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EC number: 947-744-0 | CAS number: -
- 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
Toxicity to reproduction
Administrative data
- Endpoint:
- screening for reproductive / developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 2017-09-16 to 2018-04-03
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 018
- Report date:
- 2018
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
- Version / remarks:
- adopted on 29 July 2016
- Deviations:
- no
- Principles of method if other than guideline:
- not applicable
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
- Justification for study design:
- SPECIFICATION OF STUDY DESIGN:
- Premating exposure duration for parental (P0) animals: Yes (14 days)
- Basis for dose level selection: The doses of 0, 100, 300 and 1000 mg/kg body weight for vehicle control, low dose, mid dose and high dose respectively were selected in consultation with the sponsor based on the results of Dose Range Finding Study for Reproduction/Developmental Toxicity Screening Test of Hostacerin DGSB by Oral Gavage in Sprague Dawley Rats (Bioneeds Study No.: BIO-TX 2516).
These doses were selected as the test item Hostacerin DGSB when administered orally to Sprague Dawley males for two weeks prior to mating, during mating and up to the day before sacrifice during post-mating period (total of at 30 days treatment) and females were treated for two weeks pre-mating period, during mating, pregnancy (gestation) and up to lactation day 13 after which the pups were sacrificed on lactation day 13, females (dams) were sacrificed on lactation day 14.
- Route of administration: oral (gavage) route
- Other considerations:
choice of species and strain: Rat (Rattus norvegicus) and Sprague Dawley (standard laboratory rodent species and strain used for toxicity assessment and also recommended by various regulatory authorities)
vehicle: The test item was in-soluble in distilled water and forms clear homogenous suspension in 0.5 % w/v Carboxy Methyl Cellulose at the concentration of 100 mg/mL (highest dose concentration) as evidenced by the in-house solubility and suspendibility test results. Hence, 0.5 % w/v Carboxy Methyl Cellulose was selected for the test item formulation preparation.
number of animals: 96 (48 Males + 48 Females); 12 Males + 12 Females/group as per OECD 421 guideline specification
Test material
- Reference substance name:
- Fatty acids, C16-18 (even numbered), esters with 1,2,3-propanetriol and oligomers, ethoxylated
- IUPAC Name:
- Fatty acids, C16-18 (even numbered), esters with 1,2,3-propanetriol and oligomers, ethoxylated
- Test material form:
- solid
Constituent 1
- Specific details on test material used for the study:
- SOURCE OF TEST MATERIAL
- Source and batch No.of test material: Clariant Produkte (Deutschland) GmbH
84504 Burgkirchen, Germany and DEG4338635
- Expiration date of the batch: 04.10.2018
- Purity test date: 04.10.2016
STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Ambient (21 to 29°C)
- Stability under test conditions: The stability of the test item in dose formulations was established under Bioneeds Study No.: BIO-ANM 450. The test item formulations were stable for 6 hours at room temperature and for 24 hours at 2 to 8 oC at the concentrations of 10 mg/mL and 100 mg/mL.
- Solubility of the test substance in the solvent/vehicle: 0.5 % w/v Carboxy Methyl Cellulose was used as vehicle for the preparation of formulations as the test item formed clear homogenous suspension in 0.5 % w/v Carboxy Methyl Cellulose at the concentration of 100 mg/mL (highest dose concentration) as evidenced by the in-house solubility and suspendibility test results.
FORM AS APPLIED IN THE TEST: Liquid (Suspension)
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Details on species / strain selection:
- Rat is one of the standard laboratory rodent species used for toxicity assessment and also recommended by various regulatory authorities.
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: In-house bred animals
- Females nulliparous and non-pregnant: yes
- Age at study initiation: 10 weeks
- Weight at study initiation: Males: 220.17 g to 255.97 g; Females: 201.51 g to 231.96 g
- Housing: Animals were housed in a standard polypropylene cage (size: L 430 x B 285 x H 150 mm) with stainless steel mesh top grill having facilities for holding pelleted food and drinking water in water bottle fitted with stainless steel sipper tube. Clean sterilized paddy husk was provided as bedding material.
i. Pre mating
Two animals of same sex and group per cage were housed.
ii. Mating
During mating, two animals (one male and one female) of same group were housed.
iii. Post mating
After confirming presence of sperm in the vaginal smear (Day 0 of pregnancy), the mated pairs were separated. Males were housed with their former cage mates while females were housed individually. Sterilized paper shreds were provided as a nesting material from gestation day 20 onwards.
- Diet: Altromin Maintenance diet for rats and mice 1324 manufactured by Altromin Spezialfutter GmbH & Co.
- Water: Deep bore-well water passed through reverse osmosis unit was provided in plastic water bottles with stainless steel sipper tubes.
- Acclimation period (Including Oestrus Cycle Evaluation): 18 September 2017 to 06 October 2017.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19.8 to 23.4°C
- Humidity (%): 43 to 69%
- Air changes (per hr): 12 to 15 air changes per hour.
- Photoperiod (hrs dark / hrs light): 12 hours fluorescent light and 12 hours dark cycle.
IN-LIFE DATES: From: To: 18 September 2017 to 10 December 2017 (till end of last female necropsy)
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- CMC (carboxymethyl cellulose)
- Remarks:
- 0.5 % w/v Carboxy Methyl Cellulose
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
VEHICLE
- Justification for use and choice of vehicle : The test item was in-soluble in distilled water and formed clear homogenous suspension in 0.5 % w/v Carboxy Methyl Cellulose at the concentration of 100 mg/mL (highest dose concentration) as evidenced by the in-house solubility and suspendibility test results. Hence, 0.5 % w/v Carboxy Methyl Cellulose was selected for the test item formulation preparation.
- Concentration in vehicle: G1 (vehicle control): 0 mg/mL; G2 (low dose): 10 mg/mL; G3 (mid dose): 30 mg/mL; G4 (high dose): 100 mg/mL
- Amount of vehicle: 10 mL/kg body weight
- Batch no.: BCBN1690V - Details on mating procedure:
- - M/F ratio per cage: 1:1
- Length of cohabitation: maximum of 14 days.
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy.
- After 14 days of unsuccessful pairing replacement of first male by another male with proven fertility.
- Further matings after two unsuccessful attempts: no
- After successful mating each pregnant female was caged: individually
- Any other deviations from standard protocol: no - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Homogeneity and dose formulation analysis for dose concentration verification was done by Analytical Chemistry department of Bioneeds India Private Limited.
The analysis was done as per methods detailed in the Study Plan No. BIO-ANM 450. Sampling and analysis of formulations was performed during first week of treatment and during week 4 of the treatment. The samples were collected in duplicates (20 mL each) from top, middle and bottom layer from low and mid dose concentrations, in duplicates (5 mL each) from top, middle and bottom layer from high dose concentrations and from middle layer in duplicate sets from vehicle control.
The collected samples were transferred to Analytical Chemistry department of Bioneeds India Private Limited for dose concentration analysis. One set of aliquot of each formulation was analyzed. The second aliquot was stored as a backup purpose at 2 to 8°C conditions. The second set of samples was discarded, as the analysis results of first set of samples were within the limits. Formulations were considered acceptable, as the mean results were within the range of 85 to 115% of the nominal concentration and the relative standard deviation (% RSD) is ≤10%. - Duration of treatment / exposure:
- Males: two weeks pre-mating, during mating and up to the day before sacrifice during post-mating period (total of 34 days of treatment).
Females: two weeks pre-mating period, during mating, pregnancy (gestation) and up to lactation day 13. - Frequency of treatment:
- Once daily
- Details on study schedule:
- - Age at mating of the mated animals in the study: 14 to 15 weeks
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day
- Remarks:
- vehicle control
- Dose / conc.:
- 100 mg/kg bw/day
- Remarks:
- low dose
- Dose / conc.:
- 300 mg/kg bw/day
- Remarks:
- mid dose
- Dose / conc.:
- 1 000 mg/kg bw/day
- Remarks:
- high dose
- No. of animals per sex per dose:
- 12 animals per sex per dose (group)
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale:
The doses of 0, 100, 300 and 1000 mg/kg body weight for vehicle control, low dose, mid dose and high dose respectively were selected in consultation with the sponsor based on the results of Dose Range Finding Study for Reproduction/Developmental Toxicity Screening Test of Hostacerin DGSB by Oral Gavage in Sprague Dawley Rats (Bioneeds Study No.: BIO-TX 2516).
