Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records
Reference
Endpoint:
toxicity to reproduction
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Reproductive effects observed:
not specified
Effect on fertility: via oral route
Endpoint conclusion:
no study available
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Testing is not necessary since there is enough evidence of the reproduction toxicity of the main decomposition products to conclude that this substance is not toxic to reproduction. As the substance hydrolyses rapidly (<3min) when it comes in contact with water or moisture (Scholz, T. 2010), intrinsic properties are related to the degradation products. After hydrolysis no significant reaction products other than isopropyl alcohol (IPA) and non-hazardous hydrated titanium dioxide exist.

IPA has already harmonized classification according to EU regulation No. 1272/2008 (CLP) and it is not classified as toxic to reproduction. There are also toxicity studies available for isopropyl alcohol to evaluate the reproduction and developmental toxicity of IPA. The other decomposition product of this substance is titanium dioxide which is insoluble solid hydrated precipitate. It is expected to lack bioavailability. As it is also non-classified substance it is not relevant to be further considered in the chemical safety assessment.

In order to avoid unnecessary animal testing,there is no need to investigate reproduction toxicity of titanium tetraisopropanolate.The weight of evidence on decomposition of this substance and the studies available from the isopropyl alcohol indicate that this substance is not toxic to reproduction.

In the following sections studies related reproductive toxicity on isopropyl alcohol are discussed in more detailed.

Effects on fertility

A two-generation reproductive study characterized the reproductive hazard for isopropanol associated with oral gavage exposure (Bevan et al.1995 cited in OECD, 2004). This study found that the only reproductive parameter apparently affected by isopropanol exposure was a statistically significant decrease in male mating index of the F1 males. It is possible that the change in this reproductive parameter was treatment related and significant, although the mechanism of this effect could not be discerned from the results of the study. However, the lack of a significant effect of the female mating index in either generation, the absence of any adverse effect on litter size, and the lack of histopathological findings of the testes of the high-dose males suggest that the observed reduction in male mating index may not be biologically meaningful. Additional support for this conclusion is provided by the fact that most of the females became pregnant. Furthermore, male and female fertility, and female fecundity indices of rats dosed with isopropanol were not different from those of controls by statistical analysis and were within, or relatively close to, historical control values. Exposure to 1000 mg/kg/day and to a lesser extent 500 mg/kg/day did result in a reduction in postnatal survival in both F1 and F2 litters. Derivation of an appropriate NOAEL for offspring effects was made difficult because of conflicting interpretations of the reductions in postnatal survival for the 500 mg/kg/day treatment group. In order to clarify this issue a benchmark dose (BMD) assessment was conducted for the study’s developmental and reproductive findings (Shipp et al.1996 cited in OECD, 2004). For the offspring developmental effects, BMD dosages (BMDL5) of 449 and 418 mg/kg/day were estimated for the F1 and F2 generations, respectively. Based upon the decrease in male mating index observations in the P2 males, a BMDL10 of 407 mg/kg/day was estimated for reproductive effects (OECD, 2004).


Short description of key information:
The weight of evidence on decomposition of titanium tetraisopropanolate and studies from hazardous hydrolysis product, isopropyl alcohol, indicates that this substance has no effects on fertility.

Justification for selection of Effect on fertility via oral route:
Not relevant exposure route

Justification for selection of Effect on fertility via dermal route:
Not relevant exposure route

Effects on developmental toxicity

Description of key information
The weight of evidence on decomposition of titanium tetraisopropanolate and studies from hazardous hydrolysis product, isopropyl alcohol, indicates that this substance has no effects on development. 
Link to relevant study records

