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EC number: 249-120-7 | CAS number: 28645-51-4
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Toxicity to reproduction
Administrative data
- Endpoint:
- screening for reproductive / developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Justification for type of information:
- The data is from the study report.
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)
- Deviations:
- no
- Principles of method if other than guideline:
- The Reproductive and Developmental Toxicity Screening Test was done to evaluate any toxic effects of the test substance on the ability of reproduction and also on the developmental characteristics of the Sprague Dawley rats.
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- Oxacycloheptadec-10-en-2-one
- EC Number:
- 249-120-7
- EC Name:
- Oxacycloheptadec-10-en-2-one
- Cas Number:
- 28645-51-4
- Molecular formula:
- C16H28O2
- IUPAC Name:
- oxacycloheptadec-10-en-2-one
- Test material form:
- other: liquid
- Details on test material:
- - Name of test material (as cited in study report):Oxacycloheptadec-10-ene-2- one
- Molecular formula :C16H28O2
- Molecular weight :252.395 gram/mol
- Substance type:Organic
- Physical state:Liquid
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: In-house bred animals
- Age at study initiation (P): 9 to 11 weeks
- Weight at study initiation: (P) Males: 242.03 g to 270.64 g; Females: 211.12 g to 241.96 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.
- Diet (e.g. ad libitum): Altromin Maintenance diet for rats and mice 1324 manufactured by Altromin Spezialfutter GmbH & Co. KG was provided ad libitum.
- Water (e.g. ad libitum): Water was provided ad libitum throughout the acclimatization and experimental period. Deep bore-well water passed through reverse osmosis unit was provided in plastic water bottles with stainless steel sipper tubes.
- Acclimation period: 19 days (including fourteen days of oestrus cycle evaluation).
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19.1 to 23.6 degree celsius.
- Humidity (%): 40 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:
Administration / exposure
- Route of administration:
- oral: gavage
- Type of inhalation exposure (if applicable):
- not specified
- Vehicle:
- corn oil
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
Test material dissolved in corn oil
DIET PREPARATION
- Rate of preparation of diet (frequency):
- Mixing appropriate amounts with (Type of food):
- Storage temperature of food:
VEHICLE
- Justification for use and choice of vehicle (if other than water): Test material dissolved in corn oil
- Concentration in vehicle: 0,250,500,1000mg/kg bw
- Amount of vehicle (if gavage):
- Lot/batch no. (if required):
- Purity: - Details on mating procedure:
- The males and females were placed in 1:1 ratio. Every morning, the vaginal smear of each female was examined for presence of sperm in the vaginal smear. The female was placed with the same male until pregnancy occurs by evidence of sperm in vaginal smear until two weeks have elapsed. Day ‘0’ pregnancy was confirmed by the presence of sperm in the vaginal smear. In case pairing is unsuccessful, re-mating of females with proven males of the same group was considered for further one week The females confirmed with mating but not littered were sacrificed 25 days after gestation day ‘0’.
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The test item formulations were freshly prepared before dose administration on each treatment day. The required quantity of test item was weighed into a clean beaker and there by adding little volume of the vehicle into the beaker, mixed well using glass rod and transferred into measuring cylinder. This rinsing procedure was repeated until complete transfer of test item formulation into the measuring cylinder. Finally, the volume was made up to the required quantity with vehicle to get a desired concentration of 25, 50 and 100 mg/mL of test item for low, mid and high dose groups respectively.
Chromatographic Conditions:
Column: Zorbax Eclipse Plus, C18 250 x 4.6 mm, 5 µm
Flow rate: 1.0 mL/min
Injection volume: 10 µL
Oven temperature: 35ºC
Run time: 10 minutes
Wavelength: 193 nm
Mobile Phase: Acetonitrile
Diluent: Acetonitrile - Duration of treatment / exposure:
- The male animals were dosed for a total of 37 Days. This duration included two weeks pre-mating, during mating and up to the day before sacrifice during post-mating period.
The female animals were dosed for approx. 64 days. This duration included two weeks pre-mating period, during mating, pregnancy (gestation) and up to lactation day 13. - Frequency of treatment:
- The test item or vehicle was administered to animals through oral (gavage) route once daily.