These doses were selected as the test item Hostacerin DGSB when administered orally to Sprague Dawley males for two weeks prior to mating, during mating and up to the day before sacrifice during post-mating period (total of at 30 days treatment) and females were treated for two weeks pre-mating period, during mating, pregnancy (gestation) and up to lactation day 13 after which the pups were sacrificed on lactation day 13, females (dams) were sacrificed on lactation day 14 did not reveal any treatment related effects at all the tested doses (100, 300 and 1000 mg/kg body weight).
- Rationale for animal assignment:
The animals were weighed and arranged in ascending order of their body weights. These body weight stratified animals were distributed to all the groups using Microsoft Excel Spreadsheet, such that body weight variation of animals selected for the study did not exceed ± 20% (+12.02% and -11.65% for males and +12.09% and -10.47% for females) of the mean body weight of each sex. The grouping was done one day prior to the initiation of treatment. Body weight of the animals was analyzed statistically for mean body weight to rule out the statistical significant difference between groups within each sex. - Positive control:
- not applicable
Examinations
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: once daily
- Cage side observations checked in table 1 were included.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly once were included in (table 1)
BODY WEIGHT: Yes
- Time schedule for examinations: first day of dosing, weekly thereafter and at termination. The
females were weighed on gestation days 0, 7, 14 and 20 during pregnancy and on days 1, 4, 7 and 1
3 during lactation period. (table 2, 3, 9, 10, 12 & 13)
FOOD CONSUMPTION: Food consumption for each animal determined and mean daily diet consumption calculated as
g food/kg body weight/day: Yes; weekly once; gestation days 0 to 7, 7 to 14 and 14 to 20 during
pregnancy and day 1 to 4, 4 to 7, 7 to 13 during lactation period. (table 4, 11 & 14) - Oestrous cyclicity (parental animals):
- Two weeks after five days of acclimatization to evaluate its normal oestrus cyclicity (4 to 5 days), daily from the beginning of the treatment period until evidence of mating and on the day of sacrifice for females.
- Sperm parameters (parental animals):
- Parameters examined: testis weight, epididymis weight
Special emphasis on stages of spermatogenesis and histology of interstitial testicular cell structure. - Litter observations:
- STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: no
PARAMETERS EXAMINED
The following parameters were examined in offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities, anogenital distance (AGD), presence of nipples/areolae in male pups
GROSS EXAMINATION OF DEAD PUPS:
yes, for external and internal abnormalities - Postmortem examinations (parental animals):
- SACRIFICE
- Male animals: All animals [after completion of mating period (34 days of treatment)]
- Maternal animals: All animals [on lactation day 14]
GROSS NECROPSY
- Gross necropsy consisted of [external and internal examinations including the cervical, thoracic, and abdominal viscera.]
HISTOPATHOLOGY / ORGAN WEIGHTS
The tissues indicated in Table [26 and 27] (i.e. Epidymides, Prostate and Seminal vesicles and coagulating glands, Testes Uterus with cervix Thyroid along with parathyroid) were prepared for microscopic examination and weighed, respectively. - Postmortem examinations (offspring):
- SACRIFICE
- The offspring were sacrificed on lactation day 13.
- These animals were subjected to postmortem examinations (macroscopic and/or microscopic examination) as follows:
GROSS NECROPSY
- Gross necropsy consisted of [external and internal examinations including the cervical, thoracic, and abdominal viscera.]
HISTOPATHOLOGY / ORGAN WEIGTHS
Thyroid along with parathyroid was collected from one male and one female pup per litter on lactation day 13 and were prepared for microscopic examination - Statistics:
- The data was subjected to various statistical analysis using SPSS software version 22. All analysis and comparisons were evaluated at the 95% level of confidence (P<0.05)
The statistical analysis was followed to the parameters as mentioned below table: Body weight, Change in body weight, Feed consumption, Copulatory interval, Gestation length, Organ
weights, Anogenital distance, Mean pup weight, Pre implantation loss, Pre natal loss, Post natal loss, Post implantation loss:- Parametric - One-way ANOVA with Dunnett’s post test.
Corpora lutea/dam, Implantations/dam, No. of pups/dam, Sex ratio, Litter size, Pup weight:- Non Parametric - Kruskal-Wallis followed by the Mann-Whitney test. Pregnancy rate. Dams with live pups, Dams with dead pups, No. of litters with/without dead pups, No.of litters with/without resorptions:- Cross Tabs - Chi-square test/ Fischer's Exact Test. - Reproductive indices:
- Male Fertility Index (%) = Number of Males Impregnating Females
----------------------------------------------------------- x 100
Number of Males used for Mating
Female Fertility Index (%) = Number of Females confirmed with Pregnancy
------------------------------------------------------------------ x 100
Number of Females used for Mating
Parturition (%) = Number of Parturitions
--------------------------------- x 100
Number of Pregnancies
Copulatory Interval (Days) = Date of Initiation of Cohabitation - Date of Confirmation of Mating
Gestation Length (days) = Date of Delivery - Date of Confirmation of Mating - Offspring viability indices:
- Male/Female Sex Ratio = Number Male Pups Per Dam
------------------------------------------
Number Female Pups Per Dam
Live Birth Index (%) = Number of Viable Pups Born
----------------------------------------- x 100
Number of Pups Born
Lactation Day 4
Pup Survival Index (%) = Number of Viable Pups on Lactation Day 4
---------------------------------------------------------------x 100
Number of Pups Born
Lactation Day 7
Pup Survival Index (%) = Number Of Viable Pups on Lactation Day 7
--------------------------------------------------------------- x 100
Number Of Viable Pups on Lactation Day 4
Lactation Day 13
Pup Survival Index (%) = Number Of Viable Pups on Lactation Day 13
---------------------------------------------------------------- x 100
Number Of Viable Pups on Lactation Day 7
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- There were no clinical signs of toxicity observed at any of the tested dose group animals of either sex during the experimental period.
- Dermal irritation (if dermal study):
- not specified
- Description (incidence and severity):
- not applicable
- Mortality:
- no mortality observed
- Description (incidence):
- There were no mortality/morbidity observed at any of the tested dose group animals of either sex during the experimental period
- Body weight and weight changes:
- effects observed, non-treatment-related
- Description (incidence and severity):
- There were no changes observed in mean body weight and percent change in body weight with respect to day 1 at any of the tested dose group of either sex during the experimental period.
There were no treatment related changes observed in the gestation body weight and percent change in gestation body weight during gestation period at any of the tested dose group animals when compared with vehicle control group animals. However, statistical significant increase in mean body weight on gestation day 14 at G3 group animals was observed when compared with vehicle control group animals. This change is considered as incidental as there were no changes noted during the other gestation periods and there were no effects noted in feed consumption at this period.
There were no treatment related changes observed in the lactation body weight and percent change in lactation body weight at any of the tested dose group animals when compared with vehicle control group animals. - Food consumption and compound intake (if feeding study):
- effects observed, non-treatment-related
- Description (incidence and severity):
- There were no changes observed in feed consumption at any of the tested dose group animals of either sex during the experimental period.
There were no changes observed in the feed consumption during gestation period at any of the tested dose group animals when compared with vehicle control group animals. However, statistical significant increase in mean feed consumption during gestation day 0 to 7 was noted at low and high dose group animals when compared with vehicle control group animals. This change is considered as incidental and not treatment related as there were no effects noted in mean body weight at this duration and the change is inconsistent.
There were no changes observed in the feed consumption during lactation period at any of the tested dose group animals when compared with vehicle control group animals. - Food efficiency:
- not examined
- Description (incidence and severity):
- not applicable
- Water consumption and compound intake (if drinking water study):
- not examined
- Description (incidence and severity):
- not applicable
- Ophthalmological findings:
- not examined
- Description (incidence and severity):
- not applicable
- Haematological findings:
- not examined
- Description (incidence and severity):
- not applicable
- Clinical biochemistry findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- There were no treatment related changes observed in serum T4 levels in males, females (pregnant), lactation day 4 and 13 pups at any of the tested dose groups when compared with vehicle control group.
However, statistically significant decrease in T4 levels at all the tested dose group males when compared with vehicle control group males and statistically significant decrease in T4 levels at mid and high dose group females when compared with vehicle control group females was noted.
