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Description of key information

Several acute toxicity studies in rats and mice are available for the oral, dermal and inhalation route.  Most studies were not conducted under GLP and or/to OECD guidelines, but were conducted equivalent to OECD guidelines 401, 402 and 403, and therefore have been considered to be valid. 

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1985
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The study methodology followed was equivalent or similar to OECD TG 401
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to other study
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Principles of method if other than guideline:
not applicable
GLP compliance:
yes
Test type:
standard acute method
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 UK
- Age at study initiation: 9-11 weeks old
- Weight at study initiation: Males: 203-244 grams, Females: 130-153 grams
- Fasting period before study: yes, fasted for 18 hours prior to dosing
- Housing: group housed, 2-3 animals/cage
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: yes

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-25 °C
- Humidity (%): not specified
- Air changes (per hr): not specified
- Photoperiod (hrs dark / hrs light): 12 hours light:dark cycle

IN-LIFE DATES: From: April 9, 1985 To: June 7, 1985
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
The test material was administered undiluted
Doses:
1564, 2487, 3955, 5000, 6289 and 10000 mg/kg
No. of animals per sex per dose:
5 males + 5 females
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: daily observation and body weights recorded on days 0, 7 and 14
- Necropsy of survivors performed: no
Statistics:
Finney's probit analysis
Preliminary study:
not applicable
Sex:
male
Dose descriptor:
LD50
Effect level:
6 190 - 10 000 mg/kg bw
Remarks on result:
other: LD50 not calculable
Sex:
female
Dose descriptor:
LD50
Effect level:
5 155 mg/kg bw
95% CL:
3 994 - 6 492
Remarks on result:
other: none
Sex:
male/female
Dose descriptor:
LD50
Effect level:
6 190 mg/kg bw
95% CL:
5 465 - 7 553
Remarks on result:
other: none
Mortality:
1564 mg/kg - no mortality observed (0/5 + 0/5 - 0/10)
2487 mg/kg - no mortality observed (0/5 + 0/5 - 0/10)
3955 mg/kg - no mortality observed (0/5 + 0/5 - 0/10)
5000 mg/kg - 3 females on day 4 (0/5 + 3/5 - 3/10)
6289 mg/kg - 1 female on day 3 and 3 females on day 4 (0/5 + 4/5 - 4/10)
10000 mg/kg - 1, 3 and 1 male on days 1, 2 and 3 and all females on day 1 (5/5 + 5/5 - 10/10)
Clinical signs:
Signs included gait abnormalities, increased lacrimation and/or salivation, unkept appearance and coma, refer to attachment for further details
Body weight:
All surviving animals had gained weight relative to their day 0 body weights by the end of the 14 day observation period
Gross pathology:
no data
Other findings:
- Organ weights: not examined
- Histopathology: not examined
- Potential target organs: not examined

none

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Under the conditions of the study, the LD50 of Methyl Proxitiol Acetate to male F344 rats was 6289-10000 mg/kg (LD50 was not calculable), for females was 5155 mg/kg (3994-6492 mg/kg) and for combined male and female F344 rats was 6190 mg/kg (5465-7553 mg/kg) and hence not classified
Executive summary:

In this acute oral toxicity study, groups of F344 rats (5 males + 5 females) were administered Methyl Proxitol Acetate (undiluted) at doses of 1564, 2487, 3955, 5000, 6289 and 10000 mg/kg and observed for 14 days. Observations were limited to daily recording of clinical signs of toxicity, body weight recording on days 0, 7 and 14. Necropsy was not done on any of the animals (surviving and those dying/found dead during the study). Clinical signs included gait abnormalities, increased lacrimation and/or salivation, unkept appearance and coma during the study period and all surviving animals had gained weight relative to their day 0 body weights by the end of the 14 day observation period. Under the conditions of the study, the LD50 of Methyl Proxitiol Acetate to male F344 rats was 6289-10000 mg/kg (LD50 was not calculable), for females was 5155 mg/kg (3994-6492 mg/kg) and for combined male and female F344 rats was 6190 mg/kg (5465-7553 mg/kg) and hence not classified

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
6 190 mg/kg bw
Quality of whole database:
Good (Klimisch 2)

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
Good (Klimisch 2)

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1980
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: This study was conducted prior to GLP and test guidelines, but sufficient data is available for interpretation of results.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
GLP compliance:
no
Test type:
standard acute method
Limit test:
yes
Species:
rabbit
Strain:
other: New Zealand albino
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMAL
Animal care facility was accredited by the American Association for Accreditation of Laboratory Animal Care
- Source: Langshaw Farms, Augusta, Michigan
- Age at study initiation: not specified
- Housing: Rabbits were housed singly
- Diet (e.g. ad libitum): Commercial laboratory chow (Ralston Purina Company, St. Louis, Missouri) ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 1 week


ENVIRONMENTAL CONDITIONS
- Photoperiod (hrs dark / hrs light): 12-hour light and dark cycle


Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
Twenty-four hours prior to application of the test material, the entire trunk of 2 male and 2 female rabbits was clipped free of hair with electric clippers. The undiluted test material was applied under a heavy-gauge SARAN film sleeve which was held in place with rubber bands. The plastic sleeve was covered by cloth bandage taped securely to the marginal hair. After 24 hours, the sleeves were removed, and the skins were washed with a mild soap and water, rinsed thoroughly and dried with a soft disposable towel. The rabbits were immediately fitted with a plastic collar to prevent them from ingesting any residue of the material which may still be present after washing. The collars were removed at least 72 hours later. The topical response at the site of application was evaluated after removal of the plastic sleeve.


