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EC number: 932-121-8 | CAS number: 1147459-12-8
- 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:
- 06 September 2016 - 29 September 2016
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 017
- Report date:
- 2017
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Version / remarks:
- January 2001
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.31 (Prenatal Developmental Toxicity Study)
- Version / remarks:
- May 2008
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
- Version / remarks:
- August 1998
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Remarks:
- dd 3 november 2015
- Limit test:
- no
Test material
- Reference substance name:
- N-[3-(dimethylamino)propyl] C 12-C18 alkylamide
- EC Number:
- 932-121-8
- Cas Number:
- 1147459-12-8
- Molecular formula:
- UVCB substance not applicable
- IUPAC Name:
- N-[3-(dimethylamino)propyl] C 12-C18 alkylamide
- Test material form:
- other: Paste
- Details on test material:
- - State of aggregation: paste
- Density: 0.885 g/cm3 at 20°C (solid)
- Analytical purity: 100% (UVCB)
- Color gardner 2: 7
- Purity test date: 18 May 2016
- Lot/batch No.: BS-160515001-001
- Expiration date of the lot/batch: 15 May 2021
- Storage condition of test material: At room temperature container flushed with nitrogen
- Solubility and stability of the test substance in the solvent/vehicle: stable as solution in corn oil for at least 5 hours at room temperature and 11 days in the refrigerator (confirmed over the concentration range 1 to 200 mg/mL)
OTHER SPECIFICS: no correction factor applied for purity; pH 11 at 1%.
Mean mol weight ~ 296 Range 228- 368
batch BS-160515001-001
1
- Specific details on test material used for the study:
- STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: At room temperature container flushed with nitrogen
- Solubility and stability of the test substance in the solvent/vehicle: stable as solution in corn oil for at least 5 hours at room temperature and 11 days in the refrigerator (confirmed over the concentration range 1 to 200 mg/mL)
Test animals
- Species:
- rat
- Strain:
- other: Crl:WI (Han)
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: 10-14 weeks.
- Weight at study initiation: 174-231 g
- Fasting period before study: none
- Housing: individually in Macrolon plastic cages (MIII type, height 18 cm). Sterilized sawdust as bedding material and paper as cage enrichment/nesting material were supplied.
- Diet: Free access to pelleted rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany).
- Water: Free access to tap-water
- Acclimation period: At least 5 days prior to treatment.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.7 - 21.2
- Humidity (%): 50.1 – 74.8
- Air changes (per hr): at least 10
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: 06 September 2016 (first delivery of mated females) To: 29 September 2016
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
Formulations (w/w) were prepared daily within 5 hours prior to dosing and were homogenized to a visually acceptable level. Adjustment was made for specific gravity of the test item (0.885 g/cm3 at 20 °C) and vehicle (0.92 g/cm3). No correction was made for the purity/composition of the test item.
VEHICLE
- Justification for use and choice of vehicle (if other than water): Based on trial formulations performed at Charles River Den Bosch
- Amount of vehicle (if gavage): 5 mL/kg body weight - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Analyses were conducted on a single occasion during the treatment phase (12 September 2016), according to a validated method (LC-MS/MS, validated in a range 1-250 mg/g). Samples of
formulations were analyzed for homogeneity (highest and lowest concentration) and accuracy of preparation (all concentrations).
The accuracy of preparation was considered acceptable if the mean measured concentrations were 90-110% of the target concentration. Homogeneity was demonstrated if the coefficient of variation was ≤ 10%. - Details on mating procedure:
- Untreated females were mated at the Supplier, and were at Day 0 or 1 post-coitum on arrival at the Test Facility.
- Proof of pregnancy: vaginal plug referred to as day 0 of pregnancy - Duration of treatment / exposure:
- From Days 6 to 20 post-coitum, inclusive
- Frequency of treatment:
- Once daily, 7 days/week
- Duration of test:
- 14 days
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day
- Remarks:
- concurrent vehicle controls
- Dose / conc.:
- 15 mg/kg bw/day
- Dose / conc.:
- 40 mg/kg bw/day
- Dose / conc.:
- 100 mg/kg bw/day
- No. of animals per sex per dose:
- 22 females/dose
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: based on the results of a 28-day repeated dose study (OECD 407), with a 7-day dose range finder in advance, and a combined 28-day repro screening study (OECD 422), with a 14-day dose range finder in advance.
