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Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

Combined repeated dose / reproductive toxicity testing, rat, gavage: NOAEL >=500mg/kg (OECD 422, GLP, BASF 2013)

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
05 June 2012 to 07 August 2012
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Reason / purpose:
reference to same study
Qualifier:
according to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Version / remarks:
22 March 1996
Deviations:
no
Qualifier:
according to
Guideline:
other: EPA OPPTS 870.3650
Version / remarks:
July 2000
Deviations:
no
GLP compliance:
yes (incl. certificate)
Limit test:
no
Specific details on test material used for the study:
Lot/batch No.: 110007P040
Species:
rat
Strain:
Wistar
Details on species / strain selection:
The rat is the preferred animal species for reproduction studies according to the various test guidelines and the Wistar strain was selected.
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH (male and female animals were derived from different litters to rule out mating of siblings)
- Age at study initiation: 10-11 wks
- Weight at study initiation: on average: Males: 335g; Females: 197g
- Fasting period before study: no
- Housing: single (except during mating and during lactation) in Markrolon type M III cages
- Diet: ground Kliba maintenance diet mouse-rat “GLP”, meal ad lib.
- Water: ad lib.
- Acclimation period: app. 1 week

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 desired amount of test substance was weighed, and corn oil was added up to the correct volume. To prepare a homogenous suspension, the mixture was stirred with a magnetic stirrer also during administration. The test substance preparations were produced at least once a week and were stored at room temperature.

VEHICLE
- Justification for use and choice of vehicle: The test substance is poorly soluble in water, but forms a homogenous suspension in corn oil, which is also non-toxic to rats.
- Concentration in vehicle: 1.25; 3.75; 12.5 g/100mL
- Amount of vehicle: 4 mL/ kg bw
Details on mating procedure:
- M/F ratio per cage: 1:1 over night
- Length of cohabitation: until sperm was detected in vaginal smear or for a maximum of 14 days
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
- After successful mating each pregnant female was caged: 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. The concentration control analyses of all concentrations revealed that the values were in the expected range of the target concentrations, i.e. were always in a range of about 90.0-110.0% of the nominal concentrations. Considering the low relative standard deviation in the homogeneity analysis, it can be concluded that the test substance was distributed homogeneously in corn oil.
Duration of treatment / exposure:
Males: 35 days
Females: 56 days
Frequency of treatment:
daily (except to animals being in labor)
Dose / conc.:
50 mg/kg bw/day (nominal)
Dose / conc.:
150 mg/kg bw/day (nominal)
Dose / conc.:
500 mg/kg bw/day (nominal)
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: The selection of doses was based on the results of a test study in female Wistar rats (BASF project No. 10C0457/11S163) conducted at dose levels of 0, 600 and 1000 mg/kg bw/d. In this study, a NOAEL was not established due to erosions and ulcerations in the stomach of different animals at both dose levels of 600 and 1000 mg/kg bw/d as well as clinical findings like poor general condition, piloerection and body weight loss after 1 week of treatment.
- Rationale for animal assignment: random
- Fasting period before blood sampling for clinical biochemistry: yes, for at least 16 - 20 hours
Positive control:
no
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
- Cage side observations checked in table No.1-2 were included.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: prior to the first administration, weekly thereafter
- Cage side observations checked in table No.3 were included.

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:
- Functional observation battery and motor activity measurement of 5 males and females per group 2 days prior to sacrifice (Parameters checked in table No. 4 were examined)
- Urinanalysis in 5 males and females per group one day prior to necropsy (Parameters checked in table No. 7 were examined.)
- Clinicochemical and hematological examinations 5 males and females on the day of necropsy after fasting for 16h (Parameters checked in table No. 5 and 6 were examined.)
Oestrous cyclicity (parental animals):
not examined
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 36
- Maternal animals: All surviving animals on day 57

GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations: yes

HISTOPATHOLOGY / ORGAN WEIGHTS
The tissues indicated in Table 8-9 were prepared for microscopic examination and weighed, respectively.
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.
Statistics:
See table No. 10
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:
no effects observed
Description (incidence and severity):
Almost all male and most female animals of the high dose group showed salivation within 2 hours after the administration on several days of the study. Salivation within 2 hours after treatment was also seen in several mid dose male and female animals. From the temporary, short appearance immediately after dosing it was concluded that salivation was induced by a bad taste of the test substance or local affection of the upper digestive tract.

