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EC number: 237-695-7 | CAS number: 13927-71-4
- 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:
- 20 October 2017 - 13 December 2017
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 018
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Version / remarks:
- 22 January 2001
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- Bis(dibutyldithiocarbamato-S,S')copper
- EC Number:
- 237-695-7
- EC Name:
- Bis(dibutyldithiocarbamato-S,S')copper
- Cas Number:
- 13927-71-4
- Molecular formula:
- C18H36CuN2S4
- IUPAC Name:
- bis(dibutyldithiocarbamato-S,S')copper
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: breeder: Janvier, le Genest-Saint-Isle, France
- Age at the beginning of the treatment period: approximately 10-11 weeks old
- Mean body weight at the beginning of the treatment period: 295 g (range: 235 g to 358 g)
- Fasting period before study: no
- Housing: individually
- Diet: SSNIFF R/M-H pelleted diet (free access)
- Water: tap water filtered with a 0.22 µm filter (free access)
- Acclimation period: for a period of 4 or 5 days before the beginning of the treatment period.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2°C
- Humidity (%): 50 ± 20%
- Air changes (per hr): approximately 8 to 15 cycles/hour of filtered, non-recycled air
- Photoperiod (hrs dark / hrs light): 12 h/12 h
IN-LIFE DATES: 20 November 2017 to 13 December 2017
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- other: 0.5% (w/w) methylcellulose aqueous solution
- Details on exposure:
- PREPARATION OF DOSING FORMULATIONS:
- Suspension in the vehicle
- Justification for use and choice of vehicle: suitable formulation in the selected vehicle
- Concentration in vehicle: 10, 30 and 100 mg/mL
- Volume of administration : 10 mL/kg/day - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Type of method: Ultra-Violet-Visible (UV-Vis) spectrophotometric method
Test item concentrations: were within an acceptable range of variation compared to nominal values (+/- 15%) in Weeks 1 and 4.
Homogeneity: homogenous formulations at 10 and 200 mg/mL.
Stability: not assessed, dose formulations were prepared daily. - Details on mating procedure:
- - Impregnation procedure: purchased time pregnant
- Proof of pregnancy: vaginal plug (at the breeder's facility); referred to as day 0 post coitum - Duration of treatment / exposure:
- Days 6 to 20 post coitum inclusive.
- Frequency of treatment:
- Daily.
- Duration of test:
- Day 21 post coitum.
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 100 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 300 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 1 000 mg/kg bw/day (actual dose received)
- No. of animals per sex per dose:
- 24 females
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Rationale for dose selection:
The dose levels were selected in agreement with the Sponsor, on the basis of the results of a previous OECD 421 study (reproduction/developmental toxicity screening in rats) where female Sprague-Dawley rats received the test item in 0.5% aqueous methylcellulose by gavage at 10 mL/kg at 50, 250 or 1000 mg/kg/day prior to pairing, during pairing and throughout gestation and lactation until Day 3 post-partum. There were no toxicologically significant effects in females of this study.
Therefore, the same high-dose was used in the present study. The lower doses were selected with an approximately 3-fold interval between each dose.
- Rationale for animal assignment:computerized stratification procedure.
Examinations
- Maternal examinations:
- MORTALITY/MORBIDITY:
- Time schedule: each animal was checked for mortality and morbidity once a day before the treatment period and at least twice a day during the treatment period, including weekends.
CLINICAL SIGNS:
- Time schedule: from arrival, each animal was observed once a day as part of the routine examinations. From the start of the treatment period, each animal was observed once a day, at approximately the same time.
BODY WEIGHT:
- Time schedule: the body weight of each female was recorded on Days 2, 4, 6, 9, 12, 15, 18 and 21 p.c.
FOOD CONSUMPTION:
- Time schedule: the quantity of food consumed by each female was recorded for the following intervals: Days 2-4, 4-6, 6-9, 9-12, 12-15, 15-18 and 18-21 p.c.
