Registration Dossier

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Administrative data

Description of key information

For the oral route, an OECD 422 study (GLP) is available for propylene glycol methyl ether acetate. The study has been conducted by the Japanese Ministry of Health. The full test report is not available, but it was validated by the Japanese authorities within the OECD SIDS activities. For the dermal route, no studies are available for propylene glycol methyl ether acetate.  Therefore, read-across from dermal studies with propylene glycol methyl ether was done.  A 13-week repeated-dose dermal toxicity study in rabbits was selected as the most relevant study for the risk assessment. For the inhalation route, only short-term (9-day exposure) studies are available for propylene glycol methyl ether acetate. Therefore, read-across from 90-day and 2-year inhalation toxicity studies with propylene glycol methyl ether was used.  See attached category document in Section 13 for read-across justification.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: oral
Remarks:
combined repeated dose and reproduction / developmental screening
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1998
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
The test report from the Japanese Ministry of Health & Welfare is not available, but all data have were validated by the Japanese authorities within the OECD-SIDS program and were taken into account in the EU risk assessment report on this substance by France.
Qualifier:
according to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source:
- Age at study initiation:
- Weight at study initiation:
- Fasting period before study:
- Housing:
- Diet (e.g. ad libitum):
- Water (e.g. ad libitum):
- Acclimation period:


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


IN-LIFE DATES: From: To:
Route of administration:
oral: gavage
Vehicle:
other: Distillled water
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
Males: for 44 days from 2 weeks prior to mating.
Females: from 14 days before mating to day 3 of lactation (41-45days)
Frequency of treatment:
one administration/day
Remarks:
Doses / Concentrations:
100 mg/kg/day
Basis:
nominal in water
Remarks:
Doses / Concentrations:
300 mg/kg/day
Basis:
nominal in water
Remarks:
Doses / Concentrations:
1000 mg/kg/day
Basis:
nominal in water
Control animals:
yes, concurrent vehicle
Details on study design:
Post-exposure period: none
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):
effects observed, treatment-related
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Clinical biochemistry findings:
effects observed, treatment-related
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
Dose descriptor:
NOAEL
Effect level:
>= 1 000 other: mg/kg
Sex:
male/female
Basis for effect level:
other: No adverse effects observed up to limit dose.
Critical effects observed:
not specified
Conclusions:
Based on the results of this study NOAEL for the rats is 1000 mg/kg/day
Executive summary:

Using OECD combined repeat dose and reproductive/developmental toxicity screening test SD rats received gavage propylene glycol methyl ether acetate (purity >99.9%) doses of 0 (Vehicle: distilled water), 100, 300 and 1000 mg/kg/day, for males for 44 days from 2 weeks prior to mating and for females for 41 -45 days from 14 days before mating to day 3 postpartum.

A dose of 1,000 mg/kg/day of PMA exerted some effects in both male and female rats. In males, depressions of body weight gain and a tendency for decrease in food consumption were observed. In females, low body weight gain during the premating period at 1,000 mg/kg was also observed.  Blood examination revealed decreases in glucose and inorganic phosphorus. An increase in relative weight of the adrenals was also noted. In females, body weight gain was lower than in the control during the premating period. Tissue pathology revealed none of the alteration of tissues at the highest dose group for both sexes.

 

The animals were sacrificed on the day 4 of lactation for females. No effects related to chemical exposure were observed maternally at 1,000 mg/kg, although there was a single unsuccessful copulation at this dose level which was not statistically significantly different from the control (p<0.05). Similarly, no effects related to the chemical exposure were observed in foetal data at 1,000 mg/kg. Reproductive toxicity of PGMA in rats by oral administration is not observed at the highest dose.

 

 A NOAEL was thus established at 1,000 mg/kg bw/day for both sexes.

 

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
Good (Klimisch 2)

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
Endpoint:
chronic toxicity: inhalation
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Study period:
1998
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: This study was conducted in accordance with GLP and OECD guideline 453 and TSCA guideline part 798
Justification for type of information:
Please refer to category document.
Qualifier:
according to guideline
Guideline:
OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
Qualifier:
according to guideline
Guideline:
other: TSCA Guideline Part 798
Principles of method if other than guideline:
Method: other: OECD 453
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River breeding Laboratories, Inc., Kingston, NY
- Age at study initiation: Approximately 6-7 weeks
- Weight at study initiation: Approximately 140-150 gms (male) and 110-120 - gms (female)
- Fasting period before study: None
- Housing: 2/cage in stainless steel wire cages
- Diet (ad libitum): Except during exposure
- Water (ad libitum): Except during exposure
- Acclimation period: 1 week


ENVIRONMENTAL CONDITIONS
- Temperature (°C): Standard conditions
- Humidity (%): Standard conditions
- Air changes (per hr): Standard conditions



Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
See the attachment-1
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
See the attachment-1
Duration of treatment / exposure:
2 years whole body exposure
Frequency of treatment:
6 hours/day, 5 days/week
Remarks:
Doses / Concentrations:
300 ppm
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
1000 ppm
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
3000 ppm
Basis:
nominal conc.
No. of animals per sex per dose:
50 animals/sex/dose
Control animals:
yes
Details on study design:
See the attachment-1
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily (except weekends) for signs of toxicity and checked daily for mortality (including weekends)

DETAILED CLINICAL OBSERVATIONS: Yes
These observation were made only rats belonging to group A
- Time schedule: Prior to start of exposure and weekly thereafter


BODY WEIGHT: Yes
- Time schedule for examinations: All animals were weighed prior to the initial exposure and weekly intervals for the first 13 weeks and at approximately 4- weeks thereafter.

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations:
- Dose groups that were examined: Prior to start of exposure and prior to necropsy in all animals dose group A.


HAEMATOLOGY: Yes
- Time schedule for collection of blood: After 6 months, 12 months and 18 months of exposure
- Anesthetic used for blood collection: Yes (identity) Methoxyflurane
- Animals fasted: Yes
- How many animals: For interim collection (6, 12, 18 months) 10 rats/sex/exposure randomly selected
- Parameters checked in table [No.?] were examined.


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: After 6 months, 12 months and 18 months of exposure
- Anesthetic used for blood collection: Yes (identity) Methoxyflurane
- Animals fasted: Yes
- How many animals: For interim collection (6, 12, 18 months) 10 rats/sex/exposure randomly selected
- Parameters checked in table [No.?] were examined.


URINALYSIS: Yes
- Time schedule for collection of urine: 1-6 days prior to 6, 12, 18 months blood collection and 1 day prior to 24 month blood collection
- Metabolism cages used for collection of urine: No
- Animals fasted: No
- Parameters checked in table [No.?] were examined.






