Tetrahydro-3-pentyl-2H-pyran-4-yl acetate

Toxicity to reproduction

Administrative data

Endpoint:

fertility, other

Remarks:

Repeated-dose 90-day dermal toxicity study.

Type of information:

experimental study

Adequacy of study:

key study

Study period:

Januari 2014 - November 2014

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2015

Report date:

2015

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

other: OECD 411 Subchronic dermal toxicity: 90-day study (1981)

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

other: EU method B.28 sub-chronic dermal toxicity study (2008)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Pyranol

IUPAC Name:

Pyranol

Constituent 2

Reference substance name:

63500-71-0; 65418-70-4 (trans); 65418-69-1 (cis)

IUPAC Name:

63500-71-0; 65418-70-4 (trans); 65418-69-1 (cis)

Test material form:

other: liquid (colorless, clear)

Details on test material:

- Name of test material (as cited in study report): Pyranol
- Physical state: liquid

Test animals

Species:

rat

Strain:

other: Crl:WI(Han)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services GmbH, Sulzfeld, Germany
- Age at study initiation: 63 ± 1 days
- Weight at study initiation: Males: 245.0-275.6 g; Females: 170.4-206 g
- Fasting period before study: no
- Housing: individually in polysulfonate cages (motor activity measurements were conducted in polycarbonate cages)
- Use of restrainers for preventing ingestion (if dermal): yes, covered for at least 6 hours after application using a semiocclusive dressing, consisting of 4 layers of porous gauze dressing
- Diet: ad libitum; ground Kliba maintenance diet mouse/rat “GLP”, meal, supplied by Provimi Kliba SA, Kaiseraugst, Switzerland
- Water: ad libitum, water bottles
- Acclimation period: 6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): set at 20-24
- Humidity (%): set at 30-70
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 27 January 2014 To: 30 April 2014

Administration / exposure

Route of administration:

dermal

Vehicle:

corn oil

Details on exposure:

TEST SITE
- Area of exposure: 10% of the body surface
- Type of wrap if used: The skin was covered for at least 6 hours after application using a semiocclusive dressing, consisting of 4 layers of porous gauze dressing (Absorbent gauze EP supplied by Lohmann GmbH & Co. KG, Neuwied, Germany) and a stretch bandage (Fixomull® stretch [adhesive fleece] supplied by Beiersdorf AG, Hamburg, Germany).
- Time intervals for shavings or clipplings: The animals were reclipped at least once a week (depending on hair growth).

REMOVAL OF TEST SUBSTANCE
- Washing (if done): the treated skin was washed with lukewarm water
- Time after start of exposure: After removal of the dressing.

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): The application volume was 4 mL/kg bw, based upon the latest individual body weight determination.
- Concentration (if solution):

VEHICLE
- Justification for use and choice of vehicle (if other than water): no information

USE OF RESTRAINERS FOR PREVENTING INGESTION: yes, semiocclusive dressing.

Details on mating procedure:

No data on mating. Reproductive parameters investigated in this repeated dose toxicity study are considered for the endpoint reproduction toxicity.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The stability of the test substance in corn oil at room temperature for a period of 8 days was demonstrated during the application period.
The test substance was completely miscible with corn oil and thus a solution. Therefore, the test-substance preparation was considered to be homogenous. Consequently further homogeneity analyses were not carried out.
Concentration control analyses of the test-substance preparations were performed in samples of all concentrations at the start of the application period.

Duration of treatment / exposure:

3 months

Frequency of treatment:

5 days per week

Doses / concentrations

Remarks:

Doses / Concentrations:
100, 300 and 1000 mg/kg bw/day
Basis:
other: dermal application

No. of animals per sex per dose:

10

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: at the request of the sponsor.

Examinations

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily (working days), once daily (Satudays, Sundays and public holidays)


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Day 0 and subsequently once a week.

BODY WEIGHT: Yes
- Time schedule for examinations: Day 0 and thereafter at weekly intervals.

FOOD CONSUMPTION AND COMPOUND INTAKE: Yes
Food consumption was determined weekly as representative value over a period of 1 day and calculated as mean food consumption in grams per rat and day.