This significant variation could be due to two males in G1 group (Animal No. Rc3917 and Rc3922) with a serum T4 level of 139.88 and 134.97 respectively which are significantly more than other animals of same group. In case of females the variation is not dose dependant. Hence, the variations observed in the T4 levels are considered to be incidental. - Urinalysis findings:
- not examined
- Description (incidence and severity):
- not applicable
- Behaviour (functional findings):
- not examined
- Description (incidence and severity):
- not applicable
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Description (incidence and severity):
- not applicable
- Histopathological findings: non-neoplastic:
- no effects observed
- Description (incidence and severity):
- No treatment related histopathological findings noticed in ovaries, testes and epididymides (with special emphasis on stages of spermatogenesis and histopathology of interstitial testicular cell structure) of the animals from the high dose group during histopathological examination.
Minimal grade and focally distributed interstitial mononuclear cell [MNC] infiltration, unilateral was observed in epididymis of one male animal of G4 group. This lesion was considered as incidental finding because of lack of consistency and similar finding was observed in concurrent control animal.
Testes, which were screened with special emphasis on stages of spermatogenesis and interstitial testicular cell structure, revealed normal progression of the spermatogenic cycle and presence of all expected associations. - Histopathological findings: neoplastic:
- not examined
- Description (incidence and severity):
- not applicable
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- no effects observed
- Description (incidence and severity):
- There were no changes observed in the oestrus cyclicity at any of the tested dose group females during pre-mating treatment, mating treatment and on lactation day 14.
- Reproductive function: sperm measures:
- no effects observed
- Description (incidence and severity):
- no effects were noted.
- Reproductive performance:
- no effects observed
- Description (incidence and severity):
- No effects were noted. There were no treatment related changes observed in the copulatory interval and number of conceiving days at any of the tested dose group animals when compared with vehicle control group animals. There were no changes observed in the gestation length, implantation index, pre-implantation loss, post-implantation loss, number of pups delivered, sex ratio and live birth index of each litter at any of the tested dose group animals when compared with vehicle control group animals.
Details on results (P0)
Effect levels (P0)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No adverse effects observed
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- no effects observed
- Mortality / viability:
- mortality observed, non-treatment-related
- Description (incidence and severity):
- Mean live birth index is 99.3, 87.85, 98.52 and 100 % for dose groups G1, G2, G3, and G4, respectively. Total number of dead pups at birth were 1, 3, 2 and 0 for dose groups G1, G2, G3, and G4, respectively.
Mean pup survival index (LD 1-4) is 98.48, 100, 100, and 100 % for dose groups G1, G2, G3, and G4, respectively. Total number of dead pups were 2, 0, 0 and 0 for dose groups G1, G2, G3, and G4, respectively. - Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Sexual maturation:
- no effects observed
- Description (incidence and severity):
- There were no changes observed in anogenital distance ratio of both male and female pups, recorded on lactation day 4 at any dose group litters when compared with vehicle control group litters.
There were no occurrences of nipples in male pups of dams of the tested dose group litters when compared with vehicle control group litters. - Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- no effects observed
- Histopathological findings:
- no effects observed
- Other effects:
- no effects observed
- Description (incidence and severity):
- There were no treatment related changes observed in serum T4 levels in lactation day 4 and 13 pups at any of tested dose groups when compared with vehicle control group.
Developmental neurotoxicity (F1)
- Behaviour (functional findings):
- not examined
Developmental immunotoxicity (F1)
- Developmental immunotoxicity:
- not examined
Effect levels (F1)
- Key result
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- >= 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No adverse effect s observed
Target system / organ toxicity (F1)
- Key result
- Critical effects observed:
- no
Overall reproductive toxicity
- Key result
- Reproductive effects observed:
- no
Any other information on results incl. tables
TABLE 1. SUMMARYOF CLINICAL SIGNSOF TOXICITY, DETAILED CLINICAL EXAMINATIONAND MORTALITY RECORD
Group, Sex & Dose (mg/kg body weight/day) |
No. of Animals |
Clinical Signs of Toxicity/ Detailed Clinical Examination |
Mortality (No. of Mortality/ No. of Animals dosed) |
G1, M & 0 |
12 |
N |
0/12 |
G2, M & 100 |
12 |
N |
0/12 |
G3, M & 300 |
12 |
N |
0/12 |
G4, M & 1000 |
12 |
N |
0/12 |
M: Male; N: Normal
TABLE 1 (Contd..,). SUMMARYOF CLINICAL SIGNSOF TOXICITY, DETAILED CLINICAL EXAMINATIONAND
MORTALITY RECORD
Group, Sex & Dose (mg/kg body weight/day) |
No. of Animals |
Clinical Signs of Toxicity/ Detailed Clinical Examination |
Mortality (No. of Mortality/ No. of Animals dosed) |
||||
G1, F & 0 |
12 |
N |
0/12 |
||||
G2, F & 100 |
12 |
N |
0/12 |
||||
G3, F & 300 |
12 |
N |
0/12 |
||||
G4, F & 1000 |
12 |
N |
0/12 |
F: Female; N: Normal
TABLE 2. SUMMARY OF BODY WEIGHT (g)RECORD
Group, Sex & Dose (mg/kg body weight/day) |
Body Weight (g) on Days |
|||||||
1 |
7 |
14 |
21 |
28 |
34 |
|||
G1, M & 0 |
Mean |
331.48 |
355.57 |
372.35 |
392.61 |
408.21 |
429.21 |
|
±SD |
21.09 |
25.46 |
26.61 |
30.62 |
31.33 |
35.64 |
||
n |
12 |
12 |
12 |
12 |
12 |
12 |
||
G2, M & 100 |
Mean |
333.49 |
348.67 |
366.07 |
382.71 |
394.48 |
414.61 |
|
±SD |
20.91 |
24.45 |
30.62 |
31.50 |
33.73 |
39.05 |
||
n |
12 |
12 |
12 |
12 |
12 |
12 |
||
G3, M & 300 |
Mean |
333.86 |
349.97 |
361.35 |
384.41 |
399.83 |
423.79 |
|
±SD |
20.50 |
18.44 |
22.25 |
23.24 |
26.15 |
27.88 |
||
n |
12 |
12 |
12 |
12 |
12 |
12 |
||
G4, M & 1000 |
Mean |
331.99 |
357.47 |
378.38 |
396.73 |
411.93 |
426.47 |
|
±SD |
18.56 |
18.42 |
19.85 |
21.46 |
21.62 |
23.80 |
||
n |
12 |
12 |
12 |
12 |
12 |
12 |
M: Male; SD: Standard Deviation; n: Number of Animals
TABLE 2 (Contd..,). SUMMARY OF BODY WEIGHT (g) RECORD
Group, Sex & Dose (mg/kg body weight/day) |
Body Weight (g) on Days |
||||
1 |
7 |
14 |
21# |
||
G1, F & 0 |
Mean |
263.38 |
269.72 |
279.18 |
292.40 |
±SD |
16.71 |
16.23 |
19.53 |
22.58 |
|
n |
12 |
12 |
12 |
4 |
|
G2, F & 100 |
Mean |
263.21 |
269.81 |
281.42 |
292.27 |
±SD |
16.04 |
13.15 |
13.93 |
21.16 |
|
n |
12 |
12 |
12 |
5 |
|
G3, F & 300 |
Mean |
263.38 |
269.54 |
281.01 |
281.16 |
±SD |
15.85 |
13.80 |
16.37 |
21.01 |
|
n |
12 |
12 |
12 |
6 |
|
G4, F & 1000 |
Mean |
262.96 |
269.34 |
286.13 |
284.89 |
±SD |
14.76 |
14.63 |
15.25 |
19.99 |
|
n |
12 |
12 |
12 |
5 |
F: Female; SD: Standard Deviation; n: Number of Animals
#: The statistical analysis is not performed for day 21 body weight as the presented mean and standard deviations were calculated only for the females in cohabitation.
