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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1984-01 until 1984-02
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: No analytical verification of the test substance was performed.
Cross-referenceopen allclose all
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to other study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1984
Report date:
1984

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
, the test substance was administered daily from day 6-15 of pregnancy (organogenesis period) instead of day 5-19 of pregnancy
Principles of method if other than guideline:
See above, deviations.
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
2-phosphonobutane-1,2,4-tricarboxylic acid
EC Number:
253-733-5
EC Name:
2-phosphonobutane-1,2,4-tricarboxylic acid
Cas Number:
37971-36-1
Molecular formula:
C7H11O9P
IUPAC Name:
2-phosphonobutane-1,2,4-tricarboxylic acid
Details on test material:
- 49.11% 2-Phosphonobutan-tricarbonacid-1,2,4 in water
- Lot / batch: 226/83
- Identity, stability and homogeneity were tested.

Test animals

Species:
rat
Strain:
Wistar
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: sexually mature
- Weight at study initiation: Males-above 300 gr. Females-189-231 gr.
- Fasting period before study: Not indicated
- Housing: Makrolon cages type III (males), type II (females)
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: Not directly mentioned. At least 6 days before exposure to the test substance ( the test substance is given in the 6th day of pregnancy)


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22
- Humidity (%): 40%
- Air changes (per hr): Not mentioned
- Photoperiod (hrs dark / hrs light): 12 / 12 hours rhythm


Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
DIET PREPARATION
- Rate of preparation of diet (frequency): NA
- Mixing appropriate amounts with (Type of food): NA
- Storage temperature of food: NA


VEHICLE: Water
- Justification for use and choice of vehicle (if other than water): NA
- Concentration in vehicle: Test substance was dissolved in water and given in volume of 10 mL/kg to a final concentrations of 100 mg/kg bw, 300mg/kg bw, 1000 mg/kg bw
- Amount of vehicle (if gavage): See above
- Lot/batch no. (if required): Not required
- Purity: NA
Analytical verification of doses or concentrations:
no
Details on analytical verification of doses or concentrations:
NA
Details on mating procedure:
Cohoused:
- M/F ratio per cage: 1 male / 2 females
- Length of cohabitation: over night
- Proof of pregnancy: sperm in vaginal smear, referred to as day 0 of pregnancy
Duration of treatment / exposure:
BAYHIBIT-AM was administrated from the 6th-15th day of pregnancy
Frequency of treatment:
Daily treatment
Duration of test:
20 days. At day 20 of pregnancy, embryos were taken out by abdominal delivery (cesarian surgery).
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 100, 300, 1000 mg/kg bw/day
Basis:
nominal in water
No. of animals per sex per dose:
25 Wistar rats per group (4 groups)
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale: NA
- Rationale for animal assignment (if not random): Random

Examinations

Maternal examinations:
- Time schedule: Daily examination for changes in appearance and behaviour of the pregnant rats in all the four groups (control and other 3 different test substance concentration groups)
- Time schedule for examinations: During the whole pregnancy period
- Time schedule for examinations: Daily, by gavage.





Ovaries and uterine content:
Examinations included:
- Gravid uterus weight: No
- Number of corpora lutea: No
- Number of implantations: Yes
- Number of early resorptions: No data
- Number of late resorptions: Yes
- Other: Weight of placenta
Fetal examinations:
- External examinations: Yes
- Soft tissue examinations: Yes
- Skeletal examinations: Yes
- Head examinations: No data
Statistics:
For the statistic calculations of the loss of weight, number of implantation and resorptions the WILCOXON-MANN-WHITNEY-U-TEST was used.
The Chiquadrat-Test was used for the statistic calculations of the embryotoxicity parameters
If not specified differently, the significant difference to control is under 5%.
Indices:
Examination for visceral modifications was according the modification of the WILSON technique.
The examination of the bones was done according to the DAWSON technique
Historical control data:
NA

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:no effects

Details on maternal toxic effects:
NA - no effects

Effect levels (maternal animals)

Dose descriptor:
NOEL
Effect level:
1 000 mg/kg bw/day (nominal)
Basis for effect level:
other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
NA - no effects

Effect levels (fetuses)

open allclose all
Dose descriptor:
NOEL
Effect level:
1 000 mg/kg bw/day (nominal)
Basis for effect level:
other: teratogenicity
Dose descriptor:
NOEL
Effect level:
1 000 mg/kg bw/day (nominal)
Basis for effect level:
other: embryotoxicity
Dose descriptor:
NOEL
Effect level:
1 000 mg/kg bw/day (nominal)
Basis for effect level:
other: fetotoxicity

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

No remarks.

Applicant's summary and conclusion

Conclusions:
No Maternal toxicity, no teratogenicity, no embryotoxicity under study conditions
Executive summary:

After oral application of BAYHIBIT-AM (2 -phosphonobutane-1,2,4 -tricarboxylic acid) up to maximal dosage of 1000 mg/kg no signs of maternal toxicity were found (by means of death, weight loss, changes in appearance and behaviour). Moreover, female mother rats were proved later to be fertile. No influence was observed in embryo and foetus development (resorption, placenta weight, any skeletal and internal malformation). The NOEL value for these effects is therefore determined as 1000 mg/kg bw/day.

Under the experimental conditions, the test item is considered to have no maternal and embryonic toxic effects and no teratogenicity effects in rats.

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