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EC number: 201-579-4 | CAS number: 85-00-7
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Developmental toxicity / teratogenicity
Administrative data
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 25 Apr 1988 to 03 Jun 1988
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Referenceopen allclose all
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 989
- Report date:
- 1989
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 989
- Report date:
- 1989
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 990
- Report date:
- 1990
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 995
- Report date:
- 1995
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Qualifier:
- according to guideline
- Guideline:
- EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
- Version / remarks:
- 1998
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.31 (Prenatal Developmental Toxicity Study)
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- Diquat dibromide
- EC Number:
- 201-579-4
- EC Name:
- Diquat dibromide
- Cas Number:
- 85-00-7
- Molecular formula:
- C12H12N2.2Br
- IUPAC Name:
- 1,1'-ethylene 2,2'-bipyridyldiylium dibromide
- Reference substance name:
- Water
- EC Number:
- 231-791-2
- EC Name:
- Water
- Cas Number:
- 7732-18-5
- Molecular formula:
- H2O
- IUPAC Name:
- water
- Test material form:
- liquid
Constituent 1
Constituent 2
Test animals
- Species:
- rabbit
- Strain:
- New Zealand White
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Age at study initiation: not reported
- Weight at study initiation: 3.11 - 4.03 kg
- Housing: Individually housed in mobile rabbit units
- Diet: CRB pellets, ad libitum
- Water: Drinking water, ad libitum
- Acclimation period: 6 - 7 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 26
- Humidity (%): 46 - 66
- Photoperiod (hrs dark / hrs light): 12/12
IN LIFE DATES: From 25 Apr 1988 To: 03 Jun 1988
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- other: Deionised water
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
Test substance was formulated in deionised water. The concentration of substance was adjusted to give a constant volume of 1 mL/kg body weight for each dose level. Aliquots of the dosing preparation solutions were stored at ambient conditions and fresh bottles were used for each day of the study. All animals were dosed once daily, by gavage, from days 7 - 19 inclusive of gestation with 1 mL of dosing formulation per kg body weight. The volume given to each animal was adjusted daily according to body weight. Control animals received the appropriate volume of deionised water. All animals receiving the same dose level were dosed sequentially but the order in which each group was dosed was rotated on a daily basis. Dosing was performed in the morning of each day. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- A sample of each bulk preparation was analysed prior to the start of dosing to verify the achieved concentration of substance in deionised water. Analysis was by dilution with water followed by HPLC.
- Details on mating procedure:
- Animals of proven fertility were used for this study. Semen was collected from each male using an artificial vagina. The volume of the sample obtained was measured and then diluted with sufficient physiological saline to inseminate one replicate. One mL of the diluted semen was inseminated into each female using a plastic catheter. Each replicate of females was inseminated with semen from one male. After insemination, each female was given an intravenous injection of 25 IU PROFASI 500 to promote ovulation. Any individual male inseminated a maximum of 16 females (4 replicates). The day of insemination was designated a day 1 of gestation.
- Duration of treatment / exposure:
- From Day 7 to Day 19 (inclusive) of gestation
- Frequency of treatment:
- Daily
- Duration of test:
- Until Day 30 of gestation
Doses / concentrationsopen allclose all
- Dose / conc.:
- 1 other: mg test substance cation/kg bw/day
- Remarks:
- Low dose. Group 2
- Dose / conc.:
- 3 other: mg test substance cation/kg bw/day
- Remarks:
- Mid dose. Group 3
- Dose / conc.:
- 10 other: mg test substance cation/kg bw/day
- Remarks:
- High dose. Group 4
- No. of animals per sex per dose:
- 20
- Control animals:
- yes, concurrent vehicle
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS
All animals were checked on arrival to ensure that they were physically normal externally and were subsequently checked daily.
BODY WEIGHT
The body weight of each animal was recorded on Days 1 and 4, 7 - 19 (inclusive) and on Days 22, 26 and 30 of gestation.
FOOD CONSUMPTION:
The amount of food consumed by each animal was measured by giving a weighed quantity of food on Days 1, 4, 7, 10, 13, 16, 19, 22 and 26 and calculating the amount consumed from the amount left on Days 4, 7, 10, 13, 16, 19, 22, 26 and 30 respectively.
POST-MORTEM EXAMINATIONS:
- Animals which aborted or were considered to be in extremis were killed by an intravenous injection of pentobarbitone sodium solution and given an examination post mortem. Pregnancy status was recorded.
