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Diss Factsheets

Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1979
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
The study was conducted prior to establishment of OECD testing guidelines but followed scientifically accepted standards. The study is well conducted and well documented. As it fullfills a lot of requirements of todays testing guidelines it is acceptable for evaluation purposes.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1979
Report date:
1979

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Principles of method if other than guideline:
Reproductive toxicity study (segment II) with test compound administration to rabbits during the sensitive phase of organogenesis (gestation days 7 to 19)
GLP compliance:
yes (incl. QA statement)
Limit test:
no

Test material

Constituent 1
Reference substance name:
Octopirox
IUPAC Name:
Octopirox
Constituent 2
Reference substance name:
piroctone olamine
IUPAC Name:
piroctone olamine
Constituent 3
Chemical structure
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:
rabbit
Strain:
Himalayan
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Hoe: HIMK (SPF Wiga)
- Age at study initiation: 6 to 7 month
- Weight at study initiation: 2579 +/- 162 g
- Fasting period before study: no
- Housing: individually
- Diet (e.g. ad libitum): Erka Z 6000, ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 7 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 - 23°C
- Humidity (%): 55 - 65 %
- Air changes (per hr): 16 - 20 times per hour
- Photoperiod (hrs dark / hrs light): 12 hour interval


IN-LIFE DATES: From: October 23, 1978 To: January 2, 1979

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: starch mucilar
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
Octopirox was suspended in starch mucilage (20 g starch per liter redistilled water). Suspensions were prepared fresh each day.

DIET PREPARATION
- Rate of preparation of diet (frequency):
- Mixing appropriate amounts with (Type of food):
- Storage temperature of food:


VEHICLE
- Justification for use and choice of vehicle (if other than water): recommended and accepted vehicle
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1 : 1
- Length of cohabitation: over night
- Further matings after two unsuccessful attempts: no
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
Duration of treatment / exposure:
exposure from day 7 to day 19
Frequency of treatment:
once daily
Duration of test:
until day 29 of pregnancy
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day
Dose / conc.:
16 mg/kg bw/day
Dose / conc.:
32 mg/kg bw/day
Dose / conc.:
63 mg/kg bw/day
No. of animals per sex per dose:
15 pregnant females per group
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: based on preceding exploratory study
- Rationale for animal assignment (if not random): random
- Other:

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: once a week


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes, continually


POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 29
- Organs examined: heart, liver, kidneys, spleen


OTHER:
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes / No / No data
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other: placentae, live and dead fetuses
Fetal examinations:
- External examinations: Yes, all per litter
- Soft tissue examinations: Yes, half per litter
- Skeletal examinations: Yes, half per litter
- Head examinations: No data
- 24 hour viability check
Statistics:
Dunnett`s simultaneous comparison; Nemenyi`s many-one version of H-test; Goodman`s simultaneous comparison; Wilcoxon comparison;
Student`s t-test

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
no effects observed
Mortality:
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
Behaviour (functional findings):
no effects observed
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
no effects observed

Maternal developmental toxicity

Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in pregnancy duration:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed
Changes in number of pregnant:
no effects observed
Other effects:
no effects observed
Details on maternal toxic effects:
Maternal toxic effects:no effects

Effect levels (maternal animals)

Dose descriptor:
NOEL
Effect level:
> 63 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Remarks on result:
not determinable due to absence of adverse toxic effects

Results (fetuses)

Fetal body weight changes:
not examined
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): not examined
Reduction in number of live offspring:
not examined
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
not examined
Changes in postnatal survival:
not examined
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed
Other effects:
no effects observed
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Effect levels (fetuses)

Dose descriptor:
NOEL
Effect level:
> 63 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: teratogenicity
Remarks on result:
not determinable due to absence of adverse toxic effects

Fetal abnormalities

Abnormalities:
no effects observed

Overall developmental toxicity

Developmental effects observed:
no

Applicant's summary and conclusion

Conclusions:
Based on the results of this study Piroctone olamine does not elicite maternal toxicity and is not embryotoxic and not teratogenic.
Executive summary:

Piroctone olamine was investigated for embryotoxic and/or developmental (teratogenic) toxicity using groups of 15 pregnant female rabbits. They were administered Piroctone olamine orally by gavage once daily on days 7 - 19 of gestation at dose-levels of 0, 16, 32 or 63 mg/kg body weight. On day 29 of pregnancy the dams were killed and delivered by cesarean section. On opening the uterus, live and dead fetuses, fetal resoprtion sites, placentae, and corpora lutea on the ovaries were counted and macroscopically assessed. Body weight and crown-rump length of the fetuses, the diameter of the conceptuses under resorption and placental weight were determiend. The sex of the fetuses was determined at autopsy. All fetuses underwent gross pathological evaluation. About half of the fetuses in each litter were subjected for examination of visceral and the other half of skeletal malformations. The results showed that repeated administration of Piroctone olamine in the sensitive phase of organogenesis caused no impairment of general health status of the dams and no disturbances of intrauterine development of the fetuses. The examinations of the fetuses for developmental status, externally acertainable abnormalities, visceral and skeletal malformations, and a 24 -hour viability test suggested no embryotoxic and teratogenic action of Piroctone olamine.