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EC number: 419-710-0 | CAS number: 42774-15-2 NYLOSTAB S-EED; NYSEED
- 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:
- 2017
- 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 guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
Constituent 1
- Specific details on test material used for the study:
- SOURCE OF TEST MATERIAL
- Source of test material: Clariant Plastics and Coatings(Deutschland) GmbH, BU Additives, Ludwig-Hermann-Strasse 100, 86368 Gersthofen, Germany
- Batch No.of test material: DEF2076375
- Expiration date of the batch: 17-May-2018
- Purity as per Certificate of Analysis: 98.65%
STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Ambient (+15 to + 25 °C)
- Stability under test conditions: The stability of the test item in the vehicle: 0.1%(w/v) Sodium Carboxymethyl cellulose (medium viscosity) in Milli-Q water was carried out under the Study No.: G12134. The test item was found to be stable and resuspendable in the vehicle for 4 days at room temperature, at the fortification levels of 1 mg/mL and 125 mg/mL.
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Vivo Bio Tech Ltd, Sy # 349/A, Pregnapur-502311,Gajwel Mandal, Medak District, Telangana
- Age at study initiation: 13 to 14 weeks
- Weight at study initiation:
Mean body weight(g) Body weight range(g)
G1 : 243.089 ± 18.37 210.12 to 268.16
G2 : 239.855 ± 19.42 204.58 to 268.84
G3 : 239.042 ± 20.79 206.35 to 267.97
G4 : 239.115 ± 21.14 208.16 to 268.57
- Housing: Rats were housed in standard polysulfone rat cages (size: Length 425 mm x Breadth 266 mm x Height 185 mm) with stainless steel top grill having facilities for pellet food and drinking water in polycarbonate bottle with stainless steel sipper tube.
Following was the housing pattern during different periods of the experiment:
i. Pre mating / Acclimatization: Two rats of the same sex per cage were housed.
ii. Mating: Female rats were cohabited with males in a 1:1 ratio in same cage.
iii. Post-mating / Treatment: After mating confirmation, females were housed individually.
NOTE: The male rats and the remaining extra females were euthanized after mating procedure
- Diet (e.g. ad libitum): Teklad Certified (2014C) Global 14 % Protein Rodent Maintenance Diet - Pellet (Certified) manufactured by Harlan Laboratories, P.O.Box 44220, Madison Wi 53744-4220, was provided ad libitum to the rats.
- Water (e.g. ad libitum): Deep bore-well water passed through activated charcoal filter and exposed to UV rays in ‘Aquaguard’ on-line water filter-cum-purifier manufactured by Eureka Forbes Ltd., Mumbai 400 001, India was provided ad libitum to rats in polycarbonate bottles with stainless steel sipper tubes.
- Acclimation period: 08 December 2016 to 12 December 2016
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 to 23 °C
- Humidity (%): 64 – 66 %
- Air changes (per hr): 12 to 15 air changes/hour
- Photoperiod (hrs dark / hrs light): 12 hours light and 12 hours dark cycle
IN-LIFE DATES: From: 19 December 2016 To: 09 January 2017
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- CMC (carboxymethyl cellulose)
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Dose formulations were analyzed for active ingredient concentration (a.i.) and homogeneity at the initiation of treatment and at termination of treatment period.
The prepared formulations were sampled in duplicate sets wherein one set was used for analysis and another was kept as back up set which was stored in the experimental room depending upon the obtained stability results. For each set, two replicate samples were drawn from top, middle and bottom layers of each dose formulation. In case of control, two replicate samples from middle layer were drawn.
Samples were analyzed for Nylostab S-EED P content using analytical method which was validated under Advinus Study No. G12134. The analysis was carried out within the established stability period.
Formulations were considered acceptable when the mean results (calculated using all the replicate values) of all the layers and mean of each layer was within ±15.0 % of the claimed concentration and the relative standard deviation (% RSD, calculated using all the replicate values) of assay of top, middle and bottom layers (RSD) was equal to or less than 10.0 %.
The dose formulation suspensions were analyzed for active ingredient concentrations at the initiation and termination of treatment. The results of analysis of formulations revealed that the analyzed concentrations were within the acceptable limits - Details on mating procedure:
- - Impregnation procedure: [cohoused]
- If cohoused:
- M/F ratio per cage: 1:1
- Length of cohabitation: 9 days
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0] of pregnancy - Duration of treatment / exposure:
- 15 days
- Frequency of treatment:
- Gestation day 5 to Gestation day 19
Doses / concentrationsopen allclose all
- Dose / conc.:
- 50 mg/kg bw/day (nominal)
- Remarks:
- Group 2 (Low dose)
- Dose / conc.:
- 250 mg/kg bw/day (nominal)
- Remarks:
- Group 3 (Mid dose)
- Dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- Remarks:
- Group 4 (High dose)
- No. of animals per sex per dose:
- Day '0" Pregnant rats : 24
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: As per the Sponsor’s suggestion, based on the results of a 28 day repeated dose study, the following doses were selected for the main embryo-fetal developmental toxicity study with Nylostab S-EED P in Sprague Dawley rats by oral route:
• Vehicle control (G1): 0 mg/kg/day
• Low dose(G2) : 50 mg/kg/day
• Mid dose(G3) : 250 mg/kg/day
• High dose(G4) : 1000 mg/kg/day
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice a day (pre dose and post dose)
- Cage side observations checked in table [No.2] were included.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Weekly
BODY WEIGHT: Yes
- Time schedule for examinations: All females included in the study were weighed on gestation days 0, 3, 5, 8, 11, 14, 17 and 20.
