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Diss Factsheets

Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
August 1988 - August 1992
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP-study equivalent to OECD guideline 414.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1992
Report date:
1992

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
yes (incl. QA statement)
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
1-propoxypropan-2-ol
EC Number:
216-372-4
EC Name:
1-propoxypropan-2-ol
Cas Number:
1569-01-3
Molecular formula:
C6H14O2
IUPAC Name:
1-propoxypropan-2-ol
Details on test material:
- Name of test material (as cited in study report): PROPASOL Solvent P
- Analytical purity: > 99%
- Purity test date: before and after exposure period
- Lot/batch No.: S077744

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories Inc.
- Age at study initiation: 11 weeks (males) & 10 weeks (females)
- Weight at study initiation:
- Fasting period before study: n.a.
- Housing: individually in stainless steel wire-mesh cages
- Diet (e.g. ad libitum): ad libitum (during non-exposure periods)
- Water (e.g. ad libitum): ad libitum (during non-exposure periods)
- Acclimation period: 2 weeks


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18.3-21.1°C
- Humidity (%): 40-70 % (except for a single 3.5 h interval of 70-74% and a spike (less than 30 min) of 70-84%)
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12-hour

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: rectangular shaped chambers made of glass and stainless steel (volume 4320 l); an orifice plate was positioned in the exhaust duct of the chamber and was conntected to a Dwyer Magnehelic Pressure Gauge; chambers were iluminated with artificial room light
- Method of conditioning air: Liquid PROPASOL Solvent P was metered from a piston pump into a heated glass evaporator. The temperature in the evaporator was maintained at the lowest level sufficient to vaporize the liquid. The resultant vapor was carried into the chamber by passage of conditioned air through the evaporators. Chamber atmospheres containing PROPASOL Solvent P were filtered before leaving an exhaust stack.
- Temperature, humidity, pressure in air chamber: chamber temperature and relative humidity were recorded approximately every 30 minutes during each 6-hour exposure
- Air flow rate: 1000 - 1300 l/min
- Air change rate: 14 changes per hour

TEST ATMOSPHERE
Each chamber was monitored for concentration approximately once every 30 minutes during each 6-hour exposure. Daily nominal concentrations (an estimated concentration calculated from the amount of test material delivered and the chamber airflow during the exposure period) were calculated for each chamber. Chamber distribution of PROPASOL Solvent P was evaluated at five different locations within each of the exposure chambers.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
A Perkin-Elmer Model 3920B gas chromatograph equipped with a flame ionization detector was used to monitor the concentrations of the n-propoxypropanol vapor concentrations in the exposure chambers. The GC column was an SP2100 6 ft x 1/8 in stainless steel column. The gases for the chromatograph were obtained from Linde Corporation. The nitrogen and hydrogen were Ultra High Purity grade and the air was breathing quality. A Spectra-Physics SP 4270 Computer Integrator was used to determine peak areas and to calculate concentrations.
Calibration of the gas chromatograph was done with dynamically generated gas standards of PROPASOL Solvent P prepared by syringe injection of test material into Tedler gas bag. The series of standards encompassed the entire range of vapor concentrations generated in the exposure chambers.A linear calibration curve was obtained when areas (integration counts) were plotted versus the gas standard concentration of each component of the mixture. The calibration factors (RF) were calculated as: RF=area/concentration. The mean RF for all valid injections of standard was used in subsequent microprocessor calculations. This calibration factor was checked at least once a week during the exposure period.
Details on mating procedure:
Rats were bred 1:1 (one male at least 300 g; one female at least 200g) in mating cages, and the females were examined twice daily for vaginal copulation plugs. Each male was used once in this study. The date a copulation plug was found was designated gesteational day (gd) 0. Plug-positive stufdy females (25) were housed individually after mating for the duration of the study.
Duration of treatment / exposure:
gd 6 through 15
Frequency of treatment:
6 hours/day
Duration of test:
gd 0 - gd 21
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
100 ppm
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
750 ppm
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
1500 ppm
Basis:
nominal conc.
No. of animals per sex per dose:
25
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale: target concentrations of 0, 100, 750 and 1500 ppm were determined based on an exposure range-finding study also performed on pregnant CD (Sprague-Dawley) rats.

Examinations

Maternal examinations:
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: gd 0, 6, 9, 12, 15, 18 and 21.

FOOD AND WATER CONSUMPTION : Yes
- Time schedule for examinations: measured at 3 to 4 day intervals throughout the study (gd 0 through 21) and averages for the preexposure, exposure and postexposure periods were calculated.

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 21
- Organs examined:
Gravid uterus, ovaries (including corpora lutea), cervix, vagina, and abdominal and thoracic cavities were examined grossly. Ovarian corpora lutea of pregnancy were counted. The maternal liver was weighed. Both eyes from all study females were removed and preserved in 10% neutral bufferen formalin. One eye, selected by the study director based on the ophthalmic examination, was embedded in plastic and evaluated by periodic acid-Schiff stain. Each uterus was externally examined for signs of hemorrhage, removed from the peritoneal cavity, weighed and dissected longitudinally to expose the contents. All live and dead fetuses and resorption sites (early and late) were noted and recorded. Uteri from females that appeared nongravid were placed in a 10% ammonium sulfide solution for detection of early resorptions.