Sacrifice and pathology:
GROSS PATHOLOGY: Yes
All surviving animals were fasted overnight and necropsied after approximately 24 months of exposure to PGME. Each animal was weighed, anesthetized with methoxyflurane and trachea exposed and clamped prior to decapitation. The eyes were visually examined throgh a moistened glass slide pressed against the corneal surface. Weight of brain, heart, lungs, liver, kidneys, adrenals and testes were recorded and the organ weights to final body weight ratios were calculated. The lungs were intratracheally infused to an approximately normal inspiratory volume with neutral phosphate buffered 10 % formalin. The nasal cavity was flushed by a similar method via the pharyngeal duct. Representative samples of tissues and any masses or lesions observed during necropsy were preserved in formalin. A similar procedure was followed for rats which died or were sacrificed in a moribund condition, except that blood samples, terminal body weights and organ weight data were not be collected.
HISTOPATHOLOGY: Yes
Tissues were prepared for light microscopic evaluation by procedures, sectioned at approximately 6µm and stained with hematoxylin and eosin. A complete histopathologic evaluation of all tissues was conducted on all control and 3000 ppm PGME exposure rats and from rats that died or were sacrificed in a moribund during the course of the study. In addition, microscopic examination of tissues from the low and middle exposure groups included the liver, kidneys, lungs, nasal tissues and all gross lesions.
Other examinations:
Organ weights: Weight of brain, heart, lungs, liver, kidneys, adrenals and testes were recorded.
Statistics:
See the attchment-1
Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
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:
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:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY: Overall survival was excellent for the 2 year study with mortality never exceeding 58 % for any treatment group. For males, a slight increase in mortality was observed following 700 days exposure to 3000 ppm PGME vs. controls. At study termination, the cumulative mortality in males was 40, 32, 40 and 58 % for the control, 300, 1000, 3000 ppm groups respectively. For females no treatment related increase in mortality was observed. At study termination, the cumulative mortality in females was 22, 30, 28 and 16 % for the control, 300, 1000, 3000 ppm groups respectively.
At 3000 ppm PGME the sedative effects, characterized by decreased activity and incoordination, were observed in both sexes during the first week of exposures. The animals generally recovered within hours following the six hour exposure periods. During the second week of exposures, the animals appeared to have accommodated to the test material as no further observation of sedative effects thought the first year exposures were noted. Other clinical observations were in general consistent with age related changes commonly observed in chronic studies with Fischer 344 rats and not due to PGME exposures. A number of rats in each group had external masses or nodules in various locations of the skin, subcutaneous tissues and in preputial or clitoral glands areas. These masses/nodules were distributed across all groups without regard to treatment.

BODY WEIGHT AND WEIGHT GAIN: For male rats, there were numerous instances of treatment groups having a statistically significant difference in body weights or weight gain vs controls. These differences included decreases as well as increases and did not display a dose response relationship. For females, occasional statistically identified differences from controls were also observed but lacked dose response during the 13 weeks of study. However, by 118 days treatment, the mean body weights females exposed to 3000 ppm PGME were consistently and statistically lower than control values by approximately 3-7 %. This effect on the body weights of female rats was considered to be treatment related.

OPHTHALMOSCOPIC EXAMINATION: There were no ophthalmologic abnormalities noted in any of the group A study animals that were considered to be treatment related.


HAEMATOLOGY: There were no hematological effects in male and female rats that were attributable to PGME exposures. Occasional statistical significant differences were observed that lacked dose response, were not reproducible (between the 6, 12, 18 and 24 month sampling intervals) or differed in a manner in which that was not toxicologically relevant. The only statistically identified hematological change was an increase in total leukocyte counts in 300 ppm PGME males at 6 months which was not considered treatment related as it represented an increase and not a decrease in counts, was not observed at other time points, and lacked any histopathological correlate. No effects were observed in WBC differential counts. The only statistically identified changes included, elevated leukocyte counts in females exposed to 300 and 1000 ppm PGME for 6 months, but not at 3000 ppm PGME or at later time periods, increased erythrocyte and platelet counts in females exposed to 3000 ppm PGME after 6 months but not at later times periods and slight decrease in platelet counts in females exposed to 3000 ppm PGME for 12 months but not at 18 or 24 months. These changes were all considered to be a reflection of normal biological variability. As with the males, no treatment related effects were observed in WBC differential counts and blood cell morphology.


CLINICAL CHEMISTRY: Occasional findings of statistically significant but not treatment related included, elevated BUN in rats exposed to 1000 ppm for 6 months, elevated cholesterol in rats exposed to 1000 and 3000 ppm for 6 months, elevated triglycerides levels in rats exposed to 300 and 1000 ppm for 6 months or 3000 ppm for 24 months, increased creatinine levels in rats exposed to 3000 ppm at 6, 12 and 24 months, decreased creatinine phosphokinase activity in rats exposed to 1000 ppm only for 24 months. In addition, the mean calcium level in male rats exposed to 1000 ppm for 6 months was statistically identified as elevated and the phosphorous level of rats exposed to 3000 ppm for 18 months was identified as decreased relative to controls. All of those statistically identified differences were considered to be a result of normal variability and unrelated to PGME exposure since they were not either reproducible, lacked a dose response relationship or lacked histopathological correlate. Elevated serum alkaline phosphatase activities were also observed in male rats exposed to 3000 ppm PGME for 6, 12 and 24 months or to 1000 ppm for 24 months. This enzyme is typically associated with degenerative changes or obstruction of the biliary duct system, which was morphologically unaffected by PGME exposure. Changes observed in electrolytes were statistically identified but not treatment related and lacked a dose response relationship.


URINALYSIS: The slight changes in urinalysis parameters that were observed in two weeks i.e. increased urine pH in male rats exposed to 3000 ppm PGME but these changes were not apparent in this study following 6, 12, 18, and 24 months of exposure. There were no treatment related effects evident in urinalysis including microscopic examinations of urine micro sediment from male and female rats.


ORGAN WEIGHTS: A statistically significant increase in liver weights (18.6 % absolute and 21.2 % relative to body weight) was observed in high exposure group males, relative to controls at the terminal 24 month sacrifice, similar increases were present at earlier time points. For female rats, there were no significant liver weight differences observed in the high concentration group at the terminal sacrifice, however there were statistically significant liver weight increases at earlier time points. Kidney weights were elevated in males exposed to 3000 ppm PGME following 6, 12, 18 and 24 months of exposure. At 24 months, this increase averaged 22 % for absolute kidney weights and 28 % for kidney weights relative to their body weights. Although statistically identified at all time periods were slight <5 % absolute and did not correlate to any histopathological changes in renal tissues. No other changes in organ weights interpreted to be treatment related were observed in male or female rats.


