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EC number: 253-733-5 | CAS number: 37971-36-1
Developmental toxicity / teratogenicity
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.
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 984
- 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
- 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.
Constituent 1
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 / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day
- Remarks:
- Control group
- Dose / conc.:
- 100 mg/kg bw/day
- Dose / conc.:
- 300 mg/kg bw/day
- Dose / conc.:
- 1 000 mg/kg bw/day
- 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
General toxicity (maternal animals)
- Clinical signs:
- no effects observed
- Dermal irritation (if dermal study):
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- not specified
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not specified
- 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:
- not examined
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- no effects observed
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
- Early or late resorptions:
- no effects observed
- Dead fetuses:
- no effects observed
- Changes in pregnancy duration:
- not examined
- Changes in number of pregnant:
- no effects observed
- Details on maternal toxic effects:
- Maternal toxic effects:no effects
Details on maternal toxic effects:
NA - no effects
Effect levels (maternal animals)
- Key result
- Dose descriptor:
- NOEL
- Effect level:
- 1 000 mg/kg bw/day (nominal)
- Basis for effect level:
- other: maternal toxicity
Maternal abnormalities
- Key result
- Abnormalities:
- no effects observed
Results (fetuses)
- Fetal body weight changes:
- no effects observed
- Reduction in number of live offspring:
- no effects observed
- Changes in sex ratio:
- no effects observed
- Changes in litter size and weights:
- no effects observed
- Changes in postnatal survival:
- not examined
- External malformations:
- no effects observed
- Skeletal malformations:
- no effects observed
- Visceral malformations:
- no effects observed
- Other effects:
- no effects observed
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects: no effects
Details on embryotoxic / teratogenic effects:
NA - no effects
Effect levels (fetuses)
open allclose all
- Key result
- Dose descriptor:
- NOEL
- Effect level:
- 1 000 mg/kg bw/day (nominal)
- Basis for effect level:
- other: teratogenicity
- Key result
- Dose descriptor:
- NOEL
- Effect level:
- 1 000 mg/kg bw/day (nominal)
- Basis for effect level:
- other: embryotoxicity
- Key result
- Dose descriptor:
- NOEL
- Effect level:
- 1 000 mg/kg bw/day (nominal)
- Basis for effect level:
- other: fetotoxicity
Fetal abnormalities
- Key result
- Abnormalities:
- no effects observed
Overall developmental toxicity
- Key result
- Developmental effects observed:
- no
Any other information on results incl. tables
Weight gain during pregnancy
| Group | Mean weight gain of pregnant animals in gramm during |
|
| Application | Total pregnancy | |
| Control | 24.7 | 83.7 |
| 100 mg/kg bw | 20.9 | 72.3 |
| 300 mg/kg bw | 23.0 | 82.3 |
| 1000 mg/kg bw | 22.2 | 81.7 |
Results on insemination and fertilisation
| Inseminated females | Fertilised total | Females in % of insemination | Pregnant total | Females in % of fertilisation | |
| Control | 25 | 19 | 76.0 | 19 | 100.0 |
| GRP. 1 | 25 | 20 | 80.0 | 20 | 100.0 |
| GRP. 2 | 25 | 24 | 96.0 | 22 | 91.7 |
| GRP. 3 | 25 | 23 | 92.0 | 22 | 95.7 |
Number of fetuses and examination method
| Total number of fetuses | Examination according to Wilson | Bone staining | |
| Control | 198 | 60 | 138 |
| GRP. 1 100 mg/kg | 183 | 55 | 128 |
| GRP.2 300 mg/kg | 255 | 77 | 178 |
| GRP.3 1000 mg/kg | 232 | 67 | 165 |
Effect of Bayhibit AM on pregnant rats and their fetuses
| Group | Weight gain during (G) | Number (per dam) of fetuses | Mean weight (G) | No. of fetuses examined by | Fetuses with | Runts | ||||||||
| Pregnancy | Treatment | Implant | Male | Female | Sum | Losses | Foetus | Placent. | Wilson | Dawson | Minor skeletal deviat. |
Malfor- mations |
< 3 G | |
Control |
83.7 13.8 |
24.7 4.7 |
10.8 2.4 |
4.9 1.7 |
5.5 1.7 |
10.4 2.3 |
0.4 0.6 |
3.61 0.50 |
0.59 0.05 |
3.16 0.83 |
7.26 1.59 |
2.32 1.77 |
0.0 0.0 |
0.68 1.45 |
GRP.1 |
72.3 22.4 |
20.9 7.6 |
10.8 1.6 |
4.9 2.0 |
4.2* 1.6 |
9.1 2.8 |
1.7 3.0 |
3.47 0.34 |
0.50 0.06 |
2.75 0.91 |
6.40 1.93 |
2.10 1.89 |
0.05 0.22 |
0.40 0.68 |
GRP.2 |
82.3 21.7 |
23.0 5.5 |
11.4* 2.6 |
5.2 2.4 |
5.5 2.4 |
10.6 3.7 |
0.8 1.3 |
3.39 0.28 |
0.59 0.08 |
3.50 0.74 |
8.09 1.11 |
3.82* 2.34 |
0.09 0.29 |
1.18 2.65 |
GRP.3 |
81.7 10.8 |
22.2 5.4 |
10.9 2.6 |
5.3 2.0 |
4.8 2.0 |
10.1 2.8 |
0.8 1.0 |
3.52 0.22 |
0.58 0.06 |
3.05 0.79 |
7.50 1.10 |
2.95 1.99 |
0.05 0.21 |
0.32 0.78 |
* Significant difference to control (P < 0.05)
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 a 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 teratogenic effects in rats.
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