TABLE 3. SUMMARY OF PERCENTCHANGE IN BODY WEIGHT (%) WITH RESPECT TO DAY 1 RECORD
Group, Sex & Dose (mg/kg body weight/day) |
Percent Change in Body Weight (%) with respect to Day 1 during Days |
||||||
1 to 7 |
1 to 14 |
1 to 21 |
1 to 28 |
1 to 34 |
|||
G1, M & 0 |
Mean |
7.23 |
12.33 |
18.43 |
23.16 |
29.51 |
|
±SD |
2.62 |
4.24 |
5.26 |
5.83 |
7.60 |
||
n |
12 |
12 |
12 |
12 |
12 |
||
G2, M & 100 |
Mean |
4.55 |
9.74 |
14.78 |
18.31 |
24.26 |
|
±SD |
2.94 |
5.40 |
6.29 |
6.98 |
7.56 |
||
n |
12 |
12 |
12 |
12 |
12 |
||
G3, M & 300 |
Mean |
4.94 |
8.42 |
15.37 |
19.94 |
27.21 |
|
±SD |
3.94 |
6.65 |
7.45 |
7.38 |
9.22 |
||
n |
12 |
12 |
12 |
12 |
12 |
||
G4, M & 1000 |
Mean |
7.79 |
14.23 |
19.91 |
24.49 |
28.83 |
|
±SD |
4.61 |
7.57 |
9.96 |
10.01 |
9.93 |
||
n |
12 |
12 |
12 |
12 |
12 |
M: Male; SD: Standard Deviation; n: Number of Animals
TABLE 3 (Contd..,). SUMMARY OF PERCENTCHANGE IN BODY WEIGHT (%) WITH RESPECT TO DAY 1RECORD
Group, Sex & Dose (mg/kg body weight/day) |
Percent Change in Body Weight (%) with respect to Day 1 during Days |
|||
1 to 7 |
1 to 14 |
1 to 21# |
||
G1, F & 0 |
Mean |
2.45 |
6.02 |
9.31 |
±SD |
1.97 |
3.71 |
5.11 |
|
n |
12 |
12 |
4 |
|
G2, F & 100 |
Mean |
2.59 |
7.10 |
11.07 |
±SD |
2.35 |
5.26 |
4.99 |
|
n |
12 |
12 |
5 |
|
G3, F & 300 |
Mean |
2.42 |
6.86 |
8.90 |
±SD |
3.00 |
6.13 |
6.84 |
|
n |
12 |
12 |
6 |
|
G4, F & 1000 |
Mean |
2.45 |
8.87 |
11.94 |
±SD |
1.38 |
3.28 |
8.06 |
|
n |
12 |
12 |
5 |
F: Female; SD: Standard Deviation; n: Number of Animals
#: The statistical analysis is not performed for day 21 body weight as the presented mean and standard deviations were calculated only for the females in cohabitation.
TABLE 4. SUMMARY OFFEED CONSUMPTION (g/rat/day)RECORD
Group, Sex & Dose |
Feed Consumption (g) |
||||
Week 1 (Day 1 to 7) |
Week 2 (Day 7 to 14) |
Post Mating (Day 28 to 34) |
|||
G1, M & 0 |
Mean |
23.12 |
22.81 |
29.41 |
|
±SD |
1.34 |
2.28 |
0.67 |
||
n |
12 |
12 |
12 |
||
G2, M & 100 |
Mean |
22.76 |
23.08 |
28.95 |
|
±SD |
1.71 |
1.95 |
0.76 |
||
n |
12 |
12 |
12 |
||
G3, M & 300 |
Mean |
22.66 |
23.23 |
29.49 |
|
±SD |
1.48 |
2.35 |
0.66 |
||
n |
12 |
12 |
12 |
||
G4, M & 1000 |
Mean |
24.16 |
24.26 |
29.68 |
|
±SD |
1.12 |
1.73 |
0.66 |
||
n |
12 |
12 |
12 |
M: Male;SD: Standard Deviation; n: Number ofanimals
TABLE 4 (Contd..,). SUMMARY OF FEED CONSUMPTION (g/rat/day)RECORD
Group, Sex & Dose |
Feed Consumption (g) |
|||
Week 1 (Day 1 to 7) |
Week 2 (Day 7 to 14) |
|||
G1, F & 0 |
Mean |
18.19 |
18.43 |
|
±SD |
1.13 |
1.55 |
||
n |
12 |
12 |
||
G2, F & 100 |
Mean |
18.85 |
18.65 |
|
±SD |
1.93 |
1.58 |
||
n |
12 |
12 |
||
G3, F & 300 |
Mean |
17.63 |
18.21 |
|
±SD |
1.98 |
0.86 |
||
n |
12 |
12 |
||
G4, F & 1000 |
Mean |
18.33 |
18.60 |
|
±SD |
1.18 |
0.80 |
||
n |
12 |
12 |
F: Female; SD: Standard Deviation; n: Number of animals
TABLE 5. SUMMARY OF ABSOLUTE ORGAN WEIGHT (g) RECORD
Group, Sex & Dose |
Epididymes |
Testes |
Prostate+Seminal vesicles with coagulating glands (PSC) |
Thyroid along with parathyroid# |
|||||||
G1, M & 0 |
Mean |
1.7248 |
3.3488 |
3.8053 |
0.0357 |
||||||
±SD |
0.1932 |
0.2725 |
0.5705 |
0.0033 |
|||||||
n |
12 |
12 |
12 |
12 |
|||||||
G2, M & 100 |
Mean |
1.7994 |
3.3460 |
3.7837 |
0.0370 |
||||||
±SD |
0.1389 |
0.2603 |
0.3461 |
0.0022 |
|||||||
n |
12 |
12 |
12 |
12 |
|||||||
G3, M & 300 |
Mean |
1.6893 |
3.2506 |
4.1135 |
0.0359 |
||||||
±SD |
0.1685 |
0.2056 |
0.2480 |
0.0027 |
|||||||
n |
12 |
12 |
12 |
12 |
|||||||
G4, M & 1000 |
Mean |
1.7526 |
3.3840 |
4.1498 |
0.0363 |
||||||
±SD |
0.1925 |
0.2029 |
0.4138 |
0.0020 |
|||||||
n |
12 |
12 |
12 |
12 |
M: Male;SD: Standard Deviation; n: Number of animals: #: Weighed post fixation
TABLE 5 (Contd..,). SUMMARY OF ABSOLUTE ORGAN WEIGHT (g) RECORD
Group, Sex & Dose |
|
Uterus |
Thyroid along with parathyroid# |
||||
G1, F & 0 |
Mean |
0.6154 |
0.0291 |
||||
±SD |
0.0395 |
0.0031 |
|||||
n |
11 |
11 |
|||||
G2, F & 100 |
Mean |
0.5932 |
0.0253 |
||||
±SD |
0.0270 |
0.0033 |
|||||
n |
11 |
11 |
|||||
G3, F & 300 |
Mean |
0.6264 |
0.0279 |
||||
±SD |
0.0764 |
0.0056 |
|||||
n |
11 |
11 |
|||||
G4, F & 1000 |
Mean |
0.5864 |
0.0306 |
||||
±SD |
0.0420 |
0.0048 |
|||||
n |
12 |
12 |
F: Female;SD: Standard Deviation; n: Number of dams;
#: Weighed post fixation (excluding non-pregnant animals)
TABLE 6. SUMMARY
OF FASTING BODY WEIGHT (g) AND
ORGAN WEIGHT (%) RELATIVE TO FASTING BODY WEIGHT RECORD
Group, Sex & Dose (mg/kg body weight/day) |
Fasting Body Weight (g) |
Epididymes |
Testes |
Prostate+Seminal vesicles with coagulating glands (PSC) |
Thyroid along with parathyroid |
||||||||
G1, M & 0 |
Mean |
403.62 |
0.4300 |
0.8341 |
0.9467 |
0.0089 |
|||||||
±SD |
34.33 |
0.0578 |
0.0859 |
0.1466 |
0.0011 |
||||||||
n |
12 |
12 |
12 |
12 |
12 |
||||||||
G2, M & 100 |
Mean |
391.26 |
0.4644 |
0.8645 |
0.9795 |
0.0095 |
|||||||
±SD |
37.96 |
0.0638 |
0.1260 |
0.1606 |
0.0010 |
||||||||
n |
12 |
12 |
12 |
12 |
12 |
||||||||
G3, M & 300 |
Mean |
397.31 |
0.4275 |
0.8208 |
1.0396 |
0.0091 |
|||||||
±SD |
26.57 |
0.0570 |
0.0674 |
0.0932 |
0.0008 |
||||||||
n |
12 |
12 |
12 |
12 |
12 |
||||||||
G4, M & 1000 |
Mean |
399.57 |
0.4393 |
0.8503 |
1.0407 |
0.0091 |
|||||||
±SD |
24.64 |
0.0473 |
0.0805 |
0.1104 |
0.0008 |
||||||||
n |
12 |
12 |
12 |
12 |
12 |
M: Male;SD: Standard Deviation; n: Number of animals
TABLE 6 (Contd..,). SUMMARY OF FASTING BODY WEIGHT (g) AND
ORGAN WEIGHT (%) RELATIVE TO FASTING BODY WEIGHT RECORD
Group, Sex & Dose (mg/kg body weight/day) |
|
Fasting Body Weight |
Uterus |
Thyroid along with parathyroid |
|||||
G1, F & 0 |
Mean |
304.24 |
0.2035 |
0.0096 |
|||||
±SD |
21.64 |
0.0224 |
0.0013 |
||||||
n |
11 |
11 |
11 |
||||||
G2, F & 100 |
Mean |
306.66 |
0.1943 |
0.0083 |
|||||
±SD |
23.92 |
0.0148 |
0.0012 |
||||||
n |
11 |
11 |
11 |
||||||
G3, F & 300 |
Mean |
324.21 |
0.1933 |
0.0087 |