On study days 7 and 14 in one male animal of test group 2 (150 mg/kg bw/d) showed an encrusted eye during the detailed clinical observations (DCO). The DCO on study days 0, 21, 28, 35 in male animals of test groups 0-3 (0, 50, 150 and 500 mg/kg bw/d) did not reveal any additional abnormalities. In female animals of test groups 0-3 (0, 50, 150 and 500 mg/kg bw/d), DCO on study days 0, 7, 14, 21, 28, 35, 42, 49, 56 did not reveal any abnormalities.
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, non-treatment-related
Description (incidence):
One female animal of test group 3 (500 mg/kg bw/d) was sacrificed in a moribund condition on gestation day 24.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No test substance-related changes in body weight or body weight gain were observed for male and female animal of test groups when compared to control groups.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
No test substance-related, adverse findings were noted.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
no effects observed
Description (incidence and severity):
No test substance-related, adverse findings were noted.
Ophthalmological findings:
not examined
Haematological findings:
effects observed, non-treatment-related
Description (incidence and severity):
No treatment-related changes among hematological parameters were observed.
In males of test groups 1, 2 and 3 (50, 150 and 500 mg/kg bw/d) large unstained cell (LUC) counts were lower compared to controls. Regarding this relatively short study period, only an increase but no decrease of the LUCs, which represent commonly immature cells, could have been related to a pathological effect. Therefore, this alteration was regarded as incidental and not treatment-related.
In females of test groups 1, 2 and 3 (50, 150 and 500 mg/kg bw/d) relative monocyte counts and in females of test groups 1 and 3, only, absolute monocyte cell counts were higher compared to controls. Both parameters were not dose-dependently changed. Even in test
group 3 (500 mg/kg bw/d) this was an isolated finding with no change in other differential blood cell counts. Therefore, this alteration was regarded as incidental and not treatment-related.
Clinical biochemistry findings:
effects observed, non-treatment-related
Description (incidence and severity):
No treatment-related changes among clinical chemistry parameters were observed.
In males of test group 3 (500 mg/kg bw/d), alanine aminotransferase (ALT) activities were decreased. The mean was 18% lower compared to that of the controls. There was no dosedependent decrease of the ALT activities. Therefore, this slight effect in test group 3 was regarded as incidental rather than treatment-related.
Urinalysis findings:
effects observed, non-treatment-related
Description (incidence and severity):
No treatment-related changes among urinalysis parameters were observed.
In females of test group 2 (150 mg/kg bw/d), the urine pH value was higher compared to controls. This effect was not dose-dependently altered and, therefore, it was regarded as isolated, incidental and not treatment-related.
Behaviour (functional findings):
no effects observed
Description (incidence and severity):
No test substance-related effects were observed.
One female animal 6 of the control group showed increased response after audition and very frequent vocalizations when touched. A relation to treatment was excluded.
There were no significant deviations concerning the overall motor activity (summation of all intervals) in male and female animals of all test groups in comparison to the concurrent control group. Regarding single intervals, an isolated significantly increased value was observed at interval 11 for male animals of test group 3 (500 mg/kg bw/d). The finding was considered to be incidental.
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
All findings noted were either single observations or they were biologically equally distributed between control and treatment group. All of them were considered to be incidental or spontaneous in origin and without any relation to treatment.
Histopathological findings: neoplastic:
not examined
Other effects:
no effects observed
Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
effects observed, non-treatment-related
Description (incidence and severity):
For all F0 parental males, which were placed with females to generate F1 pups, mating was confirmed. Thus, the male mating index was 100% in all test groups (0, 50, 150 and 500 mg/kg bw/d). The male fertility index ranged between 80% (500 mg/kg bw/d) and 90% (0, 50, 150 mg/kg bw/d).
The female mating index calculated after the mating period for F1 litter was 100% for all test groups (0, 50, 150 and 500 mg/kg bw/d). The female fertility index varied between 80% (500 mg/kg bw/d) and 90% (0, 50, 150 mg/kg bw/d).
The mean duration of gestation was between 22.1 and 22.6 days and did not show significant differences. Not all sperm-positive females delivered pups. Therefore, the gestation index reached 100% in test groups 0-2 and 88% in test group 3.
One high dose female animal, that was not pregnant, revealed a decrease in ovary size and a diffuse atrophy of both ovaries and no corpora lutea. This was regarded to be the cause of the infertility in this pair. All other females and their male mating partners did not show gross lesions in reproduction relevant organs which could explain the lack of offspring.
ORGAN WEIGHTS (PARENTAL ANIMALS)
All mean weight parameters (absolute and relative) did not show significant differences when compared to the control groups.