FOOD CONSUMPTION : Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
OTHER: - 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 data on maternal body weight, body weight change in interval, gravid uterine weight, body weight change corrected to gravid uterine weight, maternal food consumption were analyzed using Analysis of Variance (ANOVA) after testing for homogeneity for intra group variance using Levene’s test. Where intra group variances were heterogeneous, ANOVA was performed after suitable transformation of data. Dunnett’s pairwise comparison of the treated group means with the control group mean was performed, when the group differences were found significant.
Fetal weight for male and female were analyzed using Analysis of Convariance (ANCOVA) taking litter size as covariate for group.
Number of corpora lutea, number of implantations, early and late resorptions, pre-implantation and post-implantation loss, external, visceral and skeletal observations for variations were analyzed using Kruskal wallis test for group comparison.
The incidence of with and without resorptions in dams will be tested using Cochran Armitage trend test followed by Fisher’s exact test for group association.
Statistically significant differences (p<0.05), indicated by the aforementioned tests were designated as * throughout the report. - Indices:
- MATERNAL DATA:
Maternal Parameters and Formula used
> Mean number of corpora lutea
Total no. of CL
= ----------------------------------------
Total no. of pregnant animals
> Mean number of implantations/group
Total no. of implantations
= ----------------------------------------
Total no. of pregnant animals
> Embryonic resorption index (%)
No. of early resorptions
= --------------------------------- x 100
No. of implantations
> Fetal resorption index (%)
No. of late resorptions
= -------------------------------- x 100
No. of implantations
> Pre-implantation loss per group (%)
No. of CL - No. of implantations
= ----------------------------------------------- x 100
No. of CL
> Post-implantation loss per group (%)
No. of (early + late) resorptions
= --------------------------------------------- x 100
Total no. of implantations
> Implantation index (%)
No. of implantations sites
= ------------------------------------- x 100
No. of corpora lutea
> Corrected body weight (Carcass weight)
= Terminal body weight (body weight on GD20) - unopened uterine weight.
> Corrected body weight gain
= Corrected body weight – body weight on GD5
LITTER DATA:
Litter Parameters and Formula used
> Mean litter size per group
Total No. of fetuses
= ---------------------------------
Total No. of pregnant animals
> Percentage of abnormal fetuses
No. of abnormal fetuses
= ---------------------------------- x 100
Total No. of fetuses
> Percentage of live fetuses (Live fetus index)
No. of live fetuses
= ----------------------------- x 100
Total No. of fetuses
> Percentage of dead fetuses (Dead fetus index)
No. of dead fetuses
= ----------------------------- x 100
Total No. of fetuses
> Sex ratio (F : M)
Number of females
= ---------------------------
Number of males - Historical control data:
- The results of the study were discussed taking into consideration the historical data of this lab.
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- There were no clinical signs observed throughout the experimental period 50, 250 and 1000 mg/kg/day dose groups.
- Mortality:
- no mortality observed
- Description (incidence):
- There was no morbidity or mortality throughout the experimental period in the 50, 250 and 1000 mg/kg/day dose groups.
- Body weight and weight changes:
- effects observed, non-treatment-related
- Description (incidence and severity):
- The maternal group mean body weights were unaffected by the administration of test item Nylostab S-EED P at the doses of 50,
250 and 1000 mg/kg/day and were statistically comparable to vehicle control group.
At 50 and 250 mg/kg/day, the maternal body weight gain was comparable to vehicle control group during different periods of gestation.
At 1000 mg/kg/day, there was a significant reduction in maternal body weight gain during GD 14 to 17 (-21 %) and for entire gestation period (-14 %) as compared to vehicle control group.
The corrected body weight and corrected body weight gain was not statistically different from vehicle control group at all the tested doses. - Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- The maternal food consumption was comparable to vehicle control group at all the doses tested during different periods of gestation, except for a significant reduction in food consumption during GD 5-8 (-15 %) at
1000 mg/kg/day.
The reduction in maternal body weights along with concomitant reduction in food consumption at 1000 mg/kg/day was considered as a treatment-related effect indicating maternal toxicity. - Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- There were no gross pathological findings in any of the tested doses
Maternal developmental toxicity
- Number of abortions:
- no effects observed
- Description (incidence and severity):
- The maternal data parameters comprising of gravid uterine weights, mean numbers of corpora lutea, implantations, early and late resorptions, pre and post-implantation loss rates and dams with any resorptions were unaffected by treatment with Nylostab S-EED P at all the doses tested.
- Pre- and post-implantation loss:
- no effects observed
- Total litter losses by resorption:
- no effects observed
- Early or late resorptions:
- no effects observed
- Dead fetuses:
- no effects observed
Effect levels (maternal animals)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 250 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Basis for effect level:
- body weight and weight gain
- food consumption and compound intake
- Remarks on result:
- other:
- Remarks:
- due to treatment-related significant reduction in maternal body weight gain and food consumption at 1000 mg/kg/day
Results (fetuses)
- Fetal body weight changes:
- no effects observed
- Description (incidence and severity):
- No treatment-related changes were observed during external observations of fetuses of dams treated up to 1000 mg/kg/day.
- External malformations:
- no effects observed
- Description (incidence and severity):
- Fetal, external observations were comparable to vehicle control group at all the doses tested.