|||||
±SD |
28.55 |
0.0177 |
0.0022 |
||||||
n |
11 |
11 |
11 |
||||||
G4, F & 1000 |
Mean |
306.69 |
0.1921 |
0.0101 |
|||||
±SD |
24.23 |
0.0182 |
0.0020 |
||||||
n |
12 |
12 |
12 |
F: Female;SD: Standard Deviation; n: Number of animals
TABLE 7. SUMMARY RECORD OF VAGINAL SMEAR EXAMINATION FOR DETERMINATION OF OESTRUS CYCLICITY
Group & Dose |
No. of Females |
No. of Females with Regular Oestrus Cyclicity during Pre-mating, mating and on Lactation day 14 |
No. of Females with Irregular Oestrus Cyclicity during Pre-mating, mating and on Lactation day 14 |
||||
G1 & 0 |
12 |
12 |
0 |
||||
G2 & 100 |
12 |
12 |
0 |
||||
G3 & 300 |
12 |
12 |
0 |
||||
G4 & 1000 |
12 |
12 |
0 |
TABLE 8. SUMMARY OF COHABITATION RECORD
Group & Dose |
Copulatory Interval (Days) |
|
Conceiving Days (1 to 5) |
Conceiving Days (6 to 20) |
|||||||
G1 & 0 |
Mean |
5.83 |
n |
8 |
4 |
||||||
±SD |
4.63 |
||||||||||
n |
12 |
% |
66.7 |
33.3 |
|||||||
G2 & 100 |
Mean |
7.00 |
n |
6 |
6 |
||||||
±SD |
4.24 |
||||||||||
n |
12 |
% |
50.0 |
50.0 |
|||||||
G3 & 300 |
Mean |
7.42 |
n |
5 |
7 |
||||||
±SD |
4.60 |
||||||||||
n |
12 |
% |
41.7 |
58.3 |
|||||||
G4 & 1000 |
Mean |
7.58 |
n |
6 |
6 |
||||||
±SD |
4.80 |
||||||||||
n |
12 |
% |
50.0 |
50.0 |
SD: Standard Deviation; n: Number of animals; %: Percent
TABLE 9. SUMMARY RECORD OF BODY WEIGHT (g) DURINGGESTATION PERIOD
Group & Dose |
Body weight (g) on Gestation Days |
||||
0 |
7 |
14 |
20 |
||
G1 & 0 |
Mean |
283.86 |
297.35 |
342.70 |
421.08 |
±SD |
21.63 |
21.53 |
28.88 |
20.97 |
|
n |
11 |
11 |
11 |
11 |
|
G2 & 100 |
Mean |
291.15 |
304.38 |
349.07 |
422.35 |
±SD |
15.19 |
13.65 |
19.69 |
17.65 |
|
n |
11 |
11 |
11 |
11 |
|
G3 & 300 |
Mean |
291.93 |
307.30 |
364.18* |
440.73 |
±SD |
11.96 |
11.79 |
12.56 |
22.28 |
|
n |
11 |
11 |
11 |
11 |
|
G4 & 1000 |
Mean |
292.90 |
305.82 |
358.55 |
429.48 |
±SD |
14.68 |
15.66 |
17.10 |
24.61 |
|
n |
12 |
12 |
12 |
12 |
SD: Standard Deviation; n: Number of dams
*: Statistically significant than the control group (p<0.05)
TABLE 10. SUMMARY RECORD OF PERCENT CHANGE IN BODY WEIGHT (%) DURING GESTATION PERIOD
Group & Dose |
Percent Change in body weight (%) during Gestation |
|||
0 to 7 |
7 to 14 |
14 to 20 |
||
G1 & 0 |
Mean |
4.78 |
15.24 |
23.31 |
±SD |
0.82 |
4.95 |
6.98 |
|
n |
11 |
11 |
11 |
|
G2 & 100 |
Mean |
4.59 |
14.70 |
21.17 |
±SD |
1.38 |
4.36 |
5.18 |
|
n |
11 |
11 |
11 |
|
G3 & 300 |
Mean |
5.28 |
18.57 |
21.02 |
±SD |
1.78 |
3.46 |
4.51 |
|
n |
11 |
11 |
11 |
|
G4 & 1000 |
Mean |
4.41 |
17.30 |
19.82 |
±SD |
0.92 |
2.71 |
4.74 |
|
n |
12 |
12 |
12 |
SD: Standard Deviation; n: Number of dams
TABLE 11. SUMMARY RECORD OF FEED CONSUMPTION (g/dam/day) DURING GESTATION PERIOD
Group, Sex & Dose |
Feed Consumption (g) during Gestation |
||||
GD 0 to 7 |
GD 7 to 14 |
GD 14 to 20 |
|||
G1 & 0 |
Mean |
22.64 |
26.85 |
30.28 |
|
±SD |
1.35 |
1.46 |
1.12 |
||
n |
11 |
11 |
11 |
||
G2 & 100 |
Mean |
23.92* |
27.62 |
30.43 |
|
±SD |
0.79 |
0.96 |
0.91 |
||
n |
11 |
11 |
11 |
||
G3 & 300 |
Mean |
23.19 |
27.05 |
30.00 |
|
±SD |
0.89 |
1.49 |
1.06 |
||
n |
11 |
11 |
11 |
||
G4 & 1000 |
Mean |
23.92* |
26.79 |
30.47 |
|
±SD |
0.78 |
1.12 |
0.69 |
||
n |
12 |
12 |
12 |
SD: Standard Deviation; n: Number of
dams
*: Statistically significant than the control group (p<0.05)
TABLE 12. SUMMARY RECORD OF BODY WEIGHT (g) DURING LACTATION PERIOD
Group, Sex & Dose |
Body Weight (g) on Lactation Day |
||||
1 |
4 |
7 |
13 |
||
G1 & 0 |
Mean |
309.57 |
313.98 |
320.23 |
327.06 |
±SD |
21.76 |
22.19 |
24.05 |
21.94 |
|
n |
11 |
11 |
11 |
11 |
|
G2 & 100 |
Mean |
307.28 |
313.82 |
318.42 |
329.52 |
±SD |
30.13 |
28.65 |
28.85 |
23.41 |
|
n |
11 |
11 |
11 |
11 |
|
G3 & 300 |
Mean |
327.46 |
335.18 |
341.73 |
346.58 |
±SD |
35.21 |
31.80 |
31.26 |
28.52 |
|
n |
11 |
11 |
11 |
11 |
|
G4 & 1000 |
Mean |
306.28 |
313.07 |
318.52 |
327.51 |
±SD |
33.02 |
28.48 |
27.29 |
24.06 |
|
n |
12 |
12 |
12 |
12 |
SD: Standard Deviation; n: Number of animals
TABLE 13. SUMMARY RECORD OF PERCENT CHANGE IN BODY WEIGHT (%) DURING LACTATION PERIOD
Group, Sex & Dose |
Percent Change in body weight (%) during Lactation |
|||
1 to 4 |
4 to 7 |
7 to 13 |
||
G1 & 0 |
Mean |
1.42 |
1.97 |
2.20 |
±SD |
0.46 |
1.22 |
1.28 |
|
n |
11 |
11 |
11 |
|
G2 & 100 |
Mean |
2.20 |
1.48 |
3.70 |
±SD |
1.85 |
0.49 |
3.39 |
|
n |
11 |
11 |
11 |
|
G3 & 300 |
Mean |
2.50 |
1.98 |
1.50 |
±SD |
2.26 |
0.89 |
1.15 |
|
n |
11 |
11 |
11 |
|
G4 & 1000 |
Mean |
2.42 |
1.79 |
2.93 |
±SD |
2.73 |
0.64 |
1.70 |
|
n |
12 |
12 |
12 |
SD: Standard Deviation; n: Number of dams
TABLE 14. SUMMARY RECORD OF FEED CONSUMTION (g/dam/day) DURING LACTATION PERIOD
Group & Dose |
Feed Consumption (g) during Lactation |
||||
LD 1 to 4 |
LD 4 to 7 |
LD 7 to 13 |
|||
G1 & 0 |
Mean |
23.34 |
27.53 |
32.34 |
|
±SD |
1.26 |
1.55 |
1.22 |
||
n |
11 |
11 |
11 |
||
G2 & 100 |
Mean |
24.65 |
29.18 |
33.01 |
|
±SD |
2.32 |
2.43 |
1.04 |
||
n |
11 |
11 |
11 |
||
G3 & 300 |
Mean |
22.80 |
28.77 |
33.44 |
|
±SD |
1.89 |
3.14 |
2.17 |
||
n |
11 |
11 |
11 |
||
G4 & 1000 |
Mean |
24.67 |
28.77 |
33.64 |
|
±SD |
3.09 |
2.52 |
1.33 |
||
n |
12 |
12 |
12 |
SD: Standard Deviation; n: Number of dams; LD: Lactation Day
TABLE 15. SUMMARY RECORD OF GESTATION LENGTH (DAYS) AND DELIVERY DATA
Group & Dose |
|
Gestation Length (Days) |
|
Delivery Data |
||||||||||
Litter Size (No.) |
Live Pups (No.) |
Dead Pups (No.) |
|
Sex Ratio (M/F) at Birth |
Live Birth Index |
|||||||||
Total (No.) |
Male (No.) |
Female (No.) |
Total (No.) |
Male (No.) |
Female (No.) |
|||||||||
G1 & 0 |
Mean |
22.64 |
12.64 |
12.55 |
5.91 |
6.64 |
0.09 |
0.00 |
0.09 |
1.13 |
99.30 |
|||
±SD |
1.03 |
2.06 |
2.07 |
1.76 |
2.84 |
0.30 |
0.00 |
0.30 |
0.71 |
2.32 |
||||
n |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
||||
G2 & 100 |
Mean |
22.55 |
13.73 |
13.45 |
7.00 |
6.45 |
0.27 |
0.09 |
0.18 |
1.14 |
