Dilanthanum tricarbonate

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

October 1996

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Reference

Endpoint:

one-generation reproductive toxicity

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

October 1996

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Reason / purpose for cross-reference:

reference to same study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 415 [One-Generation Reproduction Toxicity Study (before 9 October 2017)]

Deviations:

yes

Remarks:

day of sacrifice was day 20 of pregnany, females were not allowed to deliver pups, examined parameters other than usual

Principles of method if other than guideline:

- Short description of test conditions:
In this study, males were dosed for at least 63 days before mating with treatment continued throughout the mating period until the day before necropsy. Females were dosed for 14 days before mating with treatment continued through the mating period till day 17 of pregnancy. Males were killed after the end of the mating period. Other to OECD Guideline 415, females were killed at day 20 of pregnancy and thus did not deliver and wean pups.
- Parameters analysed: Females and pups were subjected to complete necropsies after sacrifice at day 20 of pregnancy. For more details, please refer to section "examinations"

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Remarks:

(SD) IOPS-Caw strain

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: (P) males: 5-6 wks; females: 3-4 wks
- Weight at study initiation: (P) Males: 188-199 g; Females: 60-79
- Acclimation period: 1 week (males), 8 weeks (females)

Route of administration:

oral: gavage

Vehicle:

CMC (carboxymethyl cellulose)

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: Lanthanum carbonate was daily suspended in 0.5% aqueous carboxymethyl cellulose.
Dose volume: 10 mL/kg bw

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

P0 males: 63 days before mating, during mating, until day before necropsy
P0 females: 14 days before mating, during mating, until day 17 of pregnancy

Frequency of treatment:

daily

Details on study schedule:

P0 males sacrificed after mating period
P0 females sacrificed at day 20 of pregnany

Dose / conc.:

200 mg/kg bw/day

Dose / conc.:

600 mg/kg bw/day

Dose / conc.:

2 000 mg/kg bw/day

No. of animals per sex per dose:

25

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: The doses were selected based on existing toxicity data including a preliminary study in rats conducted at dose levels of 200, 600, 1000 or 2000 mg/kg bw/day. In that study, males (6/group) were dosed from 14 days prior to mating, through the mating period until the day before necropsy after the end of the mating period. Females were dosed from 14 days prior to mating, through mating and pregnancy, until the day before necropsy on day 7 post-partum. No significant treatment related effects were seen in the parental or F1 generations except that the F1 pup body weights were slightly reduced in the group treated at 2000 mg/kg bw/day. Based on these findings, 2000 mg/kg bw/day was selected as the high dose for the reproductive toxicity studies. A low dose level of 200 mg/kg bw/day was selected as the no-effect level, with an intermediate dose level of 600 mg/kg bw/day.

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily/ twice daily (mortality)
- Cage side observations checked: not further specified

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: twice weekly for males and females during the pre-mating period, daily during pregnancy

FOOD CONSUMPTION AND COMPOUND INTAKE:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes (not specified)
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No
- Time schedule: weekly (during pregnancy over days 0 to 6, 6 to 12, 12 to 17 and 17 to 20)

WATER CONSUMPTION AND COMPOUND INTAKE: No

Litter observations:

STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: no (pups were not delivered)

PARAMETERS EXAMINED
The following parameters were examined in F1 offspring: number and sex of fetuses, number of live fetuses, number of litters, fetal and litter weight and presence of gross anomalies.

GROSS EXAMINATION OF DEAD PUPS: yes, for external,visceral and skeletal abnormalities

Postmortem examinations (parental animals):

SACRIFICE
- Male animals: after mating period.
- Maternal animals: day 20 of pregnancy.

GROSS NECROPSY
- Gross necropsy: Organs and tissues showing macroscopic abnormalities were fixed for further analysis (males, females), pregnancy status was determined, numbers of corpora lutea, implantation sites, resorptions, and dead and live fetuses were recorded. The implantations were numbered separately for the right and left horns. The live fetuses and their placenta were removed, and the uterus and ovaries were fixed for further analysis.
(Effects that relate to developmental toxicity are reported and considered in the study entry under 7.8.2)

HISTOPATHOLOGY / ORGAN WEIGHTS
The following tissues were prepared for microscopic examination: testis, epididymides, placenta, uterus, ovaries. Organ weights: testis, placenta.
(Effects that relate to developmental toxicity are reported and considered in the study entry under 7.8.2)

Postmortem examinations (offspring):

SACRIFICE
- The F1 offspring was sacrificed at day 20 of pregnancy

GROSS NECROPSY
- Gross necropsy consisted of visceral external and internal examinations including the cervical, thoracic, and abdominal viscera.

