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Repeated dose toxicity: dermal

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Administrative data

Endpoint:
short-term repeated dose toxicity: dermal
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Study period:
1984
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: This study was conducted in accordance with GLP and equivalent to OECD guideline 410.
Justification for type of information:
Please refer to category document.

Data source

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

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)
GLP compliance:
yes
Limit test:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
1-methoxypropan-2-ol
EC Number:
203-539-1
EC Name:
1-methoxypropan-2-ol
Cas Number:
107-98-2
Molecular formula:
C4H10O2
IUPAC Name:
1-methoxypropan-2-ol
Details on test material:
- Name of test material (as cited in study report): Propylene Glycol Monomethyl Ether (PGME)
- Molecular weight (if other than submission substance): 90.1
- Physical state: Colorless liquid
- Analytical purity: 94.75 %
- Lot/batch No.: #EH8310.18
- Specific gravity: 0.919 @25°C

Test animals

Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Hazelton Dutchland, Inc, Denver, PA
- Age at study initiation: Approximately 4 and half month
- Weight at study initiation: Approximately 2951 gms to 2990 gms
- Housing: Rabbits were housed individually in wire bottom cages
- Diet ( ad libitum): Certified laboratory Rabbit Chow (Ralston Purina Company, st. Louis, MO)
- Water ( ad libitum): Rabbits were provided with tap water
- Acclimation period: 14 days


ENVIRONMENTAL CONDITIONS
- Temperature (°F): 66-70 °F
- Humidity (%): 40-60 %
- Photoperiod: (12 hrs dark / 12 hrs light)



Administration / exposure

Type of coverage:
occlusive
Vehicle:
water
Details on exposure:
Route of Administration: dermal
TEST SITE
- Area of exposure: Back of rabbit
- % coverage: An area of skin approximately 10 by 10 cm on the back of each rabbit
- Type of wrap if used: The test material was applied to the clipped area under a bandage of porous gauze and non absorbent cotton. The bandage was held in contact with the skin by a flannel wrap taped securely to the test animal.
- Time intervals for shavings or clippings: Weekly

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): One group received a daily application of 1000 mg undiluted PGME/kg body weight and control group received a daily application of water equivalent in volume to the PGME dose.


Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
Not specified in the report
Duration of treatment / exposure:
21 days (total of 15 applications)
Frequency of treatment:
1 application/day
Doses / concentrations
Remarks:
Doses / Concentrations:
1000 mg/kg
Basis:
nominal per unit body weight
No. of animals per sex per dose:
5 animals/sex/dose
Control animals:
yes
Details on study design:
Post-exposure period: no data
- Rationale for animal assignment : random
- Post-exposure recovery period : None

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
Time schedule: Daily
DETAILED CLINICAL OBSERVATIONS: No
DERMAL IRRITATION (if dermal study): No
BODY WEIGHT: Yes
Time schedule for examinations: Weekly
FOOD CONSUMPTION: Yes
Time schedule for examinations: 3 times in a week
WATER CONSUMPTION: No
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: Yes
- Time schedule for collection of blood: Immidiately prior to 14th application
- Anesthetic used for blood collection: No data
- Animals fasted: No
- How many animals: 10 males and 9 females
- Parameters checked in table [No.5] were examined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Immediately prior to necropsy
- Animals fasted: Yes
- How many animals:10 males and 9 females
- Parameters checked in table [No.4] were examined.

URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: No



Sacrifice and pathology:
GROSS PATHOLOGY: Yes
After 21 days on study, each surviving rabbit was anesthetized with carbon dioxide, weighed and killed by decapitation after trachea was clamped to prevent aspiration of blood. A gross pathologic examination was performed on each animal. Following examination, the brain, liver, kidneys, adrenals and testes were removed and weighed. Representative sections of the organs were collected and preserved in neutral phosphate buffered 10 % formalin.
HISTOPATHOLOGY: Yes
Hematoxylin and eosin stained sections of paraffin embedded tissues were prepared. Following tissues were examined microscopically from all animals. Liver, gallbladder, kidneys, thymus, spleen, testes, treated and non treated skin as well as a few additional tissues as lungs, pancreas and skin.
Other examinations:
Organ weights: At autopsy weights of liver and kidneys, Lung, brain, adrenal and testes weights were weighed.
Statistics:
Body weight, clinical chemistry, selected hematology, organ weight and organ to body weight ratio data were analyzed by Bartlett's test for equality of variance. Based on the outcome of Bartlett’s test, a parametric or non parametric analysis (ANOVA) was performed. This was followed by Dunett’s test or the Wilcoxon Rank sum test with Bonferroni's correction if ANOVA indicated significant differences between groups.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Dermal irritation:
effects observed, treatment-related
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
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:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY: There were no mortalities during the course of the study which were related to exposure to PGME.One control female died on the day prior to the scheduled termination. Based upon gross and histopathologic examination, the cause of death was severe inflammation of the cecum, appendix, sacculus rotundus and proximal colon. The only clinical observation attributed to treatment with PGME was slight exfoliation on the backs of all rabbits at the application sight.
BODY WEIGHT AND WEIGHT GAIN: There were no significant differences in body weights between control and treated animals.
FOOD CONSUMPTION: There were no significant differences in food consumption between control and treated animals.
HAEMATOLOGY: There were no changes observed which were considered to be a result of treatment with PGME. RBC, Hb and PCV data for female rabbits exposed to 1000 mg/kg/day PGME were statistically increased and platelets were statistically decreased relative to concurrent values. These differences were considered to be sporadic occurrences unrelated to treatment. Hematology data for male rabbits were unremarkable.