GROSS PATHOLOGY (PARENTAL ANIMALS)
All gross lesions noted were single observations and they were regarded to have developed spontaneously and unrelated to compound and treatment.

HISTOPATHOLOGY (PARENTAL ANIMALS)
All findings were considered to be incidental or spontaneous in origin and without any relation to treatment.
The high dose female animal that was sacrificed in a moribund state revealed a decidual reaction with consequent inflammation of the uterus. Decidual reaction is a proliferation of decidual cells (tissue of endometrial origin lining of the uterus, which is in contact with the fetal membranes and the placental plate). They often are assiocated with inflammation as observed in this animal. The local inflammation in the uterus can lead to disturbance of the general condition or, if the inflammation is spreading, sepsis. This was regarded to be the reason for the moribund state of this animal but was not regarded to be treatment-related.
Key result
Dose descriptor:
NOAEL
Effect level:
>= 500 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: systemic toxicity
Key result
Dose descriptor:
NOAEL
Effect level:
>= 500 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: fertility and reproductive performance
Key result
Critical effects observed:
no
Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
Ten of 14 pups in the litter of one female animal of test group 1 (50 mg/kg bw/d) showed reduced nutritional condition on PND 0. All pups in this litter died between PND 0- 1. Each one pup of two female animals of test group 2 (150 mg/kg bw/d) died on PND 0. These findings were assessed as being incidental as no dose-reponse relationship occurred. The surviving F1 pups of any test group did not show adverse clinical signs up to scheduled sacrifice on PND 4.
Dermal irritation (if dermal study):
not examined
Mortality / viability:
mortality observed, non-treatment-related
Description (incidence and severity):
Single stillborn pubs were seen in the low dose and mid dose group only. The mean number of delivered pups per dam and the rate of liveborn and stillborn pups reflect the normal range of biological variation inherent in the strain used in this study.
The viability index as indicator for pup mortality between PND 0 and 4 was 89% in the low dose group (all pups of one female died), 99% in the mid dose group (1 pup of one female died) and 100% for high dose and control females. As the decreased viability index in the low dose group was still within the historical control data, statistically not significant, and related to mentioned litter loss of only one female animal, the finding was assessed to be incidental and not related to treatment.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Mean pup body weights/pup body weight changes of all pups in all test groups were comparable to the concurrent control values. Each 1 runt was seen in test groups 1 (female pup; 50 mg/kg bw/d) and 2 (male pup; 150 mg/kg bw/d). Both values were within the range of the biological variation inherent in the strain of rats used for this study.
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Sexual maturation:
not examined
Anogenital distance (AGD):
not examined
Nipple retention in male pups:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Description (incidence and severity):
Post mortem autolysis was observed for several pups in all test groups including the control. For 11 pups of test group 1 (50 mg/kg bw/d) an empty stomach was observed. Three pups of test group 1 (50 mg/kg bw/d) were not assessed because they were cannibalized on PND 1. The findings were assessed as being spontaneous in nature and without biological relevance.
Histopathological findings:
not examined
Other effects:
no effects observed
Description (incidence and severity):
The sex distribution and sex ratios of live F1 pups on the day of birth and on PND 4 did not show biologically relevant differences between test groups.
Behaviour (functional findings):
not examined
Developmental immunotoxicity:
not examined
Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
>= 500 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: developmental toxicity
Key result
Critical effects observed:
no
Key result
Reproductive effects observed:
no
Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
500 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
GLP study according to OECD guideline
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