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: at least twice daily for mortality and viability
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: at least once daily for clinical signs from day 2 post-coitum onwards up to the day prior to necropsy.
BODY WEIGHT: Yes
- Time schedule for examinations: Days 2, 6, 9, 12, 15, 18 and 21 post-coitum
FOOD CONSUMPTION: Yes
- Time schedule for examinations: Days 2-6, 6-9, 9-12, 12-15, 15-18 and 18-21 post-coitum
WATER CONSUMPTION: Subjective appraisal was maintained during the study, but no quantitative investigation was introduced, as no treatment related effect was suspected
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 21
- Organs examined: ovaries and uterine horns
- Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes - Fetal examinations:
- - External examinations: Yes: [all per litter ]
- Soft tissue examinations: Yes: [half per litter]
- Skeletal examinations: Yes: [half per litter ]
- Head examinations: Yes: [half per litter] - Statistics:
- The following statistical methods were used to analyze the data:
• If the variables could be assumed to follow a normal distribution, the Dunnett-test (many-to-one t-test) based on a pooled variance estimate was applied for the comparison of the treated groups and the control group.
• The Steel-test (many-to-one rank test) was applied if the data could not be assumed to follow a normal distribution.
• The Fisher Exact-test was applied to frequency data.
• The Mann Whitney test was used to compare mean litter proportions (percent of litter) of the number of viable and dead fetuses, early and late resorptions, total resorptions, pre- and post-implantation loss, and sex distribution.
• Mean litter proportions (percent per litter) of total fetal malformations and developmental variations (external, visceral and skeletal), and each particular external, visceral and skeletal malformation or variation were subjected to the Kruskal-Wallis nonparametric ANOVA test to determine intergroup differences. If the ANOVA revealed statistically significant (p<0.05) intergroup variance, Dunn’s test was used to compare the compound-treated groups to the control group.
All tests were two-sided and in all cases p < 0.05 was accepted as the lowest level of significance. Group means were calculated for continuous data and medians were calculated for discrete data (scores) in the summary tables. Test statistics were calculated on the basis of exact values for means and pooled variances.
No statistics were applied for data on maternal survival, pregnancy status, group mean numbers of dead fetuses, early and late resorptions, and pre- and post-implantation loss. - Indices:
- For each litter the following calculations were performed:
Pre-implantation loss (%) = ((number of corpora lutea - number of implantation sites)/number of corpora lutea) x 100%
Post-implantation loss (%) = ((number of implantation sites - number of live fetuses)/number of implantation sites) x 100%
Viable fetuses affected/litter (%) = ((number of viable fetuses affected/litter) / (number of viable fetuses/litter)) x 100% - Historical control data:
- Historical control data from the same testing laboratories in 2014-2015 are available (see under "Any other information on results incl. tables').
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Rales and piloerection were noted at 100 mg/kg bw/day for five and one female(s), respectively. Although these signs recovered after 1-5 days, they might be related to treatment with test item.
Salivation was noted for all females at 100 mg/kg bw/day, compared to none in the other groups. This finding was considered to be a physiological response rather than a sign of systemic toxicity considering the nature and minor severity of the effect and its time of occurrence (i.e. after dosing).
Moreover, alopecia was noted for one single female at 15 mg/kg bwd/day, which was not considered to be treatment related. - Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- Treatment at 100 mg/kg bw/day resulted in two unscheduled deaths.
One female at 100 mg/kg bw/day was sacrificed in extremis on Day 7 post-coitum (before dosing), the day after having received the first dose. Observations preceding early sacrifice included squeaking, rales, labored (severe) and shallow (moderate) respiration, gasping and hypothermia. At necropsy, dark red foci were noted on the thymus. This female was pregnant and had 8 normal implantations in development.