POST-MORTEM EXAMINATION:
- Sacrifice on Day 21 post coitum
- Examined: principal thoracic and abdominal organs - Ovaries and uterine content:
- The ovaries and uterine content were examined after termination, including:
- Gravid uterus weight
- Number of corpora lutea
- Number of implantation sites
- Number of early and late resorptions
- Number of dead and live fetuses
- Number of uterine scars
- Gross evaluation of placentas - Fetal examinations:
- - External examinations: Yes: all fetuses per litter
- Soft tissue examinations: Yes: half fetuses per litter
- Skeletal examinations: Yes: half fetuses per litter
- Head examinations: Yes: half fetuses per litter
- Other: fetal weight, fetal sex - Statistics:
- Data were compared by one-way analysis of variance and Dunnett test (mean values being considered as normally distributed and variances being considered as homogeneous) or by Fisher’s exact probability test (proportions).
- Indices:
- % Pre-implantation loss = 100 * (Number of corpora lutea - Number of implantation sites) / Number of corpora lutea
% Post-implantation loss = 100 * (Number of implantation sites - Number of live fetuses) / Number of implantation sites - Historical control data:
- Cf attached document
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- effects observed, non-treatment-related
- Description (incidence and severity):
- See table 1.
There were no test item-related clinical signs. Clinical signs observed at 1000 mg/kg/day were of isolated incidence, lasted 1 or 2 days only and were of common background in laboratory rats. - Mortality:
- no mortality observed
- Description (incidence):
- There were no unscheduled deaths.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- See table 2.
There were no effects on mean body weight.
At 1000 mg/kg/day and when compared with controls, mean body weight change was slightly lower on Days 6 to 9 p.c. (+13 g vs. +18 g, p<0.01) with a return towards control values thereafter. Therefore, this finding was considered to be test item-related and non-adverse. - Food consumption and compound intake (if feeding study):
- effects observed, non-treatment-related
- Description (incidence and severity):
- There were no effects on mean food consumption.
High food consumptions noted in one control female (on Days 18 to 21 p.c.) and in one female at 300 mg/kg/day (from Days 9 to 18 p.c.) were considered to be related to food spillage which is rather common in laboratory rodents. - 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:
- effects observed, non-treatment-related
- Description (incidence and severity):
- See table 4.
There were no test item-related necropsy findings (isolated incidences, no dose-relationship and/or of common background in laboratory rats). - Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- no effects observed
- Description (incidence and severity):
- Uterus weight, carcass weight and net body weight change from Day 6 post coitum:
See table 3.
There were no effects on mean carcass weight, mean gravid uterus weight, or mean net body weight change.
Maternal developmental toxicity
- Number of abortions:
- no effects observed
- Pre- and post-implantation loss:
- effects observed, non-treatment-related
- Description (incidence and severity):
- See table 5.
Number of dams with pre-implantation loss = 17, 15, 10, 16, at 0, 100, 300, 1000 mg/kg/day, respectively
Number of dams with post-implantation loss = 12, 15, 10, 13 at 0, 100, 300, 1000 mg/kg/day, respectively - Total litter losses by resorption:
- no effects observed
- Description (incidence and severity):
- See table 5.
No dams with total resorption. - Early or late resorptions:
- effects observed, non-treatment-related
- Description (incidence and severity):
- See table 5.
Number of dams with resorptions = 12, 15, 10, 13 at 0, 100, 300, 1000 mg/kg/day, respectively - Dead fetuses:
- no effects observed
- Description (incidence and severity):
- See table 5.
No dead fetuses. - Changes in pregnancy duration:
- not examined
- Changes in number of pregnant:
- effects observed, non-treatment-related
- Description (incidence and severity):
- At hysterectomy on Day 21 p.c., there were 24/24, 22/24, 23/24 and 24/24 pregnant dams with live fetuses in the groups treated at 0, 100, 300 or 1000 mg/kg/day, respectively.
Effect levels (maternal animals)
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Remarks on result:
- not determinable due to absence of adverse toxic effects
Maternal abnormalities
- Abnormalities:
- no effects observed
Results (fetuses)
- Fetal body weight changes:
- no effects observed
- Description (incidence and severity):
- See table 6
There were no effects on mean fetal body weight.
Mean male fetal body weight: 6.04, 6.03, 6.04, 5.93 g, at 0, 100, 300 or 1000 mg/kg/day, respectively
Mean female fetal body weight: 5.63, 5.58, 5.62, 5.63 g, at 0, 100, 300 or 1000 mg/kg/day, respectively - Reduction in number of live offspring:
- no effects observed
- Description (incidence and severity):
- See table 5
- Changes in sex ratio:
- no effects observed
- Description (incidence and severity):
- See table 7
There were no effects on mean percentage of male fetuses (sex-ratio). - Changes in litter size and weights:
- no effects observed
- Changes in postnatal survival:
- not examined
- External malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- See tables 9 and 14.
