, the corrected body weight gain was calculated after terminal sacrifice (terminal
body weight on GD 20 minus weight of the unopened uterus minus body weight on GD 6).

FOOD CONSUMPTION AND COMPOUND INTAKE: Yes
The consumption of food was recorded for the intervals GD 0-1, 1-3, 3-6, 6-8, 8-10, 10-13,
13-15, 15-17, 17-19 and 19-20.

WATER CONSUMPTION AND COMPOUND INTAKE: Yes
The consumption of water was recorded for the intervals GD 0-1, 1-3, 3-6, 6-8, 8-10, 10-13,
13-15, 15-17, 17-19 and 19-20.

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs weights: thyroid glands (with parathyroid glands), spleen
- Histopathology: thyroid glands

OTHER:
- Clinical pathology
- Haematology: leukocyte count (WBC), erythrocyte count (RBC), hemoglobin (HCT),
hematocrit (HCT), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH),
mean corpuscular hemoglobin concentration (MCHC), platelet count (PLT), differential blood
count, reticulocytes (RET),

- Clinical chemistry:
Enzyme: alanine aminotransferase (ALT), aspartate aminotransferase (AST), Alkaline
phosphate (ALP), γ-Glutamyltransferase (GGT),
- Blood chemistry parameter:
inorganic phosphate (INP), calcium (Ca), urea (UREA), creatine (CREA), glucose (GLUC), total bilirubin (TBIL),
total protein (TPROT), albumin (ALB), globulins (GLOB), triglycerides (TRIG), cholesterol (CHOL).

- Thyroid hormones:
Total triiodothyronine (T3), Total thyroxine (T4), Thyroid stimulating hormone (TSH)
Ovaries and uterine content:: The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other: Dead fetuses (hypoxemic fetuses which did not breathe spontaneously after the
uterus had been opened)
Fetal examinations:: - External examinations: Yes:
At necropsy each fetus was weighed, sexed, and external tissues and all orifices were
examined macroscopically. The sex was determined by observing the distance between the
anus and the base of the genitalia.
Furthermore, the viability of the fetuses and the condition of placentas, umbilical cords, fetal
membranes, and fluids were examined. The placentas were weighed and their individual weights
were recorded.
The anogenital distance (defined as the distance from the center of the anal opening to the
base of the genital tubercle) measurements were conducted, using a measuring ocular, on all
liveborn fetuses.
After these examinations, approximately one half of the fetuses per dam were eviscerated,
skinned and fixed in ethanol; the other half was placed in Harrison’s fluid for fixation.

- Soft tissue examinations: Yes:
The fetuses fixed in Harrison’s fluid were examined for any visceral findings according to the
method of BARROW and TAYLOR. After this examination these fetuses were discarded.

- Skeletal examinations: Yes:
The skeletons of the fetuses fixed in ethanol were stained according to a modified method of
KIMMEL and TRAMMELL. Thereafter, the skeletons of these fetuses were examined under a
stereomicroscope. After this examination the stained fetal skeletons were retained individually.
Statistics:: Statistic of clinical, necropsy and fetal examinations
Simultaneous comparison of all dose groups with the control group using the DUNNETT-test
(two-sided) for the hypothesis of equal means was used for the following parameters:
Water consumption, food consumption, body weight, body weight change, corrected body weight
gain (net maternal body weight change), carcass weight, weight of unopened uterus, number of
corpora lutea, number of implantations, number of resorptions, number of live fetuses, proportions
of preimplantation loss, prop ortions of postimplantation loss, proportions of resorptions, proportion
of live fetuses in each litter, lit ter mean fetal body weight, litter mean placental weight, anogenital
distance, anogenital index

Pairwise comparison of each dose group with the control group using FISHER'S EXACT test
(one-sided) for the hypothesis of equal proportions was used for the following parameters:
Female mortality, females pregnant at terminal sacrifice, number of litters with fetal findings

Pairwise comparison of each dose group with the control group using the WILCOXON-test (onesided)
for the hypothesis of equal medians was used for the following parameters:
Proportions of fetuses with malformations, variations and/or unclassified observations in each litter.

