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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:
16 February 1998 to 14 April 1998
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1998
Report date:
1998

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Details on test material:
- Name of test material (as cited in study report): CGF-C-1607
- Physical state: solid, yellow
- Analytical purity: >98%
- Lot/batch No.: 6
- Stability under test conditions: at least 2 hours
- Storage condition of test material: closed container at room temperature

Test animals

Species:
rat
Strain:
Wistar
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: BRL, Biological Research Laboratories, Ltd.; Wölferstrasse 4, CH-4414 Füllinsdorf, Switzerland
- Age at study initiation: 11 weeks minimum at pairing
- Weight at study initiation: 180 - 263 g
- Housing: individually (except during mating) in Makrolon cages (type 3) with granulized soft wood bedding.
- Diet (e.g. ad libitum): Pelleted standard Kliba 3433 rat/mouse maintenance diet, ad libitum
- Water (e.g. ad libitum): tap, ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/-3
- Humidity (%): 40 - 70
- Air changes (per hr): 10 - 15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 16 February 1998 To: 14 April 1998

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
polyethylene glycol
Remarks:
PEG 400
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: The test article was placed into a glass beaker on a tared Mettler PM 460 balance and the vehicle added. A weight by volume dilution was prepared using a mortar and pestle and a magnetic stirrer as homogenizer. Homogeneity of the test article in the vehicle was maintained during treatment.

VEHICLE
- Concentration in vehicle: 0, 10, 30, & 100 mg/ml
- Amount of vehicle (if gavage): 10 ml/kg-bw
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Concentration, homogeneity and stability of the test article/ vehicle mixtures were determined in samples taken during the first week of treatment in the subchronic 90-day toxicity (gavage) study in the rat (RCC Project 667541). During the dosing period of this study, additional samples for confirmation of concentration, homogeneity and stability were taken on two occasions immediately after preparation and again 2 hours later. Analyses were performed by the RCC Umweltchemie, using a HPLC method.
Details on mating procedure:
After acclimatization, the females were placed in cages with sexually mature males (1:1) until evidence of copulation was observed. The females were removed and caged individually if:
a) the daily vaginal smear was sperm-positive, or
b) a copulation plug was observed.
The day of mating was designated day 0 post coitum. The male rats used for mating are in the possession of RCC. The fertility of these males was proved and was continuously controlled.
Duration of treatment / exposure:
day 6 through to day 17 post coitum
Frequency of treatment:
Once daily
Duration of test:
until day 21 post coitum
Doses / concentrationsopen allclose all
Dose / conc.:
100 mg/kg bw/day (nominal)
Dose / conc.:
300 mg/kg bw/day (nominal)
Dose / conc.:
1 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
22
Control animals:
yes, concurrent vehicle
Details on study design:
Dose selection rationale: Results of a 2 week range-finding study.

Examinations

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

BODY WEIGHT: Yes
- Time schedule for examinations: daily from day 0 until day 21 post coitum

FOOD CONSUMPTION: Yes
- Food consumption for each animal determined: Yes, for 4 time-periods (days 0-6, 6-12, 12-18, 18-21)

WATER CONSUMPTION: No

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day #21
- Gross macroscopic examination: all internal organs
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight
- Position of fetuses in the uterus
- Number of corpora lutea
- Number of implantations
- Number of early resorptions
- Number of late resorptions

If no implantation sites are evident, the uterus was placed in an aqueous solution of ammonium sulfide (Salewski et al) to accentuate possible hemorrhagic areas of implantation sites.
Fetal examinations:
- Gross external examinations: Yes, all per litter
- Soft tissue examinations: Yes, half per litter
- Skeletal examinations: Yes, half per litter

