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Repeated dose toxicity: inhalation

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Administrative data

Endpoint:
sub-chronic toxicity: inhalation
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
1983
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP-study according to OECD guideline 413.

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1983
Report date:
1983
Reference Type:
publication
Title:
Unnamed
Year:
1984

Materials and methods

Test guidelineopen allclose all
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
Qualifier:
equivalent or similar to guideline
Guideline:
EPA OPPTS 870.3465 (90-Day Inhalation Toxicity)
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Details on test material:
- Name of test material (as cited in study report): dipropylene glycol methyl ether (DPM) as surrogate for dipropylene glycol methyl ether acetate (DPMA)
- Molecular formula (if other than submission substance): C7H16O3
- Molecular weight (if other than submission substance): 148.2 g/m
- Physical state: Colorless liquid
- Analytical purity: 99.2 %
- Lot/batch No.: # QP - 811116 - 36

Test animals

Species:
other: Rat and Rabbit
Strain:
other: Fischer - 344 and New zealand White
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Rats :Charles River Breeding Laboratories (Portage, MI and Rabbits : Langshaw Rabbitry (Augusta, MI)
- Age at study initiation: 9 weeks for rats
- Weight at study initiation: Rats (140-195 gms) for male and female and for rabbits approx. 3 kg and above
- Housing: Rats (2/cage) and rabbits (1/cage) were housed in stainless steel cages with wire bottoms
- Diet (ad libitum): A standard laboratory diet (Purina Certified laboratory Chow, Ralson Purina Co., St. Louis. MO)
- Water (ad libitum): ad libitum except during exposure
- Acclimation period: 2 weeks for rats and 4 weeks for rabbits


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 -24°C
- Humidity (%): 40- 60 % (Relative humidity)

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
- Method of conditioning air:DPGME was vaporized and metered into the chambers with a compressed air flames heat torch/j-tube assembly as described by Miller.The concentration of DPGME in each chamber was measured approximately once per hour with a Varian 2400 GC with 1/8" by 6 nickel column (8%Triton X-305 on 100/120 chromosorb) 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 gas tight bag. Heat was applied to the test material to facilitate vaporirization.A series of standards which included15, 50,200 ppm were made and analyzed at least biweekly to produce standard curve.
- Temperature, humidity, in air chamber: Temperature- Mean maximum in the 4 chambers were 24-26°C
- Air flow rate: 800 l/min


TEST ATMOSPHERE :Measured mean chamber DPGME concentrations were within 1% of target concentrations (15, 50,200 ppm). Mean nominal DPGME concentrations (based on chamber air flow) were good in agreement (within 8%) with mean analytical concentrations, indicating that the test material losses were minimized in the vapor generator and exposure systems. Chamber distribution studies indicated that the test atmosphere concentrations were uniform within 10% inside each chamber.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
See the attachment-5
Duration of treatment / exposure:
90 days
Frequency of treatment:
6 hr/day, 5 days/week for 13 weeks
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 15, 50, or 200 ppm (0, 91, 303, or 1,212 mg/m3) for rats and rabbits
Basis:
nominal conc.
No. of animals per sex per dose:
Rats : 10/sex/exposure
Rabbits : 7/sex/exposure
Control animals:
other: Yes, room air.
Details on study design:
Post-exposure period: none

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Weekly once prior and after exposure.
BODY WEIGHT: Yes
- Time schedule for examinations: Weekly
FOOD EFFICIENCY: Not examined
-WATER CONSUMPTION: No
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: Yes
- Time schedule for collection of blood: After 12 weeks of exposure
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: Rats :40 male and 40 female Rabbit : 27 male and 28 female
- Parameters checked : PCV, Hgb, RBC, WBC (total and differential), Plat, RBC indices


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Blood samples from rats for clinical chemistries were taken at necropsy.
- Animals fasted: Yes
- How many animals: Rats 40 male and 40 female and Rabbits :27 male and 28 female
- Parameters checked : Alb, AP, BUN, TP, Globulin,glucose, SGPT


URINALYSIS: Yes ( For rats only)
- Time schedule for collection of urine: After 12 weeks of exposure
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters checked : Bilirubin, Glucose,Ketone, Occult blood, pH,Protein, Specific gravity and Urobilinogen

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes (see table) : See attachment 1
HISTOPATHOLOGY: Yes (see table) : See attachment 1
All surviving animals underwent a gross necropsy on the day following last exposure. Rats (but not rabbits) were deprived of food overnight prior to necropsy. Rats were anesthetized with methoxyflurane, and then decapitated. Rabbits were anesthetized with CO2, and then decapitated. The trachea of all animals was clamped after anesthesia to prevent aspiration of blood during decapitation. Each animal was examined internally and externally for gross pathological changes. The heart, liver, kidneys, brain, thymus (rats), and testes (males) 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 the tissues and organs were preserved in buffered 10% formalin.
One male rabbit from the 200 ppm exposure group was sacrificed prior to scheduled termination of the study because of a head tilt and disequlibirium.This animal was examined in a manner similar to the other rabbits, except that organs were not weighed and serum was not collected. A full set of tissues was prepared and examined microscopically.
Liver samples from male rats and rabbits (3.exposure group) were fixed in a phosphate buffered 2% gluteraldehyde and 2% formaldehyde solution, then routinely processed and embedded in EPON 812 resin for possible electron microscopy.
Other examinations:
Organ weights : The heart, liver, kidneys, brain, thymus (rats), and testes (males) 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. If group variances were homogeneous; a parametric analysis of variance was conducted to determine if any statistically significant differences exist between groups. If overall parametric ANOVA was significant at <0.10 Dunnett’s test was used to identify statistically significant differences (<0.05) between experimental groups and their corresponding controls.

