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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
from 17-SEP-2019 to 04-JUN-2020
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2020
Report date:
2020

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Version / remarks:
25 June 2018
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
Version / remarks:
August 1998
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.31 (Prenatal Developmental Toxicity Study)
Version / remarks:
31.5.2008
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Acetophenone
EC Number:
202-708-7
EC Name:
Acetophenone
Cas Number:
98-86-2
Molecular formula:
C8H8O
IUPAC Name:
1-phenylethanone
Test material form:
liquid

Test animals

Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories France, 01400 Châtillon sur Chalaronne, France
- Age at study initiation: 17 to 19 weeks old (at mating)
- Weight at study initiation: 2819 g to 4170 g (at mating)
- Housing: 2 air-conditioned rooms in a barrier protected unit. Females were individually housed in plastic cages meeting European Directive 2010/63/EU.
requirements
- Diet: approximately 200 g of food per day (Pelleted complete rabbit diet (diet Reference No. 3409) sterilised by irradiation and analysed for chemical and bacterial contaminants)
- Water: Softened and filtered (0.2 μm) mains drinking water ad libitum
- Acclimation period: 6 days between animal arrival and the start of treatment

ENVIRONMENTAL CONDITIONS
- Temperature: 20°C ± 3°C
- Humidity: > 35%
- Air changes: at least 10 air changes per hour
- Photoperiod: 12 hours light (artificial)/12 hours dark

IN-LIFE DATES: From: 16 Sep 2019 To: 25 Oct 2019

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: 0.5% (w/v) carboxymethylcellulose 400-800cPs/0.5% (w/v) Tween® 80 in purified water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
The test item was prepared weekly as an emulsion (prepared and stirred using the same method as for a suspension (magnetic stirring for at least 15 minutes) in the control item at
concentrations of 20, 56.7 and 166.7 mg/mL and divided into daily aliquots.

VEHICLE
Carboxymethylcellulose sodium 400-800 cps from Sigma Aldrich. Batch No.: SLBK6619V. Expiry Date: 18 Sep 2021.
Tween® 80 from Merck. Batch No.: K51034361. Expiry Date: 31 Dec 2020.
Water for injection from Laboratoire Aguettant. Batch Nos.: 3013728 and 3013806. Expiry Dates: 28 Feb 2021 and 31 Mar 2021.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Dose formulation samples were collected from the four testing groups for analysis on Gestational Day 6 and on Gestational Day 28.
Analyses for concentration, homogeneity and stability in the vehicle were performed by Standard HPLC-UV.
Details on mating procedure:
- Impregnation procedure: purchased timed pregnant
Duration of treatment / exposure:
from GD6 to GD28
Frequency of treatment:
once daily
Duration of test:
28 days
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (nominal)
Remarks:
1. Control
Dose / conc.:
60 mg/kg bw/day (nominal)
Remarks:
2. Low dose
Dose / conc.:
170 mg/kg bw/day (nominal)
Remarks:
3. Intermediate dose
Dose / conc.:
500 mg/kg bw/day (nominal)
Remarks:
4. High dose
No. of animals per sex per dose:
22 females
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: The dose levels were selected in agreement with the Sponsor on the basis of the results of a preliminary study of prenatal developmental toxicity where pregnant female New Zealand White rabbits were treated at 80, 250 or 700 mg/kg/day from GD6 to GD28. In dams at 700 g/kg/day, one was found dead on GD12 and all females lost weight from GD6 to GD9. Mean food consumption was lower than in the control group during the majority of the treatment period and especially from GD6 to GD9. In fetuses, a lower mean fetal weight was noted when compared with controls. At 250 mg/kg/day, body weight loss and strongly reduced food consumption were noted for a few females from GD6 to GD9. There were no toxicologically significant effects at 80 mg/kg/day. Therefore, 500 mg/kg/day was selected as the high dose level for the current study. The low dose and mid dose were selected using a ratio representing approximately a 3-fold interval (i.e., 60 and 170 mg/kg/day).

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: at least twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: a full clinical examination was performed on each weighing day (GD0, GD6, GD9, GD12, GD15, GD18, GD21, GD24, GD27 and GD29)

BODY WEIGHT: Yes
- Time schedule for examinations: GD0, GD6, GD9, GD12, GD15, GD18, GD21, GD24, GD27 and GD29

FOOD CONSUMPTION: Yes
Food consumption of each animal was measured daily from the day of arrival to GD29.
The mean (g/animal/day) was calculated for the periods GD0 to GD6, GD6 to GD9, GD9 to GD12, GD12 to GD15, GD15 to GD18, GD18 to GD21, GD21 to GD24, GD24 to GD27 and GD27 to GD29. The period GD6 to GD29 has also been calculated and reported.