GROSS PATHOLOGY: A slight increase in the incidence of dark foci in the livers of male rats exposed to 1000 and 3000 ppm PGME for 2 years was correlated with the presence of altered hepatocellular foci observed histologically .All other gross pathological observations and the occurrence of palpable mass were distributed across all groups, including controls and were typical for rats of this age and strain.


HISTOPATHOLOGY: The major toxicological effects of exposure were observed in the liver and kidneys. Effects of lesser importance were observed in nasal tissues and lungs. The clinical pathology data did not indicate significant treatment related hepatotoxicity. The lack of dose response in the incidence of tumors in males does not suggest a treatment related effect.

Dose descriptor:
NOEL
Effect level:
300 ppm
Sex:
male/female
Basis for effect level:
other: overall effects
Critical effects observed:
not specified
Conclusions:
In conclusion, PGME did not cause a dose related increase in tumors in male and female rats exposed to 0, 300, 1000 and 3000 ppm PGME vapors for 6 hours/day, 5 days/week for up to 2 years. A NOEL of 300 ppm PGME was established for this study.
Executive summary:

Groups of 50 male and 50 female Fischer 344 per sex per concentration were whole body exposed to targeted vapor concentrations of 0, 300, 1000 and 3000 ppm PGME (colorless liquid) under dynamic airflow conditions 6 hours/day, 5 days/week for up to 2 years.

Rats were received frombreeding Laboratories,. Mice were kept for acclimatization for 1 week period. At study initiation rats were of approximately 6 -7 weeks old. Rats were housed 2/sex/cage in stainless steel cages with wire bottoms. A standard laboratory diet (Purina Certified Laboratory Chow, Ralston Purina Co.) supplied to rats adlibitum except during exposure. Adlibitum water was supplied to rats except during exposure.

 

Monitored for effects included clinical observations, body weights, hematology, clinical chemistry, urinalysis, opthalmoscopy, necropsy, organ weights, gross pathology and histopathology.

Overall survival was excellent for the 2 year study with mortality never exceeding 58 % for any treatment group. For males, a slight increase in mortality was observed following 700 days exposure to 3000 ppm PGME vs. controls. At study termination, the cumulative mortality in males was 40, 32, 40 and 58 % for the control, 300, 1000, 3000 ppm groups respectively. For females no treatment related increase in mortality was observed. At study termination, the cumulative mortality in females was 22, 30, 28 and 16 % for the control, 300, 1000, 3000 ppm groups respectively. At 3000 ppm PGME the sedative effects, characterized by decreased activity and incoordination, were observed in both sexes during the first week of exposures. The animals generally recovered within hours following the six hour exposure periods. During the second week of exposures, the animals appeared to have accommodated to the test material as no further observation of sedative effects thought the first year exposures were noted. Other clinical observations were in general consistent with age related changes commonly observed in chronic studies with Fischer 344 rats and not due to PGME exposures. A number of rats in each group had external masses or nodules in various locations of the skin, subcutaneous tissues and in preputial or clitoral glands areas. These masses/nodules were distributed across all groups without regard to treatment.

For male rats, there were numerous instances of treatment groups having a statistically significant difference in body weights or weight gain vs controls. These differences included decreases as well as increases and did not display a dose response relationship. For females, occasional statistically identified differences from controls were also observed but lacked dose response during the 13 weeks of study. However, by 118 days treatment, the mean body weights females exposed to 3000 ppm PGME were consistently and statistically lower than control values by approximately 3-7 %. This effect on the body weights of female rats was considered to be treatment related.

There were no ophthalmologic abnormalities noted in any of the group A study animals that were considered to be treatment related.

There were no hematological effects in male and female rats that were attributable to PGME exposures. Occasional statistical significant differences were observed that lacked dose response, were not reproducible (between the 6, 12, 18 and 24 month sampling intervals) or differed in a manner in which that was not toxicologically relevant. The only statistically identified hematological change was an increase in total leukocyte counts in 300 ppm PGME males at 6 months which was not considered treatment related as it represented an increase and not a decrease in counts, was not observed at other time points, and lacked any histopathological correlate. No effects were observed in WBC differential counts. The only statistically identified changes included, elevated leukocyte counts in females exposed to 300 and 1000 ppm PGME for 6 months, but not at 3000 ppm PGME or at later time periods, increased erythrocyte and platelet counts in females exposed to 3000 ppm PGME after 6 months but not at later times periods and slight decrease in platelet counts in females exposed to 3000 ppm PGME for 12 months but not at 18 or 24 months. These changes were all considered to be a reflection of normal biological variability. As with the males, no treatment related effects were observed in WBC differential counts and blood cell morphology.

Occasional findings of statistically significant but not treatment related included, elevated BUN in rats exposed to 1000 ppm for 6 months, elevated cholesterol in rats exposed to 1000 and 3000 ppm for 6 months, elevated triglycerides levels in rats exposed to 300 and 1000 ppm for 6 months or 3000 ppm for 24 months, increased creatinine levels in rats exposed to 3000 ppm at 6, 12 and 24 months, decreased creatinine phosphokinase activity in rats exposed to 1000 ppm only for 24 months. In addition, the mean calcium level in male rats exposed to 1000 ppm for 6 months was statistically identified as elevated and the phosphorous level of rats exposed to 3000 ppm for 18 months was identified as decreased relative to controls. All of those statistically identified differences were considered to be a result of normal variability and unrelated to PGME exposure since they were not either reproducible, lacked a dose response relationship or lacked histopathological correlate. Elevated serum alkaline phosphatase activities were also observed in male rats exposed to 3000 ppm PGME for 6, 12 and 24 months or to 1000 ppm for 24 months. This enzyme is typically associated with degenerative changes or obstruction of the biliary duct system, which was morphologically unaffected by PGME exposure. Changes observed in electrolytes were statistically identified but not treatment related and lacked a dose response relationship.

The slight changes in urinalysis parameters that were observed in two weeks i.e. increased urine pH in male rats exposed to 3000 ppm PGME but these changes were not apparent in this study following 6, 12, 18, and 24 months of exposure. There were no treatment related effects evident in urinalysis including microscopic examinations of urine micro sediment from male and female rats.