Referenceopen allclose all

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: see 'Remark'
Remarks:
Data obtained from peer-reviewed publication. Read-across justification: The substance is hydrolytically unstable. When it comes in contact with water or moisture complete hydrolysis will take place with no significant reaction products other than alcohol and hydrated titanium dioxide. This rapid hydrolysis (hydrolysis half-life < 3 minutes to < 2 hours) is the driving force for the toxicokinetics of target substance. Because of the rapid hydrolysis, the influence of the mode of administration through inhalation, dermal and oral is related to the hazardous degradation product (alcohol) released from the target substance. The identification of degradation products from the hydrolysis study conducted for the target substance verifies that there are no impurities in the alcohol released from the target substance, which might change the hazardous properties of the target substance compared to the properties of the pure alcohol. As there is a mechanistic reasoning to the read-across, the unnecessary animal testing is avoided by using the read-across data from the degradation product (relevant alcohol) to evaluate irritation, sensitization and the short term and long-term toxicological effects and mutagenicity of the target substance.
Reason / purpose:
reference to same study
Qualifier:
equivalent or similar to
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
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Hazleton Research Products, Inc., Denver, PA
- Age at study initiation: 5.5 months
- Weight at study initiation: 2750 to 3800 g
- Fasting period before study: not reported
- Housing: singly in stainless steel cages with mesh flooring (Hoeltge, Inc., Cincinnati, OH)
- Diet (e.g. ad libitum): #5322 Purina Certified Rabbit Chow ad libitum
- Water (e.g. ad libitum): deionized/filtered tap water ad libitum
- Acclimation period: 2 weeks


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17.3 to 20.6 °C
- Humidity (%): 48.4 to 54.4%
- Air changes (per hr): not reported
- Photoperiod (hrs dark / hrs light): 12 hrs dark/ 12 hrs light

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, 60.0, 120.0 and 240.0 mg/mL, corresponding 0.0, 120.0, 240.0 and 480.0 mg/kg/day at a dosing volume of 2.0ml/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: artificial insemination
Duration of treatment / exposure:
From day 6 to 18 of gestation
Frequency of treatment:
Daily
Duration of test:
On gestation day (GD) 0 animals were distributed into groups. Test material was administered during GD 6 through GD 18. On GD 30 maternal animals were euthanized/necropsied and embryo/fetal observations were performed
Remarks:
Doses / Concentrations:
120 mg/kg bw/day
Basis:
actual ingested
Remarks:
Doses / Concentrations:
240 mg/kg bw/day
Basis:
actual ingested
Remarks:
Doses / Concentrations:
480 mg/kg bw/day
Basis:
actual ingested
No. of animals per sex per dose:
A total of 15 females per dose were treated; two females in the 120 mg/kg bw/day dose group were not pregnant at sacrifice.
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: The doses for the range-finding study in pregnant rabbits were 0, 312.5, 625, 1250 mg/kg bw/day, 10 inseminated does per group. All does at 1250mg/kg/day died or were were euthanized moribund by GD8. Seven does at 625 mg/kg/day died or were euthanized moribund by GD 12. There was no observable maternal or developmental toxicity at 312 312.5mg/kg/day. The highest dose level was chosen to induce overt maternal toxicity, but not to cause a weight loss greater than 20% when compared to concurrent controls, nor to cause greater than 10% maternal mortality. The low dose was selected to be a maternal/developmental no-observable-adverse-effect level (NOAEL). The mid-dose was halfway between the high and low doses.
- 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.
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: at least once daily on gestation days 0-5 (prior to dosing) and 19-30 (after dosing period); twice daily at dosing and 1-2 hours after dosing, throughout the dosing period (gestation days 6 through 18).
- Cage side observations checked in table [No.?] were included.

DETAILED CLINICAL OBSERVATIONS: No

BODY WEIGHT: Yes
- Time schedule for examinations: gestation days 0, 6, 9, 12, 15, 18, 24, and 30.

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 30
- Organs examined: thoracic and abdominal cavities, maternal body, liver and uterus weights recorded.
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
- Other: dead and live fetuses
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:
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, nonlive implants per litter, litters with nonlive implants, 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.
Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
For does died at 480 mg/kg/day (4/15; 26,7%). Maternal body weight change was statistically significantly reduced at 480 mg/kg/day for GD 6-18 ( 45,5% of control value). Maternal food consumption was statisticaly significantly reduced at 480mg/kg/day. Corrected maternal gestational weight change (gestational weight change minus gravid uterine weight) was substantially reduced at 480 mg/kg/day relative to the control value. Furthermore, clear signs of treatment-related toxicity was observed in the 480mg/kg/day group. At 240 and 120mg/kg/day relatively mild and transient signs of toxicity were observed.
Dose descriptor:
NOAEL
Effect level:
240 mg/kg bw/day (actual dose received)
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
480 mg/kg bw/day (actual dose received)
Basis for effect level:
other: developmental toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
There was no demonstrable developmental toxicity at a dose resulting in significant maternal toxicity (480 mg/kg/day) or at doses with only relatively mild and transient clinical signs of toxicity (240 and 120 mg/kg/day).
Abnormalities:
not specified
Developmental effects observed:
not specified