- Skeletal malformations:
- no effects observed
- Description (incidence and severity):
- Fetal, skeletal observations were comparable to vehicle control group at all the doses tested. Skeletal examinations revealed no signs of teratogenicity in any of the tested doses.
- Visceral malformations:
- no effects observed
- Description (incidence and severity):
- Fetal, visceral observations were comparable to vehicle control group at all the doses tested. Visceral examinations revealed no signs of teratogenicity in any of the tested doses.
- Details on embryotoxic / teratogenic effects:
- Fetal, external, visceral and skeletal observations were comparable to vehicle control group at all the doses tested. Visceral and skeletal examinations revealed no signs of teratogenicity in any of the tested doses.
Effect levels (fetuses)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- >= 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: Fetal developmental toxicity
Fetal abnormalities
- Key result
- Abnormalities:
- no effects observed
Overall developmental toxicity
- Key result
- Developmental effects observed:
- no
Any other information on results incl. tables
No Observed Adverse Effect Level (NOAEL) for:
- Maternal toxicity is 250 mg/kg/day due to treatment-related significant reduction in maternal body weight gain and food consumption at 1000 mg/kg/day,
- Fetal developmental toxicity is 1000 mg/kg/day as the litter data parameters were unaffected by treatment up to the high dose of 1000 mg/kg/day and
- Teratogenicity is 1000 mg/kg/day as there were no signs of teratogenicity in any of the tested dose levels up to the high dose of 1000 mg/kg/day
Table 1. Details of the Experimental Design, Treatment Schedule, Maternal and Litter Data
Parameters |
Group No. |
G1 |
G2 |
G3 |
G4 |
Dose (mg/kg/day) |
0 |
50 |
250 |
1000 |
|
Total No.of rats found sperm positive/group
|
24 |
24 |
24 |
24 |
|
Duration of treatment(days)
|
GestationDays5to19(15days)
|
||||
No.of rats sacrificed at caesarean section |
24 |
24 |
24 |
24 |
|
No.of non-pregnantrats at caesarean section |
1 |
3 |
0 |
0 |
|
No.of pregnant rats at caesarean section |
23 |
21 |
24 |
24 |
|
No.of litters examined |
23 |
21 |
24 |
24 |
|
Total no.of fetuses |
289 |
266 |
288 |
270 |
|
Numberoffetusesevaluated |
|
||||
a. External examination |
289 |
266 |
288 |
270 |
|
b. Visceral examination |
144 |
133 |
144 |
135 |
|
c. Skeletal examination |
145 |
133 |
144 |
135 |
Summary of Maternal Body Weight and Weight Gain
Table 2. Summary of Maternal Group Mean Body Weight (g)
Group Mean body weight (g) on GD (gestation day) |
Group No. |
G1 |
G2 |
G3 |
G4 |
Dose (mg/kg/day) |
0 |
50 |
250 |
1000 |
|
No. of rats |
23 |
21 |
24 |
24 |
|
0 |
Mean |
242.91 |
241.44 |
239.04 |
239.11 |
|
SD |
18.76 |
19.15 |
20.79 |
21.14 |
3 |
Mean |
258.64 |
255.01 |
252.80 |
252.77 |
|
SD |
18.66 |
20.25 |
21.92 |
21.69 |
5 |
Mean |
266.80 |
263.22 |
261.42 |
259.39 |
|
SD |
21.01 |
21.59 |
24.63 |
22.65 |
8 |
Mean |
276.27 |
273.15 |
271.55 |
265.58 |
|
SD |
25.43 |
23.85 |
27.68 |
23.66 |
11 |
Mean |
290.78 |
289.01 |
283.72 |
278.11 |
|
SD |
26.07 |
24.69 |
29.96 |
23.60 |
14 |
Mean |
305.86 |
303.03 |
299.04 |
291.91 |
|
SD |
27.65 |
27.36 |
33.63 |
25.03 |
17 |
Mean |
336.73 |
334.74 |
329.20 |
316.40 |
|
SD |
28.87 |
28.31 |
41.28 |
28.44 |
20 |
Mean |
371.30 |
370.13 |
363.57 |
349.36 |
|
SD |
34.26 |
33.11 |
50.17 |
34.91 |
Table 3. Summary of Maternal Body Weight Gain (g)
Period of treatment (days of gestation) |
Group No. |
G1 |
G2 |
G3 |
G4 |
Dose (mg/kg/day) |
0 |
50 |
250 |
1000 |
|
No. of rats |
23 |
21 |
24 |