97.85 |
|||
±SD |
1.13 |
2.15 |
2.30 |
1.95 |
1.51 |
0.47 |
0.30 |
0.40 |
0.42 |
3.74 |
||||
n |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
||||
G3 & 300 |
Mean |
22.73 |
13.00 |
12.82 |
6.36 |
6.45 |
0.18 |
0.00 |
0.18 |
1.16 |
98.52 |
|||
±SD |
1.42 |
1.95 |
2.04 |
1.86 |
2.21 |
0.40 |
0.00 |
0.40 |
0.69 |
3.31 |
||||
n |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
||||
G4 & 1000 |
Mean |
22.83 |
11.83 |
11.83 |
5.58 |
6.25 |
0.00 |
0.00 |
0.00 |
0.92 |
100.00 |
|||
±SD |
1.27 |
2.17 |
2.17 |
2.15 |
0.87 |
0.00 |
0.00 |
0.00 |
0.38 |
0.00 |
||||
n |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
M: Male; F: Female;SD: Standard Deviation; n: Number of dams; NAD: No abnormality detected; LD: Lactation Day
TABLE 16. SUMMARY OF LITTER OBSERVATION RECORD DURING LACTATION PERIOD
Group & Dose |
|
No. of Live Pups At Birth |
During LD 1 to 4 |
Sex Ratio (M/F) LD 4 |
No. of Survived Pups during LD 1 to 4 |
Pup Survival Index LD 1 to 4 |
||||||
Live Pups (No.) |
|
Dead Pups (No.) |
||||||||||
Total (No.) |
Male (No.) |
Female (No.) |
Total (No.) |
Male (No.) |
Female (No.) |
|||||||
G1 & 0 |
Mean |
12.55 |
12.36 |
5.91 |
6.45 |
0.18 |
0.00 |
0.18 |
1.15 |
11.33 |
98.48 |
|
±SD |
2.07 |
2.20 |
1.76 |
2.81 |
0.60 |
0.00 |
0.60 |
0.70 |
4.14 |
5.03 |
||
n |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
12 |
11 |
||
G2 & 100 |
Mean |
13.45 |
13.45 |
7.00 |
6.45 |
0.00 |
0.00 |
0.00 |
1.14 |
12.33 |
100.00 |
|
±SD |
2.30 |
2.30 |
1.95 |
1.51 |
0.00 |
0.00 |
0.00 |
0.42 |
4.46 |
0.00 |
||
n |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
12 |
11 |
||
G3 & 300 |
Mean |
12.82 |
12.82 |
6.36 |
6.45 |
0.00 |
0.00 |
0.00 |
1.16 |
11.75 |
100.00 |
|
±SD |
2.04 |
2.04 |
1.86 |
2.21 |
0.00 |
0.00 |
0.00 |
0.69 |
4.18 |
0.00 |
||
n |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
12 |
11 |
||
G4 & 1000 |
Mean |
11.83 |
11.83 |
5.58 |
6.25 |
0.00 |
0.00 |
0.00 |
0.92 |
11.83 |
100.00 |
|
±SD |
2.17 |
2.17 |
2.15 |
0.87 |
0.00 |
0.00 |
0.00 |
0.38 |
2.17 |
0.00 |
||
n |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
M: Male: F: Female;SD: Standard Deviation; n: Number of dams; LD: Lactation Day
TABLE 16 (Contd..,). SUMMARY OF LITTER OBSERVATION RECORD DURING LACTATION PERIOD
Group & Dose day) |
Live Pups (No.) on LD 4 |
|
Pups Sacrificed for Blood Collection on LD 4 (No.) |
|
Live Pups (No.) on LD 4 after Sacrificed for Blood Collection |
During LD 4 to 7 |
|
Sex Ratio (M/F) at |
No. of Survived Pups during LD 4-7 |
Pup Survival Index |
|||||||||||||
Live Pups (No.) |
|||||||||||||||||||||||
Male (No.) |
Female (No.) |
Total (No.) |
Male (No.) |
Female (No.) |
Total (No.) |
Male (No.) |
Female (No.) |
Total (No.) |
Male (No.) |
Female (No.) |
Total (No.) |
|
Male (No.) |
Female (No.) |
Total (No.) |
||||||||
G1 & |
Mean |
5.91 |
6.45 |
12.36 |
0.00 |
1.36 |
1.36 |
5.91 |
5.09 |
11.00 |
5.91 |
5.09 |
11.00 |
0.00 |
0.00 |
0.00 |
1.62 |
11.00 |
100.00 |
||||
±SD |
1.76 |
2.81 |
2.20 |
0.00 |
0.81 |
0.81 |
1.76 |
2.47 |
1.55 |
1.76 |
2.47 |
1.55 |
0.00 |
0.00 |
0.00 |
1.32 |
1.55 |
0.00 |
|||||
n |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
|||||
G2 & |
Mean |
7.00 |
6.45 |
13.45 |
0.00 |
1.64 |
1.64 |
7.00 |
4.82 |
11.82 |
7.00 |
4.82 |
11.82 |
0.00 |
0.00 |
0.00 |
1.65 |
11.82 |
100.00 |
||||
±SD |
1.95 |
1.51 |
2.30 |
0.00 |
0.67 |
0.67 |
1.95 |
1.47 |
1.83 |
1.95 |
1.47 |
1.83 |
0.00 |
0.00 |
0.00 |
0.81 |
1.83 |
0.00 |
|||||
n |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
|||||
G3 & |
Mean |
6.36 |
6.45 |
12.82 |
0.00 |
1.55 |
1.55 |
6.36 |
4.91 |
11.27 |
6.36 |
4.91 |
11.27 |
0.00 |
0.00 |
0.00 |
1.75 |
11.27 |
100.00 |
||||
±SD |
1.86 |
2.21 |
2.04 |
0.00 |
0.82 |
0.82 |
1.86 |
2.12 |
1.49 |
1.86 |
2.12 |
1.49 |
0.00 |
0.00 |
0.00 |
1.29 |
1.49 |
0.00 |
|||||
n |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
|||||
G4 & 1000 |
Mean |
5.58 |
6.25 |
11.83 |
0.00 |
1.00 |
1.00 |
5.58 |
5.25 |
10.83 |
5.58 |
5.25 |
10.83 |
0.00 |
0.00 |
0.00 |
1.17 |
10.83 |
100.00 |
||||
±SD |
2.15 |
0.87 |
2.17 |
0.00 |
0.95 |
0.95 |
2.15 |
1.06 |
1.40 |
2.15 |
1.06 |
1.40 |
0.00 |
0.00 |
0.00 |
0.64 |
1.40 |
0.00 |
|||||
n |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
M: Male: F: Female;SD: Standard Deviation; n: Number of dams; LD: Lactation Day
TABLE 16 (Contd..,). SUMMARY OF LITTER OBSERVATION RECORD DURING LACTATION PERIOD
Group & Dose |
Live Pups (No.) on LD 7 |
During LD 7 to 13 |
|
Sex Ratio (M/F) at LD 7 |
No. of Survived Pups during LD |
Pup Survival Index |
||||||||||
Live Pups (No.) |
||||||||||||||||
Male (No.) |
Female (No.) |
Total (No.) |
Male (No.) |
Female (No.) |
Total (No.) |
Male (No.) |
Female (No.) |
Total (No.) |
||||||||
G1 & 0 |
Mean |
5.91 |
5.09 |
11.00 |
5.91 |
5.09 |
11.00 |
0.00 |
0.00 |
0.00 |
1.62 |
11.00 |
100.00 |
|||
±SD |
1.76 |
2.47 |
1.55 |
1.76 |
2.47 |
1.55 |
0.00 |
0.00 |
0.00 |
1.32 |
1.55 |
0.00 |
||||
n |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
||||
G2 & 100 |
Mean |
7.00 |
4.82 |
11.82 |
7.00 |
4.82 |
11.82 |
0.00 |
0.00 |
0.00 |
1.65 |
11.82 |
100.00 |
|||
±SD |
1.95 |
1.47 |
1.83 |
1.95 |
1.47 |
1.83 |
0.00 |
0.00 |
0.00 |
0.81 |
1.83 |
0.00 |
||||
n |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
||||
G3 & 300 |
Mean |
6.36 |
4.91 |
11.27 |
6.36 |
4.91 |
11.27 |
0.00 |
0.00 |
0.00 |
1.75 |
11.27 |
100.00 |
|||
±SD |
1.86 |
2.12 |
1.49 |
1.86 |
2.12 |
1.49 |
0.00 |
0.00 |
0.00 |
1.29 |
1.49 |
0.00 |
||||
n |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
||||
G4 & 1000 |
Mean |
5.58 |
5.25 |
10.83 |
5.58 |
5.25 |
10.83 |
0.00 |
0.00 |
0.00 |
1.17 |
10.83 |
100.00 |
|||
±SD |
2.15 |
1.06 |
1.40 |
2.15 |
1.06 |
1.40 |
0.00 |
0.00 |
0.00 |
0.64 |
1.40 |
0.00 |
||||
n |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
M: Male: F: Female;SD: Standard Deviation; n: Number of dams; LD: Lactation Day
