Registration Dossier

Toxicological information

Developmental toxicity / teratogenicity

Currently viewing:

Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1995

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Qualifier:
according to
Guideline:
other: EPA TSCA Test Guidelines (401 CFR Parts 796, 797, 798: 798.4900 Developmental Toxicity Study, September 27, 1985, and Revised Edition May 20, 1987)
Qualifier:
according to
Guideline:
other: EC guidelines (Commision Directive 88/302/EEC, Official Journal of the European Communities L 133, May 30, 1988).
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
purity: 99,83 %

Test animals

Species:
rat
Strain:
Wistar

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Analytical verification of doses or concentrations:
yes
Details on mating procedure:
The animals were mated by placing two females in a Type III cage with one male rat overnight. If sperm was found in a vaginal smear taken on the morning following mating, this day was regarded as day 0 of gestation.
Duration of treatment / exposure:
from day 6 to day 15 p.c.
Frequency of treatment:
daily
Duration of test:
The fetuses were delivered by cesarian section on the 20th day of gestation.
Doses / concentrationsopen allclose all
Dose / conc.:
25 mg/kg bw/day (actual dose received)
Dose / conc.:
125 mg/kg bw/day (actual dose received)
Dose / conc.:
625 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
25/dose
Control animals:
yes, concurrent vehicle
Details on study design:
The dose levels were selected according to a preceding rang-finding study in 4-5 rats with doses of 300, 500, and 625 mg/kg bw/d.

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes, twice daily

DETAILED CLINICAL OBSERVATIONS: Yes, twice daily

BODY WEIGHT: Yes, on days 0, 6-15, and 20 pc

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
Ovaries and uterine content:
according to Guideline
Fetal examinations:
External, visceral and skeletal examination of the fetuses
Statistics:
Fisher's exact significance test for fertility rate and gestation rate
F-test and t-test or Welch t-test for feed intakes, body weight gains, number of corpora lutea per dam, implantations per dam, live fetuses per dam etc.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
The appearance and behavior of the dams was unaffected up to and including the dosage of 125 mg/kg.The dams of the 625 mg/kg group revealed clinical signs like bloddy mouth, staggering gait and ventral posture. The staggering gait and the ventral posture are considered to be a sign of the narcotic efficacy of TEP.
Mortality:
no mortality observed
Description (incidence):
one dam of the control group died on day 18 pc
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
body weight gains of the dams in the 625 mg/kg bw group statistically significant reduced between day 6-15 pc (15.1 versus 23.9 g in control) and day 0-20 corrected (24.5 versus 31.8 g); food consumption was lower in this dose group on day 6-11 pc.
Gross pathological findings:
no effects observed
Description (incidence and severity):
No treatment related findings were evident at necropsy up to and including the dose of 625 mg/kg bw.

Maternal developmental toxicity

Description (incidence and severity):
The number of corpora lutea, preimplantation losses and implantations were comparable in all experimental groups, with exception of the significantly lower preimplantation losses in the 25 mg/kg bw group.
Description (incidence and severity):
none
Description (incidence and severity):
the number of resorptions
Description (incidence and severity):
no changes
Description (incidence and severity):
No. of pregnants: 22, 20, 22, 20

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
125 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
clinical signs
body weight and weight gain

Maternal abnormalities

Abnormalities:
no effects observed

Results (fetuses)

Fetal body weight changes:
no effects observed
Description (incidence and severity):
none: fetal body weight. 3.48, 3.55, 3.59, 3.44 g in control, low, mid, high dose group
Reduction in number of live offspring:
no effects observed
Description (incidence and severity):
none: No. of fetuses per dam: 10.5, 11.6, 11.6, 10.6 in control, low, mid, high dose group
Changes in sex ratio:
no effects observed
External malformations:
no effects observed
Description (incidence and severity):
see Table
Skeletal malformations:
no effects observed
Description (incidence and severity):
see Table
Visceral malformations:
no effects observed
Description (incidence and severity):
see Table
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects
External, visceral and skeletal examination of the fetuses revealed no effects on intrauterine development

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
625 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no treatment related effects on development at any dose

Fetal abnormalities

Abnormalities:
no effects observed

Overall developmental toxicity

Developmental effects observed:
no

Any other information on results incl. tables

External, skeletal and visceral malformations in viable fetuses:

 Malformation  Dose (mg/kg b.w./day)         
   0  25  125  625
 fetuses/ (Litters Affected) (n)  -  -  -  -
 Microphtalmia  1  1  1  2 (2)
 Hydrocephalus internus  -  -  -  1
 Pelvis dislocated  1  -  -  -
 Malformation of vertebra  4 (3)  -  1  1
 Fusion of ribs  1  -  -  -
 Thickened cervical rib  1  -  -  -
 Malformation of forelimb bones  1  -  -  -
 Exoccipitale dysplastic  1  -  -  -
 Dislocation of atlanto-occipital joint (probably artifact +)  -  1  -  1
  Fetuses per group (n)  231  232  242  213
malformed fetuses (n)  7  2  2  5
  (%)  3,0  0,9  0,8  2,4
 Litters per Group (n)  22  20  22  20
 Litters with malformations (n)  5  2  1  3
  (%)  22,7  10,0  5,0  15,0

+ = nevertheless included in the calculation

some fetuses revealed more than one malformation, therefore the number of malformations does not necessarily reflect the number of fetuses affected.

Applicant's summary and conclusion

Executive summary:

In a developmental toxicity study following OECD 414 groups of 25 inseminated female Wistar rats per dose group were treated daily by gavage with TEP formulated in demineralised water from days 6 to day 15 p.c. in doses of 0, 25, 125 or 625 mg/kg body weight, respectively. The fetuses were delivered by cesarian section on day 20 of gestation.

The dams of the 625 mg/kg group revealed clinical signs like bloddy mouth, staggering gait and ventral posture. The staggering gait and the ventral posture are considered to be a sign of the narcotic efficacy of TEP.

Body weight gain (day 6 -15 p.c.), feed intake (day 6 -11p.c.) and accordingly the feces excretion were reduced in the 625 mg/kg group.

The intrauterine development was not affected by the treatment including external, visceral and skeletal examination of the fetuses. A teratogenic potential was not evident.

The NOAEL were:

Maternal toxicity: 125 mg/kg bw./day

Developmental toxicity: 625 mg/kg bw./day.