HISTOPATHOLOGY / ORGAN WEIGTHS
External, visceral examinations (abnormalities: half of litters) and skeletal examinations (ossification of skeleton, skeletal abnormalities and variants: half of litters) were performed.

Remarks: Structural congenital abnormalities that impair or potentially impair the survival of the fetus were classified as major abnormalities. Other defects were classified as minor abnormalities. Commonly observed variations in the degree of ossification from that expected of a day 20 gestation fetus together with common variations in the extent of renal pelvic cavitation and ureter dilatation were recorded as variants.

Statistics:

Analysis of variance (ANOVA) was performed on all parameters. Residuals from this preliminary analysis were examined for heterogeneity of variance using Levene's test. If the Levene 's test was significant at the 1% level, than the particular variable concerned was subjected to a non-parametric analysis. Otherwise, William's test was performed to compare the high dose with control at the two-sided 5% level. If this test was statistically significant, then comparisons of the subsequent doses against control were performed at the one-sided 5% level until a non-significant difference was found. If Levene's test indicated that there were significant differences in the treatment group variances, or if a parametric analysis was deemed to be inappropriate, then a Kruskal-Wallis ANOVA was performed to assess overall differences between the treatment groups, followed by Shirley's non-parametric version of Williams' test, which is based on mean ranks rather than the arithmetic means. Nominal data were analyzed using the Fisher's Exact Test.

Reproductive indices:

Copulation and fertility indices and pre- and post-implantation losses were calculated.

Clinical signs:

no effects observed

Dermal irritation (if dermal study):

not examined

Mortality:

mortality observed, non-treatment-related

Description (incidence):

600 mg/kg bw/day: 1/25 males died unscheduled on day 25
2000 mg/kg bw/day: 1/25 males died unscheduled on day 63 (since that animal was cannibalized and the remaining tissues were partly autolysed, thus the cause of death could not be determined)

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

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

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not examined

Description (incidence and severity):

Effects that relate to developmental toxicity are reported and considered in the study entry under 7.8.2.

Reproductive function: oestrous cycle:

not examined

Reproductive function: sperm measures:

not examined

Reproductive performance:

no effects observed

No treatment-related effect on number of pregnant females per group was observed. Pregnancy rates were 92, 96, 100 and 92% in control, 200, 600 and 2000 mg/kg bw/day dose groups, respectively. Mean number of implantations per female, mean number of corpora lutea, number of early/late embryo/fetal deaths, number of dead fetuses and number of viable fetuses did not differ from controls.

Key result

Dose descriptor:

NOAEL

Remarks:

general toxicity

Effect level:

2 000 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no adverse effects observed

Key result

Dose descriptor:

NOAEL

Remarks:

reproductive toxicity

Effect level:

2 000 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no adverse effect on reproduction parameters observed

Critical effects observed:

no

Clinical signs:

not examined

Dermal irritation (if dermal study):

not examined

Mortality:

not examined

Body weight and weight changes:

not examined

Food consumption and compound intake (if feeding study):

not examined

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:

not examined

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Other effects:

not examined

Reproductive function: oestrous cycle:

not examined

Reproductive function: sperm measures:

not examined

Reproductive performance:

not examined

Clinical signs:

not examined

Dermal irritation (if dermal study):

not examined

Mortality / viability:

not examined

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

not examined

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

Sexual maturation:

not examined

Anogenital distance (AGD):

not examined

Nipple retention in male pups:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

not examined

Histopathological findings:

no effects observed

Description (incidence and severity):

External, visceral and skeletal findings are reported and considered in the study entry under 7.8.2

Skeletal malformations:
200 and 2000 mg/kg bw/day: Statistically significant increased incidences of cervial rib (minor skeletal malformation), although incidences at low and high dose were out of the historical control data range, observations are not considered relevant, since a dose relationship was absent.
Incidences 0/175 (control group), 5/182 (low dose), 0/192 (mid dose), 6/172 (high dose)

