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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
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2016
Report date:
2016

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Version / remarks:
(2001)
Qualifier:
according to guideline
Guideline:
EU Method B.31 (Prenatal Developmental Toxicity Study)
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
GLP compliance:
yes (incl. QA statement)
Limit test:
no

Test material

Constituent 1
Reference substance name:
2-Acetone, condensation product with phenol
EC Number:
931-252-8
Molecular formula:
Not applicable (a generic molecular formula cannot be provided for this specific UVCB substance)
IUPAC Name:
2-Acetone, condensation product with phenol
Test material form:
solid: bulk
Details on test material:
- Test item name: 2-Acetone, condensation product with phenol
- Appearance: brownish solid
- Batch no.: 2015-05-30
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: 2015-05-30
- Expiration date of the lot/batch: 2016-05-20

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: at room temperature
- Stability under test conditions: analytically confirmed
- Solubility and stability of the test substance in the solvent/vehicle: analytically confirmed - Reactivity of the test substance with the solvent/vehicle of the cell culture medium: none
Stability for at least 5 hours at room temperature and for at least 8 days in the refrigerator in the dark is confirmed over the concentration range 1 to 200 mg/mL, Test Facility Study No. 510051.

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: The substance 2-Acetone, condensation product with phenol was filled at 130 °C into plastic covered Duran glass bottles. During the cooling down a vacuum was build which tightens the cap. Therefore, the bottles need to be heated up to 60°C in a cabinet heater before the cap could be loosed. Decanting was not possible at this temperature. Therefore, the bottles need to be heated up to 100-120 °C in a cabinet heating with loosed cap. Then decanting was possible in a fume cupboard with appropriate heat protection gloves.

Test animals

Species:
rat
Strain:
Wistar
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Strain: Crl:WI(Han) (outbred, SPF-Quality)
- Source: Charles River Deutschland, Sulzfeld, Germany
- Age at delivery: 10-14 weeks
- Housing: individually in Makrolon cages (MIII type) on sterilized sawdust as bedding material.
- Diet and water: ad libitum
- Acclimation period: at least 5 days prior to treatment


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 - 24°C
- Humidity (%): approximately 40-70 %
- Air changes (per hr): > 10 per hour
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From 2015-11-18 to 2016-02-11 (including dose range finding study)

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
polyethylene glycol
Remarks:
specific gravity 1.125
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
VEHICLE
- Justification for use and choice of vehicle (if other than water): Based on trial formulations performed at Charles River Den Bosch and on information from the sponsor.
- Amount of vehicle (if gavage): 5 mL/kg bw

METHOD of FORMULATION:
Formulations (w/w) were prepared within 8 days prior to dosing and were homogenized to visually acceptable levels. The formulations were heated on the day of formulation to a maximum of 80±5°C for at least 15 minutes to obtain visual homogeneity. Formulations were released for dosing when they had obtained a temperature of 40°C or lower. Adjustment was made for specific gravity of the vehicle. No correction was made for purity/composition of the test item.

Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Stability measurements were conducted as part of the method development and validation study (ABL Pr oject 15273). The stability of the test item in the vehicle was assured prior to the start of the main study.
Samples of formulations were analyzed for homogeneity (highest and lowest concentration) and accuracy of preparation (all concentrations, in Weeks 1, 7 and 13).
The accuracy of preparation was considered acceptable if the mean measured concentrations were 90-110% of the target concentration for solutions. Homogeneity was demonstrated if the coefficient of variation was ≤ 10%.

