Registration Dossier
Registration Dossier
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EC number: 241-629-2 | CAS number: 17647-86-8
Toxicological information
Toxicity to reproduction
Administrative data
- Endpoint:
- screening for reproductive / developmental toxicity
- Remarks:
- based on test type (migrated information)
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 2015-04-27 to 2015-07-01
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: GLP and guideline compliant study report
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 016
- Report date:
- 2016
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Remarks:
- BASF SE, Experimental Toxicology and Ecology, 67056 Ludwigshafen, Germany
- Limit test:
- no
Test material
- Reference substance name:
- Potassium N,N-dimethylglycinate
- EC Number:
- 241-629-2
- EC Name:
- Potassium N,N-dimethylglycinate
- Cas Number:
- 17647-86-8
- Molecular formula:
- C4H8NO2.K
- IUPAC Name:
- potassium 2-(dimethylamino)acetate
- Details on test material:
- - Substance type: organic salt
- Physical state: white solid
- Expiration date of the batch: 04 Sept 2016
- Storage condition of test material: at room temperature (highly hygroscopic substance)
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH
- Age at study initiation: 11 - 12 weeks
- Weight at study initiation:
- Fasting period before study:
- Housing: individually in polycarbonate cages type III (floor area of about 800 cm²)
- Diet: ad libitum, ground Kliba maintenance diet mouse-rat “GLP” (Provimi Kliba SA, Kaiseraugst, Switzerland)
- Water: ad libitum, deionized water
- Acclimation period: at least 5 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24
- Humidity (%): 30 - 70
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12
Administration / exposure
- Route of administration:
- oral: drinking water
- Vehicle:
- water
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
To prepare this solution, the appropriate amount of test substance was weighed out depending on the desired concentration. Then, deionized water was filled up to the desired volume, subsequently mixed with a magnetic stirrer. The test substance preparations were produced twice weekly. - Details on mating procedure:
- - M/F ratio per cage: 1:1
- Length of cohabitation: max. 2 weeks
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
- Further matings after unsuccessful attempts: no
- After successful mating each pregnant female was caged (how): all animals were housed individually in polycarbonate cages type III (floor area of about 800 cm²) - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The stability of the test substance in deionized water over a period of 4 days at room temperature was proven before the start of the study. Samples of the test substance preparations were sent to the analytical laboratory for verification of the concentrations. The samples taken for the concentration control analyses were also used to verify the homogeneity of the samples of the low- and high-concentrations. Three samples (one from the top, middle and bottom) were taken from the preparation vessels with the magnetic stirrer running.
- Duration of treatment / exposure:
- males: 29 days
females: 53 days - Frequency of treatment:
- daily
Doses / concentrationsopen allclose all
- Remarks:
- Doses / Concentrations:
1500, 4000, 12000 ppm
Basis:
nominal in water
- Remarks:
- Doses / Concentrations:
1592, 4246, 12739 ppm
Basis:
other: content of the test substance (94.2 g/100 g)
- No. of animals per sex per dose:
- 10
- Control animals:
- yes, concurrent no treatment
- Positive control:
- Not applicable
Examinations
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: once daily
- Cage side observations checked: any signs of morbidity, pertinent behavioral changes and signs of overt toxicity
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: prior to the administration period and thereafter at weekly intervals
- Parameters checked in table [No. 1] were examined.
BODY WEIGHT: Yes
- Time schedule for examinations: before the start of the administration period and during administration period once a week
FOOD CONSUMPTION: Yes
- Time schedule: once weekly
- Exemptions:
Food consumption was not determined during the mating period (male and female F0 animals).
Food consumption of the F0 females with evidence of sperm was determined for GD 0 - 7, 7 - 14 and 14 - 20.
Food consumption of F0 females, which gave birth to a litter was determined for PND 1 - 4.
WATER CONSUMPTION AND COMPOUND INTAKE: Yes
- Time schedule for examinations: twice a week
- Exemptions:
Water consumption was not determined during the mating period (male and female parental animals).
Additionally, during gestation (animals with evidence of sperm plugs) water consumption of the females were determined for GDs 0-1, 3-4, 6-7, 9-10, 12-13, 15-16 and 18-19 and during lactation period (animals with litter) for PNDs 0-1 and 3-4.