There were no changes observed in organ weights related to PGME exposure.There were no gross pathological findings attributable to PGME exposure in male and female rats. The gross lesions observed were generally distributed across all groups or occurred sporadically and were typical for rats of this age and strain.

There were no histopathological findings attributable to PGME exposure in male and female rats. The histopathological lesions observed were generally distributed across all groups or occurred sporadically and were typical for rats of this age and strain. The major toxicological effects of exposure were observed in the liver and kidneys. Effects of lesser importance were observed in nasal tissues and lungs. The clinical pathology data did not indicate significant treatment related hepatotoxicity. The lack of dose response in the incidence of tumors in males does not suggest a treatment related effect.

 In conclusion, PGME did not cause a dose related increase in tumors in male and female rats exposed to 0, 300, 1000 and 3000 ppm PGME vapors for 6 hours/day, 5 days/week for up to 2 years. A NOEL of 300 ppm PGME was established for this study.

 

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEC
1 650 mg/m³
Study duration:
subacute
Species:
rat
Quality of whole database:
Good (Klimisch 2)

Repeated dose toxicity: inhalation - local effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
1981
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: This study was conducted in accordance with GLP and similar to OECD gudeline 412.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River laboratories, Portage, MI
- Age at study initiation: Approximately 9 weeks
- Weight at study initiation: Approximately 100-160 gms
- Fasting period before study: None
- Housing:
- Diet (e.g. ad libitum):
- Water (e.g. ad libitum):
- Acclimation period: Yes (Not exactly specified in the report)


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


:
Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
See the attachment-1
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
See the attachment-1
Duration of treatment / exposure:
9 days
Frequency of treatment:
Six hours/day for a total of 9 days during an 11-day interval
Remarks:
Doses / Concentrations:
300 ppm
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
1000 ppm
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
3000 ppm
Basis:
nominal conc.
No. of animals per sex per dose:
5/sex/concentration
Control animals:
yes
Details on study design:
- Rationale for animal assignment: Random
- Post-exposure recovery period in satellite groups: No
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
DETAILED CLINICAL OBSERVATIONS: No

BODY WEIGHT: Yes
- Time schedule for examinations: immediately prior to first exposure and immediately prior to 3rd, 6th and 9th exposures.

HAEMATOLOGY: Yes
- Time schedule for collection of blood: immediately prior to sacrifice
- Anesthetic used for blood collection: Yes (Methoxyflurane)
- Animals fasted: Yes
- How many animals: 20 male and 20 female
- Parameters checked in table [No.5] were examined.


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: immediately prior to sacrifice
- Animals fasted: Yes
- How many animals: Yes
- Parameters checked in table [No.7] were examined.


URINALYSIS: Yes
- Time schedule for collection of blood: immediately prior to sacrifice

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
Each animal was anesthetized with methoxyflurane, decapitated. Weights of kidneys, liver, heart spleen, thymus and testes were recorded for each animal.
HISTOPATHOLOGY: Yes
Nasal tissues, lungs, liver, kidneys, thymus and bone marrow in the control and high exposure groups were examined microscopically. Tissues from animals in the high exposure group which were thought to have treatment related effects were also examined for animals in the low and middle dose groups.
Other examinations:
Organ weights: Weights of kidneys, liver, heart spleen, thymus and testes were recorded for each animal.
Statistics:
Body weights, organ weights, hematology data and clinical chemistry data were analyzed according to a statistical routine including Bartlett's test (p <0.05), ANOVA (p<0.10) and either Wilcoxon's or Dunnett's test depending on whether or not the data was non-homogenous or homogenous. Specific gravity of urine was analyzed by ANOVA and Dunnett's test (p<0.05).

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:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
effects observed, treatment-related
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:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY: There were no mortalities prior to scheduled sacrifice and no unusual clinical observations during the study for rats. All animals appeared normal and good in health throughout the course of the study.


BODY WEIGHT AND WEIGHT GAIN: Growth of male and female rats was not significantly altered by exposure to test material. The mean body weights of treatment groups of rats were not statistically different from controls at any time during the course of the study.


HAEMATOLOGY: There were no statistically significant changes in the hematologic parameters of male rats while, in female rats, there was only one sporadic statistical difference which was unrelated to exposure (increased mean PCV for females in 1000 ppm group).


CLINICAL CHEMISTRY: clinical chemistry analyses for rats were, in general unremarkable. The mean serum urea nitrogen values for male rats in the 1000 and 3000 ppm groups and the mean total bilirubin for male rats in the 1000 ppm group were statistically significantly lower than for controls. These results in male rats were clearly not diagnostic of treatment related abnormalities, and were of no toxicological significance. There were no statistically significant changes in the clinical chemistry parameters of female rats.


URINALYSIS: Urinalyses for male and female rats revealed no statistically significant abnormalities. However, the mean urinary specific gravity values for both male and female rats in the 3000 ppm group tended to be lower than controls, although not statistically significant.

ORGAN WEIGHTS: The mean relative liver weights of male rats in the 3000 ppm group was statistically significant higher than the controls, possibly as a result of exposure to the test material. However, the toxicological significance of this observation, if any is uncertain in view of the absence of any gross or histopathologic changes in livers of these animals. The mean relative spleen weight of male rats in the 300 ppm group was also statistically significantly higher than the controls. This was thought to be sporadic occurrence not related to exposure. There were no statistically significant changes in absolute or relative organ weight of female rats.


GROSS PATHOLOGY: The only observation which is suggestive of an association with PMA is slightly reticulated appearance of kidneys in the all male rats at the 3000 ppm exposure level and 2 of 5 male rats in 1000 ppm exposure group. All other observations in both male and female rats are considered spontaneous and incidental.


HISTOPATHOLOGY: Slight renal changes were observed histologically an all 5 male rats in the 3000 ppm group and in 1 of 5 male rats at the 1000 ppm level. The change noted in these animals was a slight increase in the eosinophilic granularity of the proximal convoluted tubules of the kidneys. This was consistent with the slight reticulated appearance of the kidneys noted grossly; only a segment of nephrons was affected, and that segment is most abundant in the outer cortical region. The proximal convoluted tubules of male Fisher 344 rats normally have a prominent degree of eosinophilic granularity in contrast to female rats or even male rats of other strains. The change noted in this study was an increased number and prominence of this normally occurring granularity, which accounts for the fact that similar changes were not seen in the female rats. Hence, it is uncertain whether the changes in the kidneys of male rats exposed to PMA are a toxicologic response or a physiologic manifestation.