RESULTS:
No test item was detected in the control group 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 were homogeneous (i.e. coefficient of variation ≤ 10%).
Details on mating procedure:
Untreated females were mated at the Supplier, and were at Day 0 or 1 post-coitum on arrival at the Test Facility (Day 0 post-coitum is the day of
successful mating; confirmed by vaginal plug).
Duration of treatment / exposure:
Days 6 - 20 post-coitum, inclusive
Frequency of treatment:
Once daily for 7 days per week, approximately the same time each day with a maximum of 6 hours difference between the earliest and latest dose.
Duration of test:
from day 0 to necropsy at day 21 p.c.
Doses / concentrationsopen allclose all
Dose / conc.:
20 mg/kg bw/day (actual dose received)
Dose / conc.:
60 mg/kg bw/day (actual dose received)
Dose / conc.:
150 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
22 pregnant females per dose
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: In order to set the dose levels for the main teratology study, a dose range finding study was performed. Four groups of 6 pregnant females were exposed to 60, 1500, or 300 mg/kg bw/day for Days 6 to 20 post-coitum inclusive by oral gavage. These dose levels were based on (interim) a 28-day dose-range finding study in which male and female rats received the test substance by oral gavage at dose levels of 0, 100, 250, 500, and 1000 mg/kg bw/day.
One animal treated at 300 mg/kg bw/day (No. 23) showed signs of ill health towards the end of the study, including lethargy, hunched posture, laboured and shallow respiration and rales, piloerection and chromodacryorrhoea. Body weight and food consumption were severely reduced for this animal
and at necropsy a Gi-tractus distended with gas, several black-brown foci on the glandular mucosa of the stomach and reduced spleen and thymus were noted.
Overall, body weight and food consumption were decreased at 150 and 300 mg/kg bw/day.
At necropsy, gelatinous mandibular lymph nodes and salivary glands were observed in two animals treated at 150 mg/kg bw/day, Gi-tractus distended with gas noted for one animal in Group 3 and one in Group 4. Furthermore, a small spleen and thymus were also noted for one animal treated at 150
mg/kg bw/day, for another animal in this group a reduced size and greenish discolouration of the papillary process of the liver was observed. No treatment related effect on absolute or relative liver and kidney weights was observed.
The percentage of post-implantation loss was slightly increased at 150 and 300 mg/kg bw/day.

Fetal findings
Litter sizes were within normal limits for all groups.
The male : female ratios were equal in litters of all groups.
Combined fetal body weights were decreased in the 150 and 300 mg/kg bw/day dose group compared to the vehicle control group (3.6, 4.6 and 5.2 grams, respectively). At 60 mg/kg bw/day, combined fetal weights were within the normal range (5.5 grams).
No external abnormalities were noted for any of the fetuses in any of the groups.

Based on the results of the dose range finding study, selected dose levels for the main study were 20, 60 and 150 mg/kg bw/day.

Examinations

Maternal examinations:
CLINICAL EXAMINATIONS: Yes
- Time schedule: At least once daily from Day 2 post-coitum onwards up to the day prior to necropsy.

BODY WEIGHT: Yes
- Time schedule for examinations: Days 2, 6, 9, 12, 15, 18 and 21 post-coitum.

FOOD CONSUMPTION: Yes
- Days 2-6, 6-9, 9-12, 12-15, 15-18 and 18-21 post-coitum.

WATER CONSUMPTION: Yes
- Subjective appraisal was maintained during the study, but no quantitative investigation was introduced as no treatment related effect was suspected.

POST-MORTEM EXAMINATIONS: Yes
- All animals surviving to the end of the observation period and the animal showing premature delivery were deeply anaesthetized using isoflurane and subsequently exsanguinated and subjected to an external, thoracic and abdominal examination, with
special attention being paid to the reproductive organs.


The liver and kidneys (and the animal identification marks) were collected from all females at necropsy and fixed in 10% buffered formalin (neutral phosphate buffered 4% formaldehyde solution). No histotechnology or histopathology on these organs was performed.
Based on target organs (in female rats) identified in a 28-day dose range finding study toxicity study (WIL Research Project 509883) with the test substance, the terminal body weight and the weights of the liver and kidneys were recorded for all females surviving to the planned day of necropsy.
Ovaries and uterine content:
Each ovary and uterine horn of animals surviving to planned necropsy was dissected and examined as quickly as possible to determine:
- The number of corpora lutea.
- The weight of the (gravid) uterus.
- The number and distribution of live and dead fetuses.
- The number and distribution of embryo-fetal deaths (early and late resorptions).
- The weight of each fetus.
- The sex of each fetus from the ano-genital distance (during necropsy) and also from gonadal
inspections (during further fetal examination).
- Externally visible macroscopic fetal abnormalities.