OTHER: Haematology, clinical chemistry, urinalysis, neurobehavioural examination - Oestrous cyclicity (parental animals):
- Not observed.
- Sperm parameters (parental animals):
- Parameters examined in all P male parental generations:
testis weight, epididymis weight, stages of spermatogenesis - Litter observations:
- PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
number and sex of pups, stillbirths, live births (on PND 0), postnatal mortality (on PND 0; between PND 1 - 4) , clinical symptoms (including gross-morphological findings), body weight (on PND 1 and on PND 4)
GROSS EXAMINATION OF DEAD PUPS:
yes, for external and internal abnormalities - Postmortem examinations (parental animals):
- SACRIFICE
- Male animals: All animals on study day 29
- Maternal animals: All animals on study day 53
GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera. Special intention was being given to the reproductive organs.
HISTOPATHOLOGY / ORGAN WEIGHTS
The tissues indicated in Table [2, 3] were prepared for microscopic examination and weighed, respectively. - Postmortem examinations (offspring):
- SACRIFICE
- The F1 offspring was sacrificed at 4 days of age under isoflurane anesthesia with CO2.
- These animals were subjected to postmortem examinations macroscopic and/or microscopic examination as follows:
GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera. All organs were assessed macrospcopically. All stillborn pups and all pups that died before PND 4 were examined externally, eviscerated and their organs were assessed macroscopically. All pups without notable findings or abnormalities were discarded after their macroscopic evaluation. Animals with notable findings or abnormalities were evaluated on a case-bycase basis, depending on the type of finding noted. - Statistics:
- Means and standard deviations of each test group were calculated. In addition other analysis were performed for some parameters.
- Food consumption, water consumption, body weight and body weight change, gestation days: Simultaneous comparison of all dose groups with the control group using the DUNNETT test (two-sided) for the hypothesis of equal means.
- Reproductive and offspring viability indices: Pair-wise comparison of each dose group with the control group using FISHER'S EXACT test (one-sided) for the hypothesis of equal proportions.
Mating days until day 0 pc, % postimplantation loss, pups stillborn, % perinatal loss: Pair-wise comparison of the dose group with the control group using the WILCOXON test (onesided+) with BONFERRONI-HOLM adjustment for the hypothesis of equal medians.
- Implantation sites, pups delivered, pups liveborn, live pups day x, viability Index: Pair-wise comparison of the dose group with the control group using the WILCOXON test (one-sided) with BONFERRONI-HOLM adjustment for the hypothesis of equal medians.
- % live male day x, % live female day x: Comparison of the dose group with the control group was performed using the WILCOXON test (two-sided) for the hypothesis of equal medians. - Reproductive indices:
- male/female mating index, male/female fertility index, gestation index, postimplantation loss
- Offspring viability indices:
- viability index, live birth index
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- no effects observed
- Body weight and weight changes:
- effects observed, treatment-related
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- no effects observed
- Other effects:
- no effects observed
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- not examined
- Reproductive function: sperm measures:
- no effects observed
- Reproductive performance:
- no effects observed
Details on results (P0)
CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
No animal died or was sacrificed moribund during the study period. No test substance-related clinical sgns were observed.
BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
Male animals of test group 3 (12000 ppm) showed a slight significant lower body weight on pre-mating days 7 (-6.0 %) and 13 (-5.0 %). The body weight change in male animals of test group 3 (12000 ppm) was decreased (-90.4 %) during pre-mating between day 0 and 7. The overall value for pre-mating body weight change was decreased significantly (-42.3 %). No further alterations of the body weight were observed after the first two weeks of administration in males. These findings were considered as treatment-related, but based on the degree of change as well as on its transient character they were assessed as not adverse. Body weights and body weight changes were not significantly affected in female animals during pre-mating, mating, post-mating and gestation. Food consumption was significantly decreased (-23.7 %) in male animals of test group 3 (12000 ppm) during pre-mating between study day 0 and 7. No further effects were seen in food consumption. This finding was considered as treatment-related, but based on the degree of change as well as on its transient character it was assessed as not adverse.