Another female of the 100 mg/kg bw/day group was found dead on Day 21 post-coitum, the day of planned necropsy. No toxicologically relevant clinical signs were noted for this female. Body weight and food consumption was slightly lower for this female, when compared to the other females of the 100 mg/kg bw/day group. This was considered to be (partly) caused by the number of fetuses, as she had only 3 (dead) fetuses and 4 early resorptions. No macroscopic alterations were noted at necropsy.
Although these mortality findings were incidental, it could not be excluded that these unscheduled deaths were related to treatment. - Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- There was a trend towards lower body weights at 100 mg/kg bw/day from Day 12 post-coitum onwards. Body weight gain was statistically significantly lower at 100 mg/kg bw/day than controls on Days 15 and 18 post-coitum. For uterus corrected body weight gain was considered to be unaffected by treatment up to 100 mg/kg bw/day.
Mean body weight and body weight gain at 15 and 40 mg/kg bw/day remained in the same range as controls.
One female from the control group and three females from the 100 mg/kg bw/day group had significantly lower body weights and weight gains when compared to the other females of the same group. This was considered to be (partly) due to the relatively low number of fetuses, as two females had 1 fetus, and two other females had 3 fetuses. In addition, for two females (one with one fetus and one with two fetuses) no body weight gain was observed over Days 12 to 21 post-coitum, which was considered to be a direct treatment-related effect rather than only caused by the low number of fetuses. - Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- Food consumption before and after correction for body weight was statistically significantly reduced at 100 mg/kg bw/day on Days 9 to 12 post-coitum. This recovered during the remainder of the treatment period.
At 15 and 40 mg/kg bw/day, food consumption before or after correction for body weight were similar as controls. - Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- no effects observed
- 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:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Alopecia was noted for one single female at 15 mg/kg bw/day, confirming the clinical sign observed during the in-life phase.
Dark red foci on the thymus were noted for one female at 100 mg/kg bw/day, which was early sacrificed. - Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- no effects observed
Maternal developmental toxicity
- Number of abortions:
- no effects observed
- Pre- and post-implantation loss:
- no effects observed
- Description (incidence and severity):
- Pre- or post-implantation loss were unaffected by treatment up to and including 100 mg/kg bw/day.
- 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
- Description (incidence and severity):
- Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not examined - Changes in number of pregnant:
- not examined
- Other effects:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Statistically significantly lower numbers of corpora lutea (10.7 per female) were noted in the 100 mg/kg bw/day group when compared to the concurrent control group (12.2 per female). As treatment started from implantation onwards, i.e. Day 6 post-coitum, this was not considered to be treatment related. Consequently, the number of implantation sites at 100 mg/kg bw/day were slightly lower than controls as well (9.6 versus 11.4 per female). This was not statistically significant and within the range of available historical control data and not considered to be treatment related.
Effect levels (maternal animals)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 40 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- body weight and weight gain
- clinical signs
Maternal abnormalities
- Key result
- Abnormalities:
- no effects observed
Results (fetuses)
- Fetal body weight changes:
- no effects observed
- Description (incidence and severity):
- There were no effects on fetal body weights (both sexes) noted by treatment up to 100 mg/kg bw/day.
Mean combined (male and female) fetal body weights were 5.3, 5.3, 5.2 and 5.4 gram for the control, 15, 40 and 100 mg/kg groups, respectively
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): not examined - Reduction in number of live offspring:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Mean litter sizes were 10.7, 10.7, 11.0 and 9.1 viable fetuses/litter for the control, 15, 40 and 100 mg/kg bw/day groups, respectively.
The slightly lower number of fetuses/litter at 100 mg/kg bw/day when compared to controls was not statistically significant and within the range of available historical control data. As it was related to the lower numbers of corpora lutea and implantation sites at 100 mg/kg bw/day, it was not considered to be treatment related.
There were two females, one in the control group and one in the 100 mg/kg bw/day group, which only had one viable fetus. This was considered to be chance findings. - Changes in sex ratio:
- no effects observed
- Description (incidence and severity):
- The male:female ratio was unaffected by treatment up to 100 mg/kg bw/day.
Mean sex ratios (males:females) were 55:45, 49:51, 43:57 and 50:50 for the control, 15, 40 and 100 mg/kg groups, respectively. - Changes in litter size and weights:
- effects observed, non-treatment-related
- Description (incidence and severity):
- There were no treatment-related effects on litter size of any group.