- On Day 30 of gestation the remaining animals were killed by an intravenous injection of pentobarbitone sodium solution. An examination post mortem was performed on all animals. - Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
The intact gravid uterus (minus ovaries and trimmed free of connective tissue) was removed and weighed. The ovaries and uterus were then examined and the following data were recorded:
(1) Number of corpora lutea in each ovary.
(2) Number and position of implantations subdivided into: live foetuses, early intra-uterine deaths and late intra-uterine deaths.
Intra-uterine deaths were classified as early or late intra-uterine deaths.
The implantations were assigned letters of the alphabet to identify their position in utero starting at the ovarian end of the left horn and ending at the ovarian end of the right horn. - Fetal examinations:
- External examinations: Yes: Each foetus was examined for external abnormalities and cleft palate.
Soft tissue examinations: Yes: All foetuses were then examined internally for visceral abnormalities, sexed, eviscerated and fixed in methanol. After approximately 24 hours the head of each foetus was cut along the fronto-parietal suture line and the brain was examined for macroscopic abnormalities
Skeletal examinations: Yes: The carcasses were then returned to methanol for subsequent processing and staining with Alizarin Red S. The stained foetal skeletons were examined for abnormalities and the degree of ossification was assessed. The individual bones of the manus and pes were assessed and the result converted to a five point scale. Abnormalities were classified as major (rare or possibly lethal or both) or minor (deviations from normal that are not uncommon at external visceral or skeletal examination) defects. Variations were also recorded and classified as minor defects or variants depending on the frequency of occurrence in relation to background data
Head examinations: Yes. - Statistics:
- Data relating to animals which were killed in extremis, were non-pregnant or aborted were excluded from the statistical analysis. The following data were considered by analysis of variance:
- Maternal body weight gain
- Maternal food consumption
- The numbers of implantations and live foetuses per female.
- Percentage pre-implantation loss and percentage post-implantation loss
The percentage pre-implantation loss and post-implantation loss were transformed before analysis using the double arcsine transformation of Freeman and Tukey (1950). The analyses of variance were weighted by the denominator in the proportion.
The percentage of implantations which were early intra-uterine deaths and the percentage of implantations which were late intra-uterine deaths (both calculated on an individual litter basis). The percentages were transformed before analysis using the double arcsine transformation and the analysis of variance was weighted by the number of implantations in each litter.
Gravid uterus weight, litter weight and mean foetal weight (calculated on an individual litter basis). The analysis of mean foetal weight was weighted by the number of foetuses in each litter.
Mean manus and pes score per foetus (calculated on an individual litter basis). The analyses were weighted by the number of foetuses examined in each litter. The analyses were weighted by the number of foetuses in each litter.
The percentage of foetuses with minor external/visceral defects only, and minor skeletal defects only (calculated on an individual litter basis). The percentages were transformed before analysis using the double arcsine transformation and the analyses were weighted by the number of foetuses examined in each litter.
The analyses of variance were carried out using the GLM procedure in SAS (1985). Individual treatment group means were compared with the control group mean using Student's t-test based on the error mean square in the analysis. - 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 foetuses / Number of implantations) x 100 - Historical control data:
- In addition to historical control data presented in the original report, a supplement to the report contained further information on the variant and minor defect historical control data, together with historical control data for each of the major defects seen in this study.
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- There were no treatment-related changes in the 1 or 3 mg/kg bw/day groups. In the 10 mg/kg bw/day group there were increased numbers of animals with diarrhoea/signs of diarrhoea (although no increase in the numbers of observations), a small increase in the numbers of animals recorded as subdued, a marked increase in the incidence of thinness and a number of observations of mucus, blood and little or no faeces on the tray papers
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- Six animals were killed before their scheduled termination dates. One animal from the 1 mg/kg bw/day group was killed on Day 27 following an abortion. Two 10 mg/kg bw/day animals were killed following abortion on Day 20 or Day 29. Three further animals from the 10 mg/kg bw/day group were killed in extremis on Day 17, 21 or 22.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Two 10 mg/kg bw/day females lost weight throughout dosing and then rapidly gained weight during the post-dosing period. Analyses were done both with and without these two females.
There was a clear weight loss in both the 3 mg and 10 mg/kg bw/day dose groups during the first three days of dosing. Subsequent to Day 10, weight loss (or reduced weight gain) was apparent only in certain females in the 10 mg/kg bw/day dose group (most noticeable in the same two animals). - Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- There was a clear, consistent and dose-related reduction in food consumption in both the 3 mg and 10 mg/kg bw/day dose groups during the first three days of dosing. For the remainder of the dosing period, mean food consumption was lower in the 10 mg/kg bw/day dose group but this was only apparent in certain females. In the 3 mg//kg bw/day dose group, certain females ate more food than others in the group during the latter half of the dosing period.
