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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
1988
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The study conducted according to equivalent test 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:
1988
Report Date:
1988

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
EPA OTS 798.2650 (90-Day Oral Toxicity in Rodents)
Principles of method if other than guideline:
None
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): 1,2-Dichloropropane (DCP)
- Molecular weight (if other than submission substance): 112
- Physical state: colourless liquid
- Analytical purity: 99.9%
- Lot/batch No.: 871112

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratory
- Age at receipt: 7 weeks
- Housing: singly housed in suspended stainless steel cages with wire-mesh floors with catch pans under the cages, lined with antibiotic, impregnated, absorbent cageboard
- Diet (e.g. ad libitum): Purina Certified Rodent Chow (#5002) provided, ad libitum
- Water (e.g. ad libitum): Municipal drinking water provided, ad libitum
- Acclimation period: according to SOP's


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: gavage
Vehicle:
corn oil
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: Dose solutions were prepared by diluting a weighed amount of test material to a specified final volume with corn oil. A volume of approximately 250 ml of each dose level was prepared each month as the stock supply.

VEHICLE
- Justification for use and choice of vehicle: Concentrations of 5 and 500 mg DCP/ml of corn oil have been shown to be stable for up to 65 days
- Concentration in vehicle: not specified in the report
- Amount of vehicle (if gavage): 1 ml/kg body weight
- Lot/batch no.: not specified in the report
- Purity: not specified in the report
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Refer to Table 1 for further details
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
5 days/week
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0 mg/kg body weight/day
Basis:
other: nominal concentration
Remarks:
Doses / Concentrations:
20 mg/kg body weight/day
Basis:
other: nominal concentration
Remarks:
Doses / Concentrations:
65 mg/kg body weight/day
Basis:
other: nominal concentration
Remarks:
Doses / Concentrations:
200 mg/kg body weight/day
Basis:
other: nominal concentration
No. of animals per sex per dose:
15 Fischer 344 rats/sex
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: based on previous studies conducted and literature data
- Rationale for animal assignment (if not random): computerized randomization procedure after stratification of body weight
- Rationale for selecting satellite groups: recovery of clinical signs of toxicity
- Post-exposure recovery period in satellite groups: 9 weeks
Positive control:
Not applicable

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twiice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: No

CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: monthly
- Dose groups that were examined: all groups/all animals
- Battery of functions tested: temperature / grip strength / motor activity
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Other examinations:
None
Statistics:
Body weight data analysed by Bartlett's test, ANOVA, Dunnett's test, Wilcoxon Rank-Sum Test with a Bonferroni correction
Absolute and relative brain weights analysed Bartlett's test and ANOVA with a Bonferroni correction
Grip strength, motor activity and body temperature analysed by factorial ANOVA

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY - Transient signs of tearing and blinking in DCP treated animals, in a dose-dependent manner were noted on the first day of dosing. Also, huddling behavior was noted during the initial 2 days of dosing. All rats survived the 13-week dosing period.
BODY WEIGHT AND WEIGHT GAIN - Statistically significant differences between controls and male rats treated with 200 mg/kg were noted after the first week and this persisted throughout the 13-week doing period. Non-statistically significant differences were noted in the other groups.
NEUROBEHAVIOUR - No apparent differences were noted between controls and treated rats at any of the test intervals, except for minor body temperature decrement.

ORGAN WEIGHTS - Brain weights were not considered to be directly affected by DCP ingestion

GROSS PATHOLOGY - There were no observations made at necropsy that were related to DCP treatment

HISTOPATHOLOGY: NON-NEOPLASTIC - There were no lesions attributed to DCP treatment

OTHER FINDINGS - Similar observations as described above were noted for animals of the recovery group.

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
200 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: Apart from transient clinical signs and minor body weight and temperature decreases, there were no effects attributable to DCP in the functional observation battery, grip strength, motor activity and neuropathology
Dose descriptor:
NOAEL
Effect level:
20 mg/kg bw/day (nominal)
Sex:
male
Basis for effect level:
other: Based on early transient clinical signs and minor decreases in body weight and body temperature
Dose descriptor:
NOAEL
Effect level:
65 mg/kg bw/day (nominal)
Sex:
female
Basis for effect level:
other: Based on early transient clinical signs and minor decreases in body weight and body temperature

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

None

Applicant's summary and conclusion

Conclusions:
Under the conditions of the study, aside from transient clinical signs and minor body weight and temperature decreases, there were no effects attributable to DCP in the functional observation battery, grip strength, motor activity and neuropathology.
Executive summary:

1,2 -Dichloropropane (DCP) was evaluated for potential neurotoxic effects in groups of 15 Fischer 344 rats/sex administered 0, 20, 65 and 200 mg DCP/body weight/day, 5 days/week for 13 weeks. General parameters evaluated were daily/weekly clinical observations, weekly body weights and body temperatures after 13 weeks of treatment. Specific parameters evaluated were monthly evaluation of a functional observation battery, hindlimb grip strength, motor activity and neuropathology.

Transient clinical effects were noted in a dose-responsive manner in all animals immediately after dosing, which persisted up to 3 days. A persistent reduction in body weights throughout the 13-week administration period was noted in animals treated with 200 mg/kg, while non-statistically significant reductions were noted in the other groups. No effects attributable were noted on the functional observation battery, hindlimb grip strength and motor activity. A slight reduction in body temperature was noted in the female animals of the 200 mg/kg. No gross or histopathologic effects on the nervous system were noted.

Similar observations were noted in the animals of the recovery group.

In summary, aside from transient clinical signs ans minor body weight and temperature decreases, there were no effects attributable to DCP in the functional observation battery, grip strength, motor activity and neuropathology.