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Toxicological information

Repeated dose toxicity: inhalation

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Administrative data

Endpoint:
sub-chronic toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1983
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: This study was conducted in accordance with GLP and comparable to OECD guideline 413.

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1983
Report Date:
1983
Reference Type:
publication
Title:
Dipropylene glycol monomethyl ether: A 13 week inhalation toxicity study in rats and rabbits.
Author:
Landry, T.D. and Yano, B.L. 1984. Dipropylene glycol monomethyl ether: A 13 week inhalation toxicity study in rats and rabbits.
Year:
1984
Bibliographic source:
Published in Fundam. Appl. Toxicol. 4, 612-617.

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
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): Dipropylene glycol monomethyl ether
- Molecular weight (if other than submission substance): 148.2g/M
- Physical state: Colorless liquid
- Analytical purity: 99 % with no more than 0.15 % water by weight
- Lot/batch No.: #QP-811116-36

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Rats: Charles River Breeding Laboratories
- Age at study initiation: For rats 9 weeks approximately
- Weight at study initiation: For rat 190-200 gms approximately
- Housing: Rats 2/cage were housed in stainless steel cages with wire bottoms
- Diet: A standard laboratory diet (Purina Certified Laboratory Chow, Ralston Purina Co.) adlibitum except during exposure
- Water: Adlibitum water was supplied to rats except during exposure
- Acclimation period: 2 weeks


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

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Stainless steel and glass inhalation chambers (4 m3 volume)
- Method of holding animals in test chamber: Whole body
- Method of conditioning air: DPGME was vaporized and metered into the chambers with a compressed air flame less heat torch/J-Tube assembly as described by Miller.
- Temperature, humidity, pressure in air chamber: Chamber temperature and relative humidity were controlled by a system designed to main 20-24Ca nd 40-60 % relative humidity
- Air flow rate: 800 l/m
- Air change rate: Not specified in the report
- Treatment of exhaust air: Not specified in the report


TEST ATMOSPHERE
- Brief description of analytical method used: The concentration of DPGME in each chamber was measured approximately once per hour with a Varian 2400 GC with a 1/8" by 6' nickel column and flame ionization detector. Standard bags were made by adding DPGME to a U Tube 100 l of dry filtered air was metered through the tube into a gas tight bag. Heat was applied to the test material to facilitate vaporization. A series of standards, which included 15, 50, 200 ppm were made and analyzed at least biweekly to produce a standard curve.

Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
See the attchment-1
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
6 hours/day; 5 days/week
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
15 ppm
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
50, ppm
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
200 ppm
Basis:
nominal conc.
No. of animals per sex per dose:
Rats: 10/sex/dose
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Based on the 2-week inhalation study which was conducted prior to this 13-week study
- Rationale for animal assignment (if not random): Random animal assignment
Post-exposure period: none

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice a daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: After each exposure

BODY WEIGHT: Yes
- Time schedule for examinations: Body weights were determined during the randomization procedure, on the first day exposure and weekly thereafter for the duration of study.

HAEMATOLOGY: Yes
- Time schedule for collection of blood: After 12 weeks of exposure
- Anesthetic used for blood collection: Yes
- How many animals: Rats (40 male and 40 female)
- Parameters checked in table [No. 15, 16, 17, 18] were examined.


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Prior to necropsy
- Animals fasted: Yes
- How many animals: (40 male and 40 female)
- Parameters checked in table [No.11, 12, 13, 14] were examined.


URINALYSIS: Yes Rats only
- Time schedule for collection of urine: After 12 weeks of exposure
- Metabolism cages used for collection of urine: No data
-- Parameters checked in table [No.19] were examined.

Sacrifice and pathology:
GROSS PATHOLOGY: Yes
All surviving animals underwent a gross necropsy on the day following their last exposure. Rats were deprived of food overnight prior to necropsy. Rats were anesthetized with methoxyflurane, and then decapitated. The trachea of all animals was clamped after anesthesia to prevent aspiration of blood during decapiatation.Each animal was examined internally and externally for gross pathological changes. The heart, liver, kidneys, brain, thymus (Rats) and testes were removed from each animal and weighed. Eyes of all animals were examined grossly using a microscope slide technique with fluorescent illumination. Representative portions of tissues were preserved in buffered 10 % formalin. Liver samples were fixed in a phosphate buffered 2% gluteraldehyde 2 % and formalin 2 % solution, then routinely processed and embedded in EPON 812 resin for possible electron microscopy examination.