One animal that was sacrificed before planned necropsy was subjected to relevant examinations of the ovaries and uterine horns.
In case implantations were not macroscopically visible, the uterus was stained using the Salewski technique in order to determine any former implantation sites.
Fetal examinations:
External, visceral, and skeletal findings were recorded as developmental variations (alterations in anatomic structure that are considered to have no significant biological effect on animal health or body conformity and/or represent slight deviations from normal) or malformations (those structural
anomalies that alter general body conformity, disrupt or interfere with normal body function, or may be incompatible with life).
External:
Each viable fetus was examined in detail, weighed and sexed. All live fetuses were euthanized by administration of approximately 0.05 mL (=10mg) of sodium pentobarbital into the oral cavity using a small flexible plastic or metal feeding tube.
Nonviable fetuses (the degree of autolysis was minimal or absent) were examined and weighed. For late resorptions a gross external examination performed (if possible).
Visceral (Internal):
Approximately one-half of the fetuses (live and dead) in each litter (all groups)were examined for visceral anomalies by dissection in the fresh (non-fixed) state. The thoracic and abdominal cavities were opened and dissected using a technique described by Stuckhardt and Poppe (Ref. 2). This
examination included the heart and major vessels. Fetal kidneys were examined and graded for renal papillae development as described by Woo and Hoar (Ref. 3). The sex of all fetuses was confirmed by internal examination.
The heads were removed from these fetuses and placed in Bouin's solution. Tissues were then transferred to a 70% aqueous ethanol solution for subsequent processing and soft-tissue examination of all groups using the Wilson sectioning technique. After examination, the tissues were stored in 10% buffered formalin. Any remaining tissues (from the fetuses used for fresh visceral examination) was discarded. The carcasses were processed and stained with Alizarin Red S (as described below), but not examined in first instance.
Skeletal:
From the other one-half of the fetuses (live and dead) in each litter (all groups), the sex was confirmed by internal examination. All fetuses were eviscerated, fixed in 96% aqueous ethanol, macerated in potassium hydroxide and stained with Alizarin Red S by a method similar to that described by Dawson (Ref. 5). Skeletal examination was done for one-half of the fetuses (i.e. the fetuses with heads). The specimens were archived in glycerin with bronopol as preservative. A few bones were not available for skeletal examination because they were accidentally damaged or lost during processing. The missing bones were listed in the raw data; evaluation by the fetal pathologist and study director determined there was no influence on the outcome of the individual or overall skeletal examinations, or on the integrity of the study as a whole.
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 for the comparison of the treated groups and the control group.
- 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.
Group means were calculated for continuous data and medians were calculated for discrete data (scores) in the summary tables. Test statistics were calculated on the basis of exact values for means and pooled variances. Individual values, means and standard deviations might be rounded off before printing. Therefore, two groups might display the same printed means for a given parameter, yet display different test statistics values.
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:
For each litter the following calculations were performed:
Percent Pre-implantation loss, percent Post-implantation loss
The fetal developmental findings were summarized by: 1) presenting the incidence of a given finding both as the number of fetuses and the number of litters available for examination in the group; and 2) considering the litter as the basic unit for comparison, calculating the number of affected fetuses as a
mean litter proportion on a total group basis, i.e. percent Viable fetuses affected/litter
The following definitions were applicable for implantation data:
- Fetal (late) resorptions were defined as a dead fetus with external degenerative changes and presence of distinguishable features such as head or limbs.
- Embryonic (early) resorptions were defined as evidence of implantation without presence of distinguishable features such as head or limbs.
- Dead fetus was defined as a non-viable fetus without external degenerative changes and presence of distinguishable features such as head or limbs.
- Post-implantation loss included embryonic (early) resorptions, fetal (late) resorptions and dead fetuses.
Historical control data:
yes, historical data on fetal morphology are part of the report