WATER CONSUMPTION: No

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 29
- Organs examined:
Moribund females were euthanized by sodium pentobarbitone injection and exsanguination. They were submitted to a full macroscopic examination to determine their pregnancy status, number of corpora lutea and numbers and types of uterine implantations. Any fetuses from these females were examined externally where possible and discarded.
Dead animals were also necropsied in order to establish, where possible, the cause of death and submitted to the examinations described above. When necessary, animals were refrigerated before necropsy to minimize autolysis.
All surviving females were euthanized on GD29 by intravenous injection of sodium pentobarbitone followed by exsanguination. They were submitted to a full macroscopic examination and any abnormalities observed were recorded. Abnormal organs or tissues
were sampled and preserved. For each female euthanized on GD29, the ovaries and uterus were removed and examined including examination of the placentae.
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
Fetal examinations:
- External examinations: Yes: [all per litter]
- Soft tissue examinations: Yes: [all per litter]
- Skeletal examinations: Yes: [all per litter]
- Head examinations: Yes: [half per litter]
Statistics:
Means, standard deviations, percentages, numbers, and/or incidences were reported, as appropriate by dataset.
All statistical tests were conducted at the 5% significance level. All pairwise comparisons were conducted using two sided tests and were reported at the 1% and 5% levels, unless otherwise noted.

Parametric/Non-Parametric (Body Weight, Body Weight Gains, Food Consumption, Gravid Uterine Weight and Corrected Maternal Body Weights, Litter Observations (Litter Means)):
Levene’s test was used to assess the homogeneity of group variances.
The groups were compared using an overall one-way ANOVA F-test if Levene’s test was not significant or the Kruskal-Wallis test if it was significant. If the overall F-test or Kruskal-Wallis test was found to be significant, then pairwise comparisons were conducted using Dunnett’s or Dunn’s test, respectively.

Non-Parametric (Ovarian and Uterine Examinations, Litter % of Fetuses with Gross/External/Visceral/Skeletal Abnormalities):
The groups were compared using an overall Kruskal-Wallis test. If the overall Kruskal-Wallis test was found to be significant, then the above pairwise comparisons were conducted using Dunn’s test.

Incidence (Parental Indices and Mortality):
A Fisher’s exact test was used to conduct pairwise group comparisons of interest.
Indices:
Pre-Implantation Loss (in %)
Post-Implantation Loss (in %)
Sex Ratio (% males)
Litter % of Fetuses with Abnormalities
Historical control data:
Values compiled from untreated and control New Zealand White rabbits in previous studies

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Decreased activity and/or abnormal gait, sometimes associated with low carriage, were noted for all females given 500 mg/kg/day, 1 hour after dosing, from GD6 to GD27. Animals recovered within the day. In addition, Female Nos. 74 and 76 given 500 mg/kg/day, had labored and shallow breathing,
lying on the side and subdued behavior on GD19-20 and GD9, respectively, 1-2 hours after dosing, but recovered within the day. These clinical signs were considered to be test item-related.
Few faeces were noted in all groups, including the controls, at the same incidence (20 to 22 females per group), but with a dose-related increased frequency of days affected at 170 and 500 mg/kg/day groups, which was consistent with the reduced food consumption. Therefore, the increased frequency of this finding was considered to be test item-related.
Red discharge, observed on GD29 for Female No. 31 given 60 mg/kg/day and for Female No. 53 given 170 mg/kg/day, was associated with the end of gestation. Red discharge, observed on GD15 for Female No. 83 given 170 mg/kg/day, without viable fetuses, might be associated with the numerous early resorptions. In addition, red discharge was observed on GD8 (predose) for Female No. 49 given 170 mg/kg/day, without any clear explanation.
On GD25, red discharge was observed during treatment and red traces were observed on the gavage cannula during intubation for Female No. 68 given 500 mg/kg/day. Therefore, the gavage was stopped and the animal was treated approximately 2 hours later when it had recovered. In addition, red discharge was observed during treatment for Female No. 65 given 170 mg/kg/day. These clinical signs were considered to be associated to the administration procedure.
Other clinical signs, such as thin fur or skin lesions, were observed in all groups including control and/or are commonly seen in this species. Therefore, they were considered as incidental.
Mortality:
mortality observed, treatment-related
Description (incidence):
2 females aborted in the 500 mg/kg/day dosed group. This represented 9% of the animals, more than commonly seen in the species (2% in the historical control data). Moreover, a third female given 500 mg/kg/day was found dead, with red discharge in the cage. Even if the cause of death was not clearly determined at necropy, the possibility of an association with the test item cannot be excluded.
In addition, 6 females (2, 1 and 3 in the control, 60 mg/kg/day and 170 mg/kg/day dosed groups, respectively) were found dead or sacrificed moribund due to, or probably due to, gavage error. These premature decedents were not test item-related.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
At 60 and 170 mg/kg/day, there were no major changes in body weight gain when compared with controls, only transient low body weight gain or body weight loss between GD18 and GD21 at 60 mg/kg/day and between GD15 and GD21 at 170 mg/kg/day, for a few females.
At 500 mg/kg/day, there was a body weight loss between GD6 and GD9 for all females (mean loss: -88 g ; range: -8 g to -231 g). Then, animals subsequently gained weight from GD9, as for the control group, with occasional low body weight gain or isolated body weight loss. This change had no impact on the terminal mean body weight on GD29, which was comparable in all groups.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
At 60 mg/kg/day, there were no major changes in food consumption when compared with control and pretest values.
At 170 mg/kg/day, there was lower mean food consumption from GD6 to GD21 when compared with the controls (-16% to -29%). One female had negligible food consumption from the pretest period up to GD21, which was thus considered not to be test item-related.
At 500 mg/kg/day, there was a more pronounced reduction in mean food consumption from GD6 to GD24 when compared with the controls (-15% to -51% ; -28% on average) with a particularly low food consumption for three females.
Haematological findings:
not examined
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
There were no changes in mean gravid uterus weight in treated groups when compared with controls.
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
There were no remarkable macroscopic findings at 60 and 170 mg/kg/day.
There was a dark fluid accumulation in the uterine horn for one female given 500 mg/kg/day. This isolated finding was considered as incidental.
Other findings such as cysts in the oviduct or skin scabs, were noted in control or treated groups and are commonly seen in the species. Therefore, they were considered as incidental.
Histopathological findings: non-neoplastic:
not examined