Mean litter sizes were 10.7, 10.7, 11.0 and 9.1 viable fetuses/litter for the control, 15, 40 and 100 mg/kg groups, respectively.
The slightly lower number of fetuses/litter at 100 mg/kg bw/day when compared to controls was not statistically significant and within the range of available historical control data. As it was related to the lower numbers of corpora lutea and implantation sites at 100 mg/kg bw/day, it was not considered to be treatment related. - Changes in postnatal survival:
- not examined
- External malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- There were no treatment related effects on external morphology following treatment up to 100 mg/kg bw/day.
External malformations occurred in all groups. A small lower jaw was observed in one fetus of 100 mg/kg bw/day group and was skeletally confirmed. An absent tail combined with anal atresia were found in one fetus of 40 mg/kg bw/day group, and in 15 mg/kg bw/day group an omphalocele in one fetus and anasarca in another fetus were noticed. Omphalocele and anasarca were observed in single control fetuses as well. The single occurrence and/or group distribution of the above malformations did not indicate a treatment relationship and therefore all were considered to be chance findings.
External variations were not seen in any group. - Skeletal malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- There were no treatment related effects on skeletal morphology following treatment up to 100 mg/kg bw/day.
Malformations were observed in two fetuses of 100 mg/kg bw/day group and single fetuses of control, 15 and 40 mg/kg bw/day groups. A fetus from the 100 mg/kg bw/day group (which had a small lower jaw and a variety of visceral malformations) appeared to have severely malaligned sternebrae and a bent scapula as well. Another fetus of the 100 mg/kg bw/day group had malpositioned metatarsals.
The other affected fetuses (control, 15 and 40 mg/kg bw/day groups, respectively) all had a vertebral anomaly with or without associated rib anomaly. In addition, the fetus from the 15 mg/kg bw/day group (that also had an omphalocele and malpositioned kidneys) had a sternal anomaly and bent limb bones as well. The group distribution and/or single occurrence of these malformations did not suggest any treatment relationship and therefore all were considered to be chance findings.
Skeletal variations occurred at an incidence of 86.7%, 89.3%, 78.5% and 76.0% per litter in controls, 15, 40 and 100 mg/kg bw/day, respectively. All the ones noted, were not considered treatment-related, as they occurred in the absence of a dose-dependent relationship, infrequently and/or at frequencies that were within the range of available historical control data. - Visceral malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- There were no treatment related effects on visceral morphology following treatment up to 100 mg/kg bw/day.
In total five fetuses were viscerally malformed in this study. The two fetuses of 15 mg/kg bw/day group, one fetus of the 100 mg/kg bw/day group and one control fetus that were affected externally, appeared to have one or more visceral malformations as well. The other affected fetus was a 40 mg/kg bw/day group fetus. Due to the group distribution and variety of malformation observed, all were considered not to be toxicologically relevant.
Visceral variations were observed in 10.3%, 9.1%, 7.3% and 7.5% of fetuses per litter in controls, 15, 40 and 100 mg/kg bw/day groups, respectively. These all occurred in the absence of a dose-related incidence trend, infrequently and/or at frequencies that were within the range of available historical control data. - Other effects:
- no effects observed
Effect levels (fetuses)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 100 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: no treatment-related effects observed at the highest tested dose.
Fetal abnormalities
- Key result
- Abnormalities:
- no effects observed
Overall developmental toxicity
- Key result
- Developmental effects observed:
- no
Any other information on results incl. tables
Analytical verification of the tested formulations
The concentrations analyzed in the formulations were in agreement with the target concentrations (mean accuracies 100.9% (n = 6), 98.4 (n = 2) and 99.3 (n = 6) for 15, 40 and 100 mg/kg bw/day dose solutions).
The formulations of low- and high-dose groups were homogeneous ( coefficient of variation 0.6 and 1.0, respectively (n = 6)).