External malformations observed at 100 and 300 mg/kg/day were not considered to be test item treatment related (no dose-relationship and most of them recorded at litter incidences comparable to that reported in historical control data). - Skeletal malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- See tables 13 and 14.
In test item-treated groups, none of the skeletal malformations were considered to be test item treatment related: they were noted at isolated incidences and there were no findings at 1000 mg/kg/day. - Visceral malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- See tables 11 and 14.
The malformations observed at 100 mg/kg/day were considered to be not related to the test item treatment as they were noted in only one fetus and/or found also in Historical Control Data. - Other effects:
- effects observed, non-treatment-related
- Description (incidence and severity):
- External variations
See table 8.
All external variations were considered to be incidental as there was no dose-relationship. The incidences were comparable with controls or isolated, and/or they were of common background in laboratory rats of this strain.
Skeletal examinations
Cartilage
See table 12.
None of the cartilage findings were considered to be test item treatment-related; they were noted with no dose-relationship, at isolated or low incidences, and/or can be found in Historical Control Data.
The other cartilages were present or of normal morphology.
Variations
Fetal skeletal variations were not considered to be test item-related (including the statistically higher number of fetuses with ossification point on 14th thoracic vertebra at 100 mg/kg/day when compared with controls): they were at comparable/lower incidences to/than controls, within historical control data, not dose-related, not statistical significant and/or noted at isolated/low incidence.
Soft tissue variations
See table 10.
These visceral variations were considered to be incidental as there was no dose-relationship, the incidences were comparable with (or lower than) controls, isolated, and/or of common background in laboratory rats of this strain.
Effect levels (fetuses)
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Remarks on result:
- not determinable due to absence of adverse toxic effects
Fetal abnormalities
- Abnormalities:
- effects observed, non-treatment-related
Overall developmental toxicity
- Developmental effects observed:
- no
Any other information on results incl. tables
Table 1: Clinical signs
Dose level (mg/kg/day) |
0 |
100 |
300 |
1000 |
Cutaneous lesion on neck dorsal area |
1 |
0 |
0 |
0 |
Piloerection |
0 |
0 |
0 |
1 |
Reflux at dosing |
0 |
0 |
0 |
1 |
Number of affected animals |
1/24 |
0/24 |
0/24 |
2/24 |
Table 2: Body weight and body weight change
Dose level (mg/kg/day) |
0 |
100 |
300 |
1000 |
Mean body weight |
|
|
|
|
Day 6 p.c. |
295 |
297 |
295 |
296 |
|
|
+1 |
0 |
0 |
Day 9 p.c. |
312 |
312 |
310 |
308 |
|
|
0 |
-1 |
-1 |
Day 21 p.c. |
451 |
447 |
446 |
446 |
|
|
-1 |
-1 |
-1 |
Mean body weight change |
|
|
|
|
Days 6 - 9 p.c. |
+18 |
+16 |
+15 |
+13** |
Days 9 - 21 p.c. |
+139 |
+135 |
+137 |
+138 |
Days 6 - 21 p.c. |
+156 |
+151 |
+151 |
+151 |
In italic, percentage difference (%) vs. controls,
Statistically significant vs. controls:**: p<0.01.
Table 3: Net body weight
Dose level (mg/kg/day) |
0 |
100 |
300 |
1000 |
Gravid uterus weight |
102.1 |
99.5 |
101.2 |
97.3 |
Carcass weight |
348.5 |
347.8 |
345.0 |
349.2 |
Net weight change from Day 6 p.c. |
54.0 |
51.3 |
49.9 |
53.5 |
Table 4: Macroscopic post-mortem examination
Dose level (mg/kg/day) |
0 |
100 |
300 |
1000 |
Lymph node(s) (bronchic): enlarged |
0 |
0 |
1 |
0 |
Lungs: Irregular color (reddish) |
1 |
0 |
0 |
1 |
Absence of kidney (right) |
1a |
0 |
0 |
0 |
Enlarged kidney (left) |
1a |
0 |
0 |
0 |
Segmental aplasia of uterine horn |
1a |
0 |
0 |
1 |
Enlarged placenta(s) |
0 |
1 |
1 |
1b |
Granular placenta |
0 |
0 |
0 |
1b |
No remarkable observations |
22 |
23 |
22 |
21 |
a:one female ;b: same placenta of one female.
