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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:
19th March to 16th May 1985
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study to GLP.

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1987
Report Date:
1987
Reference Type:
study report
Title:
Unnamed
Year:
1985
Report Date:
1985

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
not specified
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Phenol, (tetrapropenyl) derivatives (CAS No. 27193-86-8) . Assume 100% for purposes of formulating dosing solutions

The identity, strength, purity and composition; and synthesis, fabrication, and/or derivation of the test substance have been documented by the sponsor.
The stability of the test substance has been determined by the sponsor.

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc.
- Age at study initiation: At mating initiation males were 41 weeks old and females were 56 days old
- Weight at study initiation: At mating initiation 157.9-286.3 g
- Housing: Individually, except during the first week of the acclimation period (2 females/cage) and mating, in stainless steel suspended cages with wire mesh floors.
- Diet (e.g. ad libitum): Purina certified Rodent Chow No. 5002 (mash form) fed ad libitum.
- Water (e.g. ad libitum): Tap water delivered by an automatic watering system, ad libitum (Elizabethtown Water Company).
- Acclimation period: 21 days for females; 19th March through 8th April for males.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 69-75°F
- Humidity (%): 30-80%
- Photoperiod (hrs dark / hrs light): 12 hour light/dark cycle (7 AM to 7 PM) via automatic timer.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
The required amounts of the test material were weighed into appropriately labeled 100 ml volumetric flasks. Mazola corn oil was then added to the flasks to bring each to a volume of 100 ml. A magnetic stir bar was placed into each flask. The flasks were then placed on a magnetic stir plate and stirred for at least 30 minutes each. Each solution and stir bar was then poured into an appropriately labeled beaker.
Solutions were prepared fresh daily and were stirred fur several minutes prior to and during dosing.

VEHICLE
Mazola corn oil
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Homogeneity/stability analyses of dosing solutions were performed at each dose level prior to the initiation of the study. In addition, 10 ml samples of dosing solutions at each dose level were taken on one day of each week of treatment and analyzed to confirm dose level concentration. All analyses were performed by the Department of Metabolism and Analytical Chemistry of Bio/dynamics, Inc.
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused: The evenings for co-habitation of males with females were Scheduled to provide females at Day 20 sacrifice during the Monday-to-Friday work week. The number of females caged nightly was also controlled to limit the number of mated females sorted into groups on a particular day. In this study, the maximum number of mated females sorted into groups on a particular day was 13. When the number of females mated after an evening exceeded the number to be sorted among the groups that day, females excluded from the sorting procedure were determined using a random numbers table and the female's temporary cage card number.
- M/F ratio per cage:1:1
- Length of cohabitation: Mating was conducted on 12 days as follows:
9, 10, 12, 15 through 19 and 22 through 25 April 1985.
- Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as day 0 of pregnancy
Duration of treatment / exposure:
days 6 - 15 of gestation
Frequency of treatment:
Females only, Once/day, Treated from Gestation Day 6 through 15
Duration of test:
days 6 - 15 of gestation
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 20, 100 and 300 mg/kg/day
Basis:
actual ingested
No. of animals per sex per dose:
24 females
Control animals:
yes, concurrent vehicle
Details on study design:
No data

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily (morning and afternoon) for signs of pharmacologic or toxicologic effects and mortality.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Each female was given a detailed physical examination on Days 0, 6, 10, 12, 15 and 20 of gestation.

BODY WEIGHT: Yes
- Time schedule for examinations: Recorded on Days 0, 6, 10, 12, 15 and 20 of gestation.

FOOD CONSUMPTION: Yes
Recorded for the following intervals during gestation: 0-6, 6-10, 10-15 and 15-20 of gestation.

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20 of gestation. Lethal exposure to ether.
- Organs examined: Complete gross post-mortem examinations were performed on all mated females including those dying spontaneously. External surface, all orifices, the cranial cavity, carcass, the external surface of the spinal cord and sectioned surfaces of the brain, nasal cavity and paranasal sinuses, the thoracic, abdominal and pelvic cavities and their viscera and the cervical tissues and organs were examined for all animals, The carcass of each female was discarded at completion of the gross postmortem evaluation.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
The intact uterus (ovaries attached) was removed from the abdominal cavity and the number and location of the following were recorded for each uterine horn:
live fetuses
dead fetuses (no evidence of tissue degeneration)
late resorptions (recognizable dead fetus undergoing degeneration regardless of size)
early resorptions (evidence of implantation but no recognizable fetus)
implantation sites

The ovaries were dissected free from the uterus and evaluated for the presence and number of corpora lutea.

Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes
- Head examinations: Yes: half per litter
Statistics:
Data were analyzed between control (Group I) and treated groups (Groups II, III and V).
Indices:
No data
Historical control data:
The laboratory has historical control data in regard to teratological parameters for this strain of rat and data that this strain is also responsive to a known animal teratogen (acetylsalicylic acid).

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
At the 20 & 100 mg/kg/day dose level, no maternal or developmental toxicity was seen.
At the 300 mg/kg/day dose level, obvious maternal toxicity was seen by statistically significant reductions in mean weight gain and mean food consumption during the treatment period. Mean weight gain for the high-dose females during the Day 15-20 post-treatment interval of gestation was also significantly lower than control. During the physical in-life evaluations, the incidence of high-dose females with soft stool was increase at gestation, days 10 and 15 of the treatment period and at day 20.

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
At the 20 & 100 mg/kg/day dose level, no maternal or developmental toxicity was seen.
At the 300 mg/kg/day dose level an embryotoxic effect was evident by an increase in uterine resorption data. Fetotoxicity at the high-dose level was evident by lower fetal weight data and an increased incidence of fetuses with ossification variations. A review of the types of ossification variations noted at this dose level and the incidence of fetuses with these variations indicated a retardation in ossification. During the fetal external examinations, three fetuses from one high-dose litter had cleft palates and two fetuses (one fetus from each of two different litters) had similar digit reduction defects (i.e., ectrodactyly); however, the incidence of high-dose fetuses with external malformations (1.9% 4/214 fetuses) did not differ statistically from the control data. No increase in malformation rate was seen among the high-dose fetuses from the visceral examination. At skeletal examination, the incidence of high-dose fetuses with malformations (22.3%) was statistically higher than the control data, The skeletal malformation seen with greatest frequency among the high-dose fetuses was wavy rib. This observation was seen in 22 high-dose fetuses (21.4%). Wavy rib is seen at low frequency in the Day 20 rat fetus at our laboratory. More significant than the "wavy rib" malformation was the occurrence of malformations involving a curved scapula and/or scapular spine and abnormally shaped long bones (humerus, ulna, radius and femur) seen in several of these same fetuses. A total of 11 high-dose fetuses (10.7%) from six litters (26.1%) had major skeletal malformations involving the shape of the scapula and/or the shape of one or more of the long bones. The increase in incidence of fetuses with defects involving the scapula and/or long bones and the similarity in type of defects seen among several fetuses from different litters are noteworthy; however, it is not clear if this is indicatve of a teratogenic response or is secondary to maternal toxicity seen at this dose level.

Effect levels (fetuses)

open allclose all
Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: embryotoxicity
Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: fetotoxicity
Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: teratogenicity

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
100 mg/kg/day was considered to be the NOEL for maternal toxicity, embryotoxicity, fetotoxicity and teratogenicity. At 300 mg/kg/day the test material was maternally toxic, embryotoxic and fetotoxic. An increase in malformation rate was seen at the high dose level however, it is not clear if this was a direct effect or secondary to maternal toxicity.
Executive summary:

This study was conducted for Monsanto Company to evaluate the embryotoxic, fetotoxic and/or teratogenic potential of the test material in the pregnant CD rat. Test material was dissolved in corn oil and administered by gastric intubation during the Day 6-15 gestation interval; dosing solutions were prepared fresh daily. Dose levels were 20, 100 and 300 mg/kg/day (these dose levels were derived from a pilot study conducted at this laboratory Biodynamics Project No. 84-2882).

Included in the study was a vehicle (corn oil)-treated control group. Each study group contained 24 mated females.

Initially, the protocol designated a high-dose level of 500 mg/kg/day; however, this group was terminated due to excessive maternal mortality (31.3%). No maternal mortality occurred in the control group or in the groups treated at 20, 100 or 300 mg/kg/day.

Pregnancy rates for the control, low- and high-dose groups were 100% and 95.8% (23/24 females pregnant) for the mid-dose group.

The test material administered at a dose levels of 20 and 100 mg/kg/day to pregnant CD rats for the Day 6-15 gestation interval was not considered to be maternally toxic, embrytoxic, fetotoxic or teratogenic. At the 300 mg/kg/day dose level, the test material was maternally toxic, embryotoxic and fetotoxic. An increase in malformation rate was seen among fetuses recovered at the 300 mg/kg/day dose level; however, it is not clear if this was a direct effect or secondary to treatment (i.e., maternal toxicity).