Summary of developmental effects observed in the study
Dose level (mg/kg bw/day) |
0 |
8 |
25 |
75 |
Pregnant/total dams |
22/22 |
22/22 |
22/22 |
22/22 |
-early resorptions -late resorptions (% per litter) |
7.1 0.4 |
5.5 0.0 |
6.2 0.3 |
4.6 0.0 |
Dams with abortion, early deliveries, stillbirths, resorptions only and/or dead fetuses only |
0 |
0 |
0 |
0 |
Pre-implantation loss (number and percent) |
19 (6.2%) |
26 (9.3%) |
26 (9.1%) |
21 (10.7%) |
Post-implantation loss (number and percent) |
14 (7.5%) |
14 (5.5%) |
19 (6.5%) |
10 (4.6%) |
Body weight on day 21 |
327 |
326 |
326 |
313 |
Body weight gain day 6-21 (%) |
48 |
47 |
47 |
43 |
Gravid uterine weight (g) |
76.5 |
76.2 |
76.4 |
65.3 |
Mean live offspring (number) |
10.7 |
10.7 |
11.0 |
9.1 |
Live offspring (percent) |
92.5 |
94.5 |
93.5 |
95.4 |
Mean fetal/pup body weight males (g) |
5.5 |
5.5 |
5.3 |
5.5 |
Mean fetal body weight females |
5.1 |
5.2 |
5.1 |
5.2 |
Mean fetal body weight (sexes combined) |
5.3 |
5.3 |
5.2 |
5.4 |
Malformations (including runts) number and percent of fetuses per litter |
3 (1.4%) |
2 (0.9%) |
3 (2.3%) |
2 (1.5%) |
Variations (% per litter) -external -soft tissue -skeletal |
0 10.3 86.7 |
0 9.1 89.3 |
0 7.3 78.5 |
0 7.5 76.0 |
Historical control data (2014-2015)
Historical Control Data Rat: Crl:WI(Han) (outbred, SPF-Quality) |
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Gestation Day 21 |
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Mean of Study Means |
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Study Date Range: 2014 - 2015 |
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Endpoint |
Total |
Mean |
SD |
Median |
Min |
Max |
P5 |
P95 |
No of Studies |
13 |
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Total No. of Animals in the Control Group |
304 |
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No. of Animals that Died |
0 |
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No. of Animals that were Euthanized |
0 |
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No. of Animals that Aborted or Delivered |
3 |
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Percent Pregnant |
|
98.8 |
2.73 |
100.0 |
90.9 |
100.0 |
97.1 |
100.0 |
No. of Animals Examined at Laparohysterectomy |
301 |
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No. Nongravid |
4 |
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No. Gravid |
297 |
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No. with Only Resorptions |
2 |
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No. of Dams with Live Fetuses |
295 |
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Mean No. Viable Fetuses/Dam |
|
10.7 |
0.71 |
10.6 |
9.1 |
11.6 |
10.3 |
11.2 |
Total No. Viable Fetuses |
3194 |
