1-phenoxypropan-2-ol

Repeated dose toxicity: dermal

Administrative data

Endpoint:

sub-chronic toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1986

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP-study equivalent to OECD guideline 410.

Cross-reference

Cross-reference 1

Reason / purpose for cross-reference:

reference to same study

Cross-reference 2

Reason / purpose for cross-reference:

reference to other study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1986

Report date:

1986

Materials and methods

Test guideline

Test guideline 1

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)

Test guideline 2

Qualifier:

equivalent or similar to guideline

Guideline:

EPA OPPTS 870.3200 (Repeated Dose Dermal Toxicity -21/28 Days)

Principles of method if other than guideline:

not applicable

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

1-phenoxypropan-2-ol

EC Number:

212-222-7

EC Name:

1-phenoxypropan-2-ol

Cas Number:

770-35-4

Molecular formula:

C9H12O2

IUPAC Name:

1-phenoxypropan-2-ol

Constituent 2

Reference substance name:

1-phenylpropan-2-ol

EC Number:

211-821-0

EC Name:

1-phenylpropan-2-ol

Cas Number:

698-87-3

IUPAC Name:

1-phenylpropan-2-ol

Details on test material:

Identity: Dowanol-PPh (1-phenoxy-2-hydroxypropane or propylene glycol phenyl ether). CAS # 770-35-4 (also 41593-38-8)
Batch No.: LE08011T01
Purity: 95.55% (4.37% DiPPh, 0.08% Phenol)
Supplied as: Not reported
Vapor Pressure: <1.0 mmHg
Specific Gravity: 1.059
Appearance: Liquid

Test animals

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at dosing: Approximately 5 months of age
- Source: Hazleton-Dutchland, Inc., Denver, PA
- Acclimation period: At least 14 days
- Average weight at start of study: 3-4 kilograms
- Assignment to groups: Computer generated, random number tables
- Diet: Certified Rabbit Chow #5322 (Ralston Purina Company, St. Louis, MO)
- Access to food: Restricted to 8 ounces per day
- Access to water: Available ad libitum in glass bottles
- Method of Identification: Ear tags
- Housing: Individually in stainless steel cages with wire-mesh bottoms

ENVIRONMENTAL CONDITIONS (for non-exposure periods):
- Temperature: ~20°C (Recording frequency not reported)
- Humidity: ~50%. (Recording frequency not reported)
- Air changes: Not specified
- Photoperiod: 12 hr light/12 hr dark

Administration / exposure

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on exposure:

Propylene glycol phenyl ether was applied daily to the clipped dorsal skin of rabbits (5/sex/dose) at doses of 0, 100, 300, or 1000 mg/kg body weight/day, 5 days/week, over a period of 4 weeks (total of 19 applications). The control group was treated with approximately 1 ml/kg/day distilled water. Propylene glycol phenyl ether was applied uniformly over a 10 x 15 cm area of the back using a syringe with a blunt needle. The dose was covered with gauze, non-absorbent cotton, then an occlusive bandage, all held in place for 6 hours with a lycra/spandex jacket. After the 6 hour exposure period, the bandage was removed and the area washed clean of Propylene glycol phenyl ether with a water-dampened towel

Analytical verification of doses or concentrations:

no

Details on analytical verification of doses or concentrations:

not applicable

Duration of treatment / exposure:

28 days

Frequency of treatment:

once daily, 5 days/week (19 applications total)

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
100 mg/kg body weight/day
Basis:
nominal per unit body weight

Doses / concentrations 2

Remarks:

Doses / Concentrations:
300 mg/kg body weight/day
Basis:
nominal per unit body weight

Doses / concentrations 3

Remarks:

Doses / Concentrations:
1000 mg/kg body weight/day
Basis:
nominal per unit body weight

No. of animals per sex per dose:

5 rabbits/sex/dose

Control animals:

other: yes, distilled water (~1 ml/kg)

Details on study design:

Propylene glycol phenyl ether was applied daily to the clipped dorsal skin of rabbits (5/sex/dose) at doses of 0, 100, 300, or 1000 mg/kg body weight/day, 5 days/week, over a period of 4 weeks (total of 19 applications). The control group was treated with approximately 1 ml/kg/day distilled water. Propylene glycol phenyl ether was applied uniformly over a 10 x 15 cm area of the back using a syringe with a blunt needle. The dose was covered with gauze, non-absorbent cotton, then an occlusive bandage, all held in place for 6 hours with a lycra/spandex jacket. After the 6 hour exposure period, the bandage was removed and the area washed clean of Propylene glycol phenyl ether with a water-dampened towel.
Over the course of the study, rabbits were monitored for clinical signs of toxicity, body weight changes, hematological, clinical chemistry, and urinalysis changes, as well as gross and microscopic pathology.
Reproductive organs were weighed and subjected to gross and histopathological evaluation. Testis of the males were weighted but female reproductive organs were not. In control and high dose males, the following reproductive tissues were examined microscopically: testis, epididymides, seminal vesicles, and prostate. In control and high dose females, the following reproductive tissues were examined: mammary glands, ovaries, oviducts, uterus, cervix, and vagina

Positive control:

not applicable

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: No data

DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: daily, the skin at the application site was scored daily prior to reapplication of the test material

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Blood samples for the hematology determinations were taken from the ear vein of all animals immediately prior to necropsy, approximately 24 hours after the 19th dose
- Anaesthetic used for blood collection: No
- Animals fasted: No
- How many animals: all animals
- Parameters examined: Hematology analyses included red blood cell, white blood cell and platelet counts, packed cell volumes, hempglobin concentration and red blood cell indices. Slides for differential leukocyte counts were prepared for each animal, but differential counts were not performed for animals in the low and intermediate dose groups since treatment-related changes were not observed in the high dose group. Red blood cell osmotic fragility was determined for all animals