TEST SUBSTANCE INTAKE VIA DRINKING WATER (PARENTAL ANIMALS)
During pre-mating water consumption was significantly decreased between study day 0 and 3 in male animals of test group 3 (12000 ppm, -47.2 %) and in female animals of the same test group 3 between study day 0 and 3 (-29.9 %) as well as between study day 10 and 13 (-29.3 %). Whereas no effect can be seen in both sexes after the first two weeks of administration, it can be concluded, that the reason for this finding was assessed to be caused by the taste of the test item in the highest concentration, which the animals get accustomed to. So these findings were considered as treatment related, but not adverse. Mean daily substance intake can be found under "Any other information on results incl. tables".
REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS)
The stages of spermatogenesis in the testes of males in test group 3 (12000 ppm) were comparable to those of the controls.
REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
Males: For parental males, which were placed with females to generate F1 pups, mating was confirmed. The male mating index was 100 % in all dose groups (1-3; 1500, 4000 and 12000 ppm). Male animals of control group showed a mating index of 90 %. Fertility was proven for most of the parental males within the scheduled mating interval to produce F1 litter (please refer to table 1 under "Any other information on results incl. tables"). One male of test group 3 (12000 ppm, No. 36 mated with female No. 136), two males of test group 2 (4000 ppm, Nos. 26 and 28 mated with female No. 126 and 128) and one male of the control group (0 ppm, No. 10 mated with female No. 110) did not generate implants in utero. One male of control group (0 ppm, No. 9 mated with female No. 109) did not generate F1 pups. The male fertility index was 90 % in test group 3 (12000 ppm) and control group, 80 % in test group 2 (4000 ppm) and 100 % in test group 1 (1500 ppm).
Females: The female mating index calculated after the mating period for F1 litter was 100 % in all dose groups (1-3; 1500, 4000 and 12000 ppm). Female animals of control group showed a mating index of 90 %. The mean duration until sperm was detected (GD 0) was 2.0, 2.2, 3.4, 2.5 days in test groups 0 - 3. This finding reflected the normal range of biological variation inherent in the strain of rats used for this study as all respective values were within the range of the historical control data.
All sperm positive rats got pregnant with one exception in test group 3 (12000 ppm) and two exceptions in test group 2 (please refer to table 2 under "Any other information on results incl. tables"). Female animal No. 136 (test group 3) which was mated with male No. 36, female No. 126 (test group 2) which was mated with male No. 26 and female No. 128 (test group 2) which was mated with male No. 28 did get sperm in vaginal smear but showed no implants. The mean duration of gestation was similar in all test groups (22.0 days in test group 0; 22.3 days in test groups 1, 22.0 days in test group 2, and 21.9 days in test group 3). These findings reflected the normal range of biological variation inherent in the strain of rats used for this study as all respective values were within or nearby the range of the historical control data.
The gestation index was 89 % in test group 0, and 100 % in test groups 1 - 3 (1500, 4000 and 12000 ppm). Also in the historical control data not always 100 % of the pregnant females had live pups. Consequently, the historical control data ranges from 70 % to 100 %. Therefore, the finding did reflect the normal range of biological variation inherent in the strain of rats used for this study. The postimplantation loss was 17.8 % in control group, 6.1% in test group 1 (1500 ppm), 12.4 % in test group 2 (4000 ppm) and 6.4 % in test group 3 (12000 ppm). These findings reflected the normal range of biological variation inherent in the strain of rats used for this study as all respective values were within the range (0.7 % - 18.3 %) of the historical control data.
ORGAN WEIGHTS (PARENTAL ANIMALS)
Absolute organ weights: When compared to control group 0 (set to 100 %), the mean absolute weight of the heart was significantly decreased in females. All other mean absolute weight parameters did not show significant differences when compared to the control group 0.
Relative organ weights: All mean relative weight parameters did not show significant differences when compared to the control group 0. The significant decreases of the absolute heart weights were not clearly dose-dependently. In test groups 1 (0.704 g) and 3 (0.694 g), they were below the historical control range (0.708 - 0.912 g), but without a histopathological correlate. Relative weights were not changed and were within the range of the historical control values. Therefore, the significant decreases of absolute weight of the heart was judged as incidental.
GROSS PATHOLOGY (PARENTAL ANIMALS)
All findings occurred either individually or were biologically equally distributed over control and treatment groups. They were considered to be incidental or spontaneous in origin and without any relation to treatment.