The test substance was administered orally by gavage to groups of 10 male and 10 female Wistar rats at dose levels of 0, 50, 150, and 500 mg/kg bw/d in corn oil. The doses were selected based on a 14-day test study in female Wistar rats, conducted at dose levels of 600 and 1000 mg/kg. In this study, a NOAEL was not established due to erosions and ulcerations in the stomach of different animals at both dose levels of 600 and 1000 mg/kg bw/d as well as clinical findings like poor general condition, piloerection and body weight loss after 1 week of treatment.

The duration of treatment in the main study covered 35 days for males and 56 days for females. After 2 weeks of premating treatment the F0 animals were mated in a 1:1 ratio 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 was performed in all animals before initial test substance administration and at weekly intervals thereafter. Food consumption and body weight of the animals were determined in app. weekly intervals. 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 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.

No signs of systemic toxicity were observed up to the highest dose level of 500 mg/kg bw/d in animals of both sexes, and no difference regarding clinical parameters or histopathology were observed. Especially no effect on reproductive organs could be detected. Fertility indices for male and female animals were not impaired by test-substance administration even at a dose level of 500 mg/kg bw/d. In addition, live birth indices and viability of pups in all test groups were not altered. Thus, the no observed adverse effect levels (NOAEL) for general systemic toxicity, fertility, and developmental toxicity was set to 500 mg/kg bw/d in male and female animals.

Effects on developmental toxicity

Description of key information

Prenatal developmental toxicity study, rat, gavage: NOAEL = 1000 mg/kg bw (RA, OECD 414, GLP, Cytec, 1984)

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
17 July 1984 to 10 August 1984
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Version / remarks:
12 May 1981
Deviations:
no
GLP compliance:
yes
Limit test:
yes
Species:
rat
Strain:
other: Sprague Dawley COBS CD rats
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding laboratories, Inc., Portage, Michigan
- Age at study initiation: 13 wk
- Weight at study initiation: 225-297 g
- Housing: Individually housed in wire mesh cages suspended above cage board
- Diet: Purina certified rodent chow; ad libitum
- Water: Tap water; ad libitum
- Acclimation period: 14 d

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 0.16
- Humidity (%): 40
- Photoperiod (h dark / h light): 12 h / 12 h
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: A specified amount of the test material for each dose group was weighed (not adjusted for purity), and transferred to a volumetrie flask which was first coated with the Mazo1a4l' corn oil vehic1e, using aseries of vehicle rinses. Vehicle was then added in sufficient quantity to achieve the appropriate concentration for each group. The flasks were inverted and manually shaken several times prior to stirring. The mixtures were stirred continuously for 5 minutes until homogenous using a magnetic stir plate and bars. The mixtures were prepared fresh daily and stirred prior to dispensing. A magnetic stir plate and bars were also utilized during dose administration to ensure adequate mixture. A total volume of 100 ml per test group was prepared daily during the course of the study. The bulk chemical was stored at room temperature.