Post-dosing, some females in both the 3 mg and 10 mg/kg bw/day dose groups ate more food with consequently higher mean food consumption. The increases in food consumption during the latter period (3 mg and 10 mg/kg bw/day groups) may indicate a compensatory effect for the earlier reductions. - 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:
- no effects observed
- Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- The major findings were changes in the alimentary tract which were seen most commonly in the intercurrent deaths in the 10 mg/kg bw/day group. Of these, the most important change was haemorrhage and/or ulceration in the stomach which was also seen in two animals (one each in the 1 and 10 mg/kg bw/day groups) surviving to termination. Prominent reticular pattern in the liver was also seen in a number of animals, particularly in the intercurrent deaths. One unusual finding in the intercurrent deaths was changes in the intestinal blood vessels; in one animal, the vessels in the caecum appeared to have leaked.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- not examined
Maternal developmental toxicity
- Number of abortions:
- effects observed, treatment-related
- Description (incidence and severity):
- Three animals aborted, one in the 1 and two in the 10 mg/kg bw/day groups respectively.
- Pre- and post-implantation loss:
- no effects observed
- Total litter losses by resorption:
- not examined
- Early or late resorptions:
- no effects observed
- Dead fetuses:
- no effects observed
- Changes in pregnancy duration:
- no effects observed
- Changes in number of pregnant:
- no effects observed
Effect levels (maternal animals)
open allclose all
- Dose descriptor:
- NOAEL
- Remarks:
- Maternal toxicity
- Effect level:
- 1 mg/kg bw/day (actual dose received)
- Based on:
- other: test substance cation species
- Basis for effect level:
- body weight and weight gain
- food consumption and compound intake
- Remarks on result:
- other:
- Remarks:
- Original value presented in study
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- Maternal toxicity
- Effect level:
- 1.9 mg/kg bw/day (actual dose received)
- Based on:
- other: pure test substance
- Basis for effect level:
- body weight and weight gain
- food consumption and compound intake
- Remarks on result:
- other:
- Remarks:
- Recalculated value, expressed as pure substance, see ‘Any other information on results incl. tables’ for respective calculation
Maternal abnormalities
- Key result
- Abnormalities:
- no effects observed
Results (fetuses)
- Fetal body weight changes:
- effects observed, non-treatment-related
- Reduction in number of live offspring:
- effects observed, non-treatment-related
- Changes in sex ratio:
- effects observed, non-treatment-related
- Changes in litter size and weights:
- effects observed, non-treatment-related
- Changes in postnatal survival:
- effects observed, non-treatment-related
- External malformations:
- no effects observed
- Description (incidence and severity):
- The overall incidence of external defects was unaffected by treatment with test substance.
- Skeletal malformations:
- effects observed, treatment-related
- Description (incidence and severity):
- Overall, there was a dose-related increase in the percentage of foetuses with minor skeletal defects. The difference between the control group and the 3 mg and 10 mg/kg bw/day dose groups attained statistical significance using a foetus-based analysis (Fisher's Exact Test). However, the difference between the control group and the 1 mg/kg bw/day dose group was marginal and not statistically significant. Using a litter-based analysis (double arcsine transformation and analysis of variance) which is considered to be more appropriate for defect data, there were no statistically significant differences compared with the control group for any of the test groups.
Specific minor defects to show increased statistical incidence in any dose group were:
- Not ossified 6th sternebra, and
- partially ossified 6th sternebra.
Both these defects were statistically significantly increased at the 10 mg/kg bw/day dose level. Partially ossified 6th sternebra was also higher than control at the 3 mg substance /kg/day dose level. A re-examination of the ventral tubercle was carried out because the incidence reported was found to be inconsistent with historical data, i.e. no partially ossified ventral tubercles from control foetuses have been seen either before or after this study. It was the opinion of the re-evaluator that all of the foetuses examined exhibited ventral tubercles which were within normal limits and all are considered to be fully ossified. Therefore no ventral tubercles in this study are considered to be partially ossified following this re-evaluation.