The fetuses were removed from the uterus, sexed, weighed individually, examined for gross external abnormalities and allocated to one of the following procedures:
1) Wilson's slicing technique for examination of the viscera and brain. One half of the live fetuses from each Iitter were fixed in a mixture of ethyl alcohol, formol and acetic acid. After examination the sections were preserved in a solution of ethyl alcohol and glycerine ( one fetus per container).
2) The remaining fetuses were placed in a solution of potassium hydroxide for clearing and stained with alizarin red S (modified technique; Dawson et al). The skeletons were examined.
Statistics:
The following statistical methods were used to analyse body weights, food consumption, reproduction and skeletal examination data:
- If the variables could be assumed to follow a normal distribution, the Dunnett many-one t-test, based on a pooled variance estimate, was used for intergroup comparisons (i.e. single treatment groups against the Control group)
- The Steel test (many-one rank test) was applied when the data could not be assumed to follow a normal distribution
- Fisher's Exact test for 2x2 tables was applied if the variables could be dichotomized without loss of information.
Indices:
Pre-implantation loss (%) = number of corpora lutea - number of implantations / number of corpora lutea x 100
Post-implantation loss (%) = number of implantations - number of live fetuses / number of implantations x 100
Sex ratio of males/females (%) = number of males/females / number of fetuses x 100

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
Soft feces, a common finding in animals treated orally with PEG 400, was noted in all animals from day 2 of treatment. This finding was observed up to day 18 post coitum (one day after the last dosing).
No other reaction to treatment were observed in any female of any group during the course of this study.
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Description (incidence and severity):
The differences in mean body weight gain amongst the control group and any dose group did not reveal any test article-related effect. In all groups the mean body weight gain and the mean corrected body weight gain (corrected for uterus weight) were similar.

The statistically significant differences in the mean body weights, which existed in the dams of the mid dose group after allocation on days 0, 1, 2 and 4 post coitum were the consequence of the randomisation procedure and therefore incidental.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
Intergroup comparison of the food consumption ratios did not provide any evidence for a test article-related effect on food consumption.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
The type and frequencies of the isolated common findings noted gave no indication of test article-related macroscopic changes and were considered to be incidental.

One female each in the low and mid dose group, which were not pregnant, had dark red discoloured ovaries. Another female in the mid dose had light brown foci in the left kidney.
In the high dose group, in one female the right uterine horn and ovary was missing, one female had a light brown nodule at the left kidney and one female had a yellowish, reddish nodule in the uterine adipose tissue on the right side.
No abnormal findings were noted in the females of the control group.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
not examined

Maternal developmental toxicity

Details on maternal toxic effects:
No differences amongst the mean reproduction data of the vehicle control group and any dose group were noted which were considered to be a test article-related effect.
The statistically significant increase of the post-implantation losses (embryonic resorptions) and the consequently statistically significant reduction of the number of fetuses (% of implantation sites) in the low and high dose groups were considered to be test article-unrelated for the following reasons:
- A dose-relationship was lacking.
- The data recorded on these parameters were within the ranges of historical control data of this rat strain.

Corpora lutea (mean): 13.9, 13.1, 13.4, 12.9 in control, low, mid and high dose respectively (HC range: 13.0-14.9)
Preimplantation loss (% of corp lutea): 6.9, 9.8, 11.0, 5.6 in control, low, mid and high dose respectively (HC range: 4.8-21.7)
Postimplantation loss (mean): 0.5, 1.7, 0.7, 1.1 in control, low, mid and high dose respectively (HC range: 0.5-1.7)
Postimplantation loss (% of impl. sites): 3.5, 14.5**, 6.0, 9.0** in control, low, mid and high dose respectively (HC range: 3.9-15.9)
Embryonic resorptions (mean): 0.4, 1.6, 0.6, 0.9 in control, low, mid and high dose respectively (HC range: 0.4-1.7)
Embryonic resorptions (% of impl. sites): 2.8, 13.7**, 5.2, 7.1** in control, low, mid and high dose respectively (HC range: 3.6-15.5)
Fetal resorptions (% of impl. sites): 0.7, 0.8, 0.8, 2.0 in control, low, mid and high dose respectively (HC range: 0.0-2.5)
Total fetuses (% of impl. sites): 96.5, 85.5**, 94.0, 91.0** in control, low, mid and high dose respectively (HC range: 84.1-96.1)
**Fisher´s Exact test significant at level 1%

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: no test substance related adverse effects observed

Results (fetuses)

Fetal body weight changes:
no effects observed
Description (incidence and severity):
There were no test article-related differences amongst the mean fetal body weights of the vehicle control group and any dose group.
The marginally increased values in all dose groups were the consequence of the incidentally lower mean number of fetuses per dam and not a test article-related effect.

Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.DescriptionIncidenceAndSeverityFetalPupBodyWeightChanges): see above
Reduction in number of live offspring:
no effects observed
Description (incidence and severity):
Dead fetuses: 0, 0, 0, 0 in control, low, mid and high dose respectively
Changes in sex ratio:
no effects observed
Description (incidence and severity):
The comparison of the sex ratios from all groups gave no indication of test article-related effects. All values were within the ranges of the historical control data.
Changes in litter size and weights:
no effects observed
Description (incidence and severity):
Weights (mean on a litter base, both sexes): 4.5, 4.7, 4.7, 4.7 in control, low, mid and high dose respectively
Changes in postnatal survival:
not examined
External malformations:
effects observed, non-treatment-related
Description (incidence and severity):
At external examination of the fetuses, no indication for test article-related effects were ascertained.
Agnathia was noted in one out of 274 fetuses of the control group and in one out of 236 fetuses of the mid dose group 3. No abnormal findings were noted in the 213 fetuses of the low dose group or in the 232 fetuses
of the high dose group.
Skeletal malformations:
no effects observed
Description (incidence and severity):
Neither the type nor the incidence of the abnormal findings noted indicated test article-related effects.
The frequencies of common abnormal findings (abnormally shaped stemebrae or wavy ribs) were within the normal range of variation for fetuses of this rat strain and considered to be incidental.

No test article-related differences in the stage of skeletal development amongst the fetuses of the vehicle control and these of the dose groups were noted. All statistically significant differences demonstrate higher stages of skeletal development in the dose groups as consequence of the reduced number of fetuses per dam.
Visceral malformations:
effects observed, non-treatment-related
Description (incidence and severity):
In the fetus with agnathia in the control group (noted at external examination), in addition cleft palate was ascertained and in the fetus with agnathia in the mid dose group, microphthalmia (both eyes) and absence of the tongue were noted.
No further abnormal findings were noted in the fetuses of the control and mid dose groups and no abnormal findings were evident in the fetuses of the low and high dose groups.
Other effects:
not examined

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day
Sex:
male/female
Basis for effect level:
other: no test substance related adverse effects observed

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Up to and including a dose level of 1000 mg/kg body weight/day, administration of CGF-C-1607 did not influence the development of dams, embryos or fetuses.
Executive summary:

The purpose of this study was to detect effects on the pregnant female and development of the embryo and fetus consequent to exposure of the female to the test article from implantation to closure of the hard palate. Each group consisted of 22 mated female rats. CGF-C-1607 was administered orally by gavage once daily from day 6 through to day 17 post coitum at dose levels of 0, 100, 300, and 1000 mg/kg-bw/day. A standard dose volume of 10 mg/kg body weight with a daily adjustment to the actual body weight was used. Control animals were dosed with the vehicle, polyethylene glycol (PEG 400). Females were sacrificed on day 21 post coitum and the fetuses were removed by Caesarean section. The examination of the dams and fetuses was performed in accordance with international recommendations.

 

There were no deaths during the course of this study and with the exception of soft feces (a common finding in animals treated orally with PEG 400) no clinical signs or reaction to treatment were observed in any female of any group. Intergroup comparison did not provide any evidence for test article-related effects on food consumption or body weight development. During necropsy, no test article-related macroscopic changes were noted.

 

The differences amongst the reproduction data (post-implantation loss, number of implantations and fetuses) of the vehicle control group and the dose groups gave no indication of test article related effects. Small differences noted were within the normal range of variation for animals of this strain and age and were considered to be incidental.

 

The mean body weights of fetuses, the ratio of male and female fetuses and the results of external, visceral and skeletal examinations of fetuses gave no indication of effects caused by administration of the test article.