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

Toxicity to reproduction

Administrative data

Endpoint:

fertility, other

Remarks:

based on test type (migrated information)

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1982-1983

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study according to accepted scientific standards at time of performance and performed under internal GLP. Well conducted and documented. Reporting conclusive.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1983

Report date:

1983

Materials and methods

Test guideline

Qualifier:

no guideline available

Principles of method if other than guideline:

Segment I study. Subcutaneous injection of test material for 9 weeks (male animals) or 2 weeks (female animals) before mating and up to day 6 of gestation. Cesarean sections performed on day 18 of gestation. Visceral and skeletal anomalies were examined.

GLP compliance:

yes (incl. QA statement)

Remarks:

Internal Reliability Assurance

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

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: CLEA Japan, Inc.
- Age at study initiation: 10 - 12 weeks
- Weight at study initiation: approx. 200 g (male animals), approx. 190 g (female animals)
- Fasting period before study: no
- Housing: plastic cages (individually during gestation)
- Use of restrainers for preventing ingestion (if dermal): no
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 1 week


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 2 °C
- Humidity (%): 55 +/- 5 %
- Air changes (per hr): 12 times per hour
- Photoperiod (hrs dark / hrs light): 12 hour interval

Administration / exposure

Route of administration:

subcutaneous

Vehicle:

CMC (carboxymethyl cellulose)

Details on exposure:

Test compound was mixed with sterile 0.5% CMC at 5 mL / kg body weight ratio, converted into mg/mL/kg value (based on daily body weight)
injected subcutaneously.

Details on mating procedure:

- M/F ratio per cage: 1 : 1 ratio
- Length of cohabitation: 1 night
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
- Further matings after two unsuccessful attempts: no
- After successful mating each pregnant female was caged (how): individual
- Any other deviations from standard protocol: no

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

9 weeks before mating and through mating period (male animals), 2 weeks befor mating up to day 6 of gestation (female animals)

Frequency of treatment:

Once daily

Details on study schedule:

- F1 parental animals not mated until [...] weeks after selected from the F1 litters: n.a.
- Selection of parents from F1 generation when pups were [...] days of age: n.a.
- Age at mating of the mated animals in the study: [...] weeks: n.a.

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
20 mg/kg
Basis:
nominal conc.

Doses / concentrations 2

Remarks:

Doses / Concentrations:
50 mg/kg
Basis:
nominal conc.

Doses / concentrations 3

Remarks:

Doses / Concentrations:
100 mg/kg
Basis:
nominal conc.

Doses / concentrations 4

Remarks:

Doses / Concentrations:
500 mg/kg
Basis:
nominal conc.

No. of animals per sex per dose:

24 gestating rats in 20 mg/kg group
24 gestating rats in 50 mg/kg group
24 gestating rats in 100 mg/kg group
24 gestating rats in 500 mg/kg group

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: Based on available results from a developmental dose-range finder
- Rationale for animal assignment (if not random): random
- Other:

Positive control:

no positive control

Examinations

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily


BODY WEIGHT: Yes
- Time schedule for examinations: day 0, 4, 8, 12, 16 - 21


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): n.a.

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): n.a.


OTHER:

Oestrous cyclicity (parental animals):

no data

Sperm parameters (parental animals):

no data

Litter observations:

STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: yes
- If yes, maximum of 8 pups/litter (4/sex/litter as nearly as possible); excess pups were killed and discarded.


PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities, feed intake,


GROSS EXAMINATION OF DEAD PUPS:
yes

Postmortem examinations (parental animals):

SACRIFICE
- Male animals: All surviving animals

GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations

Statistics:

yes

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Description (incidence):

Male animals from highest dose having received test material subcutaneously for 9 weeks prior to mating due to remarkable inflammatory changes at the application side leading to a poor general health status. However, survived males at this dose level were shown to have reproductive ability.

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Food efficiency:

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

no effects observed

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Other effects:

no effects observed

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:

no effects observed

Reproductive function: sperm measures:

no effects observed

Reproductive performance:

no effects observed

Details on results (P0)

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
8 male animsls died in the highes dose group (500 mg/kg) mainly due to severe inflammation reactions at the injection side

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
Body weight gain was depressed in the male animals and in females during gestation in the highest dose group (500 mg/kg)

TEST SUBSTANCE INTAKE (PARENTAL ANIMALS)


REPRODUCTIVE FUNCTION: ESTROUS CYCLE (PARENTAL ANIMALS)


REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS)


REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)


ORGAN WEIGHTS (PARENTAL ANIMALS)


GROSS PATHOLOGY (PARENTAL ANIMALS)


HISTOPATHOLOGY (PARENTAL ANIMALS)


OTHER FINDINGS (PARENTAL ANIMALS)

Effect levels (P0)

Dose descriptor:

NOAEL

Effect level:

>= 100 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: overall effects, clinical signs, inflammation at injection side, mortality at highest dose level

Remarks on result:

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

Target system / organ toxicity (P0)

Critical effects observed:

no

Results: F1 generation

General toxicity (F1)

Clinical signs:

no effects observed

Mortality / viability:

no mortality observed

Body weight and weight changes:

no effects observed

Food efficiency:

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Sexual maturation:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

no effects observed

Histopathological findings:

no effects observed

Other effects:

no effects observed

Developmental neurotoxicity (F1)

Behaviour (functional findings):

not examined

Developmental immunotoxicity (F1)

Developmental immunotoxicity:

not examined

Details on results (F1)

No changes in any parameters examined at cesarian section. No external, visceral or skeletal anomalies. No delayed ossification.

Effect levels (F1)

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

>= 500 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no adverse effects

Remarks on result:

not determinable due to absence of adverse toxic effects

Overall reproductive toxicity

Reproductive effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

Piroctone olamine is not considered to be reproductive toxic after subcutaneous injection. Maternal toxic effects are confined to local effects at the
injection side in the highest dose group.

Executive summary:

Piroctone olamine was subcutaneously given to groups of 24 male and 24 female rats at daily doses of 0, 20, 50, 100 or 500 mg/kg body weight. Males were administered the test compound for 9 weeks before mating and through the mating period, while the females were treated for 2 weeks before mating up to day 6 of gestation. In the highest dose-group 8 male animals died probably due to remarkable inflammatory changes at the application side leading to a poor general health status. Additionally body weight gain was depressed in both male and female animals of the highest dose group. Copulation was delayed in the 500 mg/kg dosage group. However, the females and survived males at this dose level were shown to have reproductive ability. At each treatment level, fetuses exhibited no changes in any parameters examined at cesarian section. No differences occurred between treated and control animals in the incidences of visceral anomalies, skeletal anomalies and variations, and delayed ossification. Based on the results of this study, no significant reproductive toxicity is attributable to piroctone olamine.