WATER CONSUMPTION AND COMPOUND INTAKE: No
Drinking water consumption was monitored by daily visual inspection of the water bottles for any changes in volume.

OTHER:
FOB, Ophthalmoscopy, clinical chemistry, hematology, organ weights, histopathology.

Oestrous cyclicity (parental animals):

not examined

Sperm parameters (parental animals):

Parameters examined:
testis weight, histopathology (control and high dose groups) of testes, epididymides, prostate, seminal vesicles

Litter observations:

no

Postmortem examinations (parental animals):

SACRIFICE
-All animals at the end of the exposure period (3 months).

GROSS NECROPSY
- Gross necropsy according to guidelines.

HISTOPATHOLOGY / ORGAN WEIGHTS
-According to guidelines.

Postmortem examinations (offspring):

no

Statistics:

Food consumption, body weight, body weight change: A comparison of each group with the control group was performed using DUNNETT's test (twosided) for the hypothesis of equal means.
Weight parameters: Non-parametric one-way analysis using KRUSKAL WALLIS test (two-sided). If the resulting p-value was equal or less than 0.05, a pairwise comparison of each dose group with the control group was performed using WILCOXON test (two-sided) for the equal medians.

Reproductive indices:

-

Offspring viability indices:

-

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:

no effects observed

Reproductive function: sperm measures:

not examined

Reproductive performance:

not examined

Details on results (P0)

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS):
No animal died prematurely in the present study. Clinical examinations did not reveal treatment-related, adverse effects up to and including a dose level of
1000 mg/kg bw/day. Although erythema, erosions and scales were most likely related to treatment they were assessed to be non-adverse as they occurred only temporarily for a few days in individual animals.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS):
No effects on body weight parameters which were of toxicological concern were observed in this study. Body weight change values were significantly increased in female animals of 1000 mg/kg bw/day on study day 14. The finding was assessed to be incidental and not related to treatment as no clear trend in body weight development occurred. No test substance-related effects on food consumption were obtained. All values were within the range typical for animals of this strain and age.

ORGAN WEIGHTS (PARENTAL ANIMALS):
All mean absolute and mean relative weight parameters did not show significant differences when compared to the control group.

GROSS PATHOLOGY (PARENTAL ANIMALS):
All findings occurred either individually or were biologically equally distributed over control and treatment groups. They were considered to be incidental or spontaneous in origin and without any relation to treatment.

HISTOPATHOLOGY (PARENTAL ANIMALS):
All findings occurred either individually or were biologically equally distributed over control and treatment groups. They were considered to be incidental or spontaneous in origin and without any relation to treatment.

OTHER FINDINGS (PARENTAL ANIMALS):
Concerning clinical pathology, no treatment-related, adverse effects were observed up to and including a dose of the compound of 1000 mg/kg bw/day.

Effect levels (P0)

Key result

Dose descriptor:

NOAEL

Effect level:

>= 1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no treatment-related adverse effects were observed

Results: P1 (second parental generation)

General toxicity (P1)

Description (incidence):

No animal died prematurely in the present study.

Results: F1 generation

General toxicity (F1)

Body weight and weight changes:

not examined

Effect levels (F1)

Key result

Remarks on result:

other: not relevant

Overall reproductive toxicity

Key result

Reproductive effects observed:

no

Applicant's summary and conclusion

Conclusions:

No adverse effects were observed on the reproductive organs of male and female rats in a 90-day dermal repeated dose toxicity study with the read-across substance Pyranol.

Executive summary:

Pyranol was applied by dermal application to groups of 10 male and 10 female Wistar rats at dose levels of 0 mg/kg bw/day (vehicle control), 100 mg/kg bw/day, 300 mg/kg bw/day and 1000 mg/kg bw/day over a period of 3 months (5 days per week) according to OECD 411. Observations relevant for this endpoint included organ weights testes, adrenal glands and thyroid glands, and histopatological examination (control and high dose animals) of testes, epididymides, prostate, seminal vesicles, uterus, vagina, cervix, ovaries, adrenal gland, pituitary gland and thyroid gland). No treatment-related adverse effects were observed up to and including 1000 mg/kg bw/day, the highest dose tested.