Titanium tetrabutanolate

Developmental toxicity / teratogenicity

Some information in this page has been claimed confidential.

Administrative data

Endpoint:

developmental toxicity

Type of information:

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

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: study well documented, meets generally accepted scientific principles, acceptable for assessment A robust study summary including evaluation of all possible parameters for developmental toxicity study.

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Reference

Endpoint:

developmental toxicity

Type of information:

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

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study well documented, meets generally accepted scientific principles, acceptable for assessment

Reason / purpose for cross-reference:

reference to same study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Principles of method if other than guideline:

Groups of approximately 15 Sprague-Dawley rats were exposed at 8000, 6000, 3500, or 0 ppm n-butanol, for 7 hr/day on Gestation Days 1- 19 (sperm = 0). The highest concentration was selected to produce maternal toxicity. Dams were sacrificed on Gestation Day 20, and fetuses were individually weighed, tagged, and examined for external malformations. One-half of the fetuses were stained and examined for skeletal abnormalities, and the other half were examined for visceral defects using the Wilson technique

GLP compliance:

no

Species:

rat

Strain:

Sprague-Dawley

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source:Charles River breeding laboratories, Wilmington, MA
- Weight at study initiation: Female (176-200) and male (300 g)
- Housing: 32×41×18 cm stainless steel wire mesh cages for all animals except female with sperm placed in 30×34×17 cm poly carbonate cages having autoclavable polyester filter covers.
- Water (e.g. ad libitum): Purina or NIH-07 Lab chow
- Acclimation period: 1-2 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24 ± 2
- Humidity (%): 50 ± 10
- Photoperiod (hrs dark / hrs light): 12 hr

Route of administration:

inhalation: vapour

Type of inhalation exposure (if applicable):

whole body

Vehicle:

air

Details on exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Hinners type exposure chamber
- Method of holding animals in test chamber:
- Source and rate of air: heated compressed air was introduced through the second inlet of the three way valve.
- Air change rate: one change per min.
- System of generating particulates/aerosols: vapor generation equipement were housed above the exposure chamber in glove boxes which were maintain under negetive pressure


TEST ATMOSPHERE
- Brief description of analytical method used: Concentration with in the chamber was monitored by Infra red analyzer which was calibrated with in the range.
-Sample of bulk chemical were analyzed by Gas chromatography for purity.
-For independent verification of chamber concentration sample were collected by charcoal tube from chamber atmoshphere

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The concentration within the chamber was monitored continuously with a Miran 1 A general-purpose infrared analyzer

Details on mating procedure:

- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage:1
- Proof of pregnancy:vaginal plug and/or sperm in vaginal smear referred to as [day 0] of pregnancy
:

Duration of treatment / exposure:

7 hrs/day exposure were given to pregnant females from gestation days 1 to 19

Frequency of treatment:

7 h/d

Duration of test:

until day 20 of gestation

No. of animals per sex per dose:

15-18 females per group

Control animals:

yes

Details on study design:

Dose selection rationale: The doses were selected based on the results of an initial pilot study. For the teratology phase, the high concentration was selected to be maternally toxic, but not lethal, and two lower concentrations were included.

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: not specified
- Cage side observations: not specified

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: not specified


BODY WEIGHT: Yes
- Time schedule for examinations: Maternal weights were measured on Gestation Days 0, 7, 14, and 20. Females were also weighed each morning for the first week of exposure.


FOOD CONSUMPTION: Yes
Weekly food intake was measured on Gestation Days 0, 7, 14, and 20.


WATER CONSUMPTION: Yes
- Time schedule for examinations: Water intake was measured on Gestation Days 0, 7, 14, and 20.

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: uterus with ovaries attached, no futher organs specified

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No data
- 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: No data

Statistics:

For maternal data multivariate analysis was used for weight comparisions across groups. A kruskal wallis test for group comaparision of corpora lutea per animal. for fetal data, analysis of variance (ANOVA) was used to compare fetal weight and fisher's exact test used for variables including skeletal variations and visceral malformation

Indices:

no data

Historical control data:

no data

Details on maternal toxic effects:

Maternal toxic effects:yes

Details on maternal toxic effects:
The highest concentration of 1 butanol (8000 ppm) produced mortality in 2 of 18 rats. Food consuption was reduced in both at 6000 and 8000 ppm. The number of corpora leutea was not affected (shown in picture attched below).