OTHER:
Prior to initiation of exposures and following exposure on the last day of rat exposures, detailed ophthalmic examinations were performed on each study animal.
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: Yes: [half per litter]

All live fetuses were weighed, sexed and were examined for external malformations including cleft palate, and variations. Approximately 50% of the live fetuses in each litter (even-numbered fetuses from litters with an even number of live fetuses) were examined for thoracic and abdominal visceral abnormalities. The fetuses which received visceral examinations were decapitated and their heads were fixed in Bouin's solution for examination of craniofacial structures. All live fetuses (50% intact, 50% decapitated) in each litter were eviscerated and then processed for skeletal staining with alizarin red S. Intact fetuses (not decapitated) were examined for skeletal malformations and variations. All fetal skeletal preparations were retained.
Statistics:
The unit of comparison was the pregnant dam or the litter. Results of the quantitative continuous variables (e.g., maternal body weights, liver weights, etc.) were intercompared for the three exposure groups and control group by use of Levene's test for equal variances, analysis of variance (ANOVA), and t-tests with Bonferroni probabilities. The t-tests were used when the F value from the ANOVA was significant. When Levene's test indicated homogeneous variances, and the ANOCVA was significant, the pooled t-test was used for pairwise comparisons. When Levene's test indicated heterogeneous variances, all groups were compared by an ANOVA for unequal variances followed, when necessary, by the seperate variance t-test for pairwise comparisons.
Nonparametric data obtained following laparohysterectomy were statistically treated using the Kruskal-Wallis test followed by the Mann-Whitney U test when appropriate. Incidence data were compared using Fisher's Exact Test. For all statistical tests, the probability value of 0.05 (two-tailed) was used as the criterion for significance.
Indices:
not applicable

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
Maternal effects observed at 1500 ppm were eye irritation, significant reductions in body weight gain early in the exposure period (days 6-9), and reduced food consumption during the exposure period. In a single dam at 1500 ppm, corneal opacity was grossly observed. Subsequent histological evaluation confirmed the presence of corneal ulceration and associated keratitis as well as corneal and scleral mineralization and scleral granulomas.

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOEL
Effect level:
750 ppm
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOEL
Effect level:
750 ppm
Basis for effect level:
other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
Poorly ossified hindlimb phalanges were observed in litters of the 1500 ppm group.

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Exposure to PROPASOL Solvent P vapor by inhalation during organogenesis in CD (Sprague-Dawley) rats resulted in slight maternal and developmental toxicity at 1500 ppm. The "no observable effect level" (NOEL) for both maternal and developmental toxicity was 750 ppm.
Executive summary:

Timed-pregnant CD (Sprague-Dawley) rats were exposed to PROPASOL Solvent P vapor for six hours/day on gestational days (GD) 6 through 15. Twenty-five rats per group were exposed to PROPASOL Solvent P at target concentrations of 0, 100, 750, or 1500 ppm. The corresponding mean analytical concentrations were 0, 98.4, 755, and 1524 ppm. Maternal clinical signs were taken daily, and body weights were measured on gd 0, 6, 9, 12, 15, 18 and 21. Maternal food and water consumption were measured throughout gestation, gd 0 -21. In addition, prior to expsoure and immediately following the last exposure day, the eyes of dams were examined by a veterinary ophthalmologist. At scheduled sacrifice on gd 21, maternal body weight, gravid uterine weight and liver weight were measured. Maternal eyes were fixed in neutral buffered formalin for subsequent histological examination.Ovarian corpora lutea of pregnancy were counted and all uterine implantation sites were identified and recorded: resorptions (early or late), dead fetuses and live fetuses. All live fetuses were examined for external malformations (including cleft palate) and variations. Approximately 50% per litter were examined for visceral malformations and variations (including craniofacial alterations) and approximately 50% per litter (intact fetuses) were examined for skeletal malformations and variations.

Maternal effects observed at 1500 ppm were eye irritation, significant reductions in body weight gain early in the exposure period (days 6 -9), and reduced food consumption during the exposure period. In a single dam at 1500 ppm, corneal opacity was grossly observed. Subsequent histological evaluation confirmed the presence of corneal ulceration and associated keratitis as well as corneal and slecral mineralization and scleral granulomas. Gestational parameters, including number of viable implantations per litter, number of nonviable implantations per litter and sex ratio, were unaffected by test chemical exposure. Fetal body weights (total, males or females) per litter were equivalent across exposure groups. There were no treatment-related changes in the incidence of individual or pooled external, visceral or skeletal malformations or of total malformations. There were no treatment-related increases in the incidence of individual external or visceral variations at any exposure level. Poorly ossified hindlimb phalanges were observed in litters of the 1500 ppm group. The incidences of variations by category, or of total variations were equivalent across groups.

In conclusion, expsoure to PROPASOL Solvent P vapor by inhalation during organogenesis in CD (Sprague-Dawley) rats resulted in slight maternal and developmental toxicity at 1500 ppm. The "no observable effect level" (NOEL) for both maternal and developmental toxicity was 750 ppm.