- Details on study schedule:
- Not Specified
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 250 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 500 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 1 000 mg/kg bw/day (actual dose received)
- No. of animals per sex per dose:
- Total: 96 animals
0 mg/kg bw: 12 male, 12 female
250 mg/kg bw: 12 male, 12 female
500 mg/kg bw: 12 male, 12 female
1000 mg/kg bw: 12 male, 12 female - Control animals:
- yes, concurrent vehicle
- Details on study design:
- No Specified
- Positive control:
- No Specified
Examinations
- Parental animals: Observations and examinations:
- All the animals were observed once daily for clinical signs of toxicity and twice daily for mortality and morbidity. All the animals were subjected to detailed clinical examinations on day 1 before treatment and weekly thereafter during treatment. These observations were made outside the home cage and preferably at the same time. Signs noted included changes in skin, fur, eyes, mucous membranes, occurrence of secretions and excretions and autonomic activity such as lacrimation, piloerection, pupil size, and unusual respiratory pattern.
- Oestrous cyclicity (parental animals):
- Oestrus cycles were monitored for two weeks after five days of acclimatization to evaluate its normal oestrus cyclicity (4 to 5 days). Vaginal smears were monitored daily from the beginning of the treatment period until evidence of mating. When obtaining vaginal/cervical cells, care was taken to avoid disturbance of mucosa. Oestrus cyclicity was also monitored on the day of sacrifice for females.
- Sperm parameters (parental animals):
- Not Specified
- Litter observations:
- The day of littering was considered as lactation day 1. The number of pups born (dead and live) in a litter, sex, live births and external observations were recorded at birth. Individual body weight of live pups on lactation day 1 (within 24 hours of parturition), 4, 7 and 13 were recorded. The anogenital distance of each pup was measured on postnatal day 4 (lactation day 4) and the ratio of AGD to the cube root of pup body weight was calculated. All survived male pups were examined for appearance of nipples/areolae on postnatal day 13 (lactation day 13). The litter was observed daily in order to note the number of alive, dead and cannibalized pups. All the dead and sacrificed pups were examined and subjected to gross pathological examination. Fertility index for dams, sires and pup live birth index, mean litter size per group, survival index and sex ratio at birth were calculated.
- Postmortem examinations (parental animals):
- The males were sacrificed after completion of 37 days of treatment, females were sacrificed on lactation day 14 and pups were sacrificed on lactation day 13. The animals were fasted overnight, water was provided ad libitum during fasting. The next day, the body weight of all the fasted animals was recorded prior to exsanguination. The vaginal smear of females on the day of necropsy (lactation day 14) was performed and stage of oestrus cycle was recorded. The animals were euthanized using deep CO2 followed by exsanguination and subjected to gross necropsy, external and internal gross pathological examination. During necropsy, the males were randomized.
- Postmortem examinations (offspring):
- The pups were sacrificed on lactation day 13 and the sacrificed pups and dead pups were examined for gross abnormalities and the findings were recorded. The thyroid along with parathyroid was collected from one male and one female pup per litter on lactation day 13. The thyroid along with parathyroid from adults and pups were preserved in 10% v/v Neutral Buffered Formalin. The thyroid along with parathyroid from adults was weighed post fixation. The histopathological examination of thyroid from pups and adults was not conducted as there were no treatment related effects noted in T4 levels of adult males and lactation day 13 pups.
- Statistics:
- The data was subjected to various statistical analyses using SPSS software version 22. Statistical analysis of Body weight, Percent change in body weight, Feed consumption, Copulatory interval, Gestation length, Organ weights, Anogenital distance, Mean pup weight, Live birth Index, Pup survival index was done by One-way ANOVA with Dunnett’s post test. Statistical analysis of Pre/post implantation loss, Pre/post natal loss , No. of resorptions per dam, Corpora lutea per dam, Implantations per dam, No. of live/dead pups/dam, Sex ratio, Litter size was done by Kruskal-Wallis Test. And statistical analysis of Pregnancy rate, No. of litters with/without resorptions, No. of dams with/without live young born, No. of dams with/without dead pups was done by Chi-square test.
- Reproductive indices:
- Mating Indices, Fertility Indices, Copulatory Indices, Gestation Indices and Implantation Index and Pre and Post implantation Losses .
- Offspring viability indices:
- Live Birth Indices and Sex Ratio at Birth, Pup Survival Indices and Sex Ratio during lactation and Pre and Postnatal loss.
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 and the detailed clinical examination of animals did not reveal any changes at any of the tested dose group animals of either sex during the experimental period
- Dermal irritation (if dermal study):
- not specified
- 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:
- no effects observed
- 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 all the tested group animals of either sex during the experimental period.
- Food consumption and compound intake (if feeding study):
- no effects observed
- 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.
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not specified
- Haematological findings:
- not specified
- Clinical biochemistry findings:
- not specified
- Urinalysis findings:
- not specified
- Behaviour (functional findings):
- not specified
- Immunological findings:
- not specified
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Description (incidence and severity):
- No treatment related histopathological findings noticed in the present study.