Table 5: Hysterectomy data
Dose level (mg/kg/day) |
0 |
100 |
300 |
1000 |
HCD |
Number of females with live fetuses at termination |
24 |
22 |
23 |
24 |
388 |
Mean number of corpora lutea |
14.6 |
14.9 |
14.6 |
14.8 |
[13.8-16.0] |
Mean number of implantation sites |
13.2 |
13.6 |
13.5 |
13.2 |
[12.5-14.5] |
Mean pre-implantation loss (%) |
9.9 |
8.1 |
8.0 |
10.6 |
[6.2-14] |
Mean number of live fetuses |
12.5 |
12.4 |
12.6 |
12.2 |
[11.6-13.8] |
Dead fetuses (%) |
0.0 |
0.0 |
0.0 |
0.0 |
[0.0-0.5] |
Mean number of implantation scars |
0.0 |
0.0 |
0.0 |
0.0 |
np |
Mean number of early resorptions |
0.7 |
1.1 |
0.9 |
1.0 |
Early+late resoprtions:[0.5-1.35] |
Mean number of late resorptions |
0.0 |
0.1 |
0.0 |
0.1 |
|
Mean post-implantation loss (%) |
5.8 |
9.0 |
8.1 |
8.0 |
[3.5-11.1] |
HCD: Historical Control Data (2014-2016; Sprague-Dawley rats): study mean range [min-max]; np: not presented in HCD.
Table 6: Fetal body weights
Dose level (mg/kg/day) |
0 |
100 |
300 |
1000 |
Mean fetal body weight (g) |
5.84 |
5.79 |
5.80 |
5.80 |
Table 7: Fetal sex
Dose level (mg/kg/day) |
0 |
100 |
300 |
1000 |
Mean percentage of male fetuses (%) |
53.6 |
47.8 |
49.6 |
52.1 |
Table 8: External variations
Dose level (mg/kg/day) |
0 |
100 |
300 |
1000 |
HCD |
Number of litters |
24 |
22 |
23 |
24 |
388 |
Number of fetuses |
300 |
272 |
289 |
292 |
5000 |
General |
|
|
|
|
|
Local edema, F (L) |
0.3 (4.2)a |
0.0 (0.0) |
0.0 (0.0) |
0.0 (0.0) |
0.8 (9.5) |
Polyhydramnios, F (L) |
0.0 (0.0) |
0.0 (0.0) |
0.0 (0.0) |
0.3 (4.2) |
- |
Paw and digit |
|
|
|
|
|
Malrotated paw, F (L) |
0.3 (4.2)a |
0.4 (4.5)b |
0.0 (0.0) |
0.0 (0.0) |
0.4 (5.6) |
Paw hyperflexion, F (L) |
0.3 (4.2) |
0.0 (0.0) |
0.0 (0.0) |
0.0 (0.0) |
- |
Litters with external variations, n (%) |
2 (8.3) |
1 (4.5) |
0 (0.0) |
1 (4.2) |
6 (1.5) |
Fetus with external variations, n (%) |
2 (0.7) |
1 (0.4) |
0 (0.0) |
1 (0.3) |
7 (0.1) |
F: fetal incidence, L: litter incidence, n: number.
a: one fetus ,b:anotherr fetus which also had bent tail (see next § Malformations).
HCD: Historical Control Data (2014-2016; Sprague-Dawley rats): fetal maximal incidences (litter maximal incidences) for the findings, -: none in HCD.
