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Toxicological information

Repeated dose toxicity: inhalation

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Administrative data

Endpoint:
short-term repeated dose toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1985
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: This study was conducted in accordance with GLP as well as comparable to guidelines and sufficient data is available for the interpretation study results.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1985
Report date:
1985

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
[2-(2-methoxymethylethoxy)methylethoxy]propanol
EC Number:
247-045-4
EC Name:
[2-(2-methoxymethylethoxy)methylethoxy]propanol
Cas Number:
25498-49-1
Molecular formula:
C10H22O4
IUPAC Name:
[2-(2-Methoxymethylethoxy)methylethoxy]propanol
Details on test material:
- Name of test material (as cited in study report): Tripropylene glycol methyl ether
- Molecular formula (if other than submission substance): C10H22O4
- Molecular weight (if other than submission substance): 206.3 g/mole
- Physical state:Colorless liquid
- Analytical purity: 99.4% as TPM isomers
- Impurities (identity and concentrations):
- Composition of test material, percentage of components:
- Administered as: Aerosol in air
- Vapor pressure: 0.017 mmHg at 25°C
- Specific Gravity: 0.961

Test animals

Species:
other: Rat and Mice
Strain:
other: Fischer - 344 and Mice - B6C3F1
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
Source:
Rats - Charles River Breeding Laboratories. Inc, Kingston
Mice - Mice - Charles River Breeding Laboratories. Inc, Portage MI
- Age at study initiation: 7-9 weeks
- Weight at study initiation: Rats:
Rats: Male - 177 to 182 gms and Female - 127 to 129 gms
Mice: Male - 24 to 25 gms and Female - 21 to 22 gms
- Housing: Rats were housed singly in stainless steel cages with wire bottoms
- Diet ( ad libitum): Purina Certified Rodent Chow # 5002
- Water ( ad libitum): Municipal tap water except during exposure.
- Acclimation period: 7 days each for rat and mice


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22.2°C
- Humidity (%): 50 %
- Air changes (per hr):
- Photoperiod: (12 hrs dark / 12 hrs light)


IN-LIFE DATES: Not specified in the report

Administration / exposure

Route of administration:
inhalation: aerosol
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 1m³ stainless steel and glass chamber used.
- Method of holding animals in test chamber: Whole body
- Method of conditioning air:
- System of generating particulates/aerosols: The aerosol test atmospheres were generated using a spraying nozzle.
- Temperature, humidity, pressure in air chamber: Temperature 70°F and Humidity 50%
- Air flow rate: 200 lit/minute
- Method of particle size determination: Particle size distribution of the TPGME aerosol was measured once per day in each exposure chamber using an APS Aerodynamic partcle sizer and diluter.


TEST ATMOSPHERE
- Brief description of analytical method used: The aerosol concentration was measured gravimetrically approximately 4 to 5 times per day in each chamber.

Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
See the Attachment - 1
Duration of treatment / exposure:
2 weeks (total of 9 exposures)
Frequency of treatment:
6 hrs/day for a total of 9 days
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0.15 mg/l
Basis:
analytical conc.
Remarks:
Doses / Concentrations:
0.36 mg/l
Basis:
analytical conc.
Remarks:
Doses / Concentrations:
1.01 mg/l
Basis:
analytical conc.
No. of animals per sex per dose:
5/sex/dose/species
Control animals:
yes
Details on study design:
Post-exposure period: none

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: All animals were observed after each exposure period along with daily observations.
BODY WEIGHT: Yes
- Time schedule for examinations: All animals were weighed prior to 1st, 3rd, 5th and 9th days of exposure
HAEMATOLOGY: Yes
- Time schedule for collection of blood: Immediately prior to sacrifice
- Anaesthetic used for blood collection: No data
- Animals fasted: Yes
- How many animals: Rats - 20 male and 20 Female Mice- 20 Male and 18 Female
- Parameters checked: RBC, HGB, PCV, MCV, MCH, MCHC, Plat, WBC, LYM, MON, EOS


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood:Immediately prior to sacrifice
- Animals fasted: Yes
- How many animals:Rats - 20 male and 20 Female Mice- 20 Male and 18 Female
- Parameters checked: BUN, GPT, AP, GOT, GLUC, TP, ALB, and GLOB