Statistics of pathology

Weight parameters;
Non-parametric one-way analysis using KRUSKAL-WALLIS H test (two-sided). If the resulting p-value
was equal or less than 0.05, a pairwise comparison of each dose group with the control group was
performed using WILCOXON-test (two-sided) for the equal medians.
Indices:: Conception rate, pre-implantation loss, post-implantation loss,
Anogenital index
Clinical signs:: effects observed, non-treatment-related
Description (incidence and severity):: Piloerection after treatment occurred in females of test groups 2 and 3 (50 and 150 mg/kg
bw/d) from GD 6-14: in two mid-dose and six high-dose females, this finding was recorded
within the 2-hour examination interval, in 16 mid-dose and 25 high-dose females even afterwards
(>2h<5h after treatment).
Reduced attention after treatment was also recorded in females of test groups 2 and 3 from
GD 6-11: in three mid-dose and nine high-dose females, this finding was recorded within the
2-hour examination interval, in 13 mid-dose and 22 high-dose females even afterwards
(>2h<5h after treatment).
Both above mentioned unspecific clinical findings were most likely induced by the treatment
with the test substance but were not assessed as adverse per se.
One mid-dose female (50 mg/kg bw/d) had an abdominal body position after treatment on GD 6
(within the 2-hour examination interval). Since only one dam was affected without relation to
dose, it was assessed as incidental.
Furthermore, most females (23 out of 25) of the high-dose group and 6 females of the middose
group showed transient salivation during the treatment period. Salivation occurred in the
respective animals within the 2-hour examination interval after treatment (i.e. 0-2h) and was
initially observed on GD 6 (150 mg/kg bw/d) or GD 12 (50 mg/kg bw/d). Salivation occurred
most probably due to the bad taste of the test substance, was assessed to be a local effect
and, therefore, considered as not adverse.
No clinical signs or changes of general behavior, which may be attributed to the test substance,
were detected in any female of test group 1 (15 mg/kg bw/d)..
Mortality:: no mortality observed
Body weight and weight changes:: effects observed, treatment-related
Description (incidence and severity):: From GD 8 onwards until scheduled sacrifice on GD 20 the mean body weights of the highdose
dams (150 mg/kg bw/d) were lower in comparison to the concurrent control group,
attaining statistical significance during GD 10-13 (up to -5 %). The mean body weight gain of
the high-dose dams (150 mg/kg bw/d) was statistically significantly decreased during GD 6-10
showing a body weight loss during GD 6-8 (-1.4 g vs. 4.4 g in control). If calculated for the
entire treatment (GD 6-19), the mean body weight gain was 11% below the concurrent control
values (attaining statistical significance). Together with the reduction in water and food
consumption, these effects are assessed as treatment-related and adverse.
In test group 2 (50 mg/kg bw/d) the mean body weight values were below those of the
concurrent control group but without attaining statistical significance. The average body weight
gain was statistically significantly decreased on GD 6-8 (1.9 g vs. 4.4 g in control) and during
the entire treatment period (GD 6-19: 74.2 g vs. 82 g in control). This was assessed as
treatment-related.
The mean body weights and the average body weight gain of the low-dose dams (15 mg/kg
bw/d) were generally comparable to the concurrent control group throughout the entire study
period.
Food consumption and compound intake (if feeding study):: effects observed, treatment-related
Description (incidence and severity):: Consistently to the reduction in water consumption, the mean food consumption
of the high- and mid-dose dams (150 and 50 mg/kg bw/d) was statistically significantly
reduced during GD 6-13 (test group 3: up to 35%; test group 2: up to 16% below control) but
recovered afterwards. Nevertheless, if calculated for the entire treatment period (GD 6-19), the
high- and mid-dose dams consumed about 13% and 7% less food than the controls, respectively,
showing no statistical significance. The reduction in both test groups was assessed as
treatment-related.
The mean food consumption of the low-dose dams (15 mg/kg bw/d) was generally comparable
to the concurrent control group throughout the entire study period.