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Viable Fetuses (%/Litter) |
|
95.2 |
2.63 |
95.9 |
88.9 |
98.4 |
93.6 |
96.8 |
Mean No. Postimplantation Loss/Dam |
|
0.5 |
0.15 |
0.4 |
0.2 |
0.7 |
0.4 |
0.6 |
Total No. Postimplantation Losses |
134 |
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Postimplantation Loss (%/Litter) |
|
4.8 |
2.63 |
4.1 |
1.6 |
11.1 |
3.2 |
6.4 |
Dead Fetuses (%/Litter) |
|
0.0 |
0.11 |
0.0 |
0.0 |
0.4 |
0.0 |
0.1 |
Early Resorptions (%/Litter) |
|
4.7 |
2.62 |
4.1 |
1.6 |
11.1 |
3.2 |
6.3 |
Late Resorptions (%/Litter) |
|
0.0 |
0.11 |
0.0 |
0.0 |
0.4 |
0.0 |
0.1 |
Mean No. Implantations/Dam |
|
11.2 |
0.69 |
11.1 |
9.6 |
12.0 |
10.8 |
11.6 |
Mean No. Corpora Lutea/Dam |
|
11.9 |
0.71 |
11.7 |
10.9 |
13.2 |
11.5 |
12.3 |
Mean No. Preimplantation Loss/Dam |
|
0.7 |
0.32 |
0.6 |
0.2 |
1.3 |
0.5 |
0.9 |
Total No. Preimplantation Losses |
207 |
|
|
|
|
|
|
|
Preimplantation Loss (%/Litter) |
|
6.2 |
3.43 |
5.8 |
2.0 |
14.5 |
4.2 |
8.3 |
Total No. Male Fetuses |
1617 |
|
|
|
|
|
|
|
Total No. Female Fetuses |
1577 |
|
|
|
|
|
|
|
% Males/Litter |
|
50.8 |
2.12 |
50.7 |
46.6 |
53.7 |
49.5 |
52.0 |
% Female/Litter |
|
49.2 |
2.12 |
49.3 |
46.3 |
53.4 |
48.0 |
50.5 |
Mean Fetal Body Weight (g) |
|
5.2 |
0.08 |
5.2 |
5.1 |
5.3 |
5.1 |
5.2 |
Mean Male Body Weight (g) |
|
5.4 |
0.10 |
5.4 |
5.2 |
5.5 |
5.3 |
5.4 |
Mean Female Body Weight (g) |
|
5.1 |
0.07 |
5.1 |
5.0 |
5.2 |
5.0 |
5.1 |
Mean Male Placenta Weight (g)1 |
|
0.46 |
0.01 |
0.47 |
0.44 |
0.47 |
0.4 |
0.5 |
Mean Female Placenta Weight (g)1 |
|
0.44 |
0.01 |
0.44 |
0.42 |
0.45 |
0.4 |
0.5 |
1Based on 4 datasets
Historical Control Data Rat: Crl:WI(Han) (outbred, SPF-Quality) |
|
|
|
|
|
|
|
|
|
Gestation Day 21 |
|
|
|
|
|
|
|
|
|
Study Date Range: 2014 - 2015 |
|
|
|
|
|
|
|
|
|
No. of Studies |
13 |
|
|
|
|
|
|
|
|
Total No. Fetuses/Litters Examined Externally |
3194 |
295 |
|
|
|
|
|
|
|
Total No. Fetuses/Litters Examined Viscerally |
2061 |
295 |
|
|
|
|
|
|
|
Total No. Fetuses/Litters Examined Skeletally |
2059 |
295 |
|
|
|
|
|
|
|
|
Mean of Study Means |
|
|
|
|
|
Summary Incidence |
||
|
(% Per Litter Basis) |
|
|
|
|
|
(Total No. Affected) |
||
MALFORMATIONS |
Mean |
SD |
Median |
Min |
Max |
P5 |
P95 |
Fetuses |
Litters |
Total External Malformations |
|
|
|
|
|
|
|
1 |
1 |
Total Visceral Malformations |
|
|
|
|
|
|
|
7 |
7 |
Total Skeletal Malformations |
|
|
|
|
|
|
|
15 |
15 |
Total Malformations |
|
|
|
|
|
|
|
22 |
22 |
EXTERNAL |
|
|
|
|
|
|
|
|
|
Exencephaly |
0.0 |
0.14 |
0.0 |
0.0 |
0.5 |
0.0 |
0.1 |
1 |
1 |
Eye(s)- Open |
0.0 |
0.14 |
0.0 |
0.0 |
0.5 |
0.0 |
0.1 |
1 |
1 |
VISCERAL |
|
|
|
|
|
|
|
|
|
Diaphragmatic Hernia |
0.0 |
0.08 |
0.0 |
0.0 |
0.3 |
0.0 |
0.1 |
1 |
1 |
Eye(s)- Absent and/or Small |
0.1 |
0.26 |
0.0 |
0.0 |