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Blood samples for serum analyses were collected at sacrifice from severed cervical blood vessels
- Animals fasted: No
- How many animals: all animals
- Parameters examined: ALT, AST, urea nitrogen, alkaline phosphatase (ALP), glucose, total protein, albumin, globulin and total bilirubin

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
ORGAN WEIGHTS: Weights of the brain, heart, liver, kidneys and testes were recorded from animals at the scheduled sacrifice
Tissues were collected and preserved from all animals. Tissues examined microscopically from the high dose and control animals included: heart, liver, gall bladder, spleen, pancreas, brain, pituitary, spinal cord, peripheral nerve, adrenals, kidneys, esophagus, stomach, small intestine, sacculus rotundus, appendix, cecum, large intestine, uterus, cervix, vagina, ovaries, oviducts, testes, epididymides, prostate, urinary bladder, trachea, lungs, thymus, aorta, skeletal muscle, mediastinal lymph node, mesenteric lymph node, skin (treated and untreated), thyroid gland, parathyroid glands, nasal tissues, salivary glands, tongue, bone, mammary gland, eyes, larynx, bone marrow, mediastinal tissue, oral tissues, mesenteric tissues

Other examinations:

not applicable

Statistics:

Descriptive statistics (mean and standard deviation) were reported for white blood cell differential counts and red blood cell indices. Body weights, absolute and relative organ weights, clinical chemistry data and hematology data were evaluated by Bartlett's test for equality of variances. Based on the outcome of Bartlett's test, exploratory data analyses were performed by a parametric or non-parametric analysis of variance (ANOVA), followed respectively by Dunnett's test or the Wilcoxon Ran-Sum test with a Bonferroni correction for multiple comparisons. Statistical outliers were identified by a sequential test and excluded accordingly

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Dermal irritation:

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:

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 - All rabbits survived to termination of the study with no overt signs of systemic toxicity.

DERMAL IRRITATION - Mild dermal irritation characterized by slight hyperemia and moderate exfoliation was observed in the 1000 mg/kg/day animals. Slight exfoliation was observed in most of the 300 mg/kg/day animals (slight hyperemia was also present for females), while 100 mg/kg/day animals showed only very slight exfoliation. Hypermia generally appeared during the first week of application and was not noted by the end of the second week while exfoliation appeared during the first week and was noted throughout the study

BODY WEIGHT AND WEIGHT GAIN - No adverse effects noted

FOOD CONSUMPTION - not examined

OPHTHALMOSCOPIC EXAMINATION - not examined

HAEMATOLOGY - No consistent changes were noted in hematology other than a slight increase in platelet counts in males, which was statistically significant in high dose group and approached significance in mid-dose males. Females showed no platelet response to PPh exposure

CLINICAL CHEMISTRY - No adverse effects noted

URINALYSIS - not examined

NEUROBEHAVIOUR - not examined

ORGAN WEIGHTS - No adverse effects noted

GROSS PATHOLOGY - No adverse effects noted

HISTOPATHOLOGY: NON-NEOPLASTIC - Except for skin at the site of application, histopathological examination revealed no adverse changes related to PPh treatment when high dose subjects were compared to controls. In skin at the site of application, a thickening of the epidermis was detected that was considered to be an adaptive response

Effect levels

1

Dose descriptor:

NOAEL

Remarks:

for systemic toxicity

Effect level:

1 000 mg/kg bw/day (nominal)

Sex:

male/female

Basis for effect level:

other: based on overall effects

2

Dose descriptor:

NOAEL

Remarks:

for local effects on the skin

Effect level:

100 mg/kg bw/day (nominal)

Sex:

male/female

Basis for effect level:

other: based on - histopathologic examination revealed a thickening of the epidermis at the application site which was considered to be an adaptive response to treatment rather than an adverse effect

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

none

Applicant's summary and conclusion

Conclusions:

Propylene glycol phenyl ether applied dermally to the backs of rabbits for 6 hours/day, 5 days/week over a 28 day period produced no systemic toxicity at dose levels up to 1000 mg/kg/day and thus the NOAEL of 1000 mg/kg/day was considered.

Executive summary:

Propylene glycol phenyl ether was applied dermally at levels of 100, 300 and 1000 mg/kg body weight/day to the backs of rabbits (5 rabbits/sex/dose) for 6 hr/day, 5 days/wk over a 28 day period (total of 19 applications). The control group was treated with approximately 1 ml/kg/day distilled water. Propylene glycol phenyl ether was applied uniformly over a 10 x 15 cm area of the back using a syringe with a blunt needle. The dose was covered with gauze, non-absorbent cotton, then an occlusive bandage, all held in place for 6 hours with a lycra/spandex jacket. After the 6 hour exposure period, the bandage was removed and the area washed clean of Propylene glycol phenyl ether with a water-dampened towel.

All rabbits survived treatment with no changes in body weights and no overt signs of systemic toxicity. All subjects showed some dermal irritation at the site of Propylene glycol phenyl ether application, characterized by moderate exfoliation and hyperemia in the high dose group, slight exfoliation and transient hyperemia in the mid-dose group, and very slight exfoliation in the low dose group. No changes were noted in absolute or relative organ weights compared to controls. No consistent changes were noted in clinical laboratory studies other than a slight increase in platelet counts in males, which was statistically significant in high dose group and approached significance in mid-dose males. Females showed no platelet response to Propylene glycol phenyl ether exposure. No histopathological changes were noted upon examination of tissues from the high-dose subjects.

Under the conditions of the study, the NOAEL for systemic toxicity to rabbits was considered to be 1000 mg/kg body weight/day