Corrected (net) body weight gain
The corrected body weight gain (terminal body weight on GD 20 minus weight of the unopened
uterus minus body weight on GD 6) was statistically significantly lower in test groups 3 (about
27% below the concurrent control value) and 2 (about 15% below control).
The corrected body weight gain of test group 1 (15 mg/kg bw/d) revealed no difference of any
biological relevance to the corresponding control group. Moreover, mean carcass weights of
test groups 1-3 were not adversely affected.
Food efficiency:: not examined
Water consumption and compound intake (if drinking water study):: effects observed, treatment-related
Description (incidence and severity):: The mean water consumption of the dams was statistically significantly reduced during GD
6-10, respectively, in test groups 2 (50 mg/kg bw/d - up to 17% below control) and 3 (150 mg/kg
bw/d - up to 24% below control). Afterwards, the mean values of both test groups recovered
and even exceeded the control values towards the end of the study (attaining statistical
significance in test group 3 on GD 17-19). Furthermore, if calculated for the entire treatment
period (GD 6-19), the mid and high-dose dams consumed an amount of water that was
comparable to the control (26.5 g / 28.2 g versus 27.8 g in control). The transient reduction in
water consumption in both test groups in the beginning of administration was assessed as
treatment-related.
The mean water consumption of the dams in test group 1 (15 mg/kg bw/d) was comparable to
the concurrent control group throughout the entire study period.
The statistically significantly decreased water consumption value in test group 2 on GD 1-3
(pretreatment period) was assessed as incidental.
Ophthalmological findings:: not examined
Haematological findings:: effects observed, non-treatment-related
Description (incidence and severity):: At the end of gestation in dams of test groups 2 and 3 (50 and 150 mg/kg bw/d), platelet counts
were significantly increased and the means were above the historical control range (platelets
706-940 Giga/L). However, medians of platelet counts were not dose-dependently increased
and the means in test groups 2 and 3 were around 10 % higher compared to the study control
mean. The platelet counts in the study controls were already in the upper part of the historical
control range. Therefore, the increase of platelet counts in dams of test groups 2 and 3 are
regarded as incidental and not treatment-related.
In dams of test group 3 (150 mg/kg bw/d), total white blood cell (WBC) as well as absolute
neutrophil and monocyte counts were significantly increased. Neutrophil and monocyte counts
were already significantly higher in dams of test group 2 (50 mg/kg bw/d) compared to controls.
However, all means were within historical control ranges (WBC 4.47-6.50 Giga/L, absolute
neutrophils 1.62-2.25 Giga/L, absolute monocytes 0.10-0.18 Giga/L). Therefore, these
alterations were regarded as incidental and not treatment-related.
Clinical biochemistry findings:: effects observed, treatment-related
Description (incidence and severity):: At the end of gestation in dams of test groups 2 and 3 (50 and 150 mg/kg bw/d), cholesterol
and triglyceride values were statistically significantly increased. These alterations were regarded
as treatment-related and adverse.
Additionally, in rats of test groups 2 and 3 total protein, albumin and globulin values were significantly
decreased. However, lower total protein and albumin levels in test group 2 and lower
globulin levels in test groups 2 and 3 were within historical control ranges (total protein 56.50-
63.03 g/L; albumin 30.64-36.31 g/L; globulins 23.64-28.97 g/L). Therefore, total protein and
albumin increases in dams of test group 3 were regarded as treatment-related and adverse,
whereas lower total protein and albumin levels in rats of test groups 2 and 3 as well as decreased
globulin levels in dams of test groups 2 and 3 were regarded as treatment-related but
non-adverse because these alterations were marginal.
In dams of test group 3 (150 mg/kg bw/d) alkaline phosphatase (ALP) activities and creatinine
values were slightly but significantly decreased. Lower ALP values are probably due to slightly
lower carcass weights of the dams in this test group, resulting secondarily in lower activities of
bone ALP isoenzymes. This correlates with decreased creatinine values as consequence of
lower skeletal muscle mass in these individuals. Creatinine mean in dams of test group 3 was
within, that of ALP below the historical control range (creatinine 24.0-33.6 μmol/L; ALP 0.88-
1.48 μkat/L). Therefore, the creatinine and ALP decrease were regarded as treatment-related
but non-adverse per se.

