4-[2-(Dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]phenol

Endpoint summary

Key value for chemical safety assessment

Effects on developmental toxicity

Link to relevant study records

Reference

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

Mar 2003 to Dec 2004

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: OECD GLP study run to current guidelines with no protocol deviations

Principles of method if other than guideline:

The purpose of this study was to evaluate effects of the test substance in rats on mating performance, fertility, and pre-natal offspring development. The test substance was administered orally by gavage to male and female Charles River CD VAF rats (25/sex/group for reproductive toxicity assessment; 9 time-mated females/drug-treated group for pharmacokinetic [PK] assessment) at dosages of 0, 30, 100, or 300 mg/kg/day.

GLP compliance:

yes (incl. QA statement)

Limit test:

yes

Species:

rat

Strain:

Crj: CD(SD)

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source:CD rats, Crl:CD(SD) IGS BR (also referred to as Charles River CD VAF Rats)
- Age at study initiation:7 to 9 and 11 to 13 weeks old at initiation of dosing for males and females [reproductive assessment], respectively; 8 to 10 weeks for PK assessment groups; 13 to 15 weeks old for untreated females on GD
- Weight at study initiation:305 to 360 g for dosed males; 213 to 295 g for dosed reproductive assessment females; 215 to 250 g for time-mated females (PK assessment) at initiation of dosing; 220 to 316 g for untreated females on GD 0
- Fasting period before study:
- Housing:3 per cage,During vaginal smearing prior to cohabitation, females were housed 1 per cage in suspended stainless steel cages with wire mesh fronts and bottoms and automatic watering system. After mating or after the cohabitation period, females were housed 1 per cage in polycarbonate cages
- Diet (e.g. ad libitum):Certified rodent food. Ad libitum
- Water (e.g. ad libitum):Ad libitum. Facility water is routinely analyzed for levels of microbial and chemical contaminants
- Acclimation period:At least 5 days prior to study assignment

ENVIRONMENTAL CONDITIONS
- Temperature (°C):72°F ± 6°F and 50% ± 20%
- Humidity (%):relative humidity, continuously monitored.
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light):Alternating 12-hour periods of light and dark were in effect.

IN-LIFE DATES: From: To:

Route of administration:

oral: gavage

Type of inhalation exposure (if applicable):

whole body

Vehicle:

other: polysorbate 80, methylcellulose, and purified water

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:

DIET PREPARATION
- Rate of preparation of diet (frequency):every two weeks
- Mixing appropriate amounts with Appropriate quantities of polysorbate 80, NF and methylcellulose (4000 cps) are mixed with purified (Type I) water to obtain the appropriate concentrations
- Storage temperature of food:Refrigerate, protect from light

VEHICLE
- Justification for use and choice of vehicle (if other than water):
- Concentration in vehicle:0.25% polysorbate 80, 0.5% methylcellulose (4000 cps), and purified water.
- Amount of vehicle (if gavage):
- Lot/batch no. (if required):RB1636
- Purity:65.9%

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Dosage Group Dosagea(mg/kg/day) Concentrationa(mg/mL)
Reproductive Toxicity Assessment
Control 0 0
Low 30 3
Middle 100 10
High 300 30
Pharmacokinetic Assessment (gravid females)
Low 30 3
Middle 100 10
High 300 30

Details on mating procedure:

- Impregnation procedure: cohoused
- If cohoused:During the cohabitation period, they were housed
- M/F ratio per cage:1:1
- Length of cohabitation:14-day
- After ... days of unsuccessful pairing replacement of first male by another male with proven fertility.
- Further matings after two unsuccessful attempts: no
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: Presence of a copulatory plug and/or sperm in the vaginal smearreferred to as day 0 of pregnancy
- Any other deviations from standard protocol:

Duration of treatment / exposure:

14 consecutive days

Duration of test:

18 weeks

Remarks:

Doses / Concentrations:
3
Basis:
nominal conc.
mg/mL

Remarks:

Doses / Concentrations:
10
Basis:
nominal conc.
mg/mL

Remarks:

Doses / Concentrations:
30
Basis:
nominal conc.
mg/mL

No. of animals per sex per dose:

25

Control animals:

yes

Details on study design:

- Dose selection rationale:Dosages were administered based on the concentration of the active moiety at a constant dose volume of 10 mL/kg (exceptions were documented).
- Rationale for animal assignment (if not random):
- Other:

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule:Mortality Minimum of twice daily (once on day of euthanasia)
- Cage side observations checked in table [No.?] were included.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule:Clinical Observations Minimum of once daily

BODY WEIGHT: Yes
- Time schedule for examinations:Male:twice weekly thereafter until euthanasia. Female:twice weekly until mating

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes / No / No data
- 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

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

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day #GD 21, 14 days after the end of the cohabitation period [if no prior evidence of copulation], or after delivery, elective euthanasia,or death)
- Organs examined:Included gross examination of abdominal and thoracic viscera.

OTHER:

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
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:

Statistics:

Body weight, body weight gain, food consumption, estrous cycles, fecundity parameters (mating index, fertility index, time to mating), gravid uterine weight, organ weight (testes, epididymides, seminal vesicles, prostate), hysterotomy parameters, fetal weight, fetal sex,and fetal examination findings

Indices:

• Two (2) control females (numbers 109 and 119)
• Eleven (11) 30 mg/kg/day females (numbers 130, 131, 132, 134, 135, 140, 143, 144, 145,147, and 150)
• Nine (9) 100 mg/kg/day females (numbers 154, 157, 161, 162, 163, 164, 166, 174, and 175), and
• Fifteen (15) 300 mg/kg/day females (numbers 176, 184, 186, 187, 188, 189, 190, 192, 193,194, 195, 196, 197, 198, and 200)

Details on maternal toxic effects:

Maternal toxic effects:yes

Dose descriptor:

other: NTEL

Effect level:

30 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: other:

Dose descriptor:

other: NTEL

Effect level:

< 30 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: other:

Dose descriptor:

other: NTEL

Effect level:

100 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: developmental toxicity

Abnormalities:

not specified

Developmental effects observed:

not specified

Conclusions:

DVS-233 treatment of both male and female rats resulted in disrupted estrous cycles and increased time-to-mating in all DVS-233 groups, decreased fertility rate at ≥ 100 mg/kg/day, and decreased litter size and fetal weight at 300 mg/kg/day. Decreased prostate weights (all DVS-233 groups) and prostate atrophy (≥ 100 mg/kg/day) occurred in males after 18 weeks of treatment. The No Toxicological Effect Level (NTEL) for effects on fertility was 30 mg/kg/day. Although an NTEL was not identified for compound-related changes in estrous cycles and for increased time-to-mating, these effects were likely related to the pharmacologic activity (increased serotonergic activity) of DVS-233. The NTEL for decreased prostate weight would be less than 30 mg/kg/day, a dosage that produced a plasma ODV exposure in males of 2882 ± 254 ng·hr/mL. The developmental NTEL was considered 100 mg/kg/day, based on an increase of preimplantation loss and reduced fetal weights at 300 mg/kg/day. Fetal morphological development was not affected by treatment with DVS-233 at any dosage.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

adverse effect observed

Study duration:

subacute

Species:

rat

Quality of whole database:

1 (reliable without restriction)

Additional information

Justification for selection of Effect on developmental toxicity: via oral route:
OECD GLP study run to current guidelines with no protocol deviations