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
No treatment related effects were observed in animals treated at 20 mg/kg bw/day. Although the incidence and persistence of salivation showed a dose related increase, no correlated findings were noted. Therefore, the salivation is likely attributed to the taste of the test item and of no toxicological relevance.
At 60 mg/kg bw/day, piloerection was observed in 3/22 females. As the piloerecton was limited to three animals this finding was considered to be of no toxicological relevance.
At 150 mg/kg bw hunched posture was noted for 3/22 animals and piloerection for 5/22 females. Together with reduced body weight gain and food comsumption this effect was considered as treatment related and adverse.
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
At 60 mg/kg bw/day a significantly reduced body weight gain with concurrent decreased food consumption was observed at Day 9 post-coitum. As the body weight gain and food consumption recovered from Day 12 post-coitum onwards, these findings were considered to be of no toxicological relevance.
At 150 mg/kg bw/day body weight was significantly reduced between day 9 and day 15 post-coitum. Together with the reduced food consumption and the clinical signs in some animals of this group these findings were considered to be treatment related and adverse.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
At start of treatment, food consumption was significantly decreased from Day 6-9 post-coitum at 60 mg/kg bw/day and from Day 6-12 at 150 mg/kg bw/day. Additionally, at the end of treatment food consumption was slightly decreased in animals treated at 150 mg/kg bw/day compared to the vehicle controls.
Food consumption at 20 mg/kg bw/day remained within the same range as the control group.
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:
effects observed, treatment-related
Description (incidence and severity):
The weight of the liver was slightly increased in animals treated at 150 mg/kg bw/day. The approximately 7% increase was significant when corrected for body weight.
Absolute kidney weights were slightly, but significantly decreased in the 150 mg/kg bw/day Group. As considered to be of toxicological relevance.
Liver and kidney weights were unaffected by treatment at 20 and 60 mg/kg bw/day.
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
The presence of scab formation and alopecia were confirmed at necropsy for female No. 3 (Control) and 52 (60 mg/kg bw/day), respectively.
The contents of the stomach of the female that delivered early on Day 21 post-coitum was found to be reddish. This is most likely the result of cleaning of the litter after birth.
Neuropathological findings:
not examined

Maternal developmental toxicity

Number of abortions:
no effects observed
Pre- and post-implantation loss:
effects observed, non-treatment-related
Description (incidence and severity):
At 60 mg/kg bw/day, a significant increase in pre-implantation loss was observed (12.2% compared to 6.0% in the control group). Treatment was started on Day 6 post-coitum, after implantation has occurred, therefore this finding is considered not to be related to treatment. Moreover, no dose response relationship was noted.
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in pregnancy duration:
no effects observed
Description (incidence and severity):
One female (No. 30; 60 mg/kg bw/day) delivered early on Day 21 postcoitum.
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed
Changes in number of pregnant:
no effects observed
Description (incidence and severity):
All females at scheduled necropsy were pregnant except for one female (No. 20; Control) and had litters with viable fetuses.

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
60 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: no adverse effects at this dose
Dose descriptor:
LOAEL
Effect level:
150 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
body weight and weight gain
clinical signs
food consumption and compound intake

Maternal abnormalities

Abnormalities:
effects observed, treatment-related
Localisation:
other: general maternal toxicity
Description (incidence and severity):
slight at 150 mg/kg bw

Results (fetuses)