CLINICAL CHEMISTRY: There were no significant differences in clinical chemistry parameters between control and treated animals.
ORGAN WEIGHTS: Statistically significant decreases from control values were observed in both absolute and relative kidney weights of female rabbits exposed to PGME. This pattern was not observed in male rabbits nor were there any histopathologic changes in the kidney suggestive of a treatment related effect.Furthurmore, as previously stated there were no changes in clinical chemistry data to indicate an effect on renal function.

GROSS PATHOLOGY: The only gross lesion attributed to treatment to treatment was a slight amount white scales present on the back at the site where PGME was applied. This effect was noted in all rabbits, males and females treated with 1000 mg/kg/day of PGME.


HISTOPATHOLOGY: The only histopathologic effect attributed to treatment with PGME was also noted in the skin. All treated rabbits had a mild response at the site of treatment characterized by very slight thickening of epidermis and very slight accumulations of keratinized, hyperkeratosis. Additionally, 3 of 5 treated rabbits of each sex had a slight inflammatory response characterized as accumulations of mixed inflammatory cells in the superficial dermis. These effects were confined to the treated portion of the skin. The non treated site had no effects attributed to PGME applications. Some control and treated rabbits had focal skin lesions that were attributed to the bandaging tecqniques.Typically, these were linear, transversely oriented lesions located on the lateral or ventral aspect of the trunk where the bandages had been secured with tape. The skin effects attributed grossly to bandaging were examined histopathologically and found to consist of inflammation. degeneration and other protective effects which were generally slightly more severe than the effects attributed to treatment with PGME at the application site. No systemic toxicity resulted from dermally exposing male and female New Zealand white rabbits to 1000 mg/kg/day PGME 15 times in a 21 day period.


Effect levels

Dose descriptor:
NOAEL
Effect level:
> 1 000 mg/kg bw/day
Sex:
male/female
Basis for effect level:
other: overall effects

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Based on the results of this study NOAEL for systemic effects in male and female rabbits is > 1000 mg/kg bw/day via dermal route.
Executive summary:

Two Groups of male and female New Zealand White rabbits were received 15 dermal applications of 0 mg/kg/day (water control) or 1000 mg/kg/day PGME (colorlesss liquid) for a period of 21 days.

Rabbits were received from Hazelton Dutchland, Inc,,Rabbits were kept for acclimatization 14 days. At study initiation Weight rabbit was approximately 3.0 kg. Rabbit were housed 1/cage in stainless steel cages with wire bottoms. A standard laboratory diet (Purina Certified Laboratory Chow, Ralston Purina Co.) supplied to rabbits adlibitum except and adlibitum tap water was supplied rabbits during the period of 21 days.

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

There were no mortalities during the course of the study which were related to exposure to PGME.One control female died on the day prior to the scheduled termination. Based upon gross and histopathologic examination, the cause of death was severe inflammation of the cecum, appendix, sacculus rotundus and proximal colon. The only clinical observation attributed to treatment with PGME was slight exfoliation on the backs of all rabbits at the application sight.

 There were no significant differences in body weights between control and treated animals. There were no significant differences in food consumption between control and treated animals.

There were no changes observed which were considered to be a result of treatment with PGME. RBC, Hb and PCV data for female rabbits exposed to 1000 mg/kg/day PGME were statistically increased and platelets were statistically decreased relative to concurrent values. These differences were considered to be sporadic occurrences unrelated to treatment. Hematology data for male rabbits were unremarkable. There were no significant differences in clinical chemistry parameters between control and treated animals.

Statistically significant decreases from control values were observed in both absolute and relative kidney weights of female rabbits exposed to PGME. This pattern was not observed in male rabbits nor were there any histopathologic changes in the kidney suggestive of a treatment related effect. Furthurmore, as previously stated there were no changes in clinical chemistry data to indicate an effect on renal function.

The only gross lesion attributed to treatment to treatment was a slight amount white scales present on the back at the site where PGME was applied. This effect was noted in all rabbits, males and females treated with 1000 mg/kg/day of PGME.

The only histopathologic effect attributed to treatment with PGME was also noted in the skin. All treated rabbits had a mild response at the site of treatment characterized by very slight thickening of epidermis and very slight accumulations of keratinized, hyperkeratosis. Additionally, 3 of 5 treated rabbits of each sex had a slight inflammatory response characterized as accumulations of mixed inflammatory cells in the superficial dermis. These effects were confined to the treated portion of the skin. The non treated site had no effects attributed to PGME applications. Some control and treated rabbits had focal skin lesions that were attributed to the bandaging tecqniques.Typically, these were linear, transversely oriented lesions located on the lateral or ventral aspect of the trunk where the bandages had been secured with tape. The skin effects attributed grossly to bandaging were examined histopathologically and found to consist of inflammation, degeneration and other protective effects which were generally slightly more severe than the effects attributed to treatment with PGME at the application site. No systemic toxicity resulted from dermally exposing male and femalewhite rabbits to 1000 mg/kg/day PGME 15 times in a 21 day period.

Based on the results of this study the NOAEL for systemic effects in male and female rabbits is > 1000 mg/kg/day via dermal route.