Registration Dossier

Data platform availability banner - registered substances factsheets

Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Toxicological information

Developmental toxicity / teratogenicity

Currently viewing:

Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
20th January 1986 to 13th February 1986
Reliability:
1 (reliable without restriction)

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1986

Materials and methods

Test guideline
Guideline:
other: In accordance with standard operating procedures
GLP compliance:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
Ammonium 7-(2,6-dimethyl-8-(2,2-dimethylbutyryloxy)-1,2,6,7,8,8a-hexahydro-1-naphthyl)-3,5-dihydroxyheptanoate
EC Number:
404-520-2
EC Name:
Ammonium 7-(2,6-dimethyl-8-(2,2-dimethylbutyryloxy)-1,2,6,7,8,8a-hexahydro-1-naphthyl)-3,5-dihydroxyheptanoate
Cas Number:
139893-43-9
Molecular formula:
C25 H43 O6 N
IUPAC Name:
ammonium 7-{8-[(2,2-dimethylbutanoyl)oxy]-2,6-dimethyl-1,2,6,7,8,8a-hexahydronaphthalen-1-yl}-3,5-dihydroxyheptanoate
Test material form:
solid: particulate/powder

Test animals

Species:
rat
Strain:
Sprague-Dawley
Remarks:
crl:CD [SD] BR
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Wilmington, MA
- Age at study initiation: 14.5 wks
- Weight at study initiation: 218 - 317g
- Housing: females housed singly in metal cages
- Diet: Purina Certified Rodent Chow #5002
- Water: Tap Water

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-27
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: aqueous methyl-cellulose
Details on exposure:
Suspension of MK-0733 in 0.5% aqueous methyl-cellulose prepared daily.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Samples of suspensions for oral dosing were collected during the first and last weeks of dosing and assayed for concentration.
Details on mating procedure:
Each female was housed with one untreated male of the same strain. Females were selected for study when daily vaginal lavage revealed the presence of spermatozoa (Day 0 of gestation).
Duration of treatment / exposure:
Days 6 through 17 of gestation
Frequency of treatment:
Animals were dosed twice daily with a minimum of 4 hours between each dose.
Duration of test:
11 days
Doses / concentrationsopen allclose all
Dose / conc.:
3.125 mg/kg bw/day (nominal)
Dose / conc.:
6.25 mg/kg bw/day (nominal)
Dose / conc.:
12.5 mg/kg bw/day (nominal)
No. of animals per sex per dose:
25
Control animals:
yes, concurrent no treatment

Examinations

Maternal examinations:

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: animals were observed for physical signs at dosing, 5 hours post-dosing and once daily thereafter

BODY WEIGHT: Yes
- Time schedule for examinations: Days 0, 6, 8, 10, 12, 14, 16, 18 and 20 of gestation.

FOOD CONSUMPTION AND COMPOUND INTAKE: Yes
Measured every third day, starting Day 3 of gestation.

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 20
- Organs examined: skin, haircoat, thoracic and abdominal viscera.
Ovaries and uterine content:
The uterus was examined to determine the reproductive status (pregnant/non-pregnant).
Fetal examinations:
Fetuses were examined and classified as live, dead or resorption. Gross necropsy was carried out.
All fetuses were weighed and examined externally. Approximately one third of fetuses from each litter were given a visceral examination by dissection.
Statistics:
Statistical analyses were based on analysis of variance or covariance using a Least Significant Difference (LSD) procedure after normalising for non-parametric data by the Rankit method.

Parameters:

Maternal body weight changes

Percent preimplantation loss (litter mean)

Implants per pregnant female

Resorptions plus dead fetuses / implants (litter mean)

Live fetuses / pregnant female

Live fetal weight (litter mean) adjusted for litter size by covariant analysis

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 consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined

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
Dead fetuses:
no effects observed

Effect levels (maternal animals)

Key result
Dose descriptor:
NOEL
Effect level:
6.25 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
body weight and weight gain

Maternal abnormalities

Key result
Abnormalities:
no effects observed

Results (fetuses)

Fetal body weight changes:
effects observed, treatment-related
Description (incidence and severity):
There was a significant (P<0.05) decrease of 0.21g (5.4% less than control) in the mean fetal weight of the 12.5 mg/kg bw group.
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
not examined
Changes in litter size and weights:
no effects observed
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed

Effect levels (fetuses)

Key result
Dose descriptor:
NOEL
Effect level:
6.25 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
fetal/pup body weight changes

Fetal abnormalities

Key result
Abnormalities:
no effects observed

Overall developmental toxicity

Key result
Developmental effects observed:
no
Treatment related:
no

Applicant's summary and conclusion

Conclusions:
There was no evidence of a teratogenic effect at dose levels up to 12.5 mg/kg b.i.d in rats receiving MK-0733 orally. A slight but significant (P<0.05) decrease in mean fetal body weight occurred in the 12.5 mg/kg b.i.d. group. This effect is considered probably treatment related but it is clear that no other indications of embryotoxicity were apparent.
Maternal toxicity was not seen in this study. Based on this data, the no-effect level for maternal and embryotoxicity in rats given MK-0733 is 6.25 mg/kg b.i.d
Executive summary:

The objective of the study was to assess the teratogenic effect of MK-0733 when adminstered to rats orally from Day 6 through 17 of gestation. A suspension of MK-0733 in 0.5% aqueous methyl-cellulose was prepared to give dose rates of 3.125, 6.25 and 12.5 mg/kg b.i.d. Rats were treated twice daily by oral gavage. Animals were observed for physical signs and body weights were recorded at 6, 8, 10, 12, 14, 16, 18 and 20 days gestation. Food consumption was recorded every third day. 


On day 20, animals were sacrificed and their reproductive status determined. Fetuses were examined and classified as live, dead or resorption. Gross necropsy was carried out. All fetuses were weighed and examined externally. Approximately one third of fetuses from each litter were given a visceral examination by dissection.


Maternal body weight changes, Percent preimplantation loss (litter mean), Implants per pregnant female, Resorptions plus dead fetuses / implants (litter mean), Live fetuses / pregnant female, and Live fetal weight (litter mean) were measured.  


There was no evidence of a teratogenic effect at dose levels up to 12.5 mg/kg b.i.d in rats receiving MK-0733 orally. A slight but significant (P<0.05) decrease in mean fetal body weight ocurred in the 12.5 mg/kg b.i.d. group. This effect is considered probably treatment related but it is clear that no other indications of embryotoxicity were apparent.
Maternal toxicity was not seen in this study. Based on this data, the no-effect level for maternal and embryotoxicity in rats given MK-0733 is 6.25 mg/kg b.i.d