Dose descriptor:
NOAEL
Effect level:
300 ppm
Sex:
male/female
Basis for effect level:
other: overall effects
Dose descriptor:
LOAEL
Effect level:
1 000 ppm
Sex:
male/female
Basis for effect level:
other: overall effects
Critical effects observed:
not specified
Conclusions:
Based on the results of this study NOAEL for rats in this study is 300 ppm.
Executive summary:

Male and female Fischer 344 rats were exposed to 0, 300, 1000 and 3000 ppm (0, 1.62, 5.39 and 16.18 mg/l) Dowanol PM Acetate vapors 6 hours per day for a total of 9 days during an 11-day interval. There were no mortalities prior to scheduled sacrifice and all animals appeared normal and in good health during the course of the study. The exposures had no effect on growth of either rats and there were no pronounced effects on the weights of liver, kidneys, heart, spleen, thymus or testes of rats. Exposure to 3000 ppm may have had some slight effect on the liver of male rats, as indicated by statistically significant increase in the mean relative weight in this group. However, there were no treatment related gross or histopathologic changes in livers of rats.

 

Hematologic analyses for rats revealed only slight changes judged to be of no toxicologic significance. There were no changes in clinical chemistry parameters of rats which were diagnostic of treatment related adverse effects.

 

Urinalyses revealed a tendency toward lower urinary specific gravity values for male and female rats in the 3000 ppm group and the kidneys of all male rats in the 3000 ppm group and 2 of 5 male rats in 1000 ppm group had a reticulated appearance when examined during necropsy. An increased degree of normally occurring eosinophilic granularity with uncertain toxicologic significance was noted in all male rats in the 3000 ppm group as well as in 1 of 5 male rats in the 1000 ppm group. Exposure related changes were also observed histopathologically in olfactory portions of the nasal mucosa in some rats in the 3000 ppm group exposure level. No exposure related gross or histopathologic effects were identified in either male or female rats in the 300 ppm group or in female rats in the 1000 ppm group.

Based on the results of this study NOAEL for rats in this study is 300 ppm.

 

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEC
1 650 mg/m³
Study duration:
subacute
Species:
rat
Quality of whole database:
good

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: dermal
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
supporting study
Study period:
1949
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The study was conducted prior to GLP and test guidelines
Justification for type of information:
Please refer to category document.
Qualifier:
no guideline available
GLP compliance:
no
Limit test:
no
Species:
rabbit
Strain:
not specified
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Diet (e.g. ad libitum): Commercial rabbit chow ad libitum
- Water (e.g. ad libitum): ad libitum
Type of coverage:
occlusive
Vehicle:
water
Details on exposure:
TEST SITE
Test substance was applied over the abdominal skin using the following technique: a pad of adsorbent cotton about 3" x 3" in size and sufficiently thick to just adsorb the volume of the test material was applied to the clipped or shaved abdomen of the rabbit. The proper dose of the compound was added to the cotton and the pad then covered with an impervious saran film about 5"x 5". This saran was covered with a heavy cloth and the whole application was strapped onto the animal with adhesive tape. The compound was applied five times a week over a period of three months.


TEST MATERIAL
The compound was tested at four dose levels-2, 4, 7 and 10 cc/kg

VEHICLE
The control animals also received the babdaging plus the application of distilled water to the cotton


Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
3 months
Frequency of treatment:
5 times a week
Remarks:
Doses / Concentrations:
2.0 cc/kg
Basis:

Remarks:
Doses / Concentrations:
4.0 cc/kg
Basis:

Remarks:
Doses / Concentrations:
7.0 cc/kg
Basis:

Remarks:
Doses / Concentrations:
10.0 cc/kg
Basis:

No. of animals per sex per dose:
Control-5
2 cc/kg- 6
4 cc/kg- 7
7 cc/kg- 9
10 cc/kg- 11
Control animals:
yes, concurrent no treatment
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: No data

DERMAL IRRITATION (if dermal study): Yes

BODY WEIGHT: Yes

HAEMATOLOGY: Yes
- Control blood counts were taken before the start of the study and on the thirtieth and nintieth day of the application of the compounds
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- Parameters checked in attached table-Haematology data were examined.

CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Tissues taken from the liver, kidney, spleen, adrenal, heart, lung and occasionally stomach for histological examination. Such sections were stained with haematoxylin and eosin.
Statistics:
Possible significance between means was studied by student's test of t.
Clinical signs:
effects observed, treatment-related
Dermal irritation:
no effects observed
Mortality:
mortality observed, treatment-related
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:
no effects observed
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
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:
not specified
Histopathological findings: neoplastic:
not specified
Details on results:
CLINICAL SIGNS AND MORTALITY
The repeated application of large doses of propylene glycol methyl ether (7 and 10 cc per kilo) produced narcosis which generally lead to the death of the animal.

BODY WEIGHT AND WEIGHT GAIN
The repeated application of the test compound in doses between 1 and 5 cc per kilo was without effect on the gain in weight of the rabbits. Animals who became narcotized and died because of larger doses showed a terminal loss in weight, probably related to a decreased food consumption at this time. Animals that survived the large doses gained weight normally.

HAEMATOLOGY
There was no effect on the haemoglobin, red blood cell or white blood cell count or on the differential count.

ORGAN WEIGHTS
Liver and kidney weight was normal except for an increase in renal weight obtained with the 10 cc per kilo dose of the test compound

GROSS PATHOLOGY
There was no significant effect on the gross appearance of the organs of the rabbits

Skin
Control animals receiving abdominal applications of water showed various degrees of erythema, scaling and occasionally slight exudation of the skin in this area. Reactions of a similar severity were seen in animals receiving the test compound but were not greater than that produced by water alone.
Dose descriptor:
NOAEL
Effect level:
4 600 mg/kg bw/day
Sex:
male/female
Basis for effect level:
other: systemic effects
Critical effects observed:
not specified
Conclusions:
Propylene glycol methyl ether was studied to ascertain systemic effects when applied locally to the skin of rabbits for a period of 90 days.
Propylene glycol methyl ether did not produce any significant systemic effects when applied locally to the skin of rabbits for a period of 90 days.

Executive summary:

Propylene glycol methyl ether was studied to ascertain systemic effects when applied locally to the skin of rabbits for a period of 90 days.

 

Male rabbits were selected and divided into groups of five animals each. The test compound was applied to the abdominal skin five times a week over a period of three months. The compound was tested at four dose levels (2, 4, 7 and 10 cc/kg). A separate group of five animals served as controls and received distilled water.