Table 9: External malformations
Dose level (mg/kg/day) |
0 |
100 |
300 |
1000 |
HCD |
Number of litters |
24 |
22 |
23 |
24 |
388 |
Number of fetuses |
300 |
272 |
289 |
292 |
5000 |
General |
|
|
|
|
|
Anasarca, F (L) |
0.0 (0.0) |
0.0 (0.0) |
0.3 (4.3)c |
0.0 (0.0) |
- |
Mouth, jaw, palate |
|
|
|
|
|
Cleft palate, F (L) |
1.7 (4.2) |
0.0 (0.0) |
0.3 (4.3)c |
0.0 (0.0) |
0.4 (5.0) |
Trunk |
|
|
|
|
|
Short trunk, F (L) |
0.0 (0.0) |
0.4 (4.5)a |
0.0 (0.0) |
0.0 (0.0) |
0.4 (5.0) |
Anal atresia, F (L) |
0.0 (0.0) |
0.4 (4.5)a |
0.0 (0.0) |
0.0 (0.0) |
0.4 (5.0) |
Omphalocele, F (L) |
0.0 (0.0) |
0.0 (0.0) |
0.3 (4.3) |
0.0 (0.0) |
0.4 (5.3) |
Ombilical hernia, F (L) |
0.0 (0.0) |
0.0 (0.0) |
0.3 (4.3)c |
0.0 (0.0) |
0.4 (4.8) |
Tail |
|
|
|
|
|
Bent tail, F (L) |
0.0 (0.0) |
0.4 (4.5)b |
0.0 (0.0) |
0.0 (0.0) |
0.4 (5.0) |
Short tail, F (L) |
0.0 (0.0) |
0.4 (4.5)a |
0.0 (0.0) |
0.0 (0.0) |
1.0 (4.3) |
Litters with external malformations, n (%) |
1 (4.2) |
1 (4.5) |
2 (8.7) |
0 (0.0) |
11 (2.8) |
Fetus with external malformations, n (%) |
5 (1.7) |
2 (0.7) |
2 (0.7) |
0 (0.0) |
13 (0.3) |
F: fetal incidence, L: litter incidence, n: number.
a: one fetus ,b: another fetus,c: another fetus.
HCD: Historical Control Data (2014-2016; Sprague-Dawley rats): fetal maximal incidences (litter maximal incidences) for the findings, -: none in HCD.
Table 10: Soft tissue variations
Dose level (mg/kg/day) |
0 |
100 |
300 |
1000 |
HCD |
Number of litters |
24 |
22 |
23 |
24 |
387 |
Number of fetuses |
145 |
130 |
138 |
139 |
2404 |
Kidneys |
|
|
|
|
|
Dilated renal pelvis, F (L) |
0.7 (4.2) |
1.5 (9.1) |
0.7 (4.3) |
1.4 (8.3) |
9.5 (28.6) |
Vessels |
|
|
|
|
|
Absent innominate artery, F (L) |
0.7 (4.2) |
0.8 (4.5) |
0.0 (0.0) |
0.0 (0.0) |
5.1 (25.0) |
Ureter |
|
|
|
|
|
Dilated ureter, F (L) |
5.5 (20.8) |
3.1 (13.6) |
1.4 (8.7) |
3.6 (16.7) |
7.1 (28.0) |
Thymus |
|
|
|
|
|
Reddish focus, F (L) |
0.0 (0.0) |
0.0 (0.0) |
0.7 (4.3) |
0.0 (0.0) |
- |
Litters with visceral variations, n (%) |
5 (20.8) |
4 (18.2) |
3 (13.0) |
4 (16.7) |
86 (22.2) |
Fetus with visceral variations, n (%) |
8 (5.5) |
5 (3.8) |
3 (2.2) |
5 (3.6) |
119 (5.0) |
F: fetal incidence, L: litter incidence, n: number.
HCD: Historical Control Data (2014-2016; Sprague-Dawley rats): fetal maximal incidences (litter maximal incidences) for the findings, -: none in HCD.
Table 11: Soft tissue malformations
Dose level (mg/kg/day) |
0 |
100 |
300 |
1000 |
HCD |
Number of litters |
24 |
22 |
23 |
24 |
387 |
Number of fetuses |
145 |
130 |
138 |
139 |
2404 |
Mouth, jaw, palate |
|
|
|
|
|
Cleft palate, F (L) |
2.1 (4.2) |
0.0 (0.0) |
0.0 (0.0) |
0.0 (0.0) |
- |
Brain |
|
|
|
|
|
Dilated 4thcerebral ventricle, F (L) |
0.0 (0.0) |
0.8 (4.5) |
0.0 (0.0) |
0.0 (0.0) |
0.7 (4.2) |
Gonads |
|
|
|
|
|
Absent, F (L) |
0.0 (0.0) |
0.8 (4.5)a |
0.0 (0.0) |
0.0 (0.0) |
- |
Litterswith visceral malformations, n (%) |
1 (4.2) |
2 (9.1) |
0 (0.0) |
0 (0.0) |
7 (1.8) |
Fetuswith visceral malformations, n (%) |
3 (2.1) |
2 (1.5) |
0 (0.0) |
0 (0.0) |
13 (0.5) |
F: fetal incidence, L: litter incidence, n: number.