24 |
|
0-3 |
Mean |
15.73 |
13.57 |
13.76 |
13.66 |
|
SD |
4.99 |
4.30 |
4.15 |
4.53 |
3-5 |
Mean |
8.15 |
8.21 |
8.62 |
6.62 |
|
SD |
5.06 |
3.97 |
5.42 |
2.92 |
5-8 |
Mean |
9.47 |
9.93 |
10.12 |
6.19 |
|
SD |
6.24 |
5.14 |
5.46 |
4.44 |
8-11 |
Mean |
14.51 |
15.86 |
12.17 |
12.54 |
|
SD |
4.37 |
3.54 |
5.21 |
4.39 |
11-14 |
Mean |
15.08 |
14.02 |
15.32 |
13.79 |
|
SD |
4.41 |
5.08 |
5.87 |
4.70 |
14-17 |
Mean |
30.87 |
31.71 |
30.17 |
24.50* |
|
SD |
6.11 |
3.49 |
10.12 |
6.79 |
17-20 |
Mean |
34.57 |
35.39 |
34.37 |
32.95 |
|
SD |
8.98 |
8.39 |
11.20 |
8.07 |
Values at each interval group Mean +/- SD; * significant different from G1
Table 3. contd. Summary of Maternal Body Weight Gain (g)
Period of treatment (days of gestation |
Group No. |
G1 |
G2 |
G3 |
G4 |
Dose (mg/kg/day) |
0 |
50 |
250 |
1000 |
|
No. of rats |
23 |
21 |
24 |
24 |
|
Pre-treatment period (days 0-5) |
Mean |
23.88 |
21.78 |
22.38 |
20.28 |
|
SD |
8.00 |
6.76 |
6.76 |
6.0 |
Treatment period (days 5-20) |
Mean |
104.50 |
106.91 |
102.15 |
89.97 |
|
SD |
17.39 |
16.24 |
30.22 |
17.52 |
Entire gestation (days 0-20) |
Mean |
128.38 |
128.69 |
124.53 |
110.24* |
|
SD |
21.53 |
18.33 |
33.71 |
18.27 |
Values at each interval group Mean +/- SD; * significant different from G1
Table 4. Summary of Corrected Body Weight and Body Weight Gain (g)
Period of treatment (days of gestation |
Group No. |
G1 |
G2 |
G3 |
G4 |
Dose (mg/kg/day) |
0 |
50 |
250 |
1000 |
|
No. of rats |
23 |
21 |
24 |
24 |
|
Body weight on GD 5 |
Mean |
266.80 |
263.22 |
261.42 |
259.39 |
|
SD |
21.01 |
21.59 |
24.63 |
22.65 |
Terminal Body weight on GD 20 |
Mean |
371.30 |
370.13 |
363.57 |
349.36 |
|
SD |
34.26 |
33.11 |
50.17 |
34.91 |
Uterine weight |
Mean |
76.72 |
75.43 |
72.77 |
69.71 |
|
SD |
17.59 |
14.92 |
26.33 |
18.13 |
Carcass weight (corrected body weight on GD 20) |
Mean |
294.58 |
294.70 |
290.80 |
279.64 |
|
SD |
32.86 |
25.79 |
32.29 |
27.55 |
Corrected body weight gain |
Mean |
27.78 |
31.48 |
29.38 |
20.25 |
|
SD |
14.60 |
15.16 |
12.71 |
11.20 |
GD: Gestation Day
Corrected body weight on gestation day 20 (Caracass weight) = Terminal Body weight on GD 20 – unopended uterine weight.
Corrected body weight gain = caracass weight – body weight on Gestation day 5
Table 5. Summary of Maternal data
Parameters |
GroupNo. Dose(mg/kg/day) |
G1 0 |
G2 50 |
G3 250 |
G4 1000 |
|
No.of Rats |
23 |
21 |
24 |
24 |
Gravid uterine weight(g) |
Mean |
76.72 |
75.43 |
72.77 |
69.71 |
|
SD |
17.59 |
14.92 |
26.33 |
18.13 |
NumberofCorpora lutea |
Mean |
15.65 |
15.76 |
15.96 |
14.88 |
|
SD |
2.40 |
3.08 |
4.42 |
2.98 |
Numberof Implantations |
Mean |
13.48 |
13.19 |
12.75 |
11.83 |
|
SD |
2.79 |
2.46 |
4.42 |
3.38 |
Early Resorptions |
Mean |
0.87 |
0.43 |
0.71 |
0.50 |
|
SD |
1.32 |
0.60 |
1.12 |
0.83 |
Late Resorptions |
Mean |
0.04 |
0.10 |
0.04 |
0.08 |
|
SD |
0.21 |
0.30 |
0.20 |
0.28 |
Pre-implantation Loss |
Mean |
2.17 |
2.57 |
3.21 |
3.04 |
|
SD |
2.39 |
2.87 |
3.18 |
3.43 |
Post-implantation Loss |
Mean |
0.91 |
0.52 |
0.75 |
0.58 |
|
SD |
1.35 |
0.60 |
1.29 |
0.83 |
DamswithanyResorption |
Total |
12 |
10 |
11 |
10 |
Table 5. contd. Summary of Maternal data (% per litter)
Parameters |
Group No. Dose(mg/kg/day) |
G1 0 |
G2 50 |
G3 250 |
G4 1000 |
|
No.of Rats |
23 |
21 |
24 |
24 |
Early Resorptions |
Mean |
7.18 |
3.54 |
8.11 |
3.98 |
|
SD |
13.93 |
4.97 |
17.03 |
6.33 |
Late Resorptions |
Mean |
0.26 |
0.87 |
0.60 |
0.97 |
|
SD |
1.23 |
2.77 |
2.92 |
3.39 |
Pre-implantation Loss |
Mean |
13.54 |
14.94 |
21.24 |
19.65 |
|
SD |
15.78 |
15.08 |
23.41 |
22.69 |
Post-implantation Loss |
Mean |
7.43 |
4.41 |
8.71 |