Dose descriptor:

NOAEL

Effect level:

10 800 mg/m³ air

Basis for effect level:

other: maternal toxicity

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
Reduction in fetal weights at 6000 and 8000 ppm and a slight increase in skeletal malformations at 8,000 ppm were observed in offspring.

Dose descriptor:

NOAEL

Effect level:

10 800 mg/m³ air

Based on:

test mat.

Basis for effect level:

other: fetotoxicity

Abnormalities:

not specified

Developmental effects observed:

not specified

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

Conclusions:

Groups of approximately 15 pregnant Sprague-Dawley rats were exposed via inhalation to 0, 3500, 6000 or 8000 ppm (0, 10 800, 18 500, 24 700 mg/m3) of n-butanol for 7 hours/ day from gestation Day 1 - 19. The NOAEL for maternal animals was 10 800 mg/m3 and the NOAEL for offspring was 10 800 mg/m3.

Executive summary:

n-Butanol concentration of 24 700 mg/m3 produced narcosis in approximately one-half of the dams. No behavioral effects were noted at 18 500 mg/m3 n-butanol. Reduction in fetal weights at 18 500 mg/m3 and 24 700 mg/m3 and a slight increase in skeletal malformations at 24 700 mg/m3 were observed in offspring. The high dose (24 700 mg/m3) was also toxic to the dams (reduced weight gain; two deaths). Feed consumption was decreased in the 18 500 mg/m3 and 24 700 mg/m3 n-butanol exposed dams. No such effect was observed following similar exposures at 10 800 mg/m3 n-butanol. The NOAEL for maternal animals was 10 800 mg/m3 and the NOAEL for offspring was 10 800 mg/m3 (based on slight decrease in fetal weight at 18 500 mg/m3).

This value is used as weight of evidence in hazard assessment.

Data source

Reference

Reference Type:

publication

Title:

Lack of selective developmental toxicity of three butanol isomer administered by inhalation to rats

Author:

Nelson B.K., Brightwell W.S., Khan A., Burg J. R., Goad P.T.

Year:

1989

Bibliographic source:

Fundamental and applied toxicology vol 12, Page no. 469-479

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Principles of method if other than guideline:

Groups of approximately 15 Sprague-Dawley rats were exposed at 8000, 6000, 3500, or 0 ppm n-butanol, for 7 hr/day on Gestation Days 1- 19 (sperm = 0). The highest concentration was selected to produce maternal toxicity. Dams were sacrificed on Gestation Day 20, and fetuses were individually weighed, tagged, and examined for external malformations. One-half of the fetuses were stained and examined for skeletal abnormalities, and the other half were examined for visceral defects using the Wilson technique

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Titanium tetrabutanolate

EC Number:

227-006-8

EC Name:

Titanium tetrabutanolate

Cas Number:

5593-70-4

Molecular formula:

C16H36O4Ti

IUPAC Name:

titanium(4+) tetrakis(butan-1-olate)

Details on test material:

- Name of test material (as cited in study report): 1-butanol, titanium (4+) Salt, Haskell No. 15,538
- Substance type:organometal
- Physical state: liquid
- Analytical purity: 95-100%
- Impurities (identity and concentrations): Possibly 1-butanol 0-5%
- Composition of test material, percentage of components: 25% tetrabutyl titanate, 75% kerosene
- Storage condition of test material: at room temparature

Test animals

Species:

rat

Strain:

Sprague-Dawley

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source:Charles River breeding laboratories, Wilmington, MA
- Weight at study initiation: Female (176-200) and male (300 g)
- Housing: 32×41×18 cm stainless steel wire mesh cages for all animals except female with sperm placed in 30×34×17 cm poly carbonate cages having autoclavable polyester filter covers.
- Water (e.g. ad libitum): Purina or NIH-07 Lab chow
- Acclimation period: 1-2 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24 ± 2
- Humidity (%): 50 ± 10
- Photoperiod (hrs dark / hrs light): 12 hr