Visceral malformations:
2000 mg/kg bw/day: Statistically significant increase in incidences of increased pelvic caviation of kidneys (variation). The incidences of increased pelvic cavitation observed in treated groups (5.9-11.5%) were within the historical control range of 0.0 to 41.5% and thus not considered biologically relevant.
Fetal incidences: 14/341 (control group), 22/352 (low dose), 30/371(mid dose), 40/336 (high dose)
Litter incidences: 18/32 (control group), 9/24 (low dose), 15/25 (mid dose), 15/23 (high dose)

Other effects:

not specified

Description (incidence and severity):

Effects that relate to developmental toxicity are reported and considerd in the study entry under 7.8.2

Changes in sex ratio:
2000 mg/kg bw/day: Statistically Significant increase in the number of males (53.3%). Due to the low difference to the control group, the biological relevance of this increase is questionable.

Behaviour (functional findings):

not examined

Developmental immunotoxicity:

not examined

Dose descriptor:

NOAEL

Effect level:

2 000 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no adverse effects observed

Reproductive effects observed:

no

Table 1: Mean values intrauterine development

Dose (mg/kg bw/day)	control	200	600	2000
Maternal effects
Number of dams with implantations	23	24	25	23
Mean number of implantation per female	15.8	15.8	15.7	15.3
Mean number of corpora lutea per female	16.8	17.5	16.8	16.3
Mean number of implantations %	93.9	91.3	94.6	95.9
Mean pre-implantation loss %	5.7	8.9	6.3	6.9
Number of early embryo/fetal deaths (resorption)	21	28	21	14
Number of late embryo/fetal deaths (resorption)	1	0	1	2
Number of dead fetuses	0	0	0	0
Mean post-implantation loss %	6.1	8.7	5.4	4.1
Mean placental weight [g] per female	0.61	0.69	0.62	0.67
Fetal effects
Number of dams with viable fetuses	23	24	25	23
Number of viable fetuses per group	341	352	371	336
Mean number of viable fetuses per female	14.8	14.7	14.8	14.6
Number male fetuses	154	174	181	187
Number female fetuses	187	178	190	149
Mean number of male fetuses %	45.1	49.5	48.3	53.3*
Mean litter weight [g]	60.4	59.5	61.6	60.8
Mean fetal weight [g]	4.07	4.05	4.15	4.15

* p<0.05

 

Table 2: Malformations

Dose (mg/kg bw/day)	control	200	600	2000
Total number of litters examined	23	24	25	23
Total number of fetuses examined	341	352	371	336
External and visceral examination
Number with major abnormalities	1	1	7	3
Number with minor abnormalities	3	1	4	3
Number with variations	46	68	85	72
Skeletal examination
Number with major abnormalities	0	0	3	1
Number with minor abnormalities	9	19	17	21
Number with variations	169	178	187	167

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1996

Report date:

1996

Materials and methods

Principles of method if other than guideline:

A mixed reproductive/developmental toxicity study was performed in rats. In this study, males were dosed for at least 63 days before mating with treatment continued throughout the mating period until the day before necropsy. Females were dosed for 14 days before mating with treatment continued through the mating period till day 17 of pregnancy. Males were killed after the end of the mating period and females were sacrificed on day 20 of pregnancy. Animals were subjected to complete necropsies. Organs or tissues showing macroscopic abnormalities were fixed. Testes and epididymides were removed and fixed and the testes weights were determined. For females, pregnancy status, numbers of corpora lutea, implantation sites, resorptions, and dead and live fetuses were determined.
The live fetuses and their placenta were removed, and the uterus and ovaries were fixed. Fetal and placental weights, fetal sex and external fetal abnormalities were recorded. Copulation and fertility indices and pre- and post-implantation losses were calculated. One half of the live fetuses were examined for visceral abnormalities. The remaining fetuses were examined for ossification of the skeleton and skeletal variants and abnormalities.
Structural congenital abnormalities that impair or potentially impair the survival of the fetus were classified as major abnormalities. Other defects were classified as minor abnormalities. Commonly observed variations in the degree of ossification from that expected of a day 20 gestation fetus together with common variations in the extent of renal pelvic cavitation and ureter dilatation were recorded as variants.