Thyroid hormones
In dams of test groups 2 and 3 (50 and 150 mg/kg bw/d), T3 values were significantly decreased
and in dams of test groups 1, 2 and 3 (15, 50 and 150 mg/kg bw/d), TSH values were increased
(in test group 2 not statistically significantly). T4 values were not changed in any test group.
Regarding the preliminary historical control ranges, T3 values in this study were above the
range in any test group including the controls, whereas T4 values and TSH values apart from
the low TSH mean in the control group were within the historical control range (T3 0.65-0.81
nmol/L; T4 25.01-42.00 nmol/L; TSH 5.52-7.55 μg/L). No thyroid weight changes and only minimal
follicular hypertrophy/hyperplasia of the thyroid follicular epithelium and minimal altered
colloid in the thyroid follicles of only a few dams in test group 3 were observed. Therefore,
statistically lower T3 levels and higher TSH values in dosed dams including sporadic, minimal
histopathologic findings in the thyroids of test group 3 were regarded as non-adverse if at all
treatment-related.
Urinalysis findings:: not examined
Behaviour (functional findings):: not examined
Immunological findings:: not examined
Organ weight findings including organ / body weight ratios:: no effects observed
Description (incidence and severity):: Organ weights:
All mean absolute and relative weight parameters did not show significant differences when
compared to the control group 0.
Weight of the placentae:
The mean placental weights of the low-, mid- and high-dose groups were comparable to the
corresponding control group.
Gross pathological findings:: no effects observed
Description (incidence and severity):: Regarding pathology, there were neither treatment-related organ weight changes nor gross
lesions.
Neuropathological findings:: not examined
Histopathological findings: non-neoplastic:: effects observed, treatment-related
Description (incidence and severity):: In test group 3, histopathology revealed in the thyroid glands a minimal increase in the
incidence of follicular hypertrophy/hyperplasia (5 out of 24) and a minimal increase in the incidence
and grading of altered colloid (3 out of 24, minimal to slight). Since these small changes
in the dams of test group 3 were not consistent with the individual T3 and TSH values changes,
they were assumed to be most likely treatment-related but not adverse.

All other findings occurred either individually or were biologically equally distributed over control
and treatment groups. They were considered to be incidental or spontaneous in origin and
without any relation to treatment.
Histopathological findings: neoplastic:: no effects observed
Other effects:: no effects observed
Number of abortions:: no effects observed
Pre- and post-implantation loss:: no effects observed
Total litter losses by resorption:: no effects observed
Early or late resorptions:: no effects observed
Dead fetuses:: no effects observed
Changes in pregnancy duration:: no effects observed
Changes in number of pregnant:: no effects observed
Details on maternal toxic effects:: weights:
The mean gravid uterus weights of the animals of test groups 1-3 (15, 50 and 150 mg/kg bw/d)
were not influenced by the test substance. The differences between these groups and the
control group revealed no dose-dependency and were assessed to be without biological
relevance.