4.95 |
|
SD |
13.96 |
5.09 |
19.43 |
6.59 |
Implantation Index |
Mean |
86.46 |
85.06 |
78.76 |
80.35 |
|
SD |
15.78 |
15.08 |
23.41 |
22.69 |
Table 6. Summary of Litter data
Parameters |
Group No. Dose(mg/kg/day) |
G1 0 |
G2 50 |
G3 250 |
G4 1000 |
|
No.of Rats |
23 |
21 |
24 |
24 |
No.of litters |
|
23 |
21 |
24 |
24 |
Total no.of fetuses |
|
289 |
266 |
288 |
270 |
Mean litter size |
|
12.6 |
12.7 |
12.0 |
11.3 |
Total live fetuses |
|
|
|
|
|
a. Number |
|
289 |
266 |
288 |
270 |
b. Weight(g) |
Mean |
4.02 |
4.02 |
4.03 |
4.10 |
|
SD |
0.18 |
0.35 |
0.29 |
0.42 |
Live male fetuses |
|
|
|
|
|
a. Number |
|
141 |
145 |
132 |
154 |
b. Weight(g) |
Mean |
4.11 |
4.13 |
4.15 |
4.15 |
|
SD |
0.19 |
0.40 |
0.30 |
0.41 |
Live female fetuses |
|
|
|
|
|
a. Number |
|
148 |
121 |
156 |
116 |
b. Weight(g) |
Mean |
3.93 |
3.89 |
3.87 |
3.94 |
|
SD |
0.20 |
0.35 |
0.24 |
0.42 |
Sex Ratio-Male:Female |
|
1:1.05 |
1:0.83 |
1:1.18 |
1:0.75 |
Table 7. Summary of Gross Pathological findings
Group No. |
G1 |
G2 |
G3 |
G4 |
Parameters / Dose(mg/kg/day) |
0 |
50 |
250 |
1000 |
1. No. of rats subjected to caesarian section |
24 |
24 |
24 |
24 |
2. No.of rats pregnant at caesarian section |
23 |
21 |
24 |
24 |
3. No.of rats showing gross pathology |
0 |
0 |
0 |
0 |
Table 8. Summary of Fetal External Observations
Group No. |
G1 |
G2 |
G3 |
G4 |
||||||||
Dose (mg/kg/day) |
0 |
50 |
250 |
1000 |
||||||||
No. of litters examined |
23 |
21 |
24 |
24 |
||||||||
No. of fetuses examined |
289 |
266 |
288 |
270 |
||||||||
|
Inc. |
Fetus % |
Litter % |
Inc. |
Fetus % |
Litter % |
Inc. |
Fetus % |
Litter % |
Inc. |
Fetus % |
Litter % |
|
|
|
|
|
|
|
|
|
|
|
|
|
Normal Variant |
None |
|||||||||||
|
|
|
|
|
|
|
|
|
|
|
|
|
Minor Anomalies |
|
|||||||||||
|
|
|
|
|
|
|
|
|
|
|
|
|
Small fetus |
0 |
0.00 |
0.00 |
1 |
0.38 |
1.30 |
0 |
0.00 |
0.00 |
0 |
0.00 |
0.00 |
|
|
|
|
|
|
|
|
|
|
|
|
|
Major Malformations |
None |
|||||||||||
|
|
|
|
|
|
|
|
|
|
|
|
|
Table 9. Summary of Fetal Visceral Observations (incidence and percentage)
Group No. |
G1 |
G2 |
G3 |
G4 |
||||||||
Dose (mg/kg/day) |
0 |
50 |
250 |
1000 |
||||||||
No. of litters examined |
23 |
21 |
24 |
24 |
||||||||
No. of fetuses examined |
144 |
133 |
144 |
135 |
||||||||
|
Inc. |
Fetus % |
Litter % |
Inc. |
Fetus % |
Litter % |
Inc. |
Fetus % |
Litter % |
Inc. |
Fetus % |
Litter % |
|
|
|
|
|
|
|
|
|
|
|
|
|
Normal Variant |
|
|||||||||||
|
|
|
|
|
|
|
|
|
|
|
|
|
Kidney renal pelvis dila. (Rt/Lt/B) (+) |
0 |
0.00 |
0.00 |
2 |
1.50 |
3.63 |
0 |
0.00 |
0.00 |
3 |
2.22 |
8.81 |
|
|
|
|
|
|
|
|
|
|
|
|
|
Minor Anomalies |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Kidney renal pelvis dila. (Rt/Lt/B) (++) |
3 |
2.08 |
6.55 |
0 |
0.00 |
0.00 |
3 |
2.08 |
7.14 |
0 |
0.00 |
0.00 |
|
|
|
|
|
|
|
|
|
|
|
|
|
Major Malformations |
None |
|||||||||||
|
|
|
|
|
|
|
|
|
|
|
|
|
+: Slight
++: moderate
Table 10. Summary of Fetal Skeletal Observations (incidence and percentage)
Group No. |
G1 |
G2 |
G3 |
G4 |
||||||||||
Dose (mg/kg/day) |
0 |
50 |
250 |
1000 |
||||||||||
No. of litters examined |
23 |
21 |
24 |
24 |
||||||||||
No. of fetuses examined |
145 |
133 |
144 |
135 |
||||||||||
|
Inc. |
Fetus % |
Litter % |
Inc. |
Fetus % |
Litter % |
Inc. |
Fetus % |
Litter % |
Inc. |
Fetus % |
Litter % |
||
|
|
|
|
|
|
|
|
|
|
|
|
|
||
Normal Variant |
|
|||||||||||||
DSO: Stern: # 5 |
3 |
2.07 |
2.11 |
1 |
0.75 |
0.68 |
1 |
0.69 |
0.69 |
2 |
1.48 |
1.22 |
||
Stern: # 6 |
0 |
0.00 |
0.00 |
1 |
0.75 |
0.60 |
0 |
0.00 |
0.00 |
7 |
5.19 |
4.88 |
||
Stern: # 5,6 |
1 |
0.69 |
0.62 |
2 |
1.50 |
1.90 |
0 |
0.00 |
0.00 |
1 |
0.74 |
0.60 |
||