Not ossified 6th sternebra was statistically significantly increased at the 1 mg/kg bw/day dose level but the frequency was lower at 3 mg than 1 mg/kg bw/day and hence there was no dose response at least at the two lower levels. These two defects in combination showed an apparent dose response, but all values were within historical control values. The control value for the present study appears to be unusually low. Only three foetuses did not have a skeletal variant. Only three foetuses did not have a skeletal variant.
The incidence of foetuses with major defects was 2, 8, 2 and 4 in each dose group respectively. Since most specific major defects occurred as single incidences in one (or two) treatment groups they were considered to be spontaneous occurrences and not as a result of treatment with substance.
There was a clear increase in the proportion of foetuses with pes score 2 in the 10 mg/kg bw/day dose group. There was a similar increase in the proportion of foetuses with manus score 2, also in the 10 mg substance /kg/day dose group. This did not achieve statistical significance although was reflected in the mean score. There was no evidence of an effect at the two lower doses.
There was a statistically significant increase in the incidence of 27 pre-sacral vertebrae in the 10 mg/kg bw/day dose group although this was at the upper end of the control range. There was an increased incidence of 13th extra ribs in both the 3 mg and 10 mg/kg bw/day dose group. Extra 13th ribs showed a similar increase in incidence to that of 27 pre-sacral vertebrae and again the incidence at 10 mg/kg bw/day was at the upper end of the control range. - Visceral malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- The overall incidence of external/visceral defects was unaffected by treatment with test substance. Three specific minor external/visceral defects observed were:
- Friable liver which was increased in the 10 mg/kg bw/day group.
- Mottled liver which was increased in the 10 mg/kg bw/day group and tended to occur in the foetuses with friable liver.
- Gall bladder: small blood clots attached - the incidence of foetuses with this defect in the 3 mg/kg bw/day dose group was well above the historical control range but there was clearly no dose response.
Effect levels (fetuses)
open allclose all
- Dose descriptor:
- NOAEL
- Remarks:
- Developmental toxicity
- Effect level:
- 3 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: sternebra ossification
- Remarks on result:
- other:
- Remarks:
- Original value presented in study
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- Developmental toxicity
- Effect level:
- 5.6 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: sternebra ossification
- Remarks on result:
- other:
- Remarks:
- Recalculated value, expressed as pure substance, see ‘Any other information on results incl. tables’ for respective calculation
Fetal abnormalities
- Key result
- Abnormalities:
- effects observed, treatment-related
- Localisation:
- skeletal: sternum
Overall developmental toxicity
- Key result
- Developmental effects observed:
- yes
- Lowest effective dose / conc.:
- 19 mg/kg bw/day (actual dose received)
- Treatment related:
- yes
- Relation to maternal toxicity:
- not specified
- Dose response relationship:
- yes
- Relevant for humans:
- yes
Any other information on results incl. tables
Diet/dosage preparation and analysis
- Concentration analysis: Mean test substance concentrations were within 7 % of the nominal values.
- Homogeneity: The preparations formed solutions in deionised water.
- Stability: The chemical stability of test substance in deionised water after an interval of 23 days (which is the same as the dosing period in the present study) was assessed in a preliminary study in the rabbit and found to be satisfactory.
Calculation of key result
The original effect levels were expressed as cation species of the test substance. The key effect levels are re-calculated and corrected to include the counterion species by multiplying with 1.868 (344.0 g/mol molecular weight of registered substance divided by 184.2 g/mol molecular weight of cation species).:
The NOAEL for maternal toxicity = 1.868 x 1 mg/kg bw/day = 1.9 mg/kg bw/day
The NOAEL for fetal developmental toxicity = 1.868 x 3 mg/kg bw/day = 5.6 mg/kg bw/day
Table 1: Intergroup comparison of body weight gain (g) all females
| Dose Level of test substance (mg/kg/day) | ||||
Period (days) | 0 (control) | 1 | 3 | 10 (all females) | 10 mg/kg/day Excluding 2 females |
Initial wt (1) | 3418.1 | 3401.3 | 3344.5 | 3368.2 | 3357.1 |
Pre-dosing (1 – 7) | 130.2 | 131.0 | 158.4 | 171.9 | 165.0 |