0.9 |
0.0 |
0.2 |
3 |
3 |
Hydrocephaly- External |
0.0 |
0.12 |
0.0 |
0.0 |
0.5 |
0.0 |
0.1 |
1 |
1 |
Situs Inversus |
0.2 |
0.34 |
0.0 |
0.0 |
1.0 |
0.0 |
0.4 |
3 |
3 |
SKELETAL |
|
|
|
|
|
|
|
|
|
Jaw- Upper Jaw Small |
0.1 |
0.22 |
0.0 |
0.0 |
0.8 |
0.0 |
0.2 |
1 |
1 |
Jaw- Lower Jaw Absent or Small |
0.1 |
0.22 |
0.0 |
0.0 |
0.8 |
0.0 |
0.2 |
1 |
1 |
Limb Bone(s)- Bent |
0.3 |
0.44 |
0.0 |
0.0 |
1.1 |
0.0 |
0.5 |
4 |
4 |
Rib Anomaly |
0.1 |
0.31 |
0.0 |
0.0 |
1.1 |
0.0 |
0.3 |
1 |
1 |
Skull Anomaly |
0.1 |
0.34 |
0.0 |
0.0 |
1.2 |
0.0 |
0.3 |
2 |
2 |
Sternebra(e)- Fused |
0.1 |
0.29 |
0.0 |
0.0 |
1.0 |
0.0 |
0.3 |
2 |
2 |
Sternebra(e) Malaligned (Severe) |
0.0 |
0.08 |
0.0 |
0.0 |
0.3 |
0.0 |
0.1 |
1 |
1 |
Sternoschisis |
0.1 |
0.22 |
0.0 |
0.0 |
0.8 |
0.0 |
0.2 |
1 |
1 |
Vertebral Anomaly With or Without Associated Rib Anomaly |
0.2 |
0.53 |
0.0 |
0.0 |
1.9 |
0.0 |
0.5 |
3 |
3 |
Vertebral Centra Anomaly |
0.1 |
0.22 |
0.0 |
0.0 |
0.8 |
0.0 |
0.2 |
1 |
1 |
Historical Control Data Rat: Crl:WI(Han) (outbred. SPF-Quality) |
|
|
|
|
|
|
|
|
|
Gestation Day 21 |
|
|
|
|
|
|
|
|
|
|
Mean of Study Means |
|
|
|
|
Summary Incidence |
|||
|
(% Per Litter Basis) |
|
|
|
|
|
(Total No. Affected) |
||
VARIATIONS |
Mean |
SD |
Median |
Min |
Max |
P5 |
P95 |
Fetuses |
Litters |
EXTERNAL |
|
|
|
|
|
|
|
|
|
None Observed |
|
|
|
|
|
|
|
|
|
VISCERAL |
|
|
|
|
|
|
|
|
|
Kidney(s)- Renal Papilla(e) Absent and/or Small |
0.1 |
0.25 |
0.0 |
0.0 |
0.9 |
0.0 |
0.2 |
2 |
2 |
Liver- Appendix |
1.2 |
0.56 |
1.3 |
0.3 |
2.3 |
0.9 |
1.6 |
23 |
21 |
Liver- Discolored |
0.1 |
0.30 |
0.0 |
0.0 |
1.0 |
0.0 |
0.3 |
3 |
3 |
Liver- Small Supernumerary Lobe(s) |
4.0 |
1.96 |
4.0 |
1.3 |
7.7 |
2.8 |
5.2 |
69 |
58 |
Spleen- Supernumerary |
0.0 |
0.14 |
0.0 |
0.0 |
0.5 |
0.0 |
0.1 |
1 |
1 |
Thymus- Partially Undescended Horn(s) |
1.3 |
1.55 |
0.8 |
0.0 |
4.3 |
0.3 |
2.2 |
34 |
23 |
Thyroid- Discolored |
0.1 |
0.36 |
0.0 |
0.0 |
1.3 |
0.0 |
0.3 |
1 |
1 |
Ureter(s)- Convoluted |
1.0 |
2.39 |
0.0 |
0.0 |
8.7 |
0.0 |
2.5 |
43 |
28 |
Ureter(s)- Dilated |
0.9 |
2.33 |
0.0 |
0.0 |
8.5 |
0.0 |
2.3 |
44 |
19 |
SKELETAL |
|
|
|
|
|
|
|
|
|
7th Cervical Rudimentary Rib(s) |
1.7 |
1.34 |
1.2 |
0.0 |
4.4 |
0.9 |
2.5 |
30 |
26 |
7th Cervical Full Rib(s) |
0.1 |
0.36 |
0.0 |
0.0 |
1.1 |
0.0 |
0.4 |
2 |
2 |
14th Full Rib(s) |
5.7 |
4.65 |
5.2 |
0.0 |
13.1 |
2.9 |
8.5 |
88 |
64 |
14th Rudimentary Rib(s) |
44.1 |
19.84 |
54.4 |
19.0 |
72.0 |
32.1 |
56.1 |
798 |
250 |
Metacarpal(s) and/or Metatarsal(s) Unossified |
2.2 |
1.97 |
1.0 |
0.0 |
6.3 |
1.0 |
3.4 |
41 |
24 |
Pelvic Girdle- Caudal Shift |
6.6 |
3.77 |
7.1 |
1.7 |
12.8 |
4.3 |
8.9 |
127 |
71 |
Rib(s)- Bent |
10.6 |
7.78 |
10.2 |
0.8 |
22.3 |
5.9 |
15.3 |
162 |
85 |
Rib(s)- Short |
0.0 |
0.06 |
0.0 |
0.0 |
0.2 |
0.0 |