Reproduction data
The conception rate reached 96% in the test groups 0, 1 and 3 (0, 15 and 150 mg/kg bw/d)
and 100 % in test group 2 (50 mg/kg bw/d). With these rates, a sufficient number of pregnant
females were available for the purpose of this study.
There were no test substance-related and/or biologically relevant differences between the test
groups 0-3 in conception rate, in the mean number of corpora lutea and implantation sites or
in the values calculated for the pre- and post-implantation losses, the number of resorptions
and viable fetuses. All observed differences are considered to reflect the normal range of
fluctuations for animals of this strain and age.
Dose descriptor:: NOAEL
Effect level:: 15 mg/kg bw/day
Based on:: test mat.
Basis for effect level:: body weight and weight gain; clinical biochemistry; food consumption and compound intake; water consumption and compound intake
Fetal body weight changes:: effects observed, treatment-related
Description (incidence and severity):: The mean fetal weights of test groups 2 and 3 (50 and 150 mg/kg bw/d) were statistically significantly reduced (about 6% and 8% below control - both sexes combined). However, the mean values (3.4 and 3.3 g in test groups 2 and 3, respectively) were close to the mean value of the historical control (HCD, mean: 3.6 g, cf. “Attached background material”). These rather marginal decreases in mean fetal weight were in presence of maternal toxicity and assessed as consequence of that. They were not considered to be an independent effect per se and were, therefore, not assessed as a selective adverse effect.
Reduction in number of live offspring:: not examined
Changes in sex ratio:: no effects observed
Description (incidence and severity):: The sex distribution of the fetuses in test groups 1-3 (15, 50 and 150 mg/kg bw/d) was
comparable to the control fetuses.
Changes in postnatal survival:: not examined
External malformations:: effects observed, non-treatment-related
Description (incidence and severity):: Fetal external malformations
One control fetus had an external malformation (anasarca) associated with multiple skeletal
malformations. This is considered to be an incidental finding.
Fetal external variations
No external variations were recorded.
Fetal external unclassified observations
One unclassified external observation was recorded. Placentae fused were seen in one litter,
each, in test groups 1-3 (15, 50 and 150 mg/kg bw/d). This finding was not considered
biologically relevant, since it was a single event in the respective test group and can be found
in the historical control data (cf. "Attached background material").
Skeletal malformations:: effects observed, non-treatment-related
Description (incidence and severity):: Fetal skeletal malformations
Skeletal malformations were detected in two fetuses of the control group One female fetus
had multiple skeletal
malformations affecting the sternum, skull, cervical/thoracic vertebral column and ribs
compared with an additional external malformation. One male fetus ha a fused cervical arch,
Since the findings were single events recorded exclusively in the control group, they are
considered to be spontaneous in origin and not treatment-related.

Fetal skelatal variations
For all test groups, skeletal variations of different bone structures were observed, with or
without effects on corresponding cartilages. The observed skeletal variations were related to
several parts of fetal skeletons and appeared in the majority of cases without a relation to dose.
The overall affected fetuses/litter incidences of skeletal variations were statistically significantly
increased in the high-dose group (150 mg/kg bw/d).
However, the incidence in test group 3 was well within the historical control range (cf. "Attached background material"), whereas the
incidence of the control was at the lower end of the range. Therefore, it was not assessed as
treatment-related and adverse.
Skeletal variations with statistically significant differences between the control and any
treated group were: (expressed as mean percentage of affected fetuses/litter
Supraoccipital holes in test group 2 (50mg/kg) 2.3; Incomplete ossification of supraoccipital;
unchanged cartilage test group3 (150mg/kg) 27.0; Incomplete ossification of temporal 2.7
and Bipartite ossification of sternebra, unchanged cartilage 2.0 in test group 1 (15 mg/kg)
Concerning the statistically significant findings, no dose dependency was observed and/or all
values were clearly inside the historical control range (cf. "Attached background material"), thus, an association to the test substance
and a toxicological relevance is not assumed.

Fetal skeletal unclassified cartilage observations
Additionally, some isolated cartilage findings without impact on the respective bony structures,
which were designated as unclassified cartilage observations, occurred in all test groups.
The observed unclassified cartilage findings were related to the skull, the ribs and
the sternum and did not show any relation to the dose. The incidence of ‘branched rib cartilage’
was statistically significantly increased in the mid- and high-dose groups (test groups 1-3:
1.4% / 2.4%* / 1.9%* affected fetuses per litter versus 0.0% in control) but was well within the
historical control range (HCD of affected fetuses per litter: 1.4% [0.0 - 7.0]). Therefore, it was
not assessed as treatment-related. The overall incidences of skeletal unclassified cartilage
observations in the substance-treated groups did not differ significantly from the concurrent
control group.

Finally, fetal examinations revealed that there is no effect of the compound on the respective
morphological structures up to 150 mg/kg bw/d.
Visceral malformations:: effects observed, non-treatment-related
Description (incidence and severity):: Fetal soft tissue malformations
No soft tissue malformations were recorded.

Fetal soft tissue variations
Two soft tissue variations were detected, i.e. dilated renal pelvis and dilated ureter, both in test
groups 0-3. The incidences of these variations were neither statistically significantly different
from control nor dose-dependent and therefore, not considered biologically relevant.