During dosing (7 – 19) | 237.4 | 309.9 | 236.4 | 47.5** | 175.1 |
Post dosing (19 – 30) | 312.4 | 387.1 | 293.3 | 424.8* | 352.4 |
Overall (1 – 30) | 680.1 | 828.0* | 688.2 | 644.3 | 692.5 |
* Statistically significant difference from control group mean, p<0.05 (Student’s t-test, 2-sided)
** Statistically significant difference from control group mean, p<0.01 (Student’s t-test, 2-sided)
Table 2: Intergroup comparison of food consumption (g/day)
| Dose Level of test substance (mg/kg/day) | |||
Period (days) | 0 (control) | 1 | 3 | 10 |
Pre-dosing (1 – 7) | 173.2 | 162.4 | 168.8 | 172.3 |
During dosing (7 – 19) | 163.4 | 158.1 | 150.1 | 96.0** |
Post dosing (16 – 30) | 164.1 | 170.4 | 181.0* | 186.6* |
* Statistically significant difference from control group mean, p<0.05 (Student’s t-test, 2-sided)
** Statistically significant difference from control group mean, p<0.01 (Student’s t-test, 2-sided)
Table 3: Caesarean section observations for all pregnant females
Observation | Dose Level of test substance (mg/kg/day) | |||
0 (control) | 1 | 3 | 10 | |
Animals inseminated | 20 | 20 | 20 | 20 |
Animals Pregnant | 18 | 16 | 20 | 17 |
Number of females that aborted | 0 | 1 | 0 | 2 |
Number of intercurrent deaths (including females with abortions) | 0 | 0 | 0 | 3^ |
Number of females with live foetusesin uteroat termination | 18 | 15 | 20 | 13 |
Corpora Lutea/Dam | 11.50 | 11.93 | 9.35 | 10.46 |
Pre-implantation Loss (%) | 16.4 | 12.3 | 18.2 | 14.7 |
Number of females affected | 11/18 | 9/15 | 12/20 | 5/13 |
Mean number of implantations | 9.61 | 10.47 | 7.65* | 8.92 |
Post-implantation Loss (%) | 15.0 | 14.6 | 15.7 | 17.2 |
Number of females affected | 13/18 | 9/15 | 14/20 | 8/13 |
Mean number of live foetuses | 8.17 | 8.93 | 6.45* | 7.38 |
Number of intra-uterine deaths % Early Late |
6.9 8.1 |
3.8 10.8 |
6.5 9.2 |
9.5 7.8 |
Intra-uterine deaths/Dam |
|
|
|
|
Early (Proportion of litters affected) | 8/18 | 4/15 | 7/20 | 5/13 |
Late (Proportion of litters affected) | 6/18 | 7/15 | 8/20 | 5/13 |
Total number of live foetuses | 147 | 134 | 129 | 96 |
Sex Ratio (% Males per litter) | 54.4 | 49.6 | 49.6 | 47.9 |
Mean gravid uterus weight (g) | 483.1 | 539.7 | 394.9* | 413.3 |
Mean Litter Weight (g) | 325.1 | 344.8 | 271.4 | 273.6 |
Mean Foetal Weight (g) | 39.81 | 38.59 | 42.08 | 37.05 |
^ Including one animal that was not pregnant.
* Statistically significant difference from control group mean, p<0.05 (Student’s t-test, 2-sided)
** Statistically significant difference from control group mean, p<0.01 (Student’s t-test, 2-sided)
Table 4 Intergroup comparison of selected foetal defects and variants
Observation | Dose Level of test substance (mg/kg/day) | |||
0 (control) | 1 | 3 | 10 | |
No. of litters examined | 18 | 15 | 20 | 13 |
No. of foetuses examined | 147 | 134 | 129 | 96 |
Total incidence of major defects | 2 | 8 | 2 | 4 |
No. of foetuses showing major external/visceral defects | 2 | 8* | 2 | 3 |
No. of foetuses showing major skeletal defects | 1 | 3 | 1 | 1 |
No. of foetuses showing minor external/visceral defects only | 60 | 56 | 64 | 39 |
No. of foetuses showing minor skeletal defects only | 64 | 65 | 71* | 53* |
Liver – friable (foetus/litter) | 8/5 | 7/2 | 5/2 | 14*/3 |
Gall bladder – small blood clot(s) attached (foetus/litter) | 18/8 | 21/9 | 33**/13 | 14/8 |
Vertebral column – 27 pre-sacral vertebrae (foetus/litter) | 46/14 | 54/12 | 49/15 | 49**/12 |
Sternebrae – not ossified 6th(foetus/litter) | 0/0 | 6*/2 | 3/3 | 6**/5** |
Sternebrae – partially ossified 6th(foetus/litter) | 9/6 | 14/8 | 19*/8 | 16**/8 |
Extra ribs – 13thnormal length (foetus/litter) | 76/15 | 61/13 | 89**/18 | 71**/12 |
Mean manus score | 1.61 | 1.60 | 1.62 | 1.80 |
Mean pes score | 1.43 | 1.45 | 1.40 | 1.65* |
* Statistically significant difference from control group mean, p<0.05 (Student’s t-test, 2-sided)
** Statistically significant difference from control group mean, p<0.01 (Student’s t-test, 2-sided)
Applicant's summary and conclusion
- Conclusions:
- Test substance administered to rabbits by gavage during gestation at a concentration of 10 mg test substance ion/kg bw/day, equivalent to 19 mg pure test substance/kg bw/day, caused maternal toxicity and foetotoxicity. Mild maternal toxicity was seen with 3 mg test substance ion/kg bw/day, equivalent to 5.64 mg pure test substance/kg bw/day. The NOAEL for maternal toxicity was set at 1 mg test substance ion/kg bw/day, corresponding to 1.9 mg pure test substance/kg bw/day. A dose of 3 mg test substance ion/kg bw/day, equivalent to 5.64 mg pure test substance/kg bw/day, was considered to be a no-effect level for embryonic and foetal development.