Maternal developmental toxicity

Number of abortions:
effects observed, treatment-related
Description (incidence and severity):
2 females aborted in the 500 mg/kg/day dosed group. This represented 9% of the animals, more than commonly seen in the species (2% in the historical control data).
Pre- and post-implantation loss:
effects observed, treatment-related
Description (incidence and severity):
The pre-implantation data (number of corpora lutea, implantation sites and pre-implantation loss) were comparable in all groups.

There was no test item-related effect on embryo-foetal survival at 60 and 170 mg/kg/day.
At 500 mg/kg/day, the mean number of late resorptions (and thus also the total number of resorptions) was slightly higher than in the control group (0.7 vs. 0.5 for the late resorptions) and than the historical control range (0.1 to 0.6 for main embryofetal studies). This was mainly due to Female Nos. 67 and 77 (3 late resorptions) and Female No. 83 with no viable fetuses (all early resorptions). Therefore, the mean percentage post-implantation loss was slightly higher when compared with the control group (11.13% vs. 9.20%), and was close to the higher values of the historical control data (2.4% to 11.4% for main embryo-fetal studies). The mean number of live fetuses per litter remained comparable with the control group.
Total litter losses by resorption:
effects observed, treatment-related
Description (incidence and severity):
There were 17, 20, 17 and 18 pregnant females at terminal caesarean in the control, 60, 170 and 500 mg/kg/day groups, respectively, all of which had viable fetuses, except Female No. 83 given 500 mg/kg/day with no viable fetuses.
Early or late resorptions:
effects observed, treatment-related
Description (incidence and severity):
Treatment at 500 mg/kg/day induced a slightly higher number of late resorptions.
Dead fetuses:
no effects observed
Changes in number of pregnant:
not examined

Effect levels (maternal animals)

Key result
Dose descriptor:
NOAEL
Effect level:
170 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
body weight and weight gain
clinical signs
food consumption and compound intake
mortality
number of abortions

Maternal abnormalities

Abnormalities:
effects observed, treatment-related
Localisation:
other: low food consumption and body weight loss leading to 2 abortions and 1 premature death, and clinical signs such as decreased activity, abnormal gait and red discharge.