HCD: Historical Control Data (2014-2016; Sprague-Dawley rats), -: none in HCD.
a: one fetus with external malformations of the trunck/tail.
Table 12: Fetal skeletal examinations
Cartilage
Dose level (mg/kg/day) |
0 |
100 |
300 |
1000 |
HCD |
Number of litters |
24 |
22 |
23 |
24 |
388 |
Number of fetuses |
155 |
142 |
151 |
153 |
2596 |
Cervical vertebrae |
|
|
|
|
|
Bipartite cartilage of centrum, F (L) |
0.0 (0.0) |
0.7 (4.5) |
0.0 (0.0) |
0.0 (0.0) |
- |
Thoracic vertebrae |
|
|
|
|
|
Misshapen cartilage of centrum, F (L) |
0.6 (4.2) |
0.0 (0.0) |
0.0 (0.0) |
0.0 (0.0) |
- |
Bipartite cartilage of centrum, F (L) |
0.0 (0.0) |
0.7 (4.5)a |
0.0 (0.0) |
0.0 (0.0) |
0.7 (4.5) |
Caudal vertebrae |
|
|
|
|
|
Less than 15vertebrae, F (L) |
0.0 (0.0) |
0.7 (4.5) |
1.3 (8.7) |
0.0 (0.0) |
3.0 (8.0) |
Misshapen cartilage, F (L) |
0.0 (0.0) |
0.7 (4.5)a |
0.0 (0.0) |
0.0 (0.0) |
- |
Sternebrae |
|
|
|
|
|
Bipartite cartilage, F (L) |
0.0 (0.0) |
0.0 (0.0) |
0.7 (4.3)c |
0.0 (0.0) |
- |
Rib |
|
|
|
|
|
Absent cartilage, F (L) |
0.0 (0.0) |
0.0 (0.0) |
0.0 (0.0) |
0.7 (4.2) |
5.1 (21.7) |
Fused cartilages, F (L) |
0.0 (0.0) |
0.7 (4.5)a |
0.0 (0.0) |
0.0 (0.0) |
0.6 (4.3) |
F: fetal incidence, L: litter incidence, n: number.
HCD: Historical Control Data (2014-2016; Sprague-Dawley rats): fetal maximal incidences (litter maximal incidences) for the findings, -: none in HCD.
a: one fetus with the malformation supernumerary lumbar vertebra,c: another fetus.
Table 13: Fetal skeletal malformations
Dose level (mg/kg/day) |
0 |
100 |
300 |
1000 |
HCD |
Number of litters |
24 |
22 |
23 |
24 |
388 |
Number of fetuses |
155 |
142 |
151 |
153 |
2596 |
Palate |
|
|
|
|
|
Split, F (L) |
1.3 (4.2) |
0.0 (0.0) |
0.0 (0.0) |
0.0 (0.0) |
0.7 (5.0) |
Cervical vertebrae |
|
|
|
|
|
Cervical rib, F (L) |
0.0 (0.0) |
0.0 (0.0) |
0.7 (4.3) |
0.0 (0.0) |
- |
Lumbar vertebrae |
|
|
|
|
|
Supernumerary , F (L) |
0.0 (0.0) |
0.7 (4.5)b |
0.0 (0.0) |
0.0 (0.0) |
- |
Sternebrae |
|
|
|
|
|
Fused, F (L) |
0.0 (0.0) |
0.0 (0.0) |
0.7 (4.3)a |
0.0 (0.0) |
1.3 (8.7) |
Litterswith skeletal malformations, n (%) |
1 (4.2) |
1 (4.5) |
2 (8.7) |
0 (0.0) |
15 (3.9) |
Fetuswith skeletal malformations, n (%) |
2 (1.3) |
1 (0.7) |
2 (1.3) |
0 (0.0) |
18 (0.7) |
F: fetal incidence, L: litter incidence, n: number.