Fetal body weight changes:
effects observed, treatment-related
Description (incidence and severity):
Combined fetal body weights were significantly reduced at 150 mg/kg bw/day compared to the Control group (4.9 grams versus 5.3 grams, respectively).
Mean fetal body weights were unaffected at 20 and 60 mg/kg bw/day.
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
not examined
External malformations:
effects observed, non-treatment-related
Description (incidence and severity):
There were no treatment related effects on external morphology following treatment up to 150 mg/kg bw/day.
Five fetuses in this study were externally malformed. One in the 20 mg/kg bw/day Group (A039-09), three at 60 mg/kg bw/day (A046-04, A049-09, A057-12) and one at 150 mg/kg bw/day (A081-05). The nature of malformations observed in these respective fetuses (generalized subcutaneous edema, small lower jaw, hyperextended limb, small eye bulge and omphalocele) and single occurrence does not suggest a relation to treatment and therefore all were considered to be chance findings.
There were no other external malformations, and external variations were not seen in any group.
Skeletal malformations:
effects observed, non-treatment-related
Description (incidence and severity):
There were no treatment related effects on skeletal morphology following treatment up to 150 mg/kg bw/day.
Skeletal malformations were observed in 4 (2), 1 (1), 5 (3) and 2 (2) fetuses (litters) in Groups 1, 2, 3 and 4, respectively. The ones noted at 150 mg/kg bw/day, vertebral anomaly with or without associated rib anomaly (fetus A077-03) and bent limb bones (fetus A088-10) were also noted in respectively the control group (fetus A008-06 and A011-07) and at 20 mg/kg bw/day (fetus A031-07) and are as such not considered to have a relation to treatment.
At 60 mg/kg bw/day, fetuses A047-05 and -09 had a rib anomaly which was also observed in control fetuses A008-08 and -12. The other skeletally malformed fetuses in this group either had sternoschisis (fetus A046-08) or a vertebral centra anomaly (fetus A046-04 and A055-06). These two malformations did not occur in other groups, but at the low incidence observed were considered to be chance findings. Moreover, all three malformations in the 60 mg/kg bw/day Group were also noted previously in historical control fetuses.
Skeletal variations occurred at an incidence of 80.2%, 69.3%, 72.1% and 83.1% per litter in Groups 1, 2, 3 and 4, respectively. All the variations noted, were not considered treatment related as they occurred in the absence of a dose-dependent relationship, infrequently and/or at frequencies that were within the range of available historical control data.
Visceral malformations:
effects observed, non-treatment-related
Description (incidence and severity):
There were no treatment related effects on visceral morphology following treatment up to 150 mg/kg bw/day.
Apart from a fetus in the 60 mg/kg bw/day Group (A045-10), which had a small eye that was observed at soft tissue cephalic examination, there were no other viscerally malformed fetuses. The externally noted small eye bulge in 60 mg/kg bw/day Group fetus A057-12 should be mentioned here as well, but the presence of two of the same eye findings at the mid-dose level only, does not indicate a treatment related effect.
The variations that were noted in this study were small supernumerary lobe(s) and appendix of the liver, convoluted and dilated ureter(s), small renal papilla, retroesophageal right subclavian artery and abnormal lung lobation. These variations occurred at low incidences, in the absence of a dose-related incidence trend and/or in control fetuses only and therefore were not considered to be treatment related.

Effect levels (fetuses)

open allclose all
Dose descriptor:
NOAEL
Effect level:
60 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no adverse effects at this dose
Dose descriptor:
LOAEL
Effect level:
150 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
fetal/pup body weight changes

Fetal abnormalities

Abnormalities:
no effects observed

Overall developmental toxicity

Developmental effects observed:
no

Applicant's summary and conclusion

Executive summary:

In a prenatal developmental toxicity study performed according to OECD TG 414 mated female Wistar 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 20, 60 and 150 mg/kg bw/day. The rats of the control group received the vehicle, Polyethylene glycol 400, alone.

With regard to maternal toxicity no treatment related effects were observed in animals treated at 20 mg/kg bw/day. Although the incidence and persistence of salivation showed a dose related increase, no correlated findings were noted. Therefore, the salivation is likely attributed to the taste of the test item and of no toxicological relevance. At 60 mg/kg bw/day, piloerection was observed in 3/22 females. Additionally, a significantly reduced body weight gain with concurrent decreased food consumption was observed at Day 9 post-coitum. As the piloerecton was limited to three animals and the body weight gain and food consumption recovered from Day 12 post-coitum onwards, these findings were considered to be of no toxicological relevance. In females treated at 150 mg/kg bw/day, the weight of the liver was slightly increased compared to the concurrent controls. The approximately 7% increase was significant when corrected for body weight. Although this effect is likely the result of treatment, it is only minor (<10%) and therefore not considered adverse. Furthermore, in the 150 mg/kg bw/day Group hunched posture was noted for 3/22 animals and piloerection for 5/22 females. Body weight gain was significantly reduced between Day 9 and Day 15 post-coitum. Additionally, overall food consumption was reduced in these animals. Taken together these findings were considered to be treatment related and adverse.

With regard to developmental findings up to 60 mg/kg bw/day, no developmental toxicity was observed. At 150 mg/kg bw/day, fetal body weights were significantly decreased. As maternal body weights were also decreased at this dose level, this was likely related to maternal toxicity.

In conclusion and based on the results in this prenatal developmental toxicity study the maternal and developmental No Observed Adverse Effect Level (NOAEL) for 2-Acetone, condensation product with phenol was established as being 60 mg/kg bw/day.

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