 

The rabbits received a stock diet of commercial rabbit chow and water ad libitum. The rabbits were weighed before the application of daily dose of the compounds. Control blood counts were taken before the start of the study and on the thirtieth and ninetieth day of the application of the compound. On the 90thday the rabbits were autopsied and tissues taken from the liver, kidney, spleen, adrenal, heart, lung and occasionally stomach for histological examination. Such sections were stained with haematoxylin and eosin.

 

The repeated application of large doses of propylene glycol methyl ether (7 and 10 cc per kilo) produced narcosis which generally lead to the death of the animal. The repeated application of the test compound in doses between 1 and 5 cc per kilo was without effect on the gain in weight of the rabbits. Animals who became narcotized and died because of larger doses showed a terminal loss in weight, probably related to a decreased food consumption at this time. Animals that survived the large doses gained weight normally. There was no effect on the haemoglobin, red blood cell or white blood cell count or on the differential count. There was no significant effect on the gross appearance of the organs of the rabbits Liver and kidney weight was normal except for an increase in renal weight obtained with the 10 cc per kilo dose of the test compound.

 

Control animals receiving abdominal applications of water showed various degrees of erythema, scaling and occasionally slight exudation of the skin in this area. Reactions of a similar severity were seen in animals receiving the test compound but were not greater than that produced by water alone.

 

Propylene glycol methyl ether did not produce any significant systemic effects when applied locally to the skin of rabbits for a period of 90 days.

                                               

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
2 675 mg/kg bw/day
Study duration:
subchronic
Species:
rabbit
Quality of whole database:
acceptable

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Additional information

Data on PGMA: 3 repeated dose toxicicty studies are available for PGMA, an OECD 422 (in rats) via the oral route, two 9 -day inhalation studies (mice and rats) and a 4 -day inhalation study in mice and rats. Oral data: In the OECD 422, the highest dose tested (1000 mg/kg bw) was the NOAEL for repeated dose toxicity and reproductive/developmental effects in both sexes. Inhalation: In the 9 -day inhalation study in rats there were minimal toxicological effects observed. At the high dose group (3000ppm) there was a small but statistically significant increase in liver weight. This was not associated with any histopathological or clinical chemical signs of an adverse effect and was likely an adaptive response.

Urinalyses revealed a tendency toward lower urinary specific gravity values for male and female rats in the 3000 ppm group and the kidneys of all male rats in the 3000 ppm group and 2 of 5 male rats in 1000 ppm group had a reticulated appearance when examined during necropsy. An increased degree of normally occurring eosinophilic granularity with uncertain toxicologic significance was noted in all male rats in the 3000 ppm group as well as in 1 of 5 male rats in the 1000 ppm group. Exposure related changes were also observed histopathologically in olfactory portions of the nasal mucosa in some rats in the 3000 ppm group exposure level. No exposure related gross or histopathologic effects were identified in either male or female rats in the 300 ppm group or in female rats in the 1000 ppm group. Based on the results of this study NOEL for rats in this study is 300 ppm.

In the 9 -day inhalation study in mice, there was minimal evidence of systemic toxicity. Rather the key effect appears to be respiratory irritation, which occurred at all doses (300,1000 and 3000 ppm). As such the LOAEC for local effects was 300 ppm.

A 4 -day inhalation study in mice and rats was performed to assess whether the difference in irritation response to PGMA was a consequence of different breathing rates during exposure. Specifically, did rats or mice modify their breathing rates to differing degrees during exposure. Althought he study showed that both mice and rats did adjust their breathing rates during exposure, there was no evidence that this led to the more severe degree of irritation observed in mice compared to rats. Therefore it is concluded that mice are more sensitive to this effect compared to rats. It is possible this could be due more active metabolism of PGMA to PGME and acetic acid in the mice, leading to greater concentrations of the irritant acetic acid. The LOAEC for irritation in the upper respiratory tract is therefore 300 ppm in mice. In rats the NOEC is 1000 ppm.

There are no sub-chronic or chronic toxicity studies available for PGMA, however as indicated in the category document attached at section 13 of the IUCLID and briefly summarised here, read across of data from PGME is proposed to address the sub-chronic endpoint.

Data on PGME:

Several studies confirm that rapid and extensive hydrolysis of propylene glycol methyl ether acetate (PGMA) to propylene glycol methyl ether (PGME) occurs in vivo when PGMA is administered by the oral, inhalatory or dermal route. Since urinary metabolites and disposition profiles of PGMA were approximately identical to the results obtained with PGME, it is unlikely that there are substantial differences of the systemic toxicity between PGMA and PGME. See attached category document in Section 13 for read-across justification.

Inhalation

Rat

In a 2-week study by inhalation (not GLP) rats were exposed to PGME 5h/day 5d/week at doses of 2500, 5000 and 10000 ppm (9.4 – 18.7 – 37.5 mg/l) (Goldberg et al., 1964). Animals in the 5000 and 10,000 ppm group displayed a transient nonspecific depression of behaviour for the first several exposures, followed by rapid development of tolerance. Decreased growth rate was seen at 10,000 ppm. In this study the NOAEC was 2500 ppm for behavioural effects (acute narcotic effects) and 5000 ppm for general RDT toxicity..

In a GLP two-week study by inhalation route, PGME was administered to Fischer 344 rats (9 exposures) at doses of 0, 300, 1000 and 3000 ppm (0 - 1.1 – 3.75 – 11.2 mg/l) (Miller et al., 1981). No deaths occurred during PGME exposure. Rats in the 3000 ppm groups appeared to be anaesthetised or sedated during exposure. There were no gross pathologic observations or histopathologic changes in the liver or kidneys in all groups. Liver weights of rats in the 3000 ppm group were higher than controls.,. The NOAEC in this study was 1000 ppm based on effects seen at 3000 ppm.

In a two-week study by inhalation (9 exposure in 11 days), Fischer 344 rats were exposed to an unique 3000 ppm (11.2 mg/l) concentration of PGME (Stott, 92). A control untreated group was also included. Exposure to 3000 ppm produced sedation in male and female rats during the first week of exposure. Resolution of sedation correlated with increases in relative liver weights. Increases in the rate of hepatocellular proliferation (mitotic response) was observed after the first week in male rats. No other histopathologic changes were noted in the livers of exposed rats. Relative kidney weights of both sexes were slightly, but statistically increased, following two weeks of exposure. Kidney weight changes in males was accompanied by the deposition of alpha 2µ-globulin characteristic of male rat specific “protein droplet nephropathy”.