CV:centra: 1/7 |
0 |
0.00 |
0.00 |
0 |
0.00 |
0.00 |
1 |
0.69 |
0.60 |
0 |
0.00 |
0.00 |
||
CV:centra: 2/7 |
2 |
1.38 |
1.35 |
2 |
1.50 |
1.98 |
0 |
0.00 |
0.00 |
1 |
0.74 |
1.04 |
||
CV:centra: 3/7 |
4 |
2.76 |
2.69 |
1 |
0.75 |
1.19 |
2 |
1.39 |
1.19 |
0 |
0.00 |
0.00 |
||
CV:centra: 4/7 |
6 |
4.14 |
4.18 |
1 |
0.75 |
0.68 |
4 |
2.78 |
2.62 |
4 |
2.96 |
3.72 |
||
CV:centra: 5/7 |
31 |
21.38 |
20.05 |
19 |
14.29 |
14.82 |
22 |
15.28 |
14.93 |
18 |
13.33 |
13.52 |
||
CV:centra: 6/7 |
64 |
44.14 |
46.05 |
47 |
35.34 |
34.99 |
64 |
44.44 |
43.32 |
52 |
38.52 |
36.73 |
||
CV:centra: 7/7 |
38 |
26.21 |
25.68 |
63 |
47.37 |
46.34 |
51 |
35.42 |
33.17 |
60 |
44.44 |
40.82 |
||
|
|
|
|
|
|
|
|
|
|
|
|
|
||
DSO: TV:centra:1/13 |
1 |
0.69 |
0.72 |
0 |
0.00 |
0.00 |
0 |
0.00 |
0.00 |
0 |
0.00 |
0.00 |
||
CdV:centra:1/4 |
3 |
2.07 |
1.79 |
14 |
10.53 |
9.15 |
7 |
4.86 |
3.41 |
21 |
15.56 |
12.67 |
||
CdV:centra:2/4 |
1 |
0.69 |
0.62 |
0 |
0.00 |
0.00 |
0 |
0.00 |
0.00 |
1 |
0.74 |
0.60 |
||
CdV:centra:4/4 |
0 |
0.00 |
0.00 |
1 |
0.75 |
0.95 |
0 |
0.00 |
0.00 |
0 |
0.00 |
0.00 |
||
CdV:arch:1/2 |
4 |
2.76 |
2.33 |
6 |
4.51 |
3.87 |
10 |
6.94 |
5.19 |
17 |
12.59 |
10.24 |
||
CdV:arch:2/2 |
0 |
0.00 |
0.00 |
1 |
0.75 |
0.95 |
0 |
0.00 |
0.00 |
0 |
0.00 |
0.00 |
||
F limb:Metacarp.:1/4 |
6 |
4.14 |
3.57 |
11 |
8.27 |
7.53 |
6 |
4.17 |
6.71 |
9 |
6.67 |
5.41 |
||
F limb:Pr. Phal:1/2 |
0 |
0.00 |
0.00 |
3 |
2.26 |
2.07 |
10 |
6.94* |
5.82 |
11 |
8.15* |
6.56 |
||
F limb:Pr. Phal:2/2 |
2 |
1.38 |
1.16 |
4 |
3.01 |
3.11 |
2 |
1.39 |
1.39 |
9 |
6.67 |
5.70 |
||
F limb:Dt. Phal:1/4 |
1 |
0.69 |
0.62 |
1 |
0.75 |
0.68 |
0 |
0.00 |
0.00 |
2 |
1.48 |
1.12 |
||
|
|
|
|
|
|
|
|
|
|
|
|
|
||
*: Significantly different from G1
Table 10. contd. Summary of Fetal Skeletal Observations (incidence and percentage)
Group No. |
G1 |
G2 |
G3 |
G4 |
|||||||||
Dose (mg/kg/day) |
0 |
50 |
250 |
1000 |
|||||||||
No. of litters examined |
23 |
21 |
24 |
24 |
|||||||||
No. of fetuses examined |
145 |
133 |
144 |
135 |
|||||||||
|
Inc. |
Fetus % |
Litter % |
Inc. |
Fetus % |
Litter % |
Inc. |
Fetus % |
Litter % |
Inc. |
Fetus % |
Litter % |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Normal Variant |
|
||||||||||||
DSO: F limb:Dt. Phal:4/4 |
0 |
0.00 |
0.00 |
1 |
0.75 |
0.95 |
0 |
0.00 |
0.00 |
0 |
0.00 |
0.00 |
|
H limb:Dt. Phal:1/5 |
1 |
0.69 |
0.54 |
0 |
0.00 |
0.00 |
2 |
1.39 |
1.12 |
3 |
2.22 |
1.79 |
|
H limb:Dt. Phal:5/5 |
1 |
0.69 |
0.62 |
2 |
1.50 |
1.63 |
|
0.00 |
0.00 |
4 |
2.96 |
2.31 |
|
INO/PO:Stern:# 2,5 |
3 |
2.07 |
1.71 |
11 |
8.27 |
7.24 |
13 |
9.03 |
7.86 |
10 |
7.41 |
6.17 |
|
Stern:# 1 |
0 |
0.00 |
0.00 |
0 |
0.00 |
0.00 |
1 |
0.69 |
0.60 |
0 |
0.00 |
0.00 |
|
Stern:# 2 |
2 |
1.38 |
2.90 |
7 |
5.26 |
4.90 |
4 |
2.78 |
2.48 |
8 |
5.93 |
5.74 |
|
Stern:# 4 |
0 |
0.00 |
0.00 |
0 |
0.00 |
0.00 |
0 |
0.00 |
0.00 |
1 |
0.74 |
0.52 |
|
Stern:# 5 |
24 |
16.55 |
14.61 |
18 |
13.53 |
13.02 |
27 |
18.75 |
16.40 |
30 |
22.22 |
19.11 |
|
Stern:# 6 |
14 |
9.66 |
8.35 |
23 |
17.29 |
15.70 |
15 |
10.42 |
8.22 |
13 |
9.63 |
8.13 |
|
CV:centra:1/7 |
24 |
16.55 |
15.10 |
12 |
9.02 |
8.76 |
19 |
13.19 |
12.22 |
18 |
13.33 |
12.54 |
|
INO/PO:CV:centra:2/7 |
1 |
0.69 |
0.62 |
2 |
1.50 |
2.38 |
2 |
1.39 |
1.43 |
2 |
1.48 |
1.64 |
|
CV:centra:3/7 |
1 |
0.69 |
0.72 |
1 |
0.75 |
0.79 |
0 |
0.00 |
0.00 |
0 |
0.00 |
0.00 |
|
TV:centra:1/13 |
0 |
0.00 |
0.00 |
1 |
0.75 |
0.68 |
1 |
0.69 |
0.42 |
0 |
0.00 |
0.00 |
|
Minor Anomalies |
|
|
|
|
|
|
|
|
|
|
|
|
|
HYPOPLASTIC: Stern:# 2 |
0 |
0.00 |
0.00 |
1 |
0.75 |
0.79 |
1 |
0.69 |
0.60 |
0 |
0.00 |
0.00 |
|
Stern:# 5 |
8 |
5.52 |
4.92 |
4 |