HISTOPATHOLOGY (PARENTAL ANIMALS)
All findings occurred either individually or were biologically equally distributed over control and treatment groups. They were considered to be incidental or spontaneous in origin and without any relation to treatment.
OTHER FINDINGS (PARENTAL ANIMALS)
No treatment related changes were observed for hematological, urinanalysis or clinical chemistry parameters.
No animal died or was sacrificed moribund during the study period. No test substance-related clinical sgns were observed.
BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
Male animals of test group 3 (12000 ppm) showed a slight significant lower body weight on pre-mating days 7 (-6.0 %) and 13 (-5.0 %). The body weight change in male animals of test group 3 (12000 ppm) was decreased (-90.4 %) during pre-mating between day 0 and 7. The overall value for pre-mating body weight change was decreased significantly (-42.3 %). No further alterations of the body weight were observed after the first two weeks of administration in males. These findings were considered as treatment-related, but based on the degree of change as well as on its transient character they were assessed as not adverse. Body weights and body weight changes were not significantly affected in female animals during pre-mating, mating, post-mating and gestation. Food consumption was significantly decreased (-23.7 %) in male animals of test group 3 (12000 ppm) during pre-mating between study day 0 and 7. No further effects were seen in food consumption. This finding was considered as treatment-related, but based on the degree of change as well as on its transient character it was assessed as not adverse.
TEST SUBSTANCE INTAKE VIA DRINKING WATER (PARENTAL ANIMALS)
During pre-mating water consumption was significantly decreased between study day 0 and 3 in male animals of test group 3 (12000 ppm, -47.2 %) and in female animals of the same test group 3 between study day 0 and 3 (-29.9 %) as well as between study day 10 and 13 (-29.3 %). Whereas no effect can be seen in both sexes after the first two weeks of administration, it can be concluded, that the reason for this finding was assessed to be caused by the taste of the test item in the highest concentration, which the animals get accustomed to. So these findings were considered as treatment related, but not adverse. Mean daily substance intake can be found under "Any other information on results incl. tables".
REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS)
The stages of spermatogenesis in the testes of males in test group 3 (12000 ppm) were comparable to those of the controls.
REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
Males: For parental males, which were placed with females to generate F1 pups, mating was confirmed. The male mating index was 100 % in all dose groups (1-3; 1500, 4000 and 12000 ppm). Male animals of control group showed a mating index of 90 %. Fertility was proven for most of the parental males within the scheduled mating interval to produce F1 litter (please refer to table 1 under "Any other information on results incl. tables"). One male of test group 3 (12000 ppm, No. 36 mated with female No. 136), two males of test group 2 (4000 ppm, Nos. 26 and 28 mated with female No. 126 and 128) and one male of the control group (0 ppm, No. 10 mated with female No. 110) did not generate implants in utero. One male of control group (0 ppm, No. 9 mated with female No. 109) did not generate F1 pups. The male fertility index was 90 % in test group 3 (12000 ppm) and control group, 80 % in test group 2 (4000 ppm) and 100 % in test group 1 (1500 ppm).
Females: The female mating index calculated after the mating period for F1 litter was 100 % in all dose groups (1-3; 1500, 4000 and 12000 ppm). Female animals of control group showed a mating index of 90 %. The mean duration until sperm was detected (GD 0) was 2.0, 2.2, 3.4, 2.5 days in test groups 0 - 3. This finding reflected the normal range of biological variation inherent in the strain of rats used for this study as all respective values were within the range of the historical control data.
All sperm positive rats got pregnant with one exception in test group 3 (12000 ppm) and two exceptions in test group 2 (please refer to table 2 under "Any other information on results incl. tables"). Female animal No. 136 (test group 3) which was mated with male No. 36, female No. 126 (test group 2) which was mated with male No. 26 and female No. 128 (test group 2) which was mated with male No. 28 did get sperm in vaginal smear but showed no implants. The mean duration of gestation was similar in all test groups (22.0 days in test group 0; 22.3 days in test groups 1, 22.0 days in test group 2, and 21.9 days in test group 3). These findings reflected the normal range of biological variation inherent in the strain of rats used for this study as all respective values were within or nearby the range of the historical control data.