HCD: Historical Control Data (2014-2016; Sprague-Dawley rats): fetal maximal incidences (litter maximal incidences) for the findings, -: none in HCD.
a: one fetus,b: another fetus.
Table 14: Malformed fetuses
Dose level (mg/kg/day) |
0 |
100 |
300 |
1000 |
Number of litters |
24 |
22 |
23 |
24 |
Number of fetuses with external examination |
300 |
272 |
289 |
292 |
Number of fetuses with visceral examination |
145 |
130 |
138 |
139 |
Number of fetuses with skeletal examination |
155 |
142 |
151 |
153 |
|
L29393 -01, -02, -04, -10, -13: cleft/split palate |
L29418-09: short trunk, anal atresia, short tail, absent gonads |
L29458-05: anasarca, cleft palate, umbilical hernia, fused sternebrae
|
|
|
|
L29418-01: bent tail
|
|
|
|
|
L29431-02: dilated 4thcerebral ventricle
L29419-07: supernumerary lumbar vertebra |
L29443-01: omphalocele
L29449-07: cervical rib |
|
Litters with malformations, n (%) |
1 (4.2) |
3 (13.6) |
3 (13.0) |
0 (0.0) |
Fetuses with malformations, n (%) |
5 (1.7) |
4 (2.2) |
3 (1.4) |
0 (0.0) |
Applicant's summary and conclusion
- Conclusions:
- Under the experimental conditions and results of this study, the No Observed Adverse Effect Level (NOAEL) for maternal parameters and for embryo-fetal development was considered to be 1000 mg/kg/day in absence of adverse test item treatment effects at this dose level.
- Executive summary:
The objective of this GLP study was to evaluate the potential toxic effects of the test item, on the pregnant female and on embryonic and fetal development following daily oral administration (gavage) to pregnant female rats from implantation to the day prior to the scheduled hysterectomy [Days 6 to 20 post-coitum (p.c.) inclusive].
Methods
Three groups of 24 time-mated Sprague-Dawley rats were administered the test item, daily by gavage from Days 6 to 20 p.c. inclusive at 100, 300 or 1000 mg/kg/day as a suspension in the vehicle [0.5% (w/w) methylcellulose aqueous solution]. A dose volume of 10 mL/kg/day was used. One additional group of 24 females received the vehicle alone under the same experimental conditions.
Test item concentration was checked two times in formulations given to the animals.
The animals were checked daily for mortality and clinical signs. Body weight and food consumption were recorded at designated intervals.
On Day 21 p.c., surviving females were euthanized and submitted to a macroscopic post-mortem examination. Hysterectomies were performed and the numbers of corpora lutea, implantations, early and late resorptions, and live and dead fetuses were recorded. The fetuses were weighed, sexed and examined for external, soft tissue and skeletal/cartilage abnormalities.
Results
The test item concentrations determined in Weeks 1 and 4 remained within an acceptable range of -10.5% to +0.8% when compared to the nominal values (± 15% required). No test item was observed in the control dose formulations.
At hysterectomy on Day 21 p.c., there were 24/24, 22/24, 23/24 and 24/24 pregnant dams with live concepti in the groups treated at 0,100, 300 or 1000 mg/kg/day, respectively.
There were no test item treatment-related effects in the dams in terms of mortality, clinical signs, necropsy findings, mean body weight, mean food consumption, mean carcass weight, mean gravid uterus weight, mean net body weight change from Day 6 p.c., and mean hysterectomy data. Mean body weight change was slightly lower at 1000 mg/kg/day on Days 6 to 9 p.c.(+13 g vs. +18 g in controls, p<0.01); this was considered to be test item-related and non-adverse.
There were no test item treatment-related effects on sex ratio or mean fetal body weight and no test item treatment-related finding at fetal examination (external, visceral and skeletal variations or malformations).
Conclusion
Under the experimental conditions and results of this study, the No Observed Adverse Effect Level (NOAEL) for maternal parameters and for embryo-fetal development was considered to be 1000 mg/kg/day in absence of adverse test item treatment effects at this dose level.
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