1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)pyridin-2(1H)-one, compound with 2-aminoethanol (1:1)

Repeated dose toxicity: dermal

Administrative data

Endpoint:

short-term repeated dose toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1981

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

The study was conducted prior to GLP and although it was not done according to any recognised testing guideline it followed scientifically accepted standards at that time. Based hereupon it does meet many of the requirements of OECD Test Guideline 410. The study itself is also well conducted, well documented and scientifically acceptable.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1981

Report date:

1981

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

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

Deviations:

yes

Remarks:

subcutaneous injection

Principles of method if other than guideline:

Test item was subcutaneously injected

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Octopirox

IUPAC Name:

Octopirox

Constituent 2

Reference substance name:

piroctone olamine

IUPAC Name:

piroctone olamine

Constituent 3

Reference substance name:

1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)pyridin-2(1H)-one, compound with 2-aminoethanol (1:1)

EC Number:

272-574-2

EC Name:

1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)pyridin-2(1H)-one, compound with 2-aminoethanol (1:1)

Cas Number:

68890-66-4

Molecular formula:

C14H23NO2.C2H7NO

IUPAC Name:

1-hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)pyridin-2(1H)-one, compound with 2-aminoethanol (1:1)

Constituent 4

Reference substance name:

1-Hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2-pyridone, 2-aminoethanol salt

IUPAC Name:

1-Hydroxy-4-methyl-6-(2,4,4-trimethylpentyl)-2-pyridone, 2-aminoethanol salt

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Administration / exposure

Type of coverage:

other: subcutaneous injection

Vehicle:

not specified

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

5 weeks + 2 weeks recovery

Frequency of treatment:

once daily

Doses / concentrations

Doses / concentrations 1

Remarks:

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

Doses / concentrations 2

Remarks:

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

Doses / concentrations 3

Remarks:

Doses / Concentrations:
2000 mg/kg
Basis:
nominal per unit body weight

No. of animals per sex per dose:

15 male / 15 female animals per group

Control animals:

yes, concurrent no treatment

Details on study design:

- Dose selection rationale: expert judgement
- Rationale for animal assignment (if not random): random
- Rationale for selecting satellite groups: no satellite group
- Post-exposure recovery period in satellite groups: 2-week recovery group
- Section schedule rationale (if not random): random

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes

DERMAL IRRITATION (if dermal study): No data (subcutaneous injection)

BODY WEIGHT: Yes
- Time schedule for examinations: daily

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data

WATER CONSUMPTION: No data

OPHTHALMOSCOPIC EXAMINATION: Yes

HAEMATOLOGY: Yes

CLINICAL CHEMISTRY: Yes

URINALYSIS: Yes

NEUROBEHAVIOURAL EXAMINATION: No data

OTHER:

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Dermal irritation:

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):

no effects observed

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

no effects observed

Ophthalmological findings:

no effects observed

Haematological findings:

effects observed, treatment-related

Clinical biochemistry findings:

effects observed, treatment-related

Urinalysis findings:

effects observed, treatment-related

Behaviour (functional findings):

not specified

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Details on results:

CLINICAL SIGNS AND MORTALITY
General symptoms included loss of hair gloss and piloerection. One male of the 500 mg and two males of the 2000 mg/kg group died. Abnormalities in general health or deaths were not observed in the 100 mg/kg group.

BODY WEIGHT AND WEIGHT GAIN
Body weight gain was suppressed in males and females of the 500 and 2000 mg/kg group.

FOOD CONSUMPTION
Not significantly affected

FOOD EFFICIENCY
Not significantly affected

WATER CONSUMPTION
Not significantly affected

OPHTHALMOSCOPIC EXAMINATION
No abnormalities

HAEMATOLOGY
In both sexes of the 500 and 2000 mg/kg group slight anemia, low lymphocyte count, high segmented neutrophil count and in females of the 500
and 2000 mg/kg group high leucocyte count

CLINICAL CHEMISTRY
In the 2000 mg/kg group low values of total protein and A/G ratio as well as elevations of urea-nitrogen, cholesterol and alkaline phosphatase
activity

URINALYSIS
In the 500 and 2000 mg/kg group elevated values of Na+ in both sexes

NEUROBEHAVIOUR
No data

ORGAN WEIGHTS
Slight changes in absolute and relative organ weights in 500 and 2000 mg/kg group but no histopathological correlate

GROSS PATHOLOGY
Residue of test compound found at dorsal injection sites of all dose groups. Marked inflammatory changes at injection sites of the 500 and 2000 mg/kg dose group.

HISTOPATHOLOGY: NON-NEOPLASTIC
No abnormalities

HISTOPATHOLOGY: NEOPLASTIC (if applicable)
No abnormalities

HISTORICAL CONTROL DATA (if applicable)
No data

OTHER FINDINGS

Effect levels

Dose descriptor:

NOEL

Effect level:

>= 100 - <= 500 mg/kg bw/day (nominal)

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:

After repeated subcutaneous injection of Octopirox to rats , the no observed effect level (NOEL) was considered to be 100 mg/kg body weight.

Executive summary:

Piroctone olamine was administered to groups of 15 male and 15 female Sprague-Dawley rats by subcutaneous injection at dose levels of 0, 100, 500 or 2000 mg/kg body weight. The animals were treated once daily for a period of 5 weeks. Following the treatment sutviving animals were subjected to a 2 week recovery experiment. One male of the 500 mg/kg group and two males of the 2000 mg/kg group died during the treatment period. Neither abnormalities in general symptoms nor deaths were observed in the 100 mg/kg group. Changes in general health condition were noticed in the 500 mg/kg and 2000 mg/kg dose group and included loss of hair gloss, hard hairs, piloerection and depressed body weight gain in both males and females. Haematological findings included anemia, low lymphocyte count and high segmented neutrophil count in both sexes of the 500 mg/kg and 2000 mg/kg dose group. In addition, high leucocyte count in females of the medium and high dose groups could be noticed. Serum biochemistry revealed low total protein and high urea nitrogen values in the 500 mg/kg dose group and, only in females of this group, high cholesterol values. Changes in the 2000 mg/kg group included low values of total protein and in the albumin : globulin ratio as well as elevations of urea-nitrogen, cholesterol and alkaline phosphatase values. Urinalysis indicated increased values of Na+ in both sexes of the 500 mg/kg and 2000 mg/kg group. The ophthalmologic examinations revealed no abnormalities in any of the treatment groups. Although changes in absolute and relative organ weights were observed in both sexes of the 500 mg/kg and 2000 mg/kg group, no histopathological abnormalities were detected. At necropsy, the residue of the test compound was found at the dorsal injection sites of all dosage groups. In addition, marked inflammatory changes at the injection sites were seen at the gross and histopathological examinations of the animals treated with 500 mg/kg and 2000 mg/kg body weight. During the recovery period, indications of a reversible nature of the mentioned changes were found. Especially those in general symptoms, body weight, haematology and organ weights showed favorable recoveries. The no observed effect level (NOEL) after repeated subcutaneous injection to rats was placed at 100 mg/kg body weight.