The gestation index was 89 % in test group 0, and 100 % in test groups 1 - 3 (1500, 4000 and 12000 ppm). Also in the historical control data not always 100 % of the pregnant females had live pups. Consequently, the historical control data ranges from 70 % to 100 %. Therefore, the finding did reflect the normal range of biological variation inherent in the strain of rats used for this study. The postimplantation loss was 17.8 % in control group, 6.1% in test group 1 (1500 ppm), 12.4 % in test group 2 (4000 ppm) and 6.4 % in test group 3 (12000 ppm). These findings reflected the normal range of biological variation inherent in the strain of rats used for this study as all respective values were within the range (0.7 % - 18.3 %) of the historical control data.
ORGAN WEIGHTS (PARENTAL ANIMALS)
Absolute organ weights: When compared to control group 0 (set to 100 %), the mean absolute weight of the heart was significantly decreased in females. All other mean absolute weight parameters did not show significant differences when compared to the control group 0.
Relative organ weights: All mean relative weight parameters did not show significant differences when compared to the control group 0. The significant decreases of the absolute heart weights were not clearly dose-dependently. In test groups 1 (0.704 g) and 3 (0.694 g), they were below the historical control range (0.708 - 0.912 g), but without a histopathological correlate. Relative weights were not changed and were within the range of the historical control values. Therefore, the significant decreases of absolute weight of the heart was judged as incidental.
GROSS PATHOLOGY (PARENTAL ANIMALS)
All findings occurred either individually or were biologically equally distributed over control and treatment groups. They were considered to be incidental or spontaneous in origin and without any relation to treatment.
HISTOPATHOLOGY (PARENTAL ANIMALS)
All findings occurred either individually or were biologically equally distributed over control and treatment groups. They were considered to be incidental or spontaneous in origin and without any relation to treatment.
OTHER FINDINGS (PARENTAL ANIMALS)
No treatment related changes were observed for hematological, urinanalysis or clinical chemistry parameters.
Effect levels (P0)
open allclose all
- Dose descriptor:
- NOAEL
- Effect level:
- 731 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- other: corresponds to 12000 ppm (the highest tested dose) for systemic and reproductive toxicity
- Dose descriptor:
- NOAEL
- Effect level:
- 960 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- other: corresponds to 12000 ppm (the highest tested dose) for systemic and reproductive toxicity
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- no effects observed
- Mortality / viability:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Sexual maturation:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- no effects observed
- Histopathological findings:
- not examined
Details on results (F1)
VIABILITY (OFFSPRING)
The mean number of delivered F1 pups per dam was evenly distributed about test groups 0 - 3. The respective values reflect the normal range of biological variation inherent in the strain used in this study. Each one stillborn pup was found in the litter of dams Nos. 133 and 138 of test group 3 (12000 ppm). This incidence were within the normal range of the historical control data.
The viability index indicating pup mortality during lactation (PND 0 - 4) was 100.0 % (test groups 1 and 3) and 99.0% (test groups 0 and 2) based on 1 pup of the control group (0 ppm) was found dead and one pup of test group 2 (4000 ppm) was missing (cannibalized). These findings reflected the normal range of biological variation inherent in the strain of rats used for this study as all respective values were within the range of the historical control data.
The rate live birth indices were 100 % in test groups 0, 1 and 2 (0, 1500 and 4000 ppm). In test group 3 (12000 ppm) the live birth index was 98.1 %. Two pups were stillborn in test group 3 (12000 ppm), each one in the litter of dams No. 133 and No. 138. These values reflected the normal range of biological variation inherent in the strain of rats used for this study as all respective values were within the range of the historical control data.
CLINICAL SIGNS (OFFSPRING)
The surviving F1 pups of any test group did not show adverse clinical signs up to scheduled sacrifice on PND 4. However, in test group 2 (4000 ppm) one female pups could be assessed only until PND 1 because it was missed (cannibalized) on PND 2 and in test group 3 (12000 ppm) one male and one female pup from different litters could not be assessed because they were stillborn on PND 0.
BODY WEIGHT (OFFSPRING)
Mean pup body weights/pup body weight changes of all pups in all test groups were comparable to the control group. One female runt was seen in test group 0 (0 ppm) and two female runts were seen in test group 2 (4000 ppm). These values were within the range of the biological variation inherent in the strain of rats used for this study.