Unilateral, interstitial mononuclear cell (MNC) infiltration in epididymides was observed one male animal from G4 group. This lesion considered as spontaneous, incidental because of lack of consistency, and unilateral in nature.
A detailed qualitative examination of the testes was made, taking into account the tubular stages of the spermatogenic cycle. The examination was conducted in order to identify treatment related effects such as missing germ cell layers or types, retained spermatids, multinucleate or apoptotic germ cells and sloughing of spermatogenic cells into the lumen or any cell or stage specificity of testicular findings.
Testes and ovaries did not show any pathological findings/lesions - Histopathological findings: neoplastic:
- not specified
- Other effects:
- not specified
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:
- not specified
- Reproductive performance:
- no effects observed
- Description (incidence and severity):
- There were no 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.There were no changes observed in the gestation length, 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.There were no changes observed in number of corpora lutea, number of implantations and no changes were noted in pre and post-implantation loss, pre-natal loss, post-natal loss at any of the tested dose group animals when compared with vehicle control group animals. No resorptions were noted at all the dose group animals observed during necropsy.
Effect levels (P0)
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- clinical signs
- mortality
- body weight and weight gain
- food consumption and compound intake
- organ weights and organ / body weight ratios
- gross pathology
- reproductive function (oestrous cycle)
- reproductive performance
- Remarks on result:
- other: No effects on reproductive parameters.
Target system / organ toxicity (P0)
- Critical effects observed:
- not specified
- System:
- other: not specified
- Organ:
- not specified
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- There were no clinical signs and external anomalies observed in any of the pups of tested dose group animals during lactation period
- Dermal irritation (if dermal study):
- not specified
- Mortality / viability:
- no mortality observed
- Description (incidence and severity):
- There were no treatment related changes observed in the number of pups and pup survival index of each litter at any of the tested dose group animals during lactation period when compared with vehicle control group animals.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- There were no changes observed in mean pup (male and female) weight on lactation day 1, 4, 7 and 13 at any of the tested dose groups when compared with vehicle control group dams
- Food consumption and compound intake (if feeding study):
- not specified
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not specified
- Haematological findings:
- not specified
- Clinical biochemistry findings:
- not specified
- Urinalysis findings:
- not specified
- Sexual maturation:
- not specified
- Anogenital distance (AGD):
- no effects observed
- Nipple retention in male pups:
- no effects observed
- Organ weight findings including organ / body weight ratios:
- not specified
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- There were no gross pathological changes (both external and internal) observed at all the tested dose group pups of either sex at all the tested dose groups examined at termination.
- Histopathological findings:
- not specified
- Other effects:
- not specified
Developmental neurotoxicity (F1)
- Behaviour (functional findings):
- not specified
Developmental immunotoxicity (F1)
- Developmental immunotoxicity:
- not specified
Effect levels (F1)
- 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:
- viability
- clinical signs
- mortality
- body weight and weight gain
- gross pathology
- Remarks on result:
- not determinable due to absence of adverse toxic effects
Target system / organ toxicity (F1)
- Critical effects observed:
- not specified
- System:
- other: not specified
- Organ:
- not specified
Overall reproductive toxicity
- Reproductive effects observed:
- not specified
- Treatment related:
- not specified
Any other information on results incl. tables
Parameters ↓ |
Group & Dose (mg/kg body weight/day) |
||||
G1 & 0 |
G2 &250 |
G3 &500 |
G4 &1000 |
||
Reproductive Indices |
|||||
Mating Indices |
|||||
Pairs started (No.) |
12 |
12 |
12 |
12 |
|
Males showing evidence of mating (No.) within 14 days |
11 |
11 |
11 |
11 |
|
Male Mating Index (%) |
91.67 |
91.67 |
91.67 |
91.67 |
|
Females showing evidence of copulation (No.) |
12 |
12 |
12 |
12 |
|
Female Mating Index (%) |
100.00 |
100.00 |
100.00 |
100.00 |
|
|
|||||
Fertility Indices |
|||||
Females achieving pregnancy (No.) |
12 |
12 |
11 |
11 |
|
Female Fertility Index (%) |
100.00 |
100.00 |
91.67 |
91.67 |
|
|
|||||
Copulatory Indices |
|||||
Conceiving days 1 to 5 (No.) |
6 |
7 |
8 |
8 |
|
Conceiving days >6 (No.) |
6 |
5 |
4 |
4 |
|
Mean Precoital Interval (Days) |
5.92 |
5.42 |
7.42 |
8.75 |
|
|
|||||
Gestation Indices |
|||||
Pregnancy≤21 days (No.) |
0 |
0 |
0 |
0 |
|
Pregnancy = 22 days (No.) |
5 |
9 |
8 |
7 |
|
Pregnancy≥23 days (No.) |
7 |
3 |
3 |
4 |
|
Mean Gestation length (Days) |
22.58 |
22.25 |
22.27 |
22.36 |
|
Gestation Index (%) |
100.00 |
100.00 |
100.00 |
100.00 |
|
|
|||||
Dams with live young born (No.) |
12 |
12 |
11 |
11 |
|
Dams with live young at day 4 post-partum (No.) |
12 |
12 |
11 |
11 |
|
Dams with live young at day 13 post-partum (No.) |
12 |
12 |
11 |
11 |
|
|
|||||
Implantation Index and Pre and Post implantation Losses |
|||||
Implants/dam (Mean) |
12.58 |
11.33 |
11.55 |
12.18 |
|
Corpora luetea/dam (Mean) |
13.08 |
11.83 |
12.09 |
12.64 |
|
Implantation Index (%) |
96.30 |
95.83 |
95.34 |
96.42 |
|
Pre-Implantation Loss (%) |
3.70 |
4.17 |
4.66 |
3.58 |
|
Post-Implantation Loss (%) |
0.64 |
3.31 |
1.74 |
1.46 |
|
|
|||||
Offspring Viability Indices |
|||||
Live Birth Indices and Sex Ratio at Birth |
|||||
Live pups/dam at birth (mean) |
12.50 |
11.00 |
11.36 |
12.00 |
|
Litter Size (Total No. of pups born/dam) at birth (mean) |
12.58 |
11.33 |
11.55 |
12.18 |
|
Mean Live Birth Index/dam (%) |
99.36 |
96.69 |
98.26 |
98.54 |
|
Male Live pups/dam at birth (mean) |
6.25 |
5.33 |
5.82 |
5.55 |
|
Female Live pups/dam at birth (mean) |
6.25 |
5.67 |
5.55 |
6.45 |
|
Sex Ratio (male/female) |
1.15 |
1.17 |
1.10 |
0.89 |
Parameters ↓ |
Group & Dose (mg/kg body weight/day) |
|||
G1 & 0 |
G2 &250 |
G3 &500 |
G4 & 1000 |
|
Pup Survival Indices and Sex Ratio during lactation |
||||
Mean No. of Pups survived per dam ( LD1 to 4) |
12.50 |
11.00 |
11.36 |
12.00 |
Mean No. of Pups dead per dam ( LD1 to 4) |
0.00 |
0.00 |
0.00 |
0.00 |
Mean Pup Survival Index (%) per dam (LD1 to 4) |
100.00 |
100.00 |
100.00 |
100.00 |
Sex Ratio (male/female) per dam at LD 4 |
1.15 |
1.17 |
1.10 |
0.89 |
Mean No. of Pups Sacrificed for Blood Collection on LD4 |
1.42 |
1.00 |
1.18 |
1.55 |
Mean No. of Pups survived per dam (LD4 to 7) |
11.08 |
10.00 |
10.18 |
10.45 |
Mean No. of Pups dead per dam (LD4 to 7) |
0.00 |
0.00 |
0.00 |
0.00 |
Mean Pup Survival Index (%) per dam (LD4 to 7) |
100.00 |
100.00 |
100.00 |
100.00 |
Sex Ratio (male/female) per dam at LD 7 |
1.48 |
1.40 |
1.47 |
1.21 |
Mean No. of Pups survived per dam (LD7 to 13) |
11.08 |
10.00 |
10.18 |
10.45 |
Mean No. of Pups dead per dam (LD7 to 13) |
0.00 |
0.00 |
0.00 |
0.00 |
Mean Pup Survival Index (%) per dam ( LD7 to 13) |
100.00 |
100.00 |
100.00 |
100.00 |
Sex Ratio (male/female) per dam at LD 13 |
1.48 |
1.40 |
1.47 |
1.21 |
|
||||
Pre and Postnatal loss |
||||
Mean Pre-natal loss (implantations minus live births) (No.) |
3.70 |
4.17 |
4.66 |
3.58 |
Females with 0 (No.) |
7 |
6 |
6 |
6 |
Females with ≥ 1 (No.) |
5 |
6 |
5 |
5 |
Post-natal loss (live births minus alive at post natal day 13) |
||||
Females with 0 (No.) |
11 |
10 |
9 |
9 |
Females with ≥ 1 (No.) |
1 |
3 |
2 |
2 |
|
||||
Litter Observations |
||||
Male Pup weight at birth (mean) in gram |
5.84 |
6.07 |
5.84 |
6.07 |
Female Pