Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Remarks:
based on test type (migrated information)
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study
Qualifier:
according to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Version / remarks:
adopted 1996
Qualifier:
according to
Guideline:
other: EPA OPPTS 870.3650, adopted July 2000
GLP compliance:
yes (incl. certificate)
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source:Charles River Laboratories, Research Models and Services, Germany GmbH, Sulzfeld, Germany, male and female rats were derived from different litters to rule out sibling mating
- Age at study initiation: (P) 10-11 wks;
- Weight at study initiation: (P) Males: 294-338 g; Females: 201-234 g
- Fasting period before study: no
- Housing: individually (except during overnight mating and lactationin) in Makrolon type M III cages
- Diet (e.g. ad libitum): Kliba maintenance diet mouse-rat “GLP” meal, ad lib.
- Water (e.g. ad libitum): tap water ad lib.
- Acclimation period: 6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24°C
- Humidity (%): 30-70%
- Air changes (per hr):15
- Photoperiod (hrs dark / hrs light): 12h/12h
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: The test substance was applied as suspension, which was prepared daily. An appropriate amount of the test substance was weighed, and corn oil was added up to the desired volume. The suspension was kept homogenous during administration by stirring with a magnetic stirrer.

The administration volume was 4ml/kg b.w.
Details on mating procedure:
- M/F ratio per cage: 1:1
- Length of cohabitation: 2 weeks, only overnight from 3p.m. to 7-9 a.m.
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
- No replacement of first male after unsuccesluf mating.
- After successful mating each pregnant female was caged (how): individually
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Homogeneity and concentration control analyses of the test-substance preparations were performed in all concentrations at the start of the administration period. Additionally, samples from all concentrations as reverse samples for concentration control analysis were taken at the end of the study. All concentrations were in the expected target range of 90-110% of the nominal concentration.
Duration of treatment / exposure:
31days (males), 52days (females)
Frequency of treatment:
daily
Remarks:
Doses / Concentrations:
40, 100, 250 mg/kg b.w./d
Basis:
actual ingested
doses were adjusted to purity of the substance
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale:
Doses were selected based on a 14day test study in female Wistar rats. 4 rats per group were treated daily with 250, 500, and 1000 mg/kg b.w. via gavage. One animal in the high dose group was found dead on day 13, probably due to excessive irritation in the stomach and digestive system. Of the surviving three animals, one showed hyperemia in the cecum, ulceration/erosion in the glandular stomach and discoloration of the jejunum contents, two showed ulcerations / erosion in the forestomach. In the mid dose, one animal also showed erosion / ulceration in the forestomach, which were evaluated as severe enough to likely cause death throughout the much longer treatment time in the OECD422 main study. Thus the lowest dose was selected as the maximum dosage for the main study. Here, lesions in the forestomach were also observed in one animal, but severity was reduced.
Positive control:
none
Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily on workdays, daily on weekends and public holidays
- Cage side observations: check for moribund animals, pertinent behavioral changes, signs of overt toxicity, parturation, littering and lactation behavior of the dams

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: prior to the first administration, weekly thereafter
- The following parameters were examined: abnormal behavior during “handling”, fur, skin, posture, salivation, respiration, activity/arousal level, tremors, convulsions, abnormal movements, impairment of gait, lacrimation, palpebral closure, exophthalmus, feces (appearance/consistency), urine, pupil size

BODY WEIGHT: Yes
- Time schedule for examinations: day 0, weekly thereafter with the following exceptions for females: 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.

FOOD CONSUMPTION:
- Food consumption for each animal determined: Yes, except during mating

WATER CONSUMPTION: Monitored by daily visual inspection

OTHER (for details see entry for this study in the repeated dose section):
- Functional observation battery and motor activity measurement of 5 males and females per group 2 days prior to sacrifice
- Urinanalysis in 5 males and females per group one day prior to necropsy
- Clinicochemical and hematological examinations 5 males and females on the day of necropsy after fasting for 16h
Sperm parameters (parental animals):
Parameters examined in male parental animals:
testis weight, epididymis weight, stages of spermatogenesis in the male gonads
Litter observations:
PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, clinical symptoms, weight gain

GROSS EXAMINATION OF DEAD PUPS:
yes, externally and organs were assessed macroscopically
Postmortem examinations (parental animals):
SACRIFICE
- Male animals: All surviving animals on day 32 (3 days after the maximum mating period)
- Maternal animals: All surviving animals on day 53

GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations

HISTOPATHOLOGY / ORGAN WEIGHTS
The following tissues were weighed
- in all animals: epididymides, testes
- in 5 males and females of each group: adrenal glands, brain, heart, kidneys, liver, spleen, thymus
The uteri of all cohabited female parental animals were examined for the presence and number of implantation sites. The uteri of apparently non-pregnant animals or empty uterus horns were placed in 1% ammonium sulfide solutions for about 5 minutes in order to be able to identify early resorptions or implantations.
The following tissues were examined histotechnically in at least 5 animals per sex of the control and high dose group unless noted otherwise:
adrenal glands, gross lesions (all affected animals in all dosage groups), bone marrow (femur), brain, cecum, cervix, coagulation glands, colon, duodenum, epididymides, heart, ileum, jejunum, kidneys, liver, lungs, lymph nodes (auxillary and mesenteric), ovaries, oviducts, prostate gland, peyer's patches, rectum, sciatic nerve, seminal vesicles, spinal cord, spleen, stomach (also all males from the low and mid dose groups), testes, thymus, thyroid glands, trachea, urinary bladder, uterus, vagina
Postmortem examinations (offspring):
NECROPSY
- All surviving pubs were subjected to postmortem examinations: external examination and macroscopic examination of organs. Animals with notabel findings or abnormalitites were evaluated on a case-by-case basis.
Reproductive indices:
For the males, mating and fertility indices were calculated for F1 litters according to the following formulas:
Male mating index (%) = number of males with confirmed mating (vaginal sperm detected in females) / number of males placed with females x100
Male fertility index (%) = number of males proving their fertility (implants in utero) / number of males placed with females x100

For the females, mating, fertility and gestation indices were calculated for F1 litters according to the following formulas:
Female mating index (%) = number of females mated (vaginal sperm detected) / number of females placed with males x100
Female fertility index (%) = number of females pregnant (implants in utero) / number of females mated (vaginal sperm or implants in utero) x100
Gestation index (%) = number of females with live pups on the day of birth / number of females pregnant x100
Offspring viability indices:
Live birth index (%) = number of liveborn pups at birth / total number of pups born x100
Viability index (%) = number of live pups on day 4 after birth / number of live pups on the day of birth x100
CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
No mortality was observed.
Almost all animals of the high dose group showed salivation within 2 hours after substance administration, which was most likely induced by local irritation of the digestive tract of bad taste of the substance.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
unaffected by the test substance

FUNCTIONAL OBSERVATION BATTERY
All findings were equally distributed between the test and control groups and thus not considered to be treatment related.

REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS)

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
Male/female mating index = 100% for all groups
Male/female fertility index = 90% (control and low dose), 100% (mid dose), 70% (high dose), which is in the range of historical control data
Duration of gestation varied between 22.1 and 22.5 days without any significant differences. The gestation index and live birth index were 100% in all groups. Only one female in the low dose group had 3 stillborn pubs.

ORGAN WEIGHTS (PARENTAL ANIMALS)
no test substance related effects.

GROSS PATHOLOGY (PARENTAL ANIMALS)
No test substance related effects were observed. Especially, no gross lesions of reproductive organs were detected in the males and females that did not produce offspring.

HISTOPATHOLOGY (PARENTAL ANIMALS)
In 7 out of 10 males of the high dose group the forestomach showed minimal hyperkeratosis, which is probably due to local irritant properties of the test substance, that were already observed in the pre-study for dose selection. No further differences were observed.
No histopathological correlate was obeserved in females and males which failed to produce offspring. Only one of these males showed minimal testicular degeneration. This is frequently observed in these rats and usually compatible with fertility, but might have been the cause for infertility in this study.

OTHER FINDINGS (PARENTAL ANIMALS)
No test substance related effects on clinical chemistry and urinalysis parameters were observed.
Dose descriptor:
NOAEL
Remarks:
systemic toxicity
Effect level:
>= 250 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Dose descriptor:
NOAEL
Remarks:
reproductive performance
Effect level:
>= 250 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
VIABILITY (OFFSPRING)
The viability index was 100% (mid and high dose), 99.1% (low dose) and 97.8% (control)

SEX DISTRIBUTION
not affected by the test substance

CLINICAL SIGNS (OFFSPRING)
none observed

BODY WEIGHT (OFFSPRING)
Not affected by the test substance. One female runt was found in a rather large litter (16pubs) of the high dose group. Also 5 male and 9 female runts were found in two litters of the mid dose females. All except one male whose weight was within the historical control data, also belonged to a large litter of 17 pubs. These differences were no longer observed on PND 4.

GROSS PATHOLOGY (OFFSPRING)
No test substance related effects observed.
Dose descriptor:
NOAEL
Remarks:
developmental toxicity
Generation:
F1
Effect level:
>= 250 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Reproductive effects observed:
not specified
Conclusions:
Under the conditions of this Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test the oral administration by gavage to Wistar rats revealed no signs of systemic toxicity at a dose level of 250mg/kg bw/d in animals of both sexes. Thus, the no observed adverse effect level (NOAEL) for general systemic toxicity was 250 mg/kg bw/d in males and in females. The NOAEL for reproductive performance and fertility was set to 250 mg/kg bw/d in male and female Wistar rats. The NOAEL for developmental toxicity was effective 250 mg/kg bw/d.
Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
250 mg/kg bw/day
Additional information

(5-ethyl-1,3-dioxan-5-yl)methyl acrylate was administered orally by gavage to groups of 10 male and 10 female Wistar rats (F0 animals) at dose levels of 0 mg/kg body weight/day, 40mg/kg bw/d, 100mg/kg bw/d, and 250mg/kg bw/d. Corn oil served as vehicle. The dosages were adjusted to the purity of the substance (78.1g/100g). The doses were selected based on a 14day test study in female rats. During this study, one female receiving 1000mg/kg b.w. died on day 13 most likely due to severe irritation in the digestive system. Ulcerations / erosions and dicolored jejunal content were also seen in the surviving 3 females. Ulceration in one female of the mid dose receiving 500mg/kg b.w. was also judged as severe enough, that it would lead to the death of this animal throughout a longer treatment period. Thus the low dose of 250mg/kg, where slight ulcerations were also observed in one animal, was set as the high dose for the main study.

The duration of treatment in the main study covered 31days for males and 52 days for females. After 2 weeks of premating treatment the F0 animals were mated to produce F1 generation pups. Mating pairs were from the same test group. Mating was discontinued as soon as sperm was detected in the vaginal smear. A detailed clinical observation (DCO) was performed in all animals before initial test substance administration and at weekly intervals thereafter. Food consumption of the F0 parents was determined once weekly during premating. For the dams food consumption was determined for gestation days 0-7, 7-14, 14-20 and lactation days 1-4. Body weights of F0 parents were determined once a week, in males throughout the study and in females during premating and mating. During gestation and lactation period, F0 females were weighed on gestation days (GD) 0, 7, 14 and 20, after the day of parturition (postnatal day [PND] 0) and on PND 4. The pups were sexed and examined for macroscopically evident changes on PND 0. They were weighed on PND 1 and on PND 4. 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. 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. Clinicochemical and hematological examinations as well as urinalyses were also performed towards the end of the administration period 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. Aside from hyperkeratosis in 7 out of 10 males in the high dose group, which is seen as a sign of local irritation and not systemic toxicity, no test substance related effects were observed. Thus, the NOAELs for systemic toxicity, reproductive performance, and developmental toxicity were set to 250mg/kg b.w., the highest dose tested.


Short description of key information:
Combined repeated dose / reproductive toxicity testing, rat, gavage: NOAEL 250mg/kg (OECD 422, GLP, BASF 2013)

Effects on developmental toxicity

Description of key information
No developmental toxicity (OECD 414, rat, GLP, BASF 2015)
Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study
Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Version / remarks:
Adopted Jan. 2001
Qualifier:
according to
Guideline:
EU Method B.31 (Prenatal Developmental Toxicity Study)
Version / remarks:
adopted May 2008
Qualifier:
according to
Guideline:
EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
Version / remarks:
adopted August 1998
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
other: Crl:WI(Han)
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories France, L'Arbresle Cedex, France
- Age at study initiation: 10 to 14 weeks
- Weight at study initiation: 184 on average
- Fasting period before study: no
- Housing: individually in Macrolon plastic cages (MIII type)
- Diet (e.g. ad libitum): pelleted rodent diet ad lib. (SM R/M-Z from SSNIFF®)
- Water (e.g. ad libitum): tap water ad lib.
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 - 24°C
- Humidity (%): 40 - 70%
- Air changes (per hr): more than 10
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: Formulations (w/w) were prepared daily within 5 hours prior to dosing and were homogenized to a visually acceptable level. Adjustment was made for specific gravity of the vehicle and test substance. A correction was made for the purity/composition of the test substance. A correction factor of 1.28 was used. Formulations were placed on a magnetic stirrer during dosing.

VEHICLE
- Justification for use and choice of vehicle (if other than water): solubility
- Concentration in vehicle: 0.75, 2.5, 7.5%
- Amount of vehicle (if gavage): 4mL/kg b.w.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
- No test substance was detected in the Group 1 formulations.
- The concentrations analysed in the formulations of Group 2, 3 and 4 were in agreement with the target concentrations (i.e. mean accuracies between 90% and 110%).
- The formulations of Group 2 and Group 4 prepared were homogeneous (i.e. coefficient of variation ≤ 10%).
- Formulations at the entire range were stable when stored at room temperature protected from light for at least 5 hours (i.e. relative difference ≤ 10%).
- The long term storage samples were stable at ≤-70°C for 337 hours.
Details on mating procedure:
- Impregnation procedure: purchased timed pregnant
- Proof of pregnancy: vaginal plug referred to as day 0 of pregnancy
Duration of treatment / exposure:
Days 6 to 20 post-coitum, inclusive
Frequency of treatment:
daily
Remarks:
Doses / Concentrations:
30, 100, 300mg/kg b.w.
Basis:
actual ingested
No. of animals per sex per dose:
22
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Dose levels were based on an OECD 422 study with dose levels up to 250 mg/kg bw/day, but without toxicity in females. The high dose level in the current study (300 mg/kg bw/day) is based on erosions of the forestomach seen in 1 out of 4 females dosed with 250 and 500 mg/kg bw/day after 14 days administration, respectively.

- Animal randomization: On the day of receipt, by computer-generated random algorithm according to body weight, with all animals within ± 20% of the mean per subgroup. Females which were mated on the same day are classified in the same subgroup.
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily for mortality and at least once daily for clinical signs
- Cage side observations checked in table [No.?] were included.

DETAILED CLINICAL OBSERVATIONS: Yes / No / No data
- Time schedule:

BODY WEIGHT: Yes
- Time schedule for examinations: Days 1, 3, 6, 9, 12, 15, 18 and 21 post-coitum

FOOD CONSUMPTION: Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Time schedule for examinations: Days 1-3, 3-6, 6-9, 9-12, 12-15, 15-18 and 18-21 post-coitum

WATER CONSUMPTION: Subjective appraisal, no quantitative measurements

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 21
- Organs examined: Reproductive organs, stomach, all further macroscopic anomalies

OTHER: Blood was collected directly prior to necropsy
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Placenta weight (for live fetuses): Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number and distribution of early resorptions: Yes
- Number and distribution of late resorptions: Yes
- Number and distribution of life fetuses: Yes
- Fetal weight: Yes
- Sex of each fetus: Yes
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: Yes: half per litter
Statistics:
The following statistical methods were used to analyze the data:
- If the variables could be assumed to follow a normal distribution, the Dunnett-test (many-to-one t-test) based on a pooled variance estimate was applied.
- The Steel-test (many-to-one rank test) was applied if the data could not be assumed to follow a normal distribution.
- The Fisher Exact-test was applied to frequency data.
- The Mann Whitney test was used to compare mean litter proportions (percent of litter) of the number of viable and dead fetuses, early and late resorptions, total resorptions, pre- and postimplantation loss, and sex distribution.
- Mean litter proportions (percent per litter) of total fetal malformations and developmental variations (external, visceral and skeletal), and each particular external, visceral and skeletal malformation or variation were subjected to the Kruskal-Wallis nonparametric ANOVA test to determine intergroup differences. If the ANOVA revealed statistically significant (p<0.05) intergroup variance, Dunn’s test was used to compare the compound-treated groups to the control group.

All tests were two-sided and in all cases p < 0.05 was accepted as the lowest level of significance.

