Bis(ethyl acetoacetato-O1',O3)bis(propan-2-olato)titanium

Developmental toxicity / teratogenicity

Some information in this page has been claimed confidential.

Administrative data

Endpoint:

developmental toxicity

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Study period:

not reported

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Data obtained from peer-reviewed publication.

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1994

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

EPA OTS 798.4900 (Prenatal Developmental Toxicity Study)

GLP compliance:

yes

Remarks:

Conducted in compliance with the Toxic Substances Control Act (TSCA) Good Laboratory Paractices Standards (U.S. EPA, 1989a)

Limit test:

no

Test material

Test material information

Constituent 1

Constituent 2

Reference substance name:

Propan-2-ol

EC Number:

200-661-7

EC Name:

Propan-2-ol

Cas Number:

67-63-0

Molecular formula:

C3H8O

IUPAC Name:

propan-2-ol

Details on test material:

- Name of test material (as cited in study report): isopropanol (isopropyl alcohol)
- Physical state: colorless liquid
- Analytical purity: 99.95+/-0,01%
- Storage condition of test material: refrigerated

Test animals

Species:

rat

Strain:

Sprague-Dawley

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Inc., Raleigh, NC.
- Age at study initiation: Female rats = 10 weeks of age on Gestational Day 0
- Weight at study initiation: 213.6 - 274.6 g on Gestational Day 0
- Housing: Females were singly housed in solid bottom polycarbonate cages with stainless steel wire lids
- Diet (e.g. ad libitum): #5002 Purina Certified Rodent Chow ad libitum
- Water (e.g. ad libitum): Deionized/filtered tap water ad libitum


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22.2±0.50 °C
- Humidity (%): 59.9%±0.55%
- Air changes (per hr): not reported
- Photoperiod (hrs dark / hrs light): 12 hrs dark/ 12 hrs light

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: deionized/distilled water

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: Study dosing solutions were formulated at 0.0, 80.0, 160.0 and 240.0 mg/mL, corresponding 0.0, 400.0, 800.0 and 1200.0 mg/kg/day at a dosing volume of 5.0ml/kg.

Amount of vehicle: 2ml/kg bw

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Concentration of dosing formulations were confirmed by gas chromatography (Hewlet Packard 5890A), with a 30mm x 0,32mm (i.d) capillary column. All formulations were within 97.1-106% of target concentration

Details on mating procedure:

- Impregnation procedure: Cohoused
- If cohoused:
- M/F ratio per cage: Individual females were placed in the home cage of singly housed males (i.e., 1:1)
- Proof of pregnancy: Sperm in vaginal smear referred to as day 0 of pregnancy

Duration of treatment / exposure:

From day 6 to 15 of gestation

Frequency of treatment:

Daily

Duration of test:

20 days. On gestational day (GD) 0 animals were distributed into groups. Test material was administered during GD 6 through GD 15. On GD 20 maternal animals were euthanized/necropsied and embryo/fetal observations were performed

No. of animals per sex per dose:

A total of 25 females per dose were treated.

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: The doses for the range-finding study in rats were 0, 625, 1250, 2500 mg/kg bw/day, 12 sperm positive dams per group. All dams at 2500mg/kg/day died or were were euthanized moribund by GD13; two dams died at 1250mg/kg/day. Also at 1250 mg/kg/day dams exhibited reduced body weights and weight gain, reduced food consumption, and treatment related clinical signs of toxicity. At 1250mg/kg/day there was a significant decrease in fetal body weight per litter unaccompanied by any external malformations or variations. There was no maternal or developmental toxicity observed at 625mg/kg/day.

- Rationale for animal assignment (if not random): Animals were assigned to treatment groups by a stratified randomization method designed to provide uniform mean body weights across dose groups at the initiation of the study.

Examinations

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Once daily on Gestational Day 0-5 (prior to dosing period) and on Gestational Day 16-20 (after dosing period) and twice daily, at dosing and 1-2 hours after dosing, throughout the dosing period (Gestational Day 6 through 15).

DETAILED CLINICAL OBSERVATIONS: Yes
- At least once daily

BODY WEIGHT: Yes
- Time schedule for examinations: gestation days 0, 6, 9, 12, 15, 18 and 20.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: not applicable

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: thoracic and abdominal organs and cavities, maternal body, liver and uterus weights recorded.

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
- Other: dead and live fetuses

Fetal examinations:

- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: all per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: Yes: half per litter

Statistics:

Parametric statistical procedures were applied to selected measures from this toxicity study. Appropriate General Linear Models (GLM) procedures (SAS Institute Inc., 1985a, 1985b) for the proposed Analyses of Variance (ANOVA) were employed. Prior to GLM analysis, an arcsine-square root transformation was performed on all litter-derived percentage data (Snedecor and Cochran, 1967) and Bartlett’s test for homogeneity of variance (alpha level = 0.001) was performed on all data to be analyzed by ANOVA (Winer, 1962). GLM analysis was used to determine the significance of the dose-response relationships (Test for Linear Trend), and to determine whether significant dose effects had occurred for selected measures (ANOVA). When a significant (p<0.05) main effect for dose occurred, Williams’ Multiple Comparison Test (Williams, 1971; 1972) and/or Dunnett’s Multiple Comparison Test (Dunnett, 1955; 1964) was used to compare each exposed group to the vehicle control group for that measure. A one-tailed test (i.e., Williams’ Test and/or Dunnett’s Test) was used for all pairwise comparisons except that a two-tailed test was used for maternal body and organ weight parameters, maternal food consumption, fetal body weight, and percent males per litter. Nominal scale measures were analyzed by Chi-Square Test for Independence for differences among treatment groups, and by a test for linear trend on proportions (Snedecor and Cochran, 1967). When Chi-Square revealed significant (p<0.05) differences among groups, then a one-tailed Fisher’s Exact Probability Test was used for pair wise comparisons between each treated group and the vehicle control group.

Indices:

Dams: pregnancy; corpora lutea; implantation sites per litter; percent preimplantation loss; live fetuses per litter; total and percent: resorptions per litter, litters with resorptions, late fetal deaths per litter, litters with late fetal deaths, adversely affected implants per litter; male and female fetuses per litter; average fetal body weight per litter; average male fetal body weight per litter; and average female fetal body weight per litter.

Historical control data:

The designation of fetal alterations as malformations or variations was based on the literature and on historical control data in the performing laboratory.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:yes

Details on maternal toxic effects:
No pregnant surviving female aborted, delivered early or was removed from study. Two females (8%) died in the 1200 mg/kg bw/day group and one female (4%) died in the 800 mg/kg bw/day group. Maternal body weights were equivalent across all groups and for all timepoints. The statistically reduced maternal weight gain (Gestational Days 0-20) in the 1,200 mg/kg bw/day group was likely due to significantly reduced gravid uterine weights. Corrected maternal weight gain for Gestational Days 0-20 was statistically equivalent across all groups. There were no treatment related clinical signs apparent in maternal animals. Maternal food consumption was statistically equivalent across all groups for all intervals evaluated although a significant downward trend for Gestational Days 6-9 and 6-15 (treatment period) with no significant pairwise comparisons was evident.

Effect levels (maternal animals)

1

Dose descriptor:

NOAEL

Effect level:

400 mg/kg bw/day (actual dose received)

Based on:

not specified

Basis for effect level:

other: maternal toxicity

2

Dose descriptor:

NOAEL

Effect level:

400 mg/kg bw/day (actual dose received)

Based on:

not specified

Basis for effect level:

other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
A total of 22-25 litters were evaluated per group. No litter was fully resorbed. All gestational parameters were equivalent across groups, including pre- and post-implantation loss. Fetal body weights/litter were significantly reduced in the 800 and 1,200 mg/kg bw/day groups. There were no treatment-related increased incidences in individual or pooled external, visceral, skeletal or total fetal malformations or variations.

Effect levels (fetuses)

Dose descriptor:

NOAEL

Effect level:

400 mg/kg bw/day (actual dose received)

Sex:

male/female

Basis for effect level:

fetal/pup body weight changes

Remarks on result:

other:

Remarks:

A total of 22-25 litters were evaluated per group. No litter was fully resorbed. All gestational parameters were equivalent across groups, including pre- and post-implantation loss. Fetal body weights/litter were significantly reduced in the 800 and 1,200 mg/kg bw/day groups. There were no treatment-related increased incidences in individual or pooled external, visceral, skeletal or total fetal malformations or variations.

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Any other information on results incl. tables

Read-across justifications and data matrices are presented in IUCLID section 13.

Applicant's summary and conclusion

Conclusions:

Propan-2-ol was not teratogenic when administered orally during GD6-15 to rats. By the publication, the NOAEL for both maternal and developmental toxicity was 400 mg/kg/day.

Executive summary:

Possible prenatal developmental toxicity of propan-2 -ol in rats was evaluated in this study conducted according to U.S EPA guideline 40 CFR 798.4900 under U.S. EPA Good Laboratory Paractice (GLP) Standards.

Time-pregnant rats, 25/group, dosed orally with propan-2 -ol at 0, 400, 800 or 1200mg/kg bw/day, once daily on gestation days 6 throught 15. Clinical observations were made at least once daily throughout the study period. Rats were weighed and food consumption was recorded every 6 or 3 days during gestation. Maternal animals were euthanized at 1 day prior expected parturition and necropsied. Fetuses were examined for external and visceral alterations and in addition soft tissue, skeletal and head examinations were performed.

Oral administration of propan-2 -ol to rats results maternal toxicity including lethality at 800 and 1200 mg/kg/day. Propan-2 -ol administration causes developmental toxicity, expressed as reduced fetal body weights with no indication of treatment-related teratogenicity or increased incidence of variations, at doses which resulted in treatment-related maternal deaths.

Based on test results, the following No Observed Adverse Effect Levels (NOAEL) were derived:

Maternal NOAEL: 400 mg/kg/day

Developmental NOAEL: 400 mg/kg/day

The results of this study would not lead to the classification for reproduction developmental toxicity according to EU Directive 67/548/EEC and EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.