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

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1976

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 407. The study itself is also well conducted, well documented and scientifically acceptable.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1976

Report date:

1976

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)

Principles of method if other than guideline:

Subacute (30-day) oral toxicity study via gavage in rats

GLP compliance:

no

Remarks:

but performance and documentation equivalent to GLP

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:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Hoe:WISKf SPF 71
- Age at study initiation:
- Weight at study initiation: 100 - 110 g
- Fasting period before study:
- Housing: plastic cages
- Diet (e.g. ad libitum): Altromin 1324
- Water (e.g. ad libitum):Tap water
- Acclimation period:8 hours


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


IN-LIFE DATES: From: To:

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: starch mucilage

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS:

VEHICLE
- Justification for use and choice of vehicle (if other than water): starch mucilage
- Amount of vehicle (if gavage): 10 mL/kg

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

30 consecutive days

Frequency of treatment:

1 treatment per day, 7 treatments per week for 30 consecutive days

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
4 mg/kg body weight
Basis:
other: nominal in starch mucilage

Doses / concentrations 2

Remarks:

Doses / Concentrations:
15 mg/kg body weight
Basis:
other: nominal in starch mucilage

Doses / concentrations 3

Remarks:

Doses / Concentrations:
55 mg/kg body weight
Basis:
other: nominal in starch mucilage

Doses / concentrations 4

Remarks:

Doses / Concentrations:
210 mg/kg body weight
Basis:
other: nominal in starch mucilage

Doses / concentrations 5

Remarks:

Doses / Concentrations:
800 mg/kg body weight (control)
Basis:
other: starch mucilage

No. of animals per sex per dose:

10 males and 10 females

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: based on acute toxicity data, 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: no recovery group
- Section schedule rationale (if not random): random

Positive control:

not required

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily


BODY WEIGHT: Yes
- Time schedule for examinations: day 1, 3, 7, 10, 14, 17, 21, 24, 28, 30


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes


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 AND COMPOUND INTAKE (if drinking water study): No data
- Time schedule for examinations: No data


OPHTHALMOSCOPIC EXAMINATION: No data
- Time schedule for examinations: No data
- Dose groups that were examined: No data


HAEMATOLOGY: Yes
- Time schedule for collection of blood: before the beginning and at the end of the study
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: 10 male and 10 female per dose-group
- Parameters examined: erythrocyte count, thrombocyte count, hematocrit, leucocyte count, hemoglobin, differential blood count, reticulocyte, methemoglobin


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: end of study
- Animals fasted: No
- How many animals: 10 male and 10 female per dose-group
- Parameters examined: bilirubin, SGOT, glucose, SGPT, urea-N, AP


URINALYSIS: Yes
- Time schedule for collection of urine: day before the first treatment and at the end of the study
- Metabolism cages used for collection of urine: No
- Animals fasted: No
- Parameters examined: appearence, pH, color, glucose, sediment, bilirubin, protein, hemoglobin


NEUROBEHAVIOURAL EXAMINATION: No
- Time schedule for examinations: No data
- Dose groups that were examined: No data
- Battery of functions tested: sensory activity / grip strength / motor activity / other: No data


OTHER:

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Statistics:

Yes (Student t-tests; F-test; modified F-test)

Results and discussion

Results of examinations

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):

effects observed, treatment-related

Food efficiency:

not specified

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

not specified

Ophthalmological findings:

not examined

Haematological findings:

effects observed, treatment-related

Clinical biochemistry findings:

no effects observed

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:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

no effects observed

Details on results:

CLINICAL SIGNS AND MORTALITY
There were no signs of toxic effects up to 55 mg/kg in male rats and up to 210 mg/kg in female rats. Except one male and one female of the highest dose-group all animals survived the treatment.

BODY WEIGHT AND WEIGHT GAIN
The body weights of the male rats which received 800 mg/kg were significantly decreased at the end of the study. The body weights of the male animals from the remaining dose-groups and those of the female of all dose-groups were in the same range than those of the controls.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
The male rats from the 210 mg/kg and 800 mg/kg group exhibited slightly increased relative food intake at the end of the study. A comparable effect was observed in females only at the highest dose-group.

FOOD EFFICIENCY
no data

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study)
no data

OPHTHALMOSCOPIC EXAMINATION
no data

HAEMATOLOGY
The haematological investigation revealed a decrease of erythrocyte values, haemoglobin, haematocrit, and an increase in reticulocytes and thrombocytes in male and female rats of the highest dose group.

CLINICAL CHEMISTRY
No treatment related abnormalities observed.

URINALYSIS
No treatment related abnormalities observed.

NEUROBEHAVIOUR
no data

ORGAN WEIGHTS
No significant substance related differences between the relative organ weights of control and treated animals were observed up to the 210 mg/kg dose-group. A significant increase in organ weights of the highest dose group was seen for the heart, kidney and adrenals.

GROSS PATHOLOGY
Gross examination of the organs revealed no macroscopically visible changes.

HISTOPATHOLOGY: NON-NEOPLASTIC
Histopathology revealed no morphological organ changes up to 210 mg/kg. Partial damage to renal tubules was observed in three animals of the high dose group which was not considered to be treatment related.

HISTOPATHOLOGY: NEOPLASTIC (if applicable)
No neoplastic findings were observed.

HISTORICAL CONTROL DATA (if applicable)
not included

Effect levels

1

Dose descriptor:

NOEL

Effect level:

>= 55 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: Increase in relative food consumption

Remarks on result:

not determinable due to absence of adverse toxic effects

2

Dose descriptor:

NOEL

Effect level:

>= 210 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

female

Basis for effect level:

other: retarded body weight development, haematological changes

Remarks on result:

not determinable due to adverse toxic effects at highest dose / concentration tested

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

Based on the results obtained, the no toxic effect level of Octopirox was conservatively placed at 55 mg/kg body weight for males and at 210 mg/kg body weight for females.

Executive summary:

In a 30 day study piroctone olamine was administered daily to groups of 10 male and 10 female rats via gastric-tube at dose levels of 0, 4, 15, 55, 210 or 800 mg/kg body weight. Except one female of the highest dose-group all animals survived the treatment. The cause of the death was not considered to be treatment related. An increase of relative food consumption was noticed in the male animals of 210 mg/kg dose-group and in the females of the 800 mg/kg dose group. In addition retardation of body weight gain could be observed in the male animals of the 800 mg/kg dose-group. The haematological investigation revealed a decrease of erythrocyte values, haemoglobin, haematocrit and an increase in reticulocytes and thrombocytes in males and females of the highest dose-group. The clinical chemistry and urinalysis did not show any treatment related abnormalities. Gross examination of the organs revealed no macroscopically visible changes. Although signs of a partial damage of kidney tubulli could be observed in the two intercurrent deceased animals and in one animal of the highest dose-group, these changes were not considered to be treatment related since these findings were not seen in a subchronic, 90 -day study in rats. Based on the results obtained, the no-toxic effect level (NOEL) of piroctone olamine was placed at 55 mg/kg body weight and 210 mg/kg body weight for male and female animals respectively.