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

Acute Toxicity: inhalation

Administrative data

Endpoint:

acute toxicity: inhalation

Type of information:

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

Adequacy of study:

weight of evidence

Study period:

no study period 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 alcohols, ethyl acetoacetate and hydrated titanium dioxide. The half-life of hydrolysis is < 10 minutes @ 25 ˚C. This rapid hydrolysis 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 most hazardous degradation products released from the target substance. In addition, because of rapid hydrolysis the dermal effects of the target substance are similar to the irritating properties of the degradation products. The identification of degradation products from the hydrolysis study conducted for the target substance verifies that there are no impurities in the mixture of particular alcohol and ethyl acetoacetate which might change the hazardous properties of the target substance compared to the properties of the pure alcohol and ethyl acetoacetate. As there is a mechanistic reasoning to the read-across, the unnecessary animal testing is avoided by using the read-across from the most hazardous degradation products (alcohols) to evaluate irritation, sensitization and the short-term and long-term toxicological effects of the target substance.

Data source

Reference

Reference Type:

publication

Title:

Isopropanol: Acute Vapor Inhalation Neurotoxicity Study in Rats

Author:

Gill, M.W. et al.

Year:

1995

Bibliographic source:

Journal of Applied Toxicology, Vol. 15(2), 77-84

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: US EPA TSCA guidelines for neurotoxicity

GLP compliance:

not specified

Test type:

standard acute method

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

Test material form:

other: vapor

Details on test material:

- Name of test material (as cited in study report): isopropyl alcohol, isopropanol
- Physical state: liquid
- Analytical purity: > 99.9%

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan Spague-Dawley, Inc. (Indianapolis, IN)
- Age at study initiation: 9 to 11 weeks
- Weight at study initiation: 178 - 261 g males and 135 - 177 g females at the age of 10-11 weeks
- Housing: individually in stainless stell wire mesh cages
- Diet (e.g. ad libitum): Powdered food (Certified Rodent Chow 5002) ad libitum
- Water (e.g. ad libitum): Tap water ad libitum
- Acclimation period: a 3-week period during which time a pretest health screen was conducted on randomly selected animals

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-25
- Humidity (%): 40 to 70
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

other:

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: stainless steel and glass chambers
- Exposure chamber volume: 1330-liters
- Source and rate of air: filtered air at an airflow of ca. 300 l min-1
- Temperature, humidity in air chamber: recorded approximately 12 times during each exposure

TEST ATMOSPHERE
- Brief description of analytical method used: Perkin - Elmer 8500 flame ionization gas chromatographic (GC) technique
- Samples taken from breathing zone: yes

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

6 h

Concentrations:

500, 1500, 5000, 10000 ppm

No. of animals per sex per dose:

25 animals/sex/dose

Control animals:

yes

Details on study design:

- Duration of observation period following administration: 24 hours
- Frequency of observations and weighing: mortality and signs of toxicity (twice daily), body weights were recorded during each behavioral session
- Necropsy of survivors performed: no
- Other examinations performed: mortality, clinical signs, body weight, other: behavioral testing, motor activity

Statistics:

The data for continuous, parametric variables were intercompared for the dose and control groups by use of Levene’s test for homogeneity of variances,by analysis of variance, and by pooled variance t-tests. The t-tests were used, if the analysis of variance was significant (P
Intra-session motor activity data was analyzed using a repeated measures analysis with dose as grouping factor and session time as the within subject factor. Group comparisons at each reporting epoch were made (as described above) if significant dose effects or time by dose interactions were observed. The epsilon-adjustment procedure (Greenhouse-Geisser correction) was used in repeated measures analysis of motor activity data.

Frequency data from FOB tests was evaluated using Fisher’s exact probability test. All statistical tests were performed using BMDP Statistical Software (Dixon, 1985 or Dixon, 1988). A P value of 0.05 was used as the critical level of significance for all tests.

Results and discussion

Effect levels

Effect levels 1

Sex:

male/female

Dose descriptor:

other: sedation of central nervous system

Effect level:

5 000 ppm

Based on:

test mat.

Exp. duration:

6 h

Effect levels 2

Sex:

male/female

Dose descriptor:

other: decrease in motor activity

Effect level:

5 000 ppm

Based on:

test mat.

Exp. duration:

6 h

Effect levels 3

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 10 000 ppm

Based on:

test mat.

Exp. duration:

6 h

Mortality:

no mortalities observed

Clinical signs:

other: In the 10000 ppm group, prostration, severe ataxia, decreased arousal, slowed or labored respiration, decreased neuromuscular tone, hypothermia, and loss of reflex function was observed 1 and 6 hours after exposure. Concentration-related decreases in mean

Body weight:

Body weight was measured at the time of behavioral testing so that any possible confounding effect that body weight might have on behavior could be assessed. Mean body weights for the five exposure groups were not statistically significantly different at any time during the study. Mean body weight tended to be lower for animals in the 10000 ppm exposure group assigned to FOB testing at the 6-hour and 24-hour post-exposure evaluations. This decrease is considered to reflect decreased food consumption during the time period when prostration and narcosis were observed.

Gross pathology:

No gross pathology reported.

Any other information on results incl. tables

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

Applicant's summary and conclusion

Interpretation of results:

practically nontoxic

Remarks:

Migrated information Criteria used for interpretation of results: expert judgment

Conclusions:

Acute inhalation toxicity of isopropanol was evaluated using a guideline neurotoxicity testing. The LC50 value for rats calculated after single 6-hour exposure was > 10 000 ppm (>24 600mg/m3).

Executive summary:

The purpose of the present study was to investigate the exposure concentration-response profile and time-course for behavioral effects in rats following a single 6 -h exposure to isopropanol vapor. This study was conducted according to EPA TSCA guidelines for neurotoxicity testing.

Male and female rats were exposed to isopropanol vapor at 0, 500, 1500, 5000 or 10 000 ppm. Behavioral observations were performed prior to and 1, 6 and 24 h after exposure. Motor activity was evaluated prior to and immediately following exposure. Exposure to isopropanol caused a spectrum of transient effects indicative of narcosis at 10 000 ppm and sedation at 5000 ppm. Prostration or severe anemia, decresed arousal, slowed or labored respiration, decreased neuromuscular function, hypothermia and loss of reflex function were observed 1 and 6 h after exposure to 10 000 ppm isopropanol vapor. Similar, but less severe alterations were observed in animals in the 5 000 ppm exposure group 1 h after exposure. Exposure concentration-related decreases in motor-activity were observed in males and females in the 5000 and 10 000 ppm groups and slight decrease in motor activity were observed in males in the 1500 ppm group. Animals in the 1500 and 5000 ppm exposure groups recovered from these motor activity effects within 5h. Based on this study, the no-observed-effect-level (NOEL) for isopropanol was 500 ppm.

According to CLP the substance has been classified under STOT single exposure category 3, H336 - may cause drowsiness or dizziness due to transient concentration-related narcosis and central nervous system sedation effects.