URINALYSIS: Yes (only in rats)
- Time schedule for collection of urine: Urine samples were collected from rats prior to the 9th exposure
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters checked: Bilirubin, Glucose, Ketones, Blood, pH, Protein, Urobilinigen, Specific gravity
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
All surviving animals were sacrificed the day following the last exposure. Rats were fasted overnight prior to the scheduled sacrifice, mice were not fasted prior to sacrifice. All animals were weighed, anesthetized with methoxyflurane, and trachea was clamped prior to decapitation. All animals were examined for gross pathological alterations. The necropsy included in situ examination of the eyes by a glass slide technique with fluorescent illumination.
HISTOPATHOLOGY: Yes
A complete set of tissues was collected from each animal and preserved in neutral phosphate buffered formalin. The lungs were infused with buffered formalin to their approximate normal inspiratory volume and the nasal cavity was flushed with formalin via pharyngeal duct to insure rapid fixation of the tissue.Histopathologic examinations were performed on complete sets of tissues from all rats and mice in control and high exposure groups. Only target organs identified in the high exposure were examined histopathologically for animals in the middle and low exposure groups. Tissues that were examined histopathologically were processed by conventional techniques, stained with hematoxylin and eosin and evaluated by light microscopy.
Other examinations:
Organ weights: liver, kidneys, thymus, testes, heart and brain, from all surviving animals.
Statistics:
Descriptive statistics are reported for differential counts and RBC indices. Body weights, absolute and relative organ weights, clinical chemistry data, appropriate hematology data and urinary specific gravity were evaluated by Bartlett's test, for equality of variances. Based on the outcome of Bartlett's test, a parametric or non-parametric analysis of variance (ANOVA) was performed, followed respectively by Dennett’s test with a Bonferroni correction for multiple comparisons. Statistical outliers were identified by a sequential test but not excluded from statistical analyses.

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 examined
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:
effects observed, treatment-related
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: One female mouse in the control group and one in the 0.15 mg/l group died as a result of accidental traumatic injuries. All other rats and mice survived until the scheduled necropsy with no apparent indication of an adverse response to the test material except that slight nasal exudate was noted for rats in the high exposure groups following last exposure. The fur of the animals in high exposure group was slightly wet following each day of exposure as a result of the high concentration of liquid aerosol in that chamber.

BODY WEIGHT AND WEIGHT GAIN: The mean body weights of male and female rats and mice were not adversely affected by exposure to the test material. There were no statistically significant differences in the mean body weights of control and exposure groups of animals at any time the course of the study.

HAEMATOLOGY: The hematology analyses for the male and female rats and mice were unremarkable, revealing no differences between control and exposure group of animals.


CLINICAL CHEMISTRY: The clinical chemistry analyses for rats and mice indicated no changes that were considered to be diagnostic of an adverse effect on any organ or tissue.


URINALYSIS: The mean urinary specific gravity values for female rats in the 0.15 mg/l and 1.01 mg/l groups were statistically significantly lower than for the controls however; the degree of the change was not proportional to exposure concentration. In view of the absence of a clear dose -response relationship, the observed changes in urinary specific gravity in female rats were not considered to be of toxicologic significance. There were no clinical chemistry changes in these animals which were diagnostic of adverse renal effects and histopathologic changes in the kidneys.


ORGAN WEIGHTS: At necropsy the mean absolute and relative liver weights of male and female rats in the high exposure group, as well as the mean relative liver weight of male rats in the 0.36 mg/l group, were significantly higher than for the controls. Significant increases in the mean liver weights were also found in mice. The liver weights of male mice were increased an all three exposure groups in an apparent exposure concentration related manner, while the liver weights of female mice were affected only at the high 1.01 mg/l exposure concentration. The weights of brain, heart, kidneys, thymus, testes in rats and mice were not affected by exposure to the TPGME aerosol.


GROSS PATHOLOGY: At necropsy the livers of some treated animals appeared to be larger than for controls otherwise, there were no treatment related gross pathologic observations in either rats or mice.


HISTOPATHOLOGY: NON-NEOPLASTIC: Histopathologic examinations revealed no adverse exposure related changes in any organ or tissue in either rats or mice. Some of the male mice (3 of 5) in the 1.01 mg/l group had altered tinctorial properties in peripheral regions of hepatic lobules; this observation was considered to be an adaptive response rather than a degenerative phenomenon. There were no microscopic exposure related changes in the livers of rats and mice and no microscopic observations in the kidneys of female rats associated with the changes in the specific gravity of urine. The gross and histopathologic observations for two female mice that were accidentally killed during the course of the study revealed no changes related to exposure to TPGME.



Effect levels

Dose descriptor:
NOAEC
Effect level:
1 010 mg/m³ air
Sex:
male/female
Basis for effect level:
other: based on adaptive effects on the liver

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Based on the results of this study the NOAEC (based on adaptive effect on the liver) is 1.01 mg/l for both species.
Executive summary:

Fischer – 344 (5/sex/exposure concentration) and B6C3F1 mice (5/sex/exposure concentration) were exposed to 0, 0.15, 0.36, and 1.01 mg/l or 0,150, 360, 1010 mg/m3) of tripropylene glycol monomethyl ether (colorless liquid aerosol TPGME) for 6 hrs/day, for a total of 9 days.

Rats were received from Charles River Breeding Laboratories Inc. Kingston and mice were received from Charles River Breeding Laboratories Portage, MI,. Rats and mice were kept for an acclimatization period of 7 days. Rats were housed singly in stainless steel cages with wire bottoms. A standard laboratory diet (Purina Certified laboratory Chow, Ralson Purina Co., . MO) was supplied to rats and mice. Water also provided ad libitum to rats and mice except during exposure. Housing conditions were maintained at temperature of 22.4 °C with relative humidity of 50%.

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

The mean body weights of rats and mice were not adversely affected by exposure to the test material. There were no statistically significant differences in the mean body weights of control and exposure groups of animals at any time the course of the study.All animals were survived until the scheduled necropsy with no apparent indication of an adverse response to the test material except that slight nasal exudate was noted for rats in the high exposure groups following last exposure. One female mouse in the control group and one in the 0.15 mg/l group dies as a result of accidental traumatic injuries. The fur of the animals in high exposure group was slightly wet following each day of exposure as a result of the high concentration of liquid aerosol in that chamber. The haematology analyses for the male and female rats and mice were unremarkable, revealing no differences between control and exposure group of animals. The clinical chemistry analyses for rats and mice indicated no changes that were considered to be diagnostic of an adverse effect on any organ or tissue.

The mean urinary specific gravity values for female rats in the 0.15 mg/l and 1.01 mg/l groups were statistically significantly lower than for the controls however; the degree of the change was not proportional to exposure concentration. In view of the absence of a clear dose -response relationship, the observed changes in urinary specific gravity in female rats were not considered to be of toxicologic significance. There were no clinical chemistry changes in these animals which were diagnostic of adverse renal effects and histopathologic changes in the kidneys.

At necropsy the mean absolute and relative liver weights of male and female rats in the high exposure group, as well as the mean relative liver weight of male rats in the 0.36 mg/l group, were significantly higher than for the controls. Significant increases in the mean liver weights were also found in mice. The liver weights of male mice were increased an all three exposure groups in an apparent exposure concentration related manner, while the liver weights of female mice were affected only at the high 1.01 mg/l exposure concentration. The weights of brain, heart, kidneys, thymus, testes in rats and mice were not affected by exposure to the TPGME aerosol.

At necropsy the livers of some treated animals appeared to be larger than for controls otherwise, there were no treatment related gross pathologic observations in either rats or mice. Histopathologic examinations revealed no adverse exposure related changes in any organ or tissue in either rats or mice. Some of the male mice (3 of 5) in the 1.01 mg/l group had altered tinctorial properties in peripheral regions of hepatic lobules; this observation was considered to be an adaptive response rather than a degenerative phenomenon. There were no microscopic exposure related changes in the livers of rats and mice and no microscopic observations in the kidneys of female rats associated with the changes in the specific gravity of urine. The gross and histopathologic observations for two female mice that were accidentally killed during the course of the study revealed no changes related to exposure to TPGME.

Based on the results of this study the NOAEC (based on adaptive effect on the liver) is 1.01 mg/l.