HISTOPATHOLOGY: Yes
An extensive set of tissues, intended to include one or more sections of all tissues listed in table no. 1 were examined histologically from all animals in the control and high exposure groups. Gall bladder (rabbits only), nasal turbinates (rats only), liver, kidneys were also examined in the middle and low exposure groups. Tissues were processed by conventional techniques, stained with hematoxylin and eosin and evaluated by light microscopy.
Other examinations:
Organ weights: The heart, liver, kidneys, brain, thymus and testes were removed from each animal and weighed.
Statistics:
Clinical chemistry, hematology(PCV, HgB, RBC, WBC and Plat only). urinary specific gravity, organ weight, body weight and organ to body weight ratio data were evaluated by Bartlett's test for the equality of variances’ the group variances were homogenous, a parametric analysis of variances was conducted to determine if any statistically significant differences exist between groups. If the overall parametric ANOVA was significant at < 0.10, Dunnett's test was used to identify statistically significant differences between experimental groups and their corresponding control. If group variances were not homogenous, the data was evaluated by non parametric analysis of variance and if significant at p<0.1, Wilcoxon's Rank Sum test was used to identify statistically significant differences between experimental groups and their corresponding control. Outlying values for each parameter evaluated were identified, but not routinely excluded from statistical analyses. The nominal level of statistical significance, for evaluating differences between exposed and control groups was <0.05. The actual probability of erroneously rejecting the hypothesis that there are no differences between treated and control mean values.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
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:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
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:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY: There were no DPGME exposure related adverse effects on body weights in rats during the 13 week study. There were no statistically significant differences from control body weight means in male and female rats.

BODY WEIGHT AND WEIGHT GAIN: There were no DPGME exposure related adverse effects on body weights in rats during the 13 week study. There were no statistically significant differences from control body weight means in male and female rats.

HAEMATOLOGY: There were no exposure related effects on any of the measured hematology parameters in either sex of rat. There were also no statistically significant differences from control means.

CLINICAL CHEMISTRY: There were no exposure related effects on any of the measured clinical chemistry parameters in either sex of rat. The only statistically significant difference was a slight decrease in BUN in female rats exposed to 50 ppm, this had no toxicological significance.

URINALYSIS: There were no apparent effects on any of the urinalysis parameters of male and female rats.

ORGAN WEIGHTS: There were also no statistically significant differences in absolute or relative organ weights of rats exposed to DPGME, except for a slight decrease in mean relative liver weight of 50 ppm exposed males.

GROSS PATHOLOGY AND HISTOPATHOLOGY: All gross and histopathologic observations were considered to be spontaneous changes of minimal severity which were not treatment related. Based on gross observations, liver from rats exposed to DPGME appeared to be increased in size, however this observation was not supported by group mean liver weights and there was no histopathologic evidence of hepatocellular swelling.


Effect levels

Dose descriptor:
NOAEL
Effect level:
200 ppm
Sex:
male/female
Basis for effect level:
other: overall effects

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Based on the results of this study the NOAEL for dipropylene glycol methyl ether for inhalation exposure of Fischer-344 rats is 200 ppm.
Executive summary:

Fischer-344 rats (10/sex/exposure) were exposed to 0, 15, 50 and 200 ppm (0, 91, 303 and 1212 mg/m3) of dipropylene glycol monomethyl ether (DPGME) for 6 hr/day, 5 days /week for 13 weeks.

There were no DPGME exposure related adverse effects on body weights in rats during the 13 week study. There were no statistically significant differences from control body weight means in male and female rats. There were no exposure related effects on any of the measured hematology parameters in either sex of rat. There were also no statistically significant differences from control means. There were no exposure related effects on any of the measured clinical chemistry parameters in either sex of rat. The only statistically significant difference was a slight decrease in BUN in female rats exposed to 50 ppm, but this had no toxicological significance. There were no apparent effects on any of the urinalysis parameters of male and female rats. There were also no statistically significant differences in absolute or relative organ weights of rats exposed to DPGME, except for a slight decrease in mean relative liver weight of 50 ppm exposed males.

All gross and histopathologic observations were considered to be spontaneous changes of minimal severity which were not treatment related. Based on gross observations, liver from rats exposed to DPGME appeared to be increased in size, however this observation was not supported by group mean liver weights and there was no histopathologic evidence of hepatocellular swelling.

Based on the results of this study the NOAEL for dipropylene glycol methyl ether for inhalation exposure of Fischer-344 rats is 200 ppm.