TABLE 17. SUMMARY OF PUP OBSERVATIONS RECORD DURING LACTATION PERIOD
Group & Dose (mg/kg body weight/day) |
Pup Observation on LD 1 |
Pup Observation on LD 4 |
Pup Observation on LD 7 |
Pup Observation on LD 13 |
|
G1 & 0 |
N |
N |
N |
N |
|
G2 & 100 |
N |
N |
N |
N |
|
G3 & 300 |
N |
N |
N |
N |
|
G4 & 1000 |
N |
N |
N |
N |
|
LD: Lactation Day; N: Normal
TABLE 18. SUMMARY RECORD OF MEAN PUP WEIGHT (g) DURING LACTATION PERIOD
Group& Dose |
Mean Pup weight (g) on LD 1 |
|
Mean Pup weight (g) on LD 4 |
Mean Pup Weight (g) on |
Mean Pup weight (g) on LD 13 |
|||||||
Male |
Female |
Male |
Female |
Male |
Female |
Male |
Female |
|||||
G1 & 0 |
Mean |
6.68 |
5.98 |
9.99 |
8.52 |
14.55 |
12.15 |
25.65 |
21.90 |
|||
±SD |
0.49 |
0.66 |
0.76 |
0.74 |
1.12 |
1.26 |
1.63 |
2.36 |
||||
n |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
||||
G2 & 100 |
Mean |
6.24 |
5.30 |
10.26 |
8.89 |
14.99 |
13.13 |
27.22 |
22.26 |
|||
±SD |
0.68 |
0.83 |
1.15 |
1.11 |
1.54 |
1.82 |
2.26 |
2.16 |
||||
n |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
||||
G3 & 300 |
Mean |
6.39 |
5.76 |
10.22 |
8.65 |
15.63 |
13.13 |
27.11 |
21.93 |
|||
±SD |
0.59 |
0.66 |
1.41 |
0.83 |
1.14 |
1.62 |
1.48 |
3.26 |
||||
n |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
||||
G4 & 1000 |
Mean |
6.52 |
5.60 |
11.19* |
9.06 |
16.03* |
13.22 |
27.29 |
21.68 |
|||
±SD |
0.64 |
0.44 |
1.22 |
1.36 |
1.19 |
1.61 |
1.90 |
3.61 |
||||
n |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
SD: Standard Deviation; n: Number of dams;LD: Lactation Day
*: Statistically significant than the control group (p<0.05)
TABLE 19. SUMMARY OF UTERI OBSERVATIONS RECORD
Group & Dose |
No. of Corporaluetea |
No. of Implantations |
Pre-Implantation Loss |
Post-Implantation Loss |
Pre-natal Loss |
Post-natal Loss |
Post-natal Loss |
No. of Early Resorptions |
No. of |
|
G1 & 0 |
Mean |
12.82 |
12.64 |
1.22 |
0.70 |
0.09 |
1.52 |
0.18 |
0.00 |
0.00 |
±SD |
2.23 |
2.06 |
2.72 |
2.32 |
0.30 |
5.03 |
0.60 |
0.00 |
0.00 |
|
n |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
|
G2 & 100 |
Mean |
13.82 |
13.73 |
0.57 |
2.15 |
0.27 |
0.00 |
0.00 |
0.00 |
0.00 |
±SD |
2.23 |
2.15 |
1.88 |
3.74 |
0.47 |
0.00 |
0.00 |
0.00 |
0.00 |
|
n |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
|
G3 & 300 |
Mean |
13.18 |
13.00 |
1.36 |
1.48 |
0.18 |
0.00 |
0.00 |
0.00 |
0.00 |
±SD |
1.99 |
1.95 |
3.11 |
3.31 |
0.40 |
0.00 |
0.00 |
0.00 |
0.00 |
|
n |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
11 |
|
G4 & 1000 |
Mean |
12.00 |
11.83 |
1.28 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
±SD |
2.26 |
2.17 |
3.05 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
0.00 |
|
n |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
SD: Standard Deviation; n: Number of dams
TABLE 20. SUMMARY RECORD OF ANO-GENITAL DISTANCE [AGD] RATIO ON LACTATION DAY 4
Group & Dose |
|
Mean Male AGD Ratio |
Mean Female AGD Ratio |
|
G1 & 0 |
Mean |
2.53 |
1.17 |
|
±SD |
0.18 |
0.07 |
||
n |
11 |
11 |
||
G2 & 100 |
Mean |
2.66 |
1.17 |
|
±SD |
0.16 |
0.09 |
||
n |
11 |
11 |
||
G3 & 300 |
Mean |
2.65 |
1.18 |
|
±SD |
0.11 |
0.07 |
||
n |
11 |
11 |
||
G4 & 1000 |
Mean |
2.69 |
1.23 |
|
±SD |
0.21 |
0.17 |
||
n |
12 |
12 |
SD: Standard Deviation; n: Number of dams
TABLE 21. SUMMARY RECORD OF MALE PUP NIPPLE/AREOLAE RETENTION (no.) ON LACTATION DAY 13
Group & Dose |
No. of Nipples/Areolae |
||
G1 & 0 |
Mean |
0.00 |
|
±SD |
0.00 |
||
n |
12 |
||
G2 & 100 |
Mean |
0.00 |
|
±SD |
0.00 |
||
n |
11 |
||
G3 & 300 |
Mean |
0.00 |
|
±SD |
0.00 |
||
n |
11 |
||
G4 & 1000 |
Mean |
0.00 |
|
±SD |
0.00 |
||
n |
11 |
SD: Standard Deviation; n: Number of dams
TABLE 22. SUMMARY OF SERUM T4 LEVELS (ng/mL) RECORD - MALES
Group, Sex & Dose (mg/kg body weight/day) |
Serum T4 Levels (ng/mL) |
||
G1, M & 0 |
Mean |
101.492 |
|
±SD |
18.172 |
||
n |
12 |
||
G2, M & 100 |
Mean |
84.759* |
|
±SD |
5.744 |
||
n |
12 |
||
G3, M & 300 |
Mean |
82.176* |
|
±SD |
8.380 |
||
n |
12 |
||
G4, M & 1000 |
Mean |
73.659* |
|
±SD |
5.815 |
||
n |
12 |
M: Male; SD: Standard Deviation; n: Number of animals
*: Statistically significant than the control group (p<0.05)
TABLE 23. SUMMARY OF SERUM T4 LEVELS (ng/mL) RECORD - FEMALES
Group, Sex & Dose (mg/kg body weight/day) |
Serum T4 Levels (ng/mL) |
||
G1, F & 0 |
Mean |
78.821 |
|
±SD |
11.933 |
||
n |
11 |
||
G2, F & 100 |
Mean |
73.067 |
|
±SD |
7.682 |
||
n |
11 |
||
G3, F & 300 |
Mean |
64.148* |
|
±SD |
5.037 |
||
n |
11 |
||
G4, F & 1000 |
Mean |
67.385* |
|
±SD |
8.707 |
||
n |
12 |
SD: Standard Deviation; n: Number of dams
*: Statistically significant than the control group (p<0.05)
TABLE 24. SUMMARY OF SERUM T4 LEVELS (ng/mL) RECORD - LACTATION DAY 4 PUPS
Group & Dose |
Serum T4 Levels (ng/mL) |
||
G1 & 0 |
Mean |
70.985 |
|
±SD |
5.708 |
||
n |
9 |
||
G2 & 100 |
Mean |
69.599 |
|
±SD |
3.939 |
||
n |
10 |
||
G3 & 300 |
Mean |
69.114 |
|
±SD |
3.762 |
||
n |
9 |
||
G4 & 1000 |
Mean |
70.672 |
|
±SD |
5.016 |
||
n |
7 |
SD: Standard Deviation; n: Number of dams (Serum collected from pups with litter size of more than ten per dam pooled for analysis)
TABLE 25. SUMMARY OF SERUM T4 LEVELS (ng/mL) RECORD - LACTATION DAY 13 PUPS
Group & Dose |
Serum T4 Levels (ng/mL) |
||
G1 & 0 |
Mean |
73.460 |
|
±SD |
8.044 |
||
n |
11 |
||
G2 & 100 |
Mean |
71.633 |
|
±SD |
7.751 |
||
n |
11 |
||
G3 & 300 |
Mean |
71.633 |
|
±SD |
7.751 |
||
n |
11 |
||
G4 & 1000 |
Mean |
75.088 |
|
±SD |
7.169 |
||
n |
12 |
SD: Standard Deviation; n: Number of dams (Serum collected from pups per dam pooled for analysis
TABLE 26. SUMMARY OF GROSS PATHOLOGY RECORD
Organs/Lesions |
Group |
G1 |
G2 |
G3 |
G4 |
||||
Dose (mg/kg body weight/day) |
0 |
100 |
300 |
1000 |
|||||
Sex |
M |
F |
M |
F |
M |
F |
M |
F |
|
No. of Animals |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
|
No Abnormality Detected |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
