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Toxicological information

Genetic toxicity: in vivo

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Administrative data

Endpoint:
in vivo mammalian germ cell study: cytogenicity / chromosome aberration
Remarks:
Type of genotoxicity: chromosome aberration
Type of information:
experimental study
Adequacy of study:
key study
Study period:
May 15, 1989
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: The study was conducted according to EPA TSCA guidelines and in accordance with GLP.
Cross-referenceopen allclose all
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1989
Report Date:
1989

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
EPA OTS 798.5450 (Rodent Dominant Lethal Assay)
Principles of method if other than guideline:
no data
GLP compliance:
yes
Type of assay:
rodent dominant lethal assay

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Propylene Dichloride
- Physical state: colourless liquid
- Analytical purity: 99.9 %
- Lot/batch No.: TB871112/TB072088

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories
- Age at study initiation: Males - 4 weeks when purchased, females - 10 weeks when purchased
- Assigned to test groups randomly: [yes, under following basis: stratified by weight and randomly assigned to treatment and control groups]
- Housing: group housed in stainless steel cages during cohabitation, else PDC treated males housed in plastic shoe box cages with ground cob nesting naterial and animals of the positive control group housed in stainless steel cages
- Diet (e.g. ad libitum): ad libitum Purina Certified Rodent Chow no.5002
- Water (e.g. ad libitum): ad libitum


ENVIRONMENTAL CONDITIONS
- Temperature (°C): standard conditions
- Humidity (%): standard conditions
- Air changes (per hr): standard conditions
- Photoperiod (hrs dark / hrs light): standard conditions


IN-LIFE DATES: not specified in the report

Administration / exposure

Route of administration:
oral: drinking water
Vehicle:
not applicable
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: PDC was administered continuously in the drinking water at concentrations of 0, 0.024%, 0.10% and 0.24% (w/v) to groups of 30 male rats. Test solutions were prepared by diluting the test material with tap water, according to in-house SOP's. Test solutions were administered in 9" x 9", 1.6 liter capacity, sealed Tedlar Gas and Water Sampling Bags with a modified 1/4" diameter Jaco Kynar bulkhead union fitted with a pressure-activated stainless steel nipple, to prevent any loss due to evaporation. Test solutions were mixed and changed at least weekly. The bags were changed weekly and autoclaved between uses.


Duration of treatment / exposure:
14 weeks
Frequency of treatment:
Daily and continuous
Post exposure period:
2 weeks
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0 %
Basis:
nominal in water
analytical - not detected
Remarks:
Doses / Concentrations:
0.024 %
Basis:
nominal in water
analytical - 0.0211 ± 13 %
Remarks:
Doses / Concentrations:
0.10 %
Basis:
nominal in water
analytical - 0.098 ± 90 %
Remarks:
Doses / Concentrations:
0.24 %
Basis:
nominal in water
analytical - 0.2411 ± 240 %
No. of animals per sex per dose:
30 males - treated mated with naive (untreated) adult virgin females over a period of two weeks, during which each male was cohabited with two naive females/week.
Control animals:
yes
Positive control(s):
Cyclophosphamide
- Justification for choice of positive control(s): known positive control agent recommended by various guidelines and regulatory agencies
- Route of administration: per oral
- Doses / concentrations: 100 mg of cyclophosphamide/kg body weight

Examinations

Tissues and cell types examined:
Gross pathological observations conducted
Details of tissue and slide preparation:
not applicable
Evaluation criteria:
A test substance which does not produce either a statistically significant dose-related increase in the number of dominant lethals or a statistically significant and reproducible positive response at any one of the test points is considered nonmutagenic in this assay/test.
Statistics:
Body weight data analysed by Bartlett's test, ANOVA, Dunnett's test or Wilcoxon Rank_Sum Test with Bonferroni's correction
Feed and water consumption data evaluated by descriptive statistics, outliers identified by Grubb's method and excluded from analysis
Fetility indices analysed by Fischer exact probability test.
The numbers of corpora lutea and implantation analysed by ANOVA and Wilcoxon Rank-Sum Test
Pre-implantation losses and resorption rates analysed by modifed Wilcoxon test

Results and discussion

Test results
Sex:
male
Genotoxicity:
negative
Toxicity:
no effects
Vehicle controls valid:
not applicable
Negative controls valid:
yes
Positive controls valid:
yes
Additional information on results:
Refer to Tables 2- for detailed information

Any other information on results incl. tables

None

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): negative
Propylene dichloride was not considered mutagenic following a dominant lethal assay in which male Sprague Dawley rats were exposed to drinking water concentrations of 0.024 %, 0.10 % and 0.24 % (w/v) for 14 weeks. At these concentrations, water consumption was depressed in a dose-dependent manner, and body weights were decreased by 0.10 % and 0.24 %. Cyclophospahmide (100 mg/kg single oral dose), a known mutagen, induced a significant dominant lethal effect in the study.
Executive summary:

The mutagenic potential of Propylene dichloride (PDC) was evaluated in the dominant lethal assay in groups of 30 male Spargue-Dawley rats exposed to PDC in drinking water at concentrations of 0, 0.024%, 0.10% and 0.24% (w/v) continuously for a period of 14 weeks as part of a combined reproduction/dominant lethal study. (These concentrations corresponded to time-weighted average daily doses of approximately 0, 28, 91 and 162 mg PDC/kg body weight/day). Exposed males were then mated to pairs of naive, untreated adult females for two successive periods of one week each. A separate, positive control group of 30 male Sprague-Dawley rats were administered a single oral dose of 100 mg cyclophosphamide/kg body weight 48-hours prior to breeding with untreated females. The uterine contents of these females were then evaluated for evidence of a dominant lethal effect as manifested by an increase in the resorption rate.

Among PDC-treated males, concentration-related decreases in water consumption were noted at all levels treated and decreased body weights were noted in males given 0.10% and 0.24% in the water. Mating performance was unaffected in these animals. Evaluation of the resorption rates among these groups revealed that the weekly values for the females mated to PDC-treated males ranged from 2.2% to 8.1%, well within the historical control range. Resorption rates among the concurrent controls were low, ranging from 3.5% to 5.4%. Statistically significant increases from concurrent control values identified during the first week of breeding in the resorption rates in the 0.024% and 0.24% PDC-treated groups were considered within the normal limits. In contrast, single oral administration of cyclophosphamide at a dose of 100 mg/kg resulted in a 10-fold increase in the resorption rate, consistent with the reported values. The concentrations of PDC in the drinking water were at the limit of solubility in water and were approximately 10000-fold higher than levels detected in the environment. Despite these exaggerated levels, PDC was not nutagenic in this dominant lethal assay in male Sprague-Dawley rats exposed continuously to concentrations up to 0.24% in the drinking water.