3.01 |
2.68 |
3 |
2.08 |
1.71 |
4 |
2.96 |
2.54 |
|
DB: TV:centra:1/13 |
34 |
23.45 |
28.30 |
33 |
24.81 |
23.43 |
36 |
25.00 |
25.92 |
29 |
21.48 |
19.70 |
|
TV:centra:2/13 |
17 |
11.72 |
10.94 |
11 |
8.27 |
7.97 |
19 |
13.19 |
15.47 |
14 |
10.37 |
9.49 |
|
TV:centra:3/13 |
6 |
4.14 |
3.65 |
3 |
2.26 |
2.31 |
5 |
3.47 |
2.64 |
4 |
2.96 |
2.86 |
|
TV:centra:4/13 |
1 |
0.69 |
0.62 |
2 |
1.50 |
1.36 |
3 |
2.08 |
1.63 |
4 |
2.96 |
2.71 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Table 10. contd. Summary of Fetal Skeletal Observations (incidence and percentage)
Group No. |
G1 |
G2 |
G3 |
G4 |
|||||||||
Dose (mg/kg/day) |
0 |
50 |
250 |
1000 |
|||||||||
No. of litters examined |
23 |
21 |
24 |
24 |
|||||||||
No. of fetuses examined |
145 |
133 |
144 |
135 |
|||||||||
|
Inc. |
Fetus % |
Litter % |
Inc. |
Fetus % |
Litter % |
Inc. |
Fetus % |
Litter % |
Inc. |
Fetus % |
Litter % |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Minor Anomalies |
|
||||||||||||
DB: TV:centra:5/13 |
0 |
0.00 |
0.00 |
0 |
0.00 |
0.00 |
0 |
0.00 |
0.00 |
1 |
0.74 |
0.52 |
|
LV:centra:1/6 |
7 |
4.83 |
4.48 |
8 |
6.02 |
5.83 |
3 |
2.08 |
1.53 |
6 |
4.44 |
4.24 |
|
LV:centra:2/6 |
1 |
0.69 |
0.62 |
0 |
0.00 |
0.00 |
0 |
0.00 |
0.00 |
1 |
0.74 |
0.83 |
|
LV:centra:4/6 |
0 |
0.00 |
0.00 |
0 |
0.00 |
0.00 |
0 |
0.00 |
0.00 |
1 |
0.74 |
0.52 |
|
SPLIT:TV:centra:1/13 |
2 |
1.38 |
1.24 |
4 |
3.01 |
2.95 |
1 |
0.69 |
0.60 |
1 |
0.74 |
1.04 |
|
ASY DB: TV:centra:1/13 |
0 |
0.00 |
0.00 |
1 |
0.75 |
0.79 |
0 |
0.00 |
0.00 |
4 |
2.96 |
2.82 |
|
TV:centra:2/13 |
0 |
0.00 |
0.00 |
1 |
0.75 |
0.68 |
0 |
0.00 |
0.00 |
0 |
0.00 |
0.00 |
|
ASY OSSI: stern:#4,5 |
1 |
0.69 |
0.62 |
0 |
0.00 |
0.00 |
0 |
0.00 |
0.00 |
1 |
0.74 |
0.69 |
|
stern:# 3,4 |
0 |
0.00 |
0.00 |
0 |
0.00 |
0.00 |
1 |
0.69 |
0.60 |
1 |
0.74 |
0.52 |
|
stern:# 3-5 |
1 |
0.69 |
2.17 |
2 |
1.50 |
1.59 |
1 |
0.69 |
0.83 |
1 |
0.74 |
0.69 |
|
ASY SPLIT:TV:centra:1/13 |
1 |
0.69 |
0.62 |
0 |
0.00 |
0.00 |
0 |
0.00 |
0.00 |
0 |
0.00 |
0.00 |
|
EXTRA: LV:centra & arch #7 |
0 |
0.00 |
0.00 |
0 |
0.00 |
0.00 |
0 |
0.00 |
0.00 |
1 |
0.74 |
0.69 |
|
RUDIMENTARY: RIB(Rt/Lt/B):# 14 |
46 |
31.72 |
31.60 |
43 |
32.33 |
32.30 |
21 |
14.58* |
12.99 |
50 |
37.04 |
37.05 |
|
ACCESSORY: RIB(Rt/Lt/B):# 14 |
2 |
1.38 |
1.45 |
1 |
0.75 |
0.60 |
1 |
0.69 |
0.60 |
1 |
0.74 |
0.60 |
|
WAVY:RIB(Rt/Lt/B)(+/++):2/13 |
1 |
0.69 |
0.62 |
0 |
0.00 |
0.00 |
0 |
0.00 |
0.00 |
0 |
0.00 |
0.00 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Major Malformations |
None |
||||||||||||
|
|
|
|
|
|
|
|
|
|
|
|
|
|
*: Significantly different from G1
+: Slight
++: moderate
Applicant's summary and conclusion
- Conclusions:
- Based on the above findings, it is concluded that, No Observed Adverse Effect Level (NOAEL) for
- Maternal toxicity is 250 mg/kg/day due to treatment-related significant reduction in maternal body weight gain and food consumption at 1000 mg/kg/day,
- Fetal developmental toxicity is 1000 mg/kg/day as the litter data parameters were unaffected by treatment up to the high dose of 1000 mg/kg/day and
- Teratogenicity is 1000 mg/kg/day as there were no signs of teratogenicity in any of the tested dose levels up to the high dose of 1000 mg/kg/day
in Sprague Dawley rats when Nylostab S-EED P was administered orally by gavage during GD 5 to 19 under the test conditions and doses employed in this study. - Executive summary:
The objective of this study was to evaluate theembryo-fetal developmentaltoxicity of test itemNylostabS-EED Pwhen administered to pregnant Sprague Dawley rats by oral route during gestation days (GD) 5 to GD19.The results of this study helped to establish the No Observed Adverse Effect Level (NOAEL) of the test item.