In a GLP 13-week study by inhalation route (performed according to OECD guideline 413) Fischer 344 rats were exposed to PGME at doses of 300, 1000 and 3000 ppm (1.1 – 3.75 – 11.2 mg/l), 6h daily and 5 d/week (Landry et al., 1983). No treatment related effects were found in animals exposed to 300 or 1000 ppm. At 3000 ppm clinical observations indicated a transient central nervous system depression, relative liver weight increased slightly concomitant with non degenerative (adaptive) histological effects. Body weight gain was slightly decreased in females. For this study the NOAEC was 1000 ppm.

In a GLP study, Fischer 344 rats were exposed by inhalation to PGME during 13 weeks 6 hours daily and 5 days/week at doses of 0 – 300 and 3000 ppm (1.1 – 11.2 mg/l) (Cieszlak et al., 1996). Exposure to 3000 ppm produced sedation in male and female rats during first week of exposure that was ameliorated by increased hepatic mixed function oxidase activity and hepatocellular proliferation which is a normal physiologic adaptation to increased metabolic demand. No sedation or adaptive hepatic effects were observed at 300 ppm. A male rat specific alpha 2µ-globulin nephropathy was observed at 3000 ppm and to a slight extent at 300 ppm. PGME produced effects at all doses in males leading to a LOAEC of 300 ppm. In females the NOAEC was 300 ppm.

In a 6 month study performed on rats by inhalation route, PGME was administered during 7h/day 5d/week (Rowe et al., 1954). A NOAEC greater than 1500 ppm was observed.

In a chronic GLP toxicity/carcinogenicity study (see section 4.1.2.8), animals were exposed 2 years at PGME concentrations of 0, 300, 1000 and 3000 ppm (0 - 1.1 – 3.75 – 11.2 mg/l) (Cieszlak et al., 1998a). PGME-induced sedation at 3000 ppm resolved in all animals during the second week of exposure in conjunction with the appearance of adaptive changes in the liver (MFO induction and hepatocellular proliferation-from previous work). MFO activities (PROD) subsequently dropped to near control values by week 52, coinciding with a return of sedation at 3000 ppm PGME. In male rats, the loss of metabolic adaptation was followed by a dose-related increase in eosinophilic foci of altered hepatocytes after two years of exposure to 1000 or 3000 ppm PGME. Kidney toxicity was observed in male rats only, which was confirmed immunohistochemically as an alpha 2µ-globin nephropathy. The 300 ppm exposure level was established as an NOAEL in rats based on liver effects.

Mouse

B6C3F1 mice were exposed to PGME by inhalation route at concentrations of 0, 300, 1000 and 3000 ppm (0 - 1.1 – 3.75 – 11.2 mg/l) 6h/day during 11 days (9 exposure) (Miller et al., 1981). This test was performed according GLP. No deaths occurred during PGME exposure. Mice in the 3000 ppm groups appeared to be anaesthetised or sedated during exposure. There were no gross pathologic observations or histopathologic changes in the liver or kidneys in all groups. All affected parameters (relative liver weight of female mice at 3000 ppm) recovered to normal levels after 6 weeks. In this study the NOAEC was 1000 ppm based on effects seen at 3000 ppm.

PGME was administered by inhalation during 2 weeks (9 exposures in 11 days) to B6C3F1 mice at doses of 0 and 3000 ppm (11.2 mg/l) 6 hours daily (Stott, 92). Exposure to 3000 ppm produced sedation in male and female mice during the first week of exposure. Resolution of sedation correlated with increases in relative liver weights. Increases in the rate of hepatocellular proliferation (mitotic response) was observed after the first week in both sexes, and after the second week of exposures in females. No other histopathologic changes were noted in the livers of exposed mice.

In a GLP study, B6C3F1 mice were exposed by inhalation to PGME during 13 weeks 6 hours daily and 5 days/week (Cieszlak et al., 1996). Two groups were evaluated in this study: a first subgroup for standard subchronic toxicity assessment and dosed with 0, 300, 1000 or 3000 ppm (0 - 1.1 – 3.75 – 11.2 mg/l) and a second subgroup evaluated for enzyme induction and cellular proliferation (dose levels: 300 and 3000 ppm). Exposure to 3000 ppm produced sedation in male and female mice during the first three days of exposure. An accelerated atrophy of the X zone of the adrenal gland of female mice was observed at 3000 ppm and to a very slight degree at 1000 ppm. A slight numerical increase in renal and hepatic cellular proliferation, significantly increased hepatic enzyme induction was observed at 3000 ppm in both sexes; increased liver weight (females only) was also observed at 3000 ppm. No effects were observed at 300 ppm. The NOAEC in this study was 1000 ppm (whichever the subgroup). Atrophy of the X-zone of the adrenal gland was described as an age related event in mice and was considered to be a non-specific, non adverse effect.

In a chronic GLP toxicity/carcinogenicity study (see section 4.1.2.8), animals were exposed 2 years at PGME concentrations of 0, 300, 1000 and 3000 ppm (0 - 1.1 – 3.75 – 11.2 mg/l) (Cieszlak et al., 1998b). A transient sedation of mice inhaling 3000 ppm PGME during the first week of exposures was observed; however, this resolved during the second week concomitant with adaptive changes in the livers of these animals (previous study results). Mice exposed to 3000 ppm had increased mortality (males), decreased in-life body weights and body weight gains relative to controls, over much of the exposure period, as well as minimal increases in absolute and relative liver weights and hepatic MFO activity. No treatment-related histopatholgical changes accompanied these liver effects, nor were histopathological changes observed in any other tissues. These data, along with the occurrence of chronic, albeit small increases in hepatocellular proliferation in mice inhaling 3000 ppm suggested minimal regenerative response in the liver, likely related to shorted life span metabolically stressed hepatocytes. Minimal decreases in body weights (average 3%) were also observed, in both sexes exposed to 1000 ppm but less consistently than in the high exposure mice. A NOAEL of 1000 ppm was established based on an increased mortality in the high dose (3000 ppm) male group that may have been related to minimal liver toxicity. Effects seen on the body weight were not taken into account because they were minimal and not accompanied with other toxicological effects.

Rabbit

In a 3-6 months inhalation study performed on rabbits, PGME was administered at doses of 800, 1500, 3000 and 6000 ppm (3 – 5.6 – 11.2 – 22.3 mg/l) 7h/day, 5d/week (Rowe et al., 1954). Toxicological effects from repeated vapour exposures were Slightly increased liver weights in females and slight histological changes of liver and lungs at 1500, 3000 and 6000 ppm (no histological changes of the liver for the only animal of the 6000 ppm group. There were no observable treatment-related effects with repeated exposure to 800 ppm. In this study, the NOAEC was 800 ppm based on effects seen at 1500 ppm.