Fetal soft tissue unclassified observations:
No soft tissue unclassified observations were recorded.
Other effects:: no effects observed
Description (incidence and severity):: Anogenital distance/anogenital index
The anogenital distance and anogenital index of all male and female fetuses in the test groups
1-3 was comparable to the concurrent control values.
: Key result
Dose descriptor:: NOAEL
Effect level:: 150 mg/kg bw/day
Based on:: test mat.
Sex:: male/female
Basis for effect level:: other: no adverse treatment-related effects observed
: Key result
Abnormalities:: no effects observed
: Key result
Developmental effects observed:: no
Treatment related:: no
Conclusions:: Under the conditions of this prenatal developmental toxicity study, the oral administration of 5- Methyl-3-vinyloxazolidin-2-on to pregnant Wistar rats from implantation to one day prior to the expected day of parturition (GD 6-19) caused evidence of systemic maternal toxicity, such as a reduction of water and food consumption, a decrease in (corrected) body weight gain and changes in clinical pathology parameters in mid- and high-dose dams (50 and 150 mg/kg bw/d).
In conclusion, the no observed adverse effect level (NOAEL) for maternal toxicity is the low-dose of 15 mg/kg bw/d and for prenatal developmental
toxicity the high dose of 150 mg/kg bw/d. Under the conditions of this study the test item is not teratogenic.

Effect on developmental toxicity: via oral route

Endpoint conclusion:: no adverse effect observed
Dose descriptor:: NOAEL
: 150 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

In a prenatal developmental toxicity study according to OECD 414, 5-Methyl-3-vinyloxazolidin-2-on was administered to pregnant Wistar rats daily by gavage from implantation to one day prior to the expected day of parturition (GD 6-19) to evaluate its potential maternal and prenatal developmental toxicity. Concerning clinical examination, systemic maternal toxicity was observed in a dose dependent manner in the mid- and high-dose groups (groups 2 and 3; 50 and 150 mg/kg bw/d). No treatment-related, adverse findings were observed at the low-dose group (group 1; 15 mg/kg bw/d). Clinical signs, such as piloerection and reduced attention, were observed in several dams of the mid- and high-dose groups. Water consumption of the mid- and high-dose dams was statistically significantly reduced in the beginning of the treatment. Consistently, food consumption of the mid- and high- dose was statistically significantly reduced during GD 6-13 as well as during the entire treatment period.

Consistently with the above-mentioned findings, body weight change in mid- and high- dose dams were decreased highest in the beginning of administration showing a statistically significant decrease in mid-dose dams and a body weight loss of high-dose dams during GD 6-8. Calculated for the entire treatment period (GD 6-19), mid- and high-dose dams gained statistically significantly less body weight than the control animals. This became even more apparent in the parameter corrected body weight gain which was statistically significantly and markedly lower in mid- and high- dose dams compared to control.

Regarding clinical pathology, increased cholesterol and triglyceride values in dams of test groups 2 and 3 (50 and 150 mg/kg bw/d) and decreased total protein and albumin values in dams of test group 3 indicated a changed liver cell metabolism. No differences of toxicological relevance between the control and the treated groups (15, 50 or 150 mg/kg bw/d) were determined for any reproductive parameters, such as conception rate, mean number of corpora lutea, mean number of implantations, as well as pre- and postimplantation loss. Similarly, no toxicologically relevant influence of the test substance on sex distribution and anogenital distance/index of the fetuses was noted at any dose. The mean fetal weights of test groups 2 and 3 (50 and 150 mg/kg bw/d) were statistically significantly reduced (about 6% and 8% below control - both sexes combined). However, the mean values (3.4 and 3.3 g in test groups 2 and 3, respectively) were close to the mean value of the historical control (mean: 3.6 g). These rather marginal decreases in mean fetal weight were assessed as consequence of maternal toxicity. Overall, there was no evidence for toxicologically relevant adverse effects of the test substance on fetal morphology at any dose.

In conclusion, the no observed adverse effect level (NOAEL) for maternal toxicity is the low dose of 15 mg/kg bw/d and for prenatal developmental toxicity the high dose of 150 mg/kg bw/d.

Justification for classification or non-classification

Classification is not warranted according to the criteria of EU Regulation 1272/2008/EC (CLP).

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