Administration / exposure

Route of administration:

inhalation: vapour

Type of inhalation exposure (if applicable):

whole body

Vehicle:

air

Details on exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Hinners type exposure chamber
- Method of holding animals in test chamber:
- Source and rate of air: heated compressed air was introduced through the second inlet of the three way valve.
- Air change rate: one change per min.
- System of generating particulates/aerosols: vapor generation equipement were housed above the exposure chamber in glove boxes which were maintain under negetive pressure


TEST ATMOSPHERE
- Brief description of analytical method used: Concentration with in the chamber was monitored by Infra red analyzer which was calibrated with in the range.
-Sample of bulk chemical were analyzed by Gas chromatography for purity.
-For independent verification of chamber concentration sample were collected by charcoal tube from chamber atmoshphere

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The concentration within the chamber was monitored continuously with a Miran 1 A general-purpose infrared analyzer

Details on mating procedure:

- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage:1
- Proof of pregnancy:vaginal plug and/or sperm in vaginal smear referred to as [day 0] of pregnancy
:

Duration of treatment / exposure:

7 hrs/day exposure were given to pregnant females from gestation days 1 to 19

Frequency of treatment:

7 h/d

Duration of test:

until day 20 of gestation

No. of animals per sex per dose:

15-18 females per group

Control animals:

yes

Details on study design:

Dose selection rationale: The doses were selected based on the results of an initial pilot study. For the teratology phase, the high concentration was selected to be maternally toxic, but not lethal, and two lower concentrations were included.

Examinations

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: not specified
- Cage side observations: not specified

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: not specified


BODY WEIGHT: Yes
- Time schedule for examinations: Maternal weights were measured on Gestation Days 0, 7, 14, and 20. Females were also weighed each morning for the first week of exposure.


FOOD CONSUMPTION: Yes
Weekly food intake was measured on Gestation Days 0, 7, 14, and 20.


WATER CONSUMPTION: Yes
- Time schedule for examinations: Water intake was measured on Gestation Days 0, 7, 14, and 20.

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: uterus with ovaries attached, no futher organs specified

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No data
- 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: No data

Statistics:

For maternal data multivariate analysis was used for weight comparisions across groups. A kruskal wallis test for group comaparision of corpora lutea per animal. for fetal data, analysis of variance (ANOVA) was used to compare fetal weight and fisher's exact test used for variables including skeletal variations and visceral malformation

Indices:

no data

Historical control data:

no data

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:yes

Details on maternal toxic effects:
The highest concentration of 1 butanol (8000 ppm) produced mortality in 2 of 18 rats. Food consuption was reduced in both at 6000 and 8000 ppm. The number of corpora leutea was not affected (shown in picture attched below).

Effect levels (maternal animals)

Dose descriptor:

NOAEL

Effect level:

10 800 mg/m³ air

Basis for effect level:

other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
Reduction in fetal weights at 6000 and 8000 ppm and a slight increase in skeletal malformations at 8,000 ppm were observed in offspring.

Effect levels (fetuses)

Dose descriptor:

NOAEL

Effect level:

10 800 mg/m³ air

Based on:

test mat.

Basis for effect level:

other: fetotoxicity

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:

Groups of approximately 15 pregnant Sprague-Dawley rats were exposed via inhalation to 0, 3500, 6000 or 8000 ppm (0, 10 800, 18 500, 24 700 mg/m3) of n-butanol for 7 hours/ day from gestation Day 1 - 19. The NOAEL for maternal animals was 10 800 mg/m3 and the NOAEL for offspring was 10 800 mg/m3.

Executive summary:

n-Butanol concentration of 24 700 mg/m3 produced narcosis in approximately one-half of the dams. No behavioral effects were noted at 18 500 mg/m3 n-butanol. Reduction in fetal weights at 18 500 mg/m3 and 24 700 mg/m3 and a slight increase in skeletal malformations at 24 700 mg/m3 were observed in offspring. The high dose (24 700 mg/m3) was also toxic to the dams (reduced weight gain; two deaths). Feed consumption was decreased in the 18 500 mg/m3 and 24 700 mg/m3 n-butanol exposed dams. No such effect was observed following similar exposures at 10 800 mg/m3 n-butanol. The NOAEL for maternal animals was 10 800 mg/m3 and the NOAEL for offspring was 10 800 mg/m3 (based on slight decrease in fetal weight at 18 500 mg/m3).

This value is used as weight of evidence in hazard assessment.