0.0 |
1 |
1 |
Skull- Reduced Ossification |
2.7 |
2.55 |
1.8 |
0.0 |
7.0 |
1.2 |
4.3 |
81 |
46 |
Skull- Supernumerary Site |
0.0 |
0.14 |
0.0 |
0.0 |
0.5 |
0.0 |
0.1 |
1 |
1 |
Sternebra(e) #1, #2, #3 and/or #4 Unossified |
0.2 |
0.31 |
0.0 |
0.0 |
0.8 |
0.0 |
0.3 |
3 |
3 |
Sternebra(e) #5 and/or #6 Unossified |
0.9 |
1.33 |
0.0 |
0.0 |
4.1 |
0.1 |
1.7 |
37 |
23 |
Sternebrae- Malaligned (Slight or Moderate) |
11.1 |
5.72 |
8.9 |
4.4 |
21.3 |
7.6 |
14.5 |
188 |
131 |
Sternum- Supernumerary Ossification Site |
0.1 |
0.31 |
0.0 |
0.0 |
1.1 |
0.0 |
0.3 |
1 |
1 |
Vertebral Centra- Reduced Ossification |
0.6 |
0.88 |
0.4 |
0.0 |
3.0 |
0.1 |
1.2 |
12 |
12 |
Applicant's summary and conclusion
- Conclusions:
- In a GLP-compliant guideline study with rats, the administration of the test substance by oral gavage to pregnant rats during gestation days 6-21 did not result in developmental effects on the offspring at the highest tested dose of 100 mg/kg bw/day. This level was considered to be a NOAEL for developmental effects. Based on the clinical signs and reduced body weight gain at the highest dose level in maternal animals, the NOAEL for maternal toxicity was set at 40 mg/kg bw/day.
- Executive summary:
In a GLP-compliant OECD guideline 414 study, the test substance was administered to groups of 22 pregnant rats at dose levels of 0 (concurrent vehicle controls), 15, 40 and 100 mg/kg bw/day. Two mortalities occurred at the highest dose level (day 7 and day 21); however, in the absence of corroborative gross pathological and histopathological findings these deaths are likely to have been incidental. Rales and piloerection were observed in 5 and 1 female of the high-dose group, respectively, but disappeared after 1 -5 days. Lower body weight gains were observed on days 15 and 18 of gestation. Based on these effects the maternal NOAEL was set at 40 mg/kg bw/day.
Statistically significantly lower numbers of corpora lutea were noted in the high-dose group in comparison to the controls, resulting in a lower number of implantation sites; however, as the treatment started after the implantation, i.e. from day 6 post-coitum, this finding was considered to be not related to the treatment. Furthermore, the number of implantation sites was within the range of historical control data. There were no effects on the number of early and late resorption, post-implantation losses or the number of viable fetuses. Body weights and sex ratio of fetuses were unaffected by the treatment. There were no treatment-related external, visceral or skeletal variations or
malformations at any dose level. Based on this, the NOAEL for developmental toxicity was set at the highest tested dose of 100 mg/kg bw/day.
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