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

Conclusions:
Propan-2-ol was not teratogenic when administered orally during GD6-18 to rabbits. By the publication, the NOAEL for maternal toxicity was 240 mg/kg/day and the NOAEL for developmental toxicity was 480 mg/kg/day.
Executive summary:

Possible prenatal developmental toxicity of propan-2 -ol in rabbits 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.

Artificially inseminated rabbits were, 15/group, dosed orally with propan-2 -ol at 0, 120, 240 or 480mg/kg bw/day once daily on gestation days 6 throught 18. Clinical observations were made at least once daily throughout the study period. Rabbits 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.

Treatment with propan-2 -ol up to 240 mg/kg bw/day was well tolerated by the rabbits. Clinical signs, if any, at 120 and 240mg/kg/day is not clear; these signs were slight and transient and most probably indicators of stress. Maternal rabbits exhibited increased mortality, reduced weight gain and food consumption, and specific clinical signs at a 480mg/kg bw/day dose. There was no indication of developmental toxicity, even at a dose which resulted in 26,7% maternal mortality.

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

Maternal NOAEL: 240 mg/kg/day

Developmental NOAEL: 480 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.

Endpoint:
developmental toxicity
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Abnormalities:
not specified
Developmental effects observed:
not specified
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
480 mg/kg bw/day
Species:
rabbit
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

Developmental toxicity

The developmental toxicity of isopropyl alcohol has been characterized in rat and rabbit developmental toxicity studies (Tyl, R. W.et al.1994). The rats were dosed by oral gavage at 400, 800 or 1200 mg/kg from gestational days 6 through 15. The rabbits were dosed by oral gavage at 120, 240 or 480 mg/kg from gestational days 6 through 18. These studies indicate that isopropyl alcohol (IPA) is not a selective developmental hazard.

Maternal toxic effect

Rats: 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 time points. 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 pair wise comparisons was evident. Based on these results, maternal toxicity for rats was 400mg bw/day.

Rabbits:Profound maternal toxicity at 480 mg/kg/day, expressed as 26.7% mortality, reduced body weight gain during the treatment period and for the gestational period corrected for the contribution of the gravid uterus, reduced food consumption during the treatment period and relatively severe clinical signs of toxicity. At 240 and 120 mg/kg/day, the only findings were transient, relatively mild and nonspecific clinical signs of toxicity. Thus, the maternal toxicity NOAEL for rabbits was concluded to be 240 mg/kg bw/day.

Teratogenic effects

Rats: 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.The developmental NOAEL was concluded to be 400 mg/kg bw/day for rats.

Rabbits: There was no demonstrable developmental toxicity at a dose resulting in significant maternal toxicity (480 mg/kg/day) or at doses with only relatively mild and transient clinical signs of toxicity (240 and 120 mg/kg/day). Thus, based on these results the developmental NOAEL for rabbits was 480 mg/kg bw/day.

Isopropyl alcohol has also been tested for developmental toxicity in rats via oral gavage (Bates, H. K.et al. 1994). The rats were dosed at 200, 700 and 1200 mg/kg from gestational days 6 through 21. No exposure-related effects were noted on motor activity, weights of the four regions of the brain, developmental landmarks, or morphological changes to the tissues of the central nervous tissue. These data suggest the developmental neurotoxicity NOAEL for rats is 1200 mg/kg.


Justification for selection of Effect on developmental toxicity: via oral route:
No studies available for the target substance which is highly reactive. Data is obtained from the only reliable study available for the main decomposition product, IPA.

Justification for selection of Effect on developmental toxicity: via dermal route:
Not relevant exposure route

Justification for classification or non-classification

The weight of evidence on decomposition of this substance and the studies available from the main decomposition product, isopropyl alcohol, indicate that there is currently no need for classification of titanium tetraisopropanolate concerning toxicity to reproduction or teratogenicity according to the CLP Regulation (EC) 1272/2008 and EU Directive 67/548/EEC.