GLP compliance:

yes

Limit test:

no

Test material

Test material information

1

Reference substance name:

Dilanthanum tricarbonate

EC Number:

209-599-5

EC Name:

Dilanthanum tricarbonate

Cas Number:

587-26-8

Molecular formula:

La2(CO3)3

IUPAC Name:

dilanthanum tricarbonate

Test animals

Species:

rat

Strain:

Sprague-Dawley

Remarks:

(SD) IOPS-Caw strain

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: 5 - 6 weeks (males), 3 - 4 (females)
- Weight at study initiation: 188-199 g (males), 60-79 g (females)
- Acclimation period: 1 week (males), 8 weeks (females)

Administration / exposure

Route of administration:

oral: gavage

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: Lanthanum carbonate was daily suspended in 0.5% aqueous carboxymethyl cellulose.
Dose volume: 10 mL/kg bw

Analytical verification of doses or concentrations:

not specified

Details on mating procedure:

- Impregnation procedure: cohoused

Duration of treatment / exposure:

P0 males: 63 days before mating, during mating, until day before necropsy
P0 females: 14 days before mating, during mating, until day 17 of pregnancy

Frequency of treatment:

daily

Duration of test:

P0 males: 63 day before mating until end of mating period
P0 females: 14 days before mating until day 20 of pregnancy

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

200 mg/kg bw/day

Doses / concentrations 2

Dose / conc.:

600 mg/kg bw/day

Doses / concentrations 3

Dose / conc.:

2 000 mg/kg bw/day

No. of animals per sex per dose:

25

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: The doses were selected based on existing toxicity data including a preliminary study in rats conducted at dose levels of 200, 600, 1000 or 2000 mg/kg bw/day. In that study, males (6/group) were dosed from 14 days prior to mating, through the mating period until the day before necropsy after the end of the mating period. Females were dosed from 14 days prior to mating, through mating and pregnancy, until the day before necropsy on day 7 post-partum. No significant treatment related effects were seen in the parental or F1 generations except that the F1 pup body weights were slightly reduced in the group treated at 2000 mg/kg bw/day. Based on these findings, 2000 mg/kg bw/day was selected as the high dose for the reproductive toxicity studies. A low dose level of 200 mg/kg bw/day was selected as the no-effect level, with an intermediate dose level of 600 mg/kg bw/day.

Examinations

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily/ twice daily (mortality)
- Cage side observations checked: not further specified

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: females during the pre-mating period, daily during pregnancy

FOOD CONSUMPTION AND COMPOUND INTAKE:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes (not specified
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No
- Time schedule: weekly (during pregnancy over days 0 to 6, 6 to 12, 12 to 17 and 17 to 20)

WATER CONSUMPTION AND COMPOUND INTAKE: No

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: all organs or tissues showing macroscopic abnormalities were fixed for further analysis. Females: uterus, ovaries and placenta

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No data
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other: Total numbers of live fetuses per group, mean number of fetuses per dam, numbers of male and female fetuses, mean litter weight and mean fetal and placental weights. Pre- and post- implantation losses were determined.

Fetal examinations:

- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: No
- Other: sex ratio

Statistics:

Analysis of variance (ANOVA) was performed on all parameters. Residuals from this preliminary analysis were examined for heterogeneity of variance using Levene's test. If the Levene 's test was significant at the 1% level, then the particular variable concerned was subjected to a non-parametric analysis. Otherwise, William's test was performed to compare the high dose with control at the two-sided 5% level. If this test was statistically significant, than comparisons of the subsequent doses against control were performed at the one-sided 5% level until a non-significant difference was found. If Levene's test indicated that there were significant differences in the treatment group variances, or if a parametric analysis was deemed to be inappropriate, then a Kruskal-Wallis ANOVA was performed to assess overall differences between the treatment groups, followed by Shirley's non-parametric version of Williams' test, which is based on mean ranks rather than the arithmetic means. Nominal data were analyzed using the Fisher's Exact Test.