- Executive summary:
A study, complying to GLP and OECD guideline 414, investigated the effect of the test substance when administered by gavage during the period of organogenesis on the embryonic and foetal development of the rabbit. Groups of 20 young adult female New Zealand White rabbits were dosed by gavage with 1, 3 or 10 mg test substance cation/kg bw/day in deionised water from Days 7 - 19 (inclusive) of gestation which thus included the period of major organogenesis. A control group of animals received deionised water alone. The day of insemination was designated Day 1 of gestation. On Day 30 of gestation the females were killed and their uteri examined for live foetuses and intra-uterine deaths. The foetuses were weighed, killed, examined for external and visceral abnormalities, sexed, eviscerated and stained for skeletal examination.
Administration of 10 mg/kg bw/day resulted in maternal toxicity which was apparent as weight loss and reduced food consumption. Five animals (including two which aborted) from this group were killed prematurely. Similar but less severe effects on body weight and food consumption were seen at 3 mg/kg bw/day. There were no treatment-related effects on numbers of corpora lutea, pre-or post-implantation loss, litter size, sex distribution, gravid uterus weight or litter weight. Foetal weight was marginally lower at 10 mg/kg bw/day. Sixteen foetuses were seen with major abnormalities (2, 8, 2 and 4 foetuses in the control, 1, 3 and 10 mg/kg bw/day groups, respectively). There was no evidence that the type or distribution of these was related to treatment. The overall incidence of foetuses with minor external/visceral defects was not affected by treatment although the incidence of mottled and friable livers was increased at 10 mg/kg bw/day. There was a small increase in the percentage of foetuses with minor skeletal defects at 3 and 10 mg test substance/kg/day. The incidences were not statistically significant using a litter-based method of analysis. Specifically, there were increased numbers of partially ossified 6th sternebra at both levels while not ossified 6th sternebra showed an increase at 10 mg/kg bw/day only. A re-examination of the ventral tubercle was carried out because the incidence reported was found to be inconsistent with historical data, i.e. no partially ossified ventral tubercles from control foetuses have been seen either before or after this study. It was the opinion of the re-evaluator that all of the foetuses examined exhibited ventral tubercles which were within normal limits and all are considered to be fully ossified. Therefore no ventral tubercles in this study are considered to be partially ossified following this re-evaluation. The frequency of the skeletal variant 27 pre-sacral vertebrae was increased at 10 mg/kg bw/day while the incidence of extra thoracic ribs was increased at both 3 and 10 mg/kg bw/day although in all cases these were within recent historical control incidences. Manus and pes scores were increased at 10 mg test substance cation/kg/day. These scores, which are generally sensitive indicators of reduced ossification, were similar in the 1 and 3 mg/kg bw/day groups to those of the controls.
Test substance administered to rabbits by gavage during gestation at 10 mg test substance cation/kg bw/day, corresponding to 19 mg pure test substance/kg bw/day, caused maternal toxicity and foetotoxicity. Mild maternal toxicity was seen at 3 mg test substance cation/kg bw/day, equivalent to 5.64 mg pure test substance/kg bw/day. The NOAEL for maternal toxicity was determined to be 1.9 mg pure test substance /kg bw/day. The dose of 3 mg test substance ion/kg bw/day, equivalent to 5.64 mg pure test substance salt/kg bw/day, was considered to be the NOAEL for embryonic and foetal development.
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