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EC number: 209-599-5 | CAS number: 587-26-8
- 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:
- 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
- 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:
- 1 996
- 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
- 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
1
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 / concentrationsopen allclose all
- 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.
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)
open allclose all
- 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
- 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 |
Applicant's summary and conclusion
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
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