Indices:

Copulation and fertility indices and pre- and post-implantation losses were calculated.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:

no effects observed

Dermal irritation (if dermal study):

not examined

Mortality:

mortality observed, non-treatment-related

Description (incidence):

600 mg/kg bw/day: 1/25 males died unscheduled on day 25
2000 mg/kg bw/day: 1/25 males died unscheduled on day 63 (since that animal was cannibalized and the remaining tissues were partly autolysed, thus the cause of death could not be determined)

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

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:

no effects observed

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not examined

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

Other effects:

not examined

Effect levels (maternal animals)

1

Key result

Dose descriptor:

NOAEL

Remarks:

general toxicity

Effect level:

2 000 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: no adverse effects observed

2

Key result

Dose descriptor:

NOAEL

Remarks:

developmental toxicity

Effect level:

2 000 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: no adverse effects on developmental parameters observed

Maternal abnormalities

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:

effects observed, treatment-related

Description (incidence and severity):

2000 mg/kg bw/day: Statistically significant increase in the number of males (53.3%). Due to the low difference to the control group, the biological relevance is questionable.

Changes in litter size and weights:

no effects observed

Changes in postnatal survival:

not examined

External malformations:

no effects observed

Skeletal malformations:

effects observed, non-treatment-related

Description (incidence and severity):

200 and 2000 mg/kg bw/day: Statistically significant increased incidences of cervical rib (minor skeletal malformation), although incidences at low and high dose were out of the historical control data range, observations are not considered relevant, since a dose relationship was absent.
Incidences 0/175 (control group), 5/182 (low dose), 0/192 (mid dose), 6/172 (high dose)

Visceral malformations:

effects observed, non-treatment-related

Description (incidence and severity):

2000 mg/kg bw/day: Statistically significant increase in incidences of increased pelvic caviation of kidneys (variation). The incidences of increased pelvic cavitation observed in treated groups (5.9-11.5%) were within the historical control range of 0.0 to 41.5% and thus not considered biologically relevant.
Fetal incidences: 14/341 (control group), 22/352 (low dose), 30/371(mid dose), 40/336 (high dose)
Litter incidences: 18/32 (control group), 9/24 (low dose), 15/25 (mid dose), 15/23 (high dose)

Other effects:

not examined

Effect levels (fetuses)

Key result

Dose descriptor:

NOAEL

Effect level:

2 000 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no adverse effect on fetal development observed

Fetal abnormalities

Abnormalities:

no effects observed

Overall developmental toxicity

Developmental effects observed:

no

Any other information on results incl. tables

Table 1: Mean values intrauterine development

Dose (mg/kg bw/day)	control	200	600	2000
Maternal effects
Number of dams with implantations	23	24	25	23
Mean number of implantation per female	15.8	15.8	15.7	15.3
Mean number of corpora lutea per female	16.8	17.5	16.8	16.3
Mean number of implantations %	93.9	91.3	94.6	95.9
Mean pre-implantation loss %	5.7	8.9	6.3	6.9
Number of early embryo/fetal deaths (resorption)	21	28	21	14
Number of late embryo/fetal deaths (resorption)	1	0	1	2
Number of dead fetuses	0	0	0	0
Mean post-implantation loss %	6.1	8.7	5.4	4.1
Mean placental weight [g] per female	0.61	0.69	0.62	0.67
Fetal effects
Number of dams with viable fetuses	23	24	25	23
Number of viable fetuses per group	341	352	371	336
Mean number of viable fetuses per female	14.8	14.7	14.8	14.6
Number male fetuses	154	174	181	187
Number female fetuses	187	178	190	149
Mean number of male fetuses %	45.1	49.5	48.3	53.3*
Mean litter weight [g]	60.4	59.5	61.6	60.8
Mean fetal weight [g]	4.07	4.05	4.15	4.15

* p<0.05

 

Table 2: Malformations

Dose (mg/kg bw/day)	control	200	600	2000
Total number of litters examined	23	24	25	23
Total number of fetuses examined	341	352	371	336
External and visceral examination
Number with major abnormalities	1	1	7	3
Number with minor abnormalities	3	1	4	3
Number with variations	46	68	85	72
Skeletal examination
Number with major abnormalities	0	0	3	1
Number with minor abnormalities	9	19	17	21
Number with variations	169	178	187	167