Results (fetuses)

Fetal body weight changes:
effects observed, treatment-related
Description (incidence and severity):
Consistent with the maternal toxicity, there was a slight dose-related lower mean fetal weight in the 170 and 500 mg/kg/day groups, when compared with the controls (-7.0% and -9.5%, respectively). At 500 mg/kg/day, the difference was statistically significant (p < 0.05) and the mean value was lower than the historical control range (37.44 g vs. 38.4-43.2 g for main embryo-fetal studies). This finding was more pronounced for female fetuses than for the males (difference compared with controls: -12.9% for females vs. -9.1% for males, at 500 mg/kg/day). This change was not associated with any ossification delay.
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
no effects observed
Description (incidence and severity):
There were no changes in mean gravid uterus weight in treated groups when compared with the controls.
The mean number of live fetuses per litter is comparable with the control group.
Changes in postnatal survival:
not examined
External malformations:
no effects observed
Description (incidence and severity):
There were no test item-related external malformations in any group.
The abnormalities noted in treated groups, such as hyperflexion of forepaw or short tail, are part of the historical control data and were incidental.
Skeletal malformations:
no effects observed
Description (incidence and severity):
There were 2 (2) fetuses (litters) with branched rib and/or multiple vertebral malformations in the 60 mg/kg/day group compared with none in the control group. There was 1 (1) fetus (litter) with absent caudal vertebra in the 60 mg/kg/day group, compared with none in the control group. There was also 1 (1) fetus (litter) with fused nasals in the 170 mg/kg/day group, compared with none in the control group.
These malformations were observed only at the low doses and/or are part of the background of changes noted for this strain of rabbit and were therefore considered as incidental.
Less severe skeletal anomalies were noted with sporadic incidence and/or are a part of the background data for this strain of rabbit and were considered as incidental.
Visceral malformations:
no effects observed
Description (incidence and severity):
There were 2 (2) and 2 (2) fetuses (litters) with retroesophagial subclavian artery in the 170 and 500 mg/kg/day groups, respectively, compared with none in the control group.
However, this malformation is part of the background of changes noted for this strain of rabbit (7 cases between 2016 and 2018, with individual study frequency of up to approximately 1%, as noted in the current study) and these cases were therefore considered incidental in view of the lack of any dose-related increase in the incidence.
Other malformations were noted in the control and/or treated groups at the same incidence and thus were also considered as incidental.
Soft tissue anomalies were noted with sporadic incidence and/or are a part of the background data for this strain of rabbit and were considered as incidental.

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Effect level:
170 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
fetal/pup body weight changes

Fetal abnormalities

Key result
Abnormalities:
no effects observed

Overall developmental toxicity

Key result
Developmental effects observed:
yes
Lowest effective dose / conc.:
170 mg/kg bw/day (nominal)
Treatment related:
yes
Relation to maternal toxicity:
developmental effects as a secondary non-specific consequence of maternal toxicity effects

Any other information on results incl. tables

Summary of malformations - Individual descriptions:

Dose Level

(mg/kg/day)

Female

No.

Fetus

No.

Malformation(s) including external, visceral and skeletal examinations.

0

6

1

Aortic arch, interrupted

(terminating with left carotid artery)

Heart, muscular ventricular septal defect

Small lung

Left subclavian artery originmalpositioned

Sternebra, 1 or more, fused, severe (1st to 5th)

8

8

Right kidneymalpositioned(caudally, centrally)

17

5

Dilatation of aortic arch

Narrowed ductus arteriosus

Pulmonary trunk atresia

60

25

8

Rib, L5, branched

36

11

Vertebra, general, multiple malformations (first lumbar centrum small and misaligned; first right lumbar arch absent; first left lumbar arch fused with 12th left thoracic arch; 12th left rib branched; scoliosis)

38

2

Short tail and caudal vertebra absent (9th to 14th)

170

47

1

Both nasals fused

50

6

Hyperflexion of left forepaw

Subclavian artery, right, retroesophageal (arising between left subclavian artery and ductus arteriosus)

52

5

Subclavian artery, right, retroesophageal (arising between left subclavian artery and ductus arteriosus)

62

1

Aortic arch, interrupted (aortic arch terminating with left subclavian artery)

500

68

7

Subclavian artery, right, retroesophageal (arising from the descending aorta)

71

5

Heart, muscular ventricular septal defect

78

5

Right kidneymalpositioned(caudally, centrally)

88

8

Subclavian artery, right, retroesophageal (arising from the descending aorta)

 

See also tables attached:

- Summary of Clinical Observations: Gestation

- Summary of Body Weights: Gestation

- Summary of Body Weight Gains: Gestation

- Summary of Food Consumption: Gestation

- Summary of Macroscopic Pathology: Gestation

- Summary of Gravid Uterine Weights and Corrected Body Weights: Gestation

- Summary of Ovarian and Uterine Examinations and Litter Observations

- Summary of Fetal Abnormalities by Finding

Applicant's summary and conclusion

Conclusions:
In this prenatal developmental toxicity study in rabbit with acetophenone:
The No Observed Adverse Effect Level (NOAEL) for maternal toxicity was considered to be 170 mg/kg/day.
The No Observed Adverse Effect Level (NOAEL) for embryo-fetal development was considered to be 170 mg/kg/day.
Despite the maternal toxicity with associated embryo-fetal effects, there was no evidence of a teratogenic potential of Acetophenone, or delays in skeletal ossification.
Executive summary:

In this prenatal developmental toxicity study in rabbit (OECD TG 414, GLP), acetophenone was administered by daily oral gavage at dose levels of 60, 170 and 500 mg/kg/day to groups of 22 mated female New Zealand White rabbits from Days 6 to 28 of gestation (GD6 to GD28). A control group of 22 rabbits received the vehicle (0.5% (w/v) carboxymethylcellulose 400-800cPs/0.5% (w/v) Tween® 80 in purified water) at the same dose volume (3 mL/kg/day).

Clinical condition, body weights and food consumption were monitored throughout the study. The females were submitted to a caesarean examination on GD29 and litter parameters were recorded. At necropsy, the females were examined macroscopically and the gravid uterus was weighed. All live fetuses were weighed. Each fetus was examined for external defects and all live fetuses were killed by oral administration of sodium pentobarbitone. All live fetuses were examined viscerally and sexed at the time of caesarean section. The heads of approximately half of the fetuses were fixed for internal examination by serial sectioning. The eviscerated carcasses of all fetuses were processed for skeletal examination.

Results

At 500 mg/kg/day, 2 females aborted and a third one was found dead, with red discharge in the cage. These premature decedents were considered to be associated with test item-related maternal toxicity. In addition, 6 females from the control, 60 or 170 mg/kg/day dosed groups were found dead or sacrificed moribund, due to, or probably due to, gavage error.

Decreased activity and abnormal gait, sometimes associated with low carriage, labored breathing, lying on the side or subdued behavior, were noted after dosing in all females given 500 mg/kg/day, throughout the study. In addition, a higher frequency of few faeces was noted at 170 and 500 mg/kg/day, when compared with controls.

At 500 mg/kg/day, there was body weight loss between GD6 and GD9, without any impact on the body weight on GD29. At 60 and 170 mg/kg/day, there were no major changes in body weight gain when compared with control.

At 170 and 500 mg/kg/day, there was lower mean food consumption during the study when compared with controls, which was more pronounced at the high dose. At 60 mg/kg/day, there were no remarkable changes in food consumption.

At necropsy, there were no test item-related macroscopic findings in treated groups.

There were no changes in mean gravid uterus weight in treated groups when compared with the controls.

There were 17, 20, 17 and 18 pregnant females at terminal caesarean in the control, 60, 170 and 500 mg/kg/day groups, respectively, all of which had viable fetuses, except one female given 500 mg/kg/day with no viable fetuses.

The pre-implantation data were comparable in all groups.

There was no test item-related effect on embryo-fetal survival at 60 and 170 mg/kg/day. At 500 mg/kg/day, the mean number of late resorptions (and thus total resorptions) was slightly higher than the control group and slightly higher than the historical control data.

Consistent with the maternal toxicity, there were slight dose-related lower mean foetal weights in the 170 and 500 mg/kg/day groups, when compared with controls. At 500 mg/kg/day, this change was statistically significant and the mean value was lower than the historical control data. This finding was more pronounced for female fetuses than for the males and was not associated with any ossification delay.

There were no test item-related fetal external, visceral or skeletal abnormalities.

Conclusion

Daily oral (gavage) administration of Acetophenone at doses of 60, 170 and 500 mg/kg/day in the pregnant female New Zealand White rabbit from implantation through to the day before caesarean section (Gestation Days 6 to 28) was associated with marked maternal toxicity in the high dose group including low food consumption and body weight loss leading to 2 abortions and 1 premature death, and clinical signs such as decreased activity, abnormal gait and red discharge. Treatment at 170 mg/kg/day induced slightly lower food consumption, considered as non-adverse, due to the low incidence and severity.

The No Observed Adverse Effect Level (NOAEL) for maternal toxicity was therefore considered to be 170 mg/kg/day.

Consistent with the severity of maternal toxicity, treatment at 500 mg/kg/day induced a slightly higher number of late resorptions and lower mean fetal weight. Treatment at 60 and 170 mg/kg/day was not associated with any adverse embryo-fetal effects.

The No Observed Adverse Effect Level (NOAEL) for embryo-fetal development was considered to be 170 mg/kg/day.

Despite the maternal toxicity with associated embryo-fetal effects, there was no evidence of a teratogenic potential of Acetophenone, or delays in skeletal ossification.