VEHICLE: CORN OIL
- Purity: 100 %
Analytical verification of doses or concentrations:
no
Details on mating procedure:
- Impregnation procedure: Cohoused
- If cohoused:
- M/F ratio per cage: 1:1
- Verification of same strain and source of both sexes: Yes
- Proof of pregnancy: Presence of vaginal plug referred to as Day 0 of pregnancy
Duration of treatment / exposure:
10 d, from Day 6 to 15 of gestation, inclusive
Frequency of treatment:
Once daily
Duration of test:
25 d
Dose / conc.:
1 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
30 females/dose
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Based on the results of a range-finding study, the test dosage (1000 mg/kg bw/d) was selected since it was anticipated to induce some degree of maternal toxicity but one which would not likely affect maternal survival.
- Rationale for animal assignment: On a given day, the first mated female and the appropriate gestation day 0 designation were entered on the form and the fe male was assigned to group 1, the second mated female was assigned to group 2, and the third to group 3, etc. This process was continued daily until 30 females had been placed into each group.
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: From Day 0 through 20 of gestation

BODY WEIGHT: Yes
- Time schedule for examinations: Day 0, 6, 9, 12, 16 and 20
- Mean body weight changes were calculated for each corresponding interval of gestation additionally for Day 6-16, 16-20 and 0-20.

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation Day 20
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: 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: all per litter
Statistics:
1. The fetal sex ratios were compared by the Chi-square test with Yates' correction factor.
2. The number of litters with malformations and developmental variations were compared by Fisher's Exact Test
3. The numbers of early and late resorptions, dead fetuses and postimplantation losses were compared by the Mann-Whitney U-test
4. Mean numbers of corpora lutea, total implantations, viable fetuses, mean fetal and maternal body weights, and maternal body weight gain at each interval were analyzed by a one-way ANOVA and Dunnett's test.
Indices:
- Fetal sex ratios, number of litters with malformations and developmental variations, numbers of early and late resorptions, dead fetuses and postimplantation losses
- Numbers of corpora lutea, total implantations and viable fetuses
Historical control data:
Yes
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Clinical signs of toxicity, expressed by salivation prior to and following dosing, were observed in the test material groups onIy. Urogenital matting and hair loss from various body surfaces occurred at a higher incidence in the test material groups.
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, non-treatment-related
Description (incidence):
Two rats died due to an intubation error.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
A slight decrease in mean body weight gain was observed in each treated group during the first three days of treatment, gestation days 6-9. A slight decrease in mean body weight gain was also observed during the last days of the treatment period, gestation days 12-16. Over the entire treatment period, gestation interval 6-16, mean body weight gains were significantly decreased in all test material groups.
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Description (incidence and severity):
There were no gross internal morphological changes among the dams at the terminal sacrifice which could be considered treatment induced.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
not examined
Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
There were no biologically meaningful or statistically significant differences concerning the mean numbers of viable fetuses, early or late resorptions, postimplantation loss, implantation sites or corpora lutea between the control and alI test material groups.
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Description (incidence and severity):
There were no biologically meaningful or statistically significant differences concerning the mean numbers of viable fetuses, early or late resorptions, postimplantation loss, implantation sites or corpora lutea between the control and alI test material groups.
Dead fetuses:
no effects observed
Changes in pregnancy duration:
not examined
Changes in number of pregnant:
not examined
Other effects:
not examined
Details on maternal toxic effects:
Maternal toxic effects: yes
Key result
Dose descriptor:
LOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
body weight and weight gain
Key result
Abnormalities:
no effects observed
Fetal body weight changes:
no effects observed
Description (incidence and severity):
The mean fetal weights were not affected by treatment.
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Description (incidence and severity):
The fetal sex ratios were not affected by treatment.
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
not examined
External malformations:
effects observed, non-treatment-related
Description (incidence and severity):
One malformed fetuses occurred. The malformation observed was of single incidence and dissimilar.
Skeletal malformations:
no effects observed
Visceral malformations:
effects observed, non-treatment-related
Description (incidence and severity):
One malformed fetuses occurred. The malformation observed was of single incidence and dissimilar.
Other effects:
not examined
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects: no effects
Key result
Dose descriptor:
NOAEL
Effect level:
> 1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Remarks on result:
not determinable due to absence of adverse toxic effects
Key result
Abnormalities:
no effects observed
Key result
Developmental effects observed:
no
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
GLP study according to OECD guideline.
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

Aside from the limited results on developmental toxicity that were obtained from the combined repeated dose/developmental toxicity screening assay, no further information exist for the test item. However, valid data for the structural analogue Propylidynetrimethanol, ethoxylated, esters with acrylic acid (CAS no. 28961-43-5) and 2-ethyl-2-[[(1-oxoallyl)oxy]methyl]-1,3-propanediyl diacrylate (CAS no. 15625-98-5) are available and were used in a read-across approach to assess the potential to induce developmental toxicity of the source substance.