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 specified
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not examined
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 apparent clinical effects and mortality due to DPGME exposure. Several minor observations were noted, including a case of ear mites in a male rabbit (treated topically with mineral oil), facial alopecia in 2 female rabbits, and a possible ruptured abscess in a female rabbit. One male rabbit which had been exposed to 200 ppm developed an ear infection and was sacrificed prior to the scheduled necropsy.


BODY WEIGHT AND WEIGHT GAIN: There were no exposure related adverse effects on body weights in either species during the 13 week study. There were no statistically significant differences from control body weight means in male and female rats or in male rabbits. The mean body weights of female rabbits in the 50 ppm group were slightly higher than the controls at the beginning of the study and at various intervals thereafter. This was not considered to be exposure related, due to absence of any effect on body weights of female rabbits in the high exposure group


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


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


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


ORGAN WEIGHTS: There were 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. There were several statistical differences in mean organ weights of rabbits but these also did not occur at the highest concentration tested, and were therefore not considered to be exposure related. There was an increase in mean relative kidney weight of female rabbits exposed to 200 ppm. The absolute mean kidney weights of 50 ppm and 200 ppm exposed female rabbits were also increased. However, both the absolute and relative mean kidney weights of DPGME exposed rabbits were within the range of historical control values. Because there was no evidence of nephrotoxicity, the increased kidney weights in the female rabbits were thought to be unrelated to the treatment.


GROSS PATHOLOGY: There were no exposure related changes observed at the necropsy in rats and rabbits. The changes observed during necropsy that were considered to be spontaneous changes of minimal severity which were not treatment related.


HISTOPATHOLOGY: NON-NEOPLASTIC: There were no DPGME exposure related microscopically changes observed in rats and rabbit. All histopathological observations were considered to be spontaneous changes of minimal severity which were not treatment related


Effect levels

open allclose all
Dose descriptor:
NOAEL
Remarks:
(Rat and Rabbit)
Effect level:
200 ppm
Sex:
male/female
Dose descriptor:
NOAEC
Effect level:
1 212.27 mg/m³ air (nominal)
Sex:
male/female

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Based on the results of this study NOAEL in rat and rabbit was 200 ppm which is the highest attainable concentration due to the low vapor pressure of dipropylene glycol methyl ether.
Executive summary:

Fischer – 344 (10/sex/exposure concentration )  and New Zealand white rabbits ( 7/sex/exposure concentration ) were exposed to 0, 15,50,200 ppm (0,91,303,1212 mg/m3) of dipropylene glycol monomethyl ether (colorless liquid DPGME) for 6 hrs/day, 5 days/week for 13 weeks.

Rats were received from Charles River Breeding Laboratories (, ) and Rabbits were received from Langshaw Rabbitry (, ).Rats and rabbits were kept for an acclimatization period of 2 weeks and 4 weeks respectively. Rats were housed (2/cage) and rabbits (1/cage) in stainless steel cages with wire bottoms. A standard laboratory diet (Purina Certified laboratory Chow, Ralson Purina Co., . MO) was supplied to rats and rabbits. Water also provided ad libitum to rats and rabbits except during exposure. Housing conditions were maintained at temperature of 20 -24 °C with relative humidity of 40-60 %.

Monitored for effects included general observations, body weights, clinical chemistry, hematology, urinalysis (Rats only), necropsy, organ weights and histopathology.

There were no exposure related adverse effects on body weights in either species during the 13 week study. There were no statistically significant differences from control body weight means in male and female rats or in male rabbits. The mean body weights of female rabbits in the 50 ppm group were slightly higher than the controls at the beginning of the study and at various intervals thereafter. This was not considered to be exposure related, due to absence of any effect on body weights of female rabbits in the high exposure group.

There were no apparent clinical effects and mortality due to DPGME exposure. There were no exposure related effects on any measured hematology parameters in either sex of rat and rabbit. There were also no statistically significant differences from control means. There were no apparent effects on any of urinalysis parameters of male and female rats.

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 ’s test for the equality of variances.

All surviving animals underwent a gross necropsy on the day following last exposure. Rats (but not rabbits) were deprived of food overnight prior to necropsy. Rats were anesthetized with methoxyflurane, and then decapitated. Rabbits were anesthetized with CO2, and then decapitated. The trachea of all animals was clamped after anesthesia to prevent aspiration of blood during decapitation. Each animal was examined internally and externally for gross pathological changes. The heart, liver, kidneys, brain, thymus (rats), and testes (males) 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 the tissues and organs were preserved in buffered 10% formalin.

One male rabbit from the 200 ppm exposure group was sacrificed prior to scheduled termination of the study because of a head tilt and disequlibirium.This animals was examined in a manner similar to the other rabbits, except that organs were not weighed and serum was not collected. A full set of tissues was prepared and examined microscopically.

Liver samples from male rats and rabbits (3 exposure group) were fixed in a phosphate buffered 2%gluteraldehyde and 2% formaldehyde solution, then routinely processed and embedded in EPON 812 resin for possible electron microscopy.

There were no exposure related changes observed at the necropsy in rats and rabbits. There were no DPGME exposure related microscopically changes observed in rats and rabbits. All histopathological observations were considered to be spontaneous changes of minimal severity which were not treatment related.

Based on the results of this study NOAEL in rat and rabbit was 200 ppm.  Under conditions of this study the low vapor pressure of DPGME, and results in this 13 week study DPGME appears to have a low subchronic vapor inhalation toxicity hazard.