No statistics were applied for data on maternal survival, pregnancy status, group mean numbers of dead fetuses, early and late resorptions, and pre- and post-implantation loss.
Indices:
Pre-implantation loss (%) = (number of corpora lutea - number of implantation sites) / number of corpora lutea * 100
Post-implantation loss (%) = (number of implantation sites - number of live fetuses) / number of implantation sites * 100
Viable fetuses affected / litter (%) = (number of viable fetuses affected per litter) / number of viable fetuses per litter * 100
Historical control data:
Available for 5 studies performed in 2014/2015
Details on maternal toxic effects:
Maternal toxic effects:no effects

Details on maternal toxic effects:
No mortality occured.
Salivation was observed in 12/22 females treated with 100mg/kg and all females treated with 300mg/kg. In addition, piloerection was seen in 1/22 and 3/22 animals treated at 100 and 300 mg/kg bw/day, respectively. Salivation was likely related to the taste or irritating properties of the test formulation applied and was not considered an adverse effect. In addition, piloerection was considered of no toxicological significance based on its low incidence within both dose groups.
There were no differences in body weight, body weight gain, or food consumption. Macroscopic examination revealed no substance related effect.
There was also no effect on the number of corpora lutea, implantation sites, or pre- or post-implantation loss in all dose groups. All females were pregnant with viable fetuses.
Dose descriptor:
NOAEL
Effect level:
>= 300 mg/kg bw/day (nominal)
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
>= 300 mg/kg bw/day (nominal)
Basis for effect level:
other: developmental toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
Mean litter sizes were 10.2, 11.5, 10.6 and 10.4 fetuses/litter for the vehicle control, 30, 100 and 300 mg/kg bw/day groups, respectively.
Mean sex ratios (males:females) were 51:49, 51:49, 57:43 and 42:58 for the vehicle control, 30, 100 and 300 mg/kg bw/day, respectively.
Mean combined (male and female) fetal body weights were 5.3, 5.2, 5.3 and 5.2 grams for the vehicle control, 30, 100 and 300 mg/kg bw/day, respectively.
Mean male/female placenta weights were 0.44/0.42, 0.45/0.43, 0.46/0.44 and 0.45/0.42 grams for the vehicle control, 30, 100 and 300 mg/kg bw/day, respectively.
The numbers of fetuses (litters) available for morphological examination were 224(22), 254(22), 234(22) and 228(22) in Groups 1, 2, 3, and 4, respectively.
There were no external developmental malformations or variations for any fetuses following treatment up to 300 mg/kg/day.
There were no treatment related effects on visceral morphology following treatment up to 300 mg/kg. Visceral malformations were noted in one fetus each of the low and high dose group. Visceral variations were observed for 8.6%, 6.2%, 6.7% and 5.1% of fetuses per litter in the control, 30, 100 and 300 mg/kg groups, respectively.
There were no treatment related effects on skeletal morphology following treatment up to 300 mg/kg. Skeletal malformations were noted in one fetus in each of the control, 30, 100 and 300 mg/kg groups. Skeletal variations were observed for 87.9%, 82.0%, 84.5% and 81.4% of fetuses per litter in the control, 30, 100 and 300 mg/kg groups, respectively.

Abnormalities:
not specified
Developmental effects observed:
not specified
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
300 mg/kg bw/day
Species:
rat
Additional information

Mated female Wistar Han rats were assigned to four dose groups, each containing twenty-two animals. The test item was administered once daily by gavage from Day 6 to 20 post-coitum at doses of 30, 100 and 300 mg/kg bw/day (Groups 2, 3 and 4 respectively). The rats of the control group (Group 1) received the vehicle, corn oil, alone. Accuracy, homogeneity and stability of formulations were demonstrated by analyses.

Maternal findings

No maternal toxicity was observed in the 30, 100 and 300 mg/kg bw/day groups.

Developmental findings

No developmental toxicity was observed in the 30, 100 and 300 mg/kg bw/day groups.

In conclusion, based on the results in this prenatal developmental toxicity study the maternal and developmental No Observed Adverse Effect Level (NOAEL) for Laromer LR 8887 was established as being at least 300 mg/kg bw/day.

Justification for classification or non-classification

No effects on fertility or developmental toxicity have been observed in the available studies. Thus (5-ethyl-1,3-dioxan-5-yl)methyl acrylate does not have to be classified according to 67/548/EEC or CLP/EU-GHS.