Reaction mass of 2-methylpentane and Hexanol, branched and linear and diisopropyl ether

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1996

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference

Reference Type:

publication

Title:

Subchronic and Developmental Toxicity Studies of Vaporized Diisopropyl Ether in Rats

Author:

Dalbey W & Feuston M

Year:

1996

Bibliographic source:

Journal of Toxicology and Environmental Health. (1996) 49:29-43

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

no

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Diisopropyl ether

EC Number:

203-560-6

EC Name:

Diisopropyl ether

Cas Number:

108-20-3

Molecular formula:

C6H14O

IUPAC Name:

Diisopropylether

Test material form:

other: liquid

Details on test material:

- Name of test material (as cited in study report): Diisopropyl ether (DIPE)
- Physical state: Colorless liquid
- Analytical purity: Approximately 92%
- Lot/batch No.: Not reported
- Stability under test conditions: Not reported
- Storage condition of test material: Stored refrigerated with nitrogen in the upper part of the can

Test animals

Species:

rat

Strain:

Sprague-Dawley

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories, Kingston, NY
- Age at study initiation: Rats were approximately 9 weeks old when received and approximately 11 weeks old when breeding began
- Weight at study initiation: Not reported
- Fasting period before study: None
- Housing: Individually housed in 1 cubic metre (H-1000) inhalation chambers.
- Diet (e.g. ad libitum): Certified Purina Rodent Chow 5002 ad libitum except during exposure period
- Water (e.g. ad libitum): Ad libitum except during exposure period
- Acclimation period: 2 weeks


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 to 22 ºC
- Humidity (%): 40 to 60%
- Air changes (per hr): At least 12/hour
- Photoperiod (hrs dark / hrs light): 12 hours: 12 hours

Administration / exposure

Route of administration:

inhalation: vapour

Type of inhalation exposure (if applicable):

whole body

Vehicle:

unchanged (no vehicle)

Details on exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: H-1000 1 cubic-metre chambers
- Source and rate of air: HEPA-filtered room air; rate of air flow = 290 lpm
- Temperature, humidity, pressure in air chamber: Mean temperature within the chambers was in the range of 23 to 24 ºC and relative humidity was 60 to 67%. Pressure was not reported.
- Air flow rate: 290 lpm
- Air change rate: 12 changes/hour
- Treatment of exhaust air: Air exiting the chambers was cleaned by passage through charcoal beds


TEST ATMOSPHERE
- Brief description of analytical method used: Samples of air (approximately 50 to 250 µL) from the chambers were drawn into a gas-tight syringe and the air was injected directly into a gas chromatograph with a flame ionization detector and a fused silica column. In addition, 500 µL samples of air from the chambers were periodically taken for analysis by gas chromatography/mass spectroscopy.

VEHICLE (if applicable)
- Justification for use and choice of vehicle: No vehicle

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Samples of air (approximately 50 to 250 µL) from the chambers were drawn into a gas-tight syringe and the air was injected directly into a gas chromatograph with a flame ionization detector and a fused silica column. Analyzed concentrations included both DIPE and total hydrocarbons. In addition, 500 µL samples of air from the chambers were periodically taken for analysis by gas chromatography/mass spectroscopy. Time points of analysis were not reported.

Details on mating procedure:

- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1:1
- Length of cohabitation: Not reported
- Proof of pregnancy: sperm plug/sperm in the vaginal lavage fluid referred to as day 0 of pregnancy

Duration of treatment / exposure:

6 hours/day on Days 6 to 15 of gestation

Frequency of treatment:

6 hours/day on Days 6 to 15 of gestation

Duration of test:

Approximately 5 weeks (acclimation = 2 weeks and study duration = approximately 3 weeks)

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

430 ppm (analytical)

Remarks:

equivalent to 1800 mg/m³, basis analytical conc.

Doses / concentrations 2

Dose / conc.:

3 095 ppm (analytical)

Remarks:

equivalent to 12940 mg/m³, basis analytical conc.

Doses / concentrations 3

Dose / conc.:

6 745 ppm (analytical)

Remarks:

equivalent to 28200 mg/m³, basis analytical conc.

No. of animals per sex per dose:

22 females/group

Control animals:

yes, concurrent no treatment

yes, sham-exposed

Examinations

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes
- Time schedule for examinations: Recorded on Days 0, 6, 13, 16, 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 data

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 20
- Organs examined: Publication states that "all organs were examined grossly;" however, specific organs were not reported.

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

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:

ANOVA, Fisher's exact, or Dunnett's tests were used

Indices:

None reported

Historical control data:

None reported

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects: yes

Details on maternal toxic effects:
Lacrimation and salivation were noted in a few DIPE-exposed females at the highest concentration during, or immediately following, exposures. The animals returned to normal appearance shortly after cessation of each daily exposure.

In general, animals housed in chambers gained less weight and consumed less food during the exposure period than the untreated controls (statistically significant at 6745 ppm relative to both of the control groups).

No treatment-related effects were noted at the time of macroscopic examination.

Serum chemistry endpoints were not adversely affected by exposure to DIPE vapors.

Statistically significant decrease in body weight gains were seen on gestation days 6 to 16 at all dose levels (compared to untreated controls for the low- and mid-dose groups and compared to both controls at the high-dose group).

Statistically significant decrease was seen in food consumption on gestation days 6 to 16 at the mid- and high-dose groups (compared to untreated controls on gestation days 6 to 13 and compared to both control groups on gestation days 13 to 16).

Reproductive parameters (i.e., number of pregnant females, percent preimplantation loss, percent resorptions, and litter sizes) were not affected by exposure.

Effect levels (maternal animals)

Dose descriptor:

NOEC

Effect level:

430 ppm (analytical)

Based on:

test mat. (dissolved fraction)

Basis for effect level:

other: maternal toxicity

Remarks on result:

not determinable

Remarks:

no NOAEC identified by the authors, as these effects were considered transient and non-adverse by the authors arguing that this "variation" is not conclusive evidence of developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
Fetal development (i.e., fetal body weight) was not affected by exposure.

Evaluations of fetal skeletons revealed a significant increase in rudimentary (small, discrete ossification) or short (less than one-half the length of the preceding rib) 14th ribs in fetuses exposed to DIPE at concentrations of 3095 and 6745 ppm. All of the observed 14th ribs were rudimentary except for 2 fetuses from each of the mid- and high-dose groups that had either bilateral short 14th ribs or bilateral short and rudimentary 14th ribs. No other exposure-related findings were noted at the time of fetal evaluations. The study authors have stated that "the observed increase in the incidence of rudimentary 14th ribs does not appear to be indicative of an adverse effect on development" at the concentrations tested.

Effect levels (fetuses)

Dose descriptor:

NOEC

Effect level:

430 ppm (analytical)

Based on:

test mat. (dissolved fraction)

Sex:

male/female

Basis for effect level:

other: slight skeletal effects

Remarks on result:

other: no NOAEC identified by the authors, as these effects were considered transient and non-adverse by the authors arguing that this "variation" is not conclusive evidence of developmental toxicity

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

No developmental effects in the absence of maternal toxicity were observed. The NOAEC in this study for maternal effects as well as developmental effects can be set to 430 ppm.

Executive summary:

A NOAEC was not reported by the study authors. Review of the study data suggests that a NOAEC of 430 ppm can be derived for maternal toxicity based on the decrease in body weight gain and food consumption at higher concentrations, and a NOAEC of 430 ppm can be derived for foetal toxicity based on increases in rudimentary/short 14th ribs at higher concentrations (although the authors argue that this "variation" is not conclusive evidence of developmental toxicity).