12 |
Note: The numeral indicates number of animal/s without lesion. M: Male; F: Female
TABLE 27. SUMMARY OF HISTOPATHOLOGY RECORD
Group No. |
G1 |
G4 |
||
Dose (mg/kg body weight/day) |
0 |
1000 |
||
Sex |
M |
F |
M |
F |
No. of Animals |
12 |
12 |
12 |
12 |
ORGANS AND OBSERVATIONS |
||||
EPIDIDYMIDES |
|
|
|
|
Interstitial MNC infiltration ; unilateral |
1 |
X |
1 |
X |
Note: The numeral indicates number of animal/s with lesion; M: Male; F: Female; X: Organs not subjected for histopathological examination due to sex difference.
Applicant's summary and conclusion
- Conclusions:
- Based on the results of the OECD 421 screening study in rats discussed, the No Observed Adverse Effect Level (NOAEL) of the test item Hostacerin DGSB was found to be 1000 mg/kg body weight when administered to the males for two weeks pre-mating, during mating and up to the day before sacrifice during post-mating period (total of 34 days), to the females for two weeks pre-mating, during mating, pregnancy (gestation) and up to lactation day 13 observation under the experimental conditions employed in the study.
- Executive summary:
The test item, Hostacerin DGSB was evaluated for possible adverse effects following repeated oral dosing to males for 34 days, to females for two weeks pre-mating period, during mating period, during pregnancy (gestation) and up to lactation day 13 to evaluate effects of test item on male and female reproductive performance such as gonadal function, mating behaviour, conception, development of the conceptus, parturition, and early neonatal development.
A total of 96 (48 males + 48 females) Sprague Dawley rats were distributed to four groups. Each group (G1, G2, G3and G4) consisted of 12 males and 12 females. The animals in G1 group were administered with vehicle[0.5% w/v Carboxy Methyl Cellulose],animals in G2, G3 and G4groups were administered withtest itemat dose levels of100, 300 and 1000 mg/kg body weight for low dose, mid dose and high dose groups respectively. The vehicle and test item formulations were administered orally by gavage at the dose volume of 10 mL/kg body weight. Males were treated for two weeks pre-mating, during mating and up to the day before sacrifice during post-mating period (total of 34 days of treatment). The females were treated for two weeks pre-mating period, during mating, pregnancy (gestation) and up to lactation day 13 after which the pups were sacrificed on lactation Day 13 and females (dams) were sacrificed on lactation day 14 after overnight fasting (water allowed). Dose formulation analysis for homogeneity and concentration verification was performed during week 1 and 4 of the treatment period and the results are found to be within the acceptable range of 85 to 115 % the nominal concentration and the % RSD is less than 10.0%.All animals were observed for clinical signs once daily, mortality and morbidity twice daily, detailed clinical examination weekly once, body weight and feed consumption weekly once.The serum collected from adult males and females and from lactation day 4 and 13 pups representing each per litter was screened for T4 levels. Females were observed for oestrus cyclicity during pre-mating treatment and mating treatment period and the dams on lactation day 14 prior to sacrifice. The females were observed for copulatory interval and all the adult animals were observed for mating and fertility index. Each litter was examined after delivery (lactation day 1) and the number and sex of pups (litter size), stillbirths (dead pups born on day 1) and live births were recorded. The dams were observed for body weights and feed consumption during gestation and lactation periods, gestation length, live birth index, number of pups, sex ratio and pup survival indexthroughout the lactation period. The pups were observed forclinical signs and once daily from PND 1 to 13. The both male and female pupweights were recorded separately on lactation days 1, 4, 7 and 13.The anogenital distance of each pup was measured on lactation day 4. The numbers of nipples/areolae in male pups were counted on lactation day 13.Gross pathology and organ weighing were performed on day 35 for males. The gross pathology was performed on lactation day 13 for pups, lactation day 14 for dams. The number of corpora lutea and implantation sites for dams were recorded during necropsy.
All animals did not reveal any clinical signs of toxicity, no mortality or morbidity observed throughout the experimental period. No treatment related changes in body weight, percent change in body weight, feed consumption, organ weights (both absolute and relative) were observed in both the sex of all tested dose group animals. There were no treatment related changes observed in serum T4 levels of adult animals and in serum T4 levels of pups at any of the tested dose groups.
Females did not reveal any treatment related changes in oestrus cyclicity, copulatory interval, fertility index, body weights and feed consumption during gestation and lactation periods, gestation length, implantation index, pre-implantation loss, post-impalntation loss, number of pups delivered, live birth index of each litter, sex ratio and pup survival index at all the tested dose groups throughout the lactation periodwhen compared with vehicle control group animals.
All pups did not reveal any clinical signs or external anomalies throughout the lactation period. No treatment related changes in pup weights, anogenital distance ratio were noted. No occurrences of nipples in male pups at any of the tested dose groups and vehicle control group.
All animals of all dose groups did not reveal any treatment related gross pathological and histopathological findings compared to vehicle control group.
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