In this study, each group (G1, G2, G3 and G4) consisted of 24 presumed pregnant Sprague Dawley rats (gestation day 0). Day `0' of gestation for each individual female rat in the study was considered as the day on which vaginal plug was observed or vaginal smear was found sperm positive.
The test item,NylostabS-EED Pwas suspended in vehicle [0.1% (w/v) Sodium Carboxymethyl cellulose (medumviscosity) in Milli-Q water] and administered orally (by gavage) to presumed pregnant rats once daily from GD 5 to 19 at the dose levels of 50, 250 and 1000 mg/kg/day for low (G2), mid (G3) and high (G4) dose group rats, respectively. The rats in the vehicle control (G1) group received the vehicle alone. A constant dose volume of 10 mL/kg body weight was administered to all groups.
The dose formulation suspensions were analyzed for active ingredient concentrations at the initiation and termination of treatment. The results of analysis of formulations revealed that the analyzed concentrations were within the acceptable limits.
The mated females were observed twice daily for clinical signs, mortality and morbidity. Body weights were recorded on GD0, 3, 5, 8, 11, 14, 17 and 20. About 200 g (food input) was provided on Day ‘0’. The food left over was recorded and replenished to about 200 g on GD 3, 5, 8, 11, 14 and 17. The food left over was also recorded on Day 20 of presumed gestation. The intermittent body weight gain and food intake was calculated and presented for rats found pregnant at caesarean section.
Caesarean section was performed for all the rats on GD 20 and dams were examined for gross pathological changes. The uterus from all the dams was removed (by laparotomy) and the contents were examined.The uteri were weighed and examined for the number of implantation sites, early and late resorptions, and number of live and deadfetuses. The number of corpora lutea was counted on each ovary. All thefetuseswere sexed, weighed and examined for external malformations.Approximately half the number of fetuses from each dam was examined for visceral malformations and the remaining half was evaluated for skeletal malformations.
Results of the study are presented below:
· There were no mortalities and clinical signs at all the doses tested.
· There was significant reduction in maternal body weights and food consumption at 1000 mg/kg/day as compared to vehicle control group indicating maternal toxicity.
· The other maternal and litter data parameters were comparable to vehicle control group up to the high dose of 1000 mg/kg/day.
· Fetal, external, visceral and skeletal observations were comparable to vehicle control group at all the doses tested. Visceral and skeletal examinations revealed no signs of teratogenicity in any of the tested doses.
Based on the above findings, it is concluded that, No Observed Adverse Effect Level (NOAEL) for
· Maternal toxicity is 250 mg/kg/day due to treatment-related significant reduction in maternal body weight gain and food consumption at 1000 mg/kg/day,
· Fetaldevelopmental toxicity is 1000 mg/kg/day as the litter data parameters were unaffected by treatment up to the high dose of
1000 mg/kg/day and· Teratogenicity is 1000 mg/kg/day as there were no signs of teratogenicity in any of the tested dose levels up to the high dose of 1000 mg/kg/day
in Sprague Dawley rats whenNylostabS-EED Pwas administered orally by gavage during GD 5 to 19 under the test conditions and doses employed in this study.
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