Duration of exposure:
24 hours
Doses:
5000 mg/kg
No. of animals per sex per dose:
2 males and 2 females
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: The animals were observed frequently during exposure and the following two weeks for signs of toxicity. Body weights were recorded before and after the 24 hour exposure period and at 1 and 2 weeks post treatment
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight
Sex:
male/female
Dose descriptor:
LD0
Effect level:
> 5 000 mg/kg bw
Mortality:
No mortality
Clinical signs:
Topical responses observed when the sleeves of test rabbits were removed included very slight (3/4) erythema and slight (1/3) edema. All rabbits were lethargic following dosage
Body weight:
No treatment related changes were observed. Animal gained body weight post treatment.
Gross pathology:
No treatment related lesions were observed upon gross pathological examination of all rabbits at 2 weeks following treatment.
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
As the LD50 value was greater than 5000 mg/kg, the test material is not classified according to EU criteria.
Executive summary:

A sample of Dowanol* PM Acetate also known as Propylene Glycol Methyl Ether Acetate and identified as DPC 203-92 # 3 was submitted for acute percutaneous absorption testing. Male and femalealbino rabbits were used in the study.

 

Twenty-four hours prior to application of the test material, the entire trunk of 2 male and 2 female rabbits/dose level (5000 mg/kg) was clipped free of hair with electric clippers. The undiluted test material was applied under a heavy-gauge SARAN film sleeve which was held in place with rubber bands. The plastic sleeve was covered by cloth bandage taped securely to the marginal hair. After 24 hours, the sleeves were removed, and the skins were washed with a mild soap and water, rinsed thoroughly and dried with a soft disposable towel. The rabbits were immediately fitted with a plastic collar to prevent them from ingesting any residue of the material which may still be present after washing. The collars were removed at least 72 hours later. The topical response at the site of application was evaluated after removal of the plastic sleeve.

 

The animals were observed frequently during exposure and the following 2 weeks for signs of toxicity. Body weights were recorded before and after the 24 hour exposure period and at 1 and 2 weeks post treatment. All rabbits were submitted for a gross pathological examination 2 weeks post treatment.

 

The acute percutaneous absorption LD50 was >5000 mg/kg. Topical responses observed when the sleeves of test rabbits were removed included very slight (3/4) erythema, slight (1/3) edema. All rabbits were lethargic following dosage. No treatment-related lesions were observed upon gross pathological examination of all rabbits at 2 weeks following treatment. As a result test material is not classified according to EU criteria.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
Good (Klimisch 2)

Additional information

The studies selected as key studies are considered to be valid as they are reliable, either without restrictions (Klimisch rating 1) or with some restrictions (Klimisch rating 2). The results of the studies indicate that the acute toxicity of propylene glycol methyl ether acetate in rodents is low. The LD50 values are greater than 5000 mg/kg bw by the oral and dermal route and the LC0 value is greater than 8100 mg/m3 by inhalation.

Oral - The first key study selected is the Shell (1985) study in rats and the LD50 (male and female) is 6190 mg/kg body weight and the second key study is the Dow (1980) study in rats and the LD50 (male) is > 10000 mg/kg body weight and the LD50 (female) is 8532 mg/kg body weight.

Inhalation - These identified key studies are mist/aerosol inhalation studies and the key study selected is the Dow (1985) in rats (head only exposure) and the LC0 is greater than 2000 ppm (duration 3 hours), equivalent to approximately 10800 mg/m3 or 10.8 mg/l. Using Haber's law for converting this 3 -hour exposure to a 4 -hour exposure, the equivalent LC0 value is 8100 mg/m3 or 8.10 mg/l.

Dermal - There are two key studies available - Shell (1985) in rats and Dow (1980) in rabbits. The LD50 in rats is greater than 2000 mg/kg body weight (limit dose tested) and in rabbits, the LD0 is greater than 5000 mg/kg body weight.


Justification for selection of acute toxicity – oral endpoint
The study methodology followed was equivalent or similar to OECD TG 401

Justification for selection of acute toxicity – dermal endpoint
The study methodology followed was equivalent or similar to OECD TG 402

Justification for classification or non-classification

The LD50 values for acute toxicity are greater than 5000 mg/kg bw by the oral and dermal route and the LC0 value is greater than 8100 mg/m3 by inhalation. According to the EU criteria for classification and labeling, propylene glycol methyl ether acetate does not need to be classified for acute toxicity for any route of exposure.

Lethargy was noted in two oral studies, one Key study (Dow, 1980c) and one Supporting study (Dow, 1980d), in Fischer rats, supporting classification of PGMEA under Specific Target Organ Toxicity - Single Exposure, Category 3. The noted lethargy was transient and narcotic effects are considered to be of low hazard potential; therefore, no DNEL specific to this transient effect is required.