In a 13-week study by inhalation route, rabbits were exposed to PGME by inhalation route at doses of 0, 300, 1000 and 3000 ppm (0 - 1.1 – 3.75 – 11.2 mg/l), 6 hours daily and 5d/week (Landry et al., 1983). This test was performed according to OECD guideline 413 and was GLP. No treatment related effects were found in animals exposed to 300 or 1000 ppm. At 3000 ppm clinical observations indicated a transient central nervous depression and serum alkaline phosphatase was increased. The NOAEC was 1000 ppm based on effects seen at 3000 ppm.

Summary inhalation route :

In the majority of the studies, transient CNS depression was seen at doses of 3000 ppm leading to a NOAEL of 1000 ppm for this effect (acute effect). In rats evidence of specific male nephropathy was noticed in almost all studies, this effect is not relevant for human and will therefore not be taken into account for the risk assessment. The main toxicological effects noticed in rats were liver effects: increases in liver and relative liver weight, induction of hepatic enzyme and cellular proliferation. Concerning this effect, a NOAEC of 300 ppm (1122 mg/m3) is derived from a well performed 2-year rat study.

Dermal

In a 21 day dermal study, New Zealand White rabbits were applied daily a dose of 0 or 1000 mg/kg PGME (15 applications) (Calhoun and Johnson, 1984). Rabbits receiving 1000 mg/kg PGME showed no signs of systemic effects in various parameters including hematologic analysis and histopathology. The only treatment related effect was slight scaling and minimal inflammation with a protective thickening response of the skin. In this study the NOAEL was not determined due to the effect seen at the only dose tested.

In a 90 day dermal study, rabbits were administered PGME at doses of 0 to 10 ml/kg 5d/week (Rowe et al., 1954). Larger doses (7 to 10 ml/kg) produced narcosis which generally led to the death of the animal (8/9 deaths at 7 ml/kg, 11/11 deaths at 10 ml/kg). Repeated applications in doses of 1 to 5 ml/kg were generally without effect. Histologic examination of tissues of surviving animals were within normal limits. Slight narcosis at 3676 mg/kg (4 ml/kg) was observed. In this study a NOAEL of 2 ml/kg bw was taken regarding the effects seen at 4 ml/kg bw.

Oral

Rat

In a 35 day study by oral route, rats were administered PGME by gavage at doses of 0, 91.9, 275.7, 919 and 2757 mg/kg (Rowe et al., 1954). No mortalities were found. At 2757 mg/kg, some animals initially lost body weight, but they recovered quickly. The final body weight was not significantly different from that of controls. 2757 mg/kg produced only minor effects on liver and kidney.

In a 13 weeks oral route study, CFE rats were exposed to PGME at concentrations of 459.5, 919, 1836 and 3672 mg/kg (Stenger et al., 1972). Mild to severe central nervous system depression was observed. This caused a growth depression due to reduced feed intake. Livers were enlarged, especially at doses > 919 mg/kg. Cell necrosis was observed, mainly in the peripheral portions of the lobules. There was minor kidney injury at higher doses. In this study, no NOAEL could be identified because effects were seen at the lowest dose tested (459.5 mg/kg).

Rabbit

Three rabbits were dosed orally with 1840 mg/kg/d of PGME (BASF, 65). Only three animals were used for this study. One animal died after 9 applications. The treatment led to a slight decrease of erythrocytes and lymphocytes. PGME had no effect on the testes.

Dog

Male Dogs were feed orally with PGME at doses of 0.5; 1; 3 and 3 ml/kg/d (459.5; 919; 1836 and 3672 mg/kg) for a period of 14 weeks (5 treatments a week) (Stenger et al., 1972). Mild to severe central nervous system depression in a dose-related manner was observed. Male dogs developed numerous spermiophages in the epididymis. There were minor kidney changes at higher doses. In this study the NOAEL was found to be lower than 459.5 mg/kg based on effects seen at 459.5 mg/kg. As no data is available on purity, the relevance of spermiophages in the epididymis is unclear. As this effect was not seen in the well performed fertility studies and only in dogs in this study it can be consider to be not related to PGME.

Summary RDT oral route:

Only four studies were performed to assess the repeated dose toxicity properties of PGME by oral route. None was made according GLP and guidelines. Overall for oral route, a LOAEL of 460 mg/kg can be taken into account (from a rat and a dog study) based on slight CNS depression seen from this dose in rats and dogs (13-week study for rats and 14-week study for dogs) and a NOAEL of 919 mg/kg by oral route for systemic effects (hepatic effects).

For the Risk characterisation of PGMA, the Inhalation NOAEL of 300 ppm could be taken into account for systemic effects based on the 2-year rat study performed with PGME and leading to liver effects at doses of 1000 ppm. For local effects, the 9 -day inhalation study using PGMA with a LOAEC of 300ppm is taken forward to the risk characterisation. This is the study used by SCOEL to establish an OEL for this substance. Based on the molecular weight of PGMA, 300ppm is equivalent to approximately 160 mg/m3. In absence of dermal data for PGMA, dermal data on PGME will be used for dermal risk characterisation. Three studies are available to assess effects of repeated dermal exposure to PGME. The only systemic effect seen was narcosis from 3676 mg/kg and higher (moreover this effect can be considered as an acute effect). A 13-week repeated dose dermal toxicity study in rabbits was selected as the most relevant study for the risk assessment. The NOAEL for systemic effects via the dermal route is 1832 mg/kg bw/day. Since this NOAEL comes from a study on an analoge, the NOAEL is adjusted by a factor of 1.46 to account for differences in molecular weight, thus the adjusted NOAEL taken forward to the risk characterisation is: 2675 mg/kg bw. The NOAEL of 1000 mg/kg bw/day from the oral OECD 422 in rats is taken forward as the key study for the oral route.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
The study methodology followed was equivalent or similar to OECD TG 422

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
Read across from PGME and this study duration covered 2 years (longer duration as compared to a 13-week study) and was conducted in accordance with GLP and OECD guideline 453 and TSCA guideline part 798.

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:
Study showing the most sensitive effect - respiratory tract irritation.

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:
provides clear NOAEL.

Repeated dose toxicity: inhalation - systemic effects (target organ) digestive: liver

Justification for classification or non-classification

The no observed adverse effect levels for propylene glycol methyl ether acetate exceed the values triggering classification via all routes of exposure. Therefore no classification for prolonged exposure is required.

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