 

Propylidynetrimethanol, ethoxylated, esters with acrylic acid (CAS no. 28961-43-5) was tested in an oral teratology screening study in rats conducted in equivalence to OECD Guideline No. 414 and in compliance with GLP (Cytec, 1984). The substance was administered orally, admixed in corn oil, to one group of 30 female Spraque Dawley rats at a dosage level of 1000 mg/kg bw/day, from gestation Day 6 through 15. 30 control animals received the 10 mL/kg corn oil on a comparable regimen. Throughout gestation, all rats were observed twice daily for signs of toxicity. Body weights were recorded at appropriate intervals. All surviving animals were sacrificed on gestation Day 20 for the scheduled Cesarean section. Fetuses were sexed, weighed and examined for external, skeletal and soft tissue anomalies and developmental variations. Clinical signs of toxicity such as salivation prior to and following dosing, urogenital matting and hair loss from various body surfaces were observed. Mean body weight gains were significantly reduced over the entire treatment period. No embryotoxic effects were apparent. Developmental variations were not remarkably different between the control and test material group. No statistically significant or biologically meaningful differences occurred between the control and treatment regarding the occurrence of malformations. In conclusion, the structural analogue to the test item produced substantial maternal toxicity at a dose level of 1000 mg/kg bw/day but did not induce a developmental or embryotoxic effect in rats.

 

The result was confirmed by two developmental toxicity studies according to OECD TG no. 414 with 2-ethyl-2-[[(1-oxoallyl)oxy]methyl]-1,3-propanediyl diacrylate (CAS no. 15625-98-5) conducted in rat and rabbit, respectively.

In rats, the test substance produced substantial maternal toxicity at a dose level of 500 mg/kg bw/day, the highest dose tested (Cytec, 1983). Since no teratogenic or embryotoxic effects were observed the NOAEL for developmental toxicity was 500 mg/kg bw/day.

In rabbits, the NOAELs for maternal and developmental toxicity were at least 130 mg/kg bw/day (Reach Centrum, 2016). Data from a previous dose range finding study revealed insufficient tolerance (including an early delivery) at 150 mg/kg bw/day and unscheduled deaths at 200 mg/kg bw/day.

 

Conclusion

No alteration of live birth indices and viability of pups was observed in a Combined Repeated Dose Toxicity Study with the Reproductive Toxicity Screening Test with the test substance up to 500 mg/kg bw/day. In addition, a structural analogue to the test substance (CAS no. 28961-43-5) produced substantial maternal toxicity at a dose level of 1000 mg/kg bw/day but did not induce a developmental or embryotoxic effect in rats. Furthermore, no impairment of pre-natal development was observed in rats and rabbits exposed to another structural analogue (CAS no. 15625-89-5) up to doses leading to significant maternal toxicity. The NOAELs for developmental toxicity were 500 mg/kg bw/day and 130 mg/kg bw/day, respectively.

It is therefore concluded that the test substance does not exhibit a potential to induce adverse effects on the development of the unborn offspring.

Justification for classification or non-classification

Classification, Labelling, and Packaging Regulation (EC) No 1272/2008

The available data are reliable and suitable for classification purposes under Regulation (EC) No 1272/2008. Based on available data, the substance is considered to be classified neither for reproductive nor developmental toxicity under Regulation (EC) No 1272/2008, as amended for the twelfth time in Regulation (EU) 2019/521.