GROSS PATHOLOGY (OFFSPRING)
One male pup of test group 3 (12000 ppm) and one female pup of control group (0 ppm) showed post mortem autolysis. Furthermore, in test group 2 (4000 ppm) one female pup could not be assessed because it was missing (cannibalized). These findings were assessed as being spontaneous in nature and thereby not related to treatment. No other findings were seen in any pup of any test group.
The mean number of delivered F1 pups per dam was evenly distributed about test groups 0 - 3. The respective values reflect the normal range of biological variation inherent in the strain used in this study. Each one stillborn pup was found in the litter of dams Nos. 133 and 138 of test group 3 (12000 ppm). This incidence were within the normal range of the historical control data.
The viability index indicating pup mortality during lactation (PND 0 - 4) was 100.0 % (test groups 1 and 3) and 99.0% (test groups 0 and 2) based on 1 pup of the control group (0 ppm) was found dead and one pup of test group 2 (4000 ppm) was missing (cannibalized). These findings reflected the normal range of biological variation inherent in the strain of rats used for this study as all respective values were within the range of the historical control data.
The rate live birth indices were 100 % in test groups 0, 1 and 2 (0, 1500 and 4000 ppm). In test group 3 (12000 ppm) the live birth index was 98.1 %. Two pups were stillborn in test group 3 (12000 ppm), each one in the litter of dams No. 133 and No. 138. These values reflected the normal range of biological variation inherent in the strain of rats used for this study as all respective values were within the range of the historical control data.
CLINICAL SIGNS (OFFSPRING)
The surviving F1 pups of any test group did not show adverse clinical signs up to scheduled sacrifice on PND 4. However, in test group 2 (4000 ppm) one female pups could be assessed only until PND 1 because it was missed (cannibalized) on PND 2 and in test group 3 (12000 ppm) one male and one female pup from different litters could not be assessed because they were stillborn on PND 0.
BODY WEIGHT (OFFSPRING)
Mean pup body weights/pup body weight changes of all pups in all test groups were comparable to the control group. One female runt was seen in test group 0 (0 ppm) and two female runts were seen in test group 2 (4000 ppm). These values were within the range of the biological variation inherent in the strain of rats used for this study.
GROSS PATHOLOGY (OFFSPRING)
One male pup of test group 3 (12000 ppm) and one female pup of control group (0 ppm) showed post mortem autolysis. Furthermore, in test group 2 (4000 ppm) one female pup could not be assessed because it was missing (cannibalized). These findings were assessed as being spontaneous in nature and thereby not related to treatment. No other findings were seen in any pup of any test group.
Overall reproductive toxicity
- Reproductive effects observed:
- not specified
Any other information on results incl. tables
Table 1: Male fertility indices
|
Test group 0 (0 ppm) |
Test group 1 (1500 ppm) |
Test group 2 (4000 ppm) |
Test group 3 (12000 ppm) |
Male fertiltiy index [%] |
90 |
100 |
80 |
90 |
* p ≤ 0.05; ** p ≤ 0.01
Table 2: Female fertility indices
|
Test group 0 (0 ppm) |
Test group 1 (1500 ppm) |
Test group 2 (4000 ppm) |
Test group 3 (12000 ppm) |
Female fertility index [%] |
100 |
100 |
80 |
90 |
* p ≤ 0.05; ** p ≤ 0.01
The sex distribution and sex ratios of live F1 pups on the day of birth and PND 4 did not show substantial differences between the control and the test substance-treated groups; slight differences were regarded to be spontaneous in nature.
Table 3: Pup sex ratio
PND 0 |
Test group 0 (0 ppm) |
Test group 1 (1500 ppm) |
Test group 2 (4000 ppm) |
Test group 3 (12000 ppm) |
Live males [%] |
54.4 |
49.3 |
46.1 |
52.0 |
Live females [%] |
45.6 |
50.7 |
53.9 |
48.0 |
PND 4 |
|
|
|
|
Live males [%] |
54.7 |
49.3 |
46.5 |
52.0 |
Live females [%] |
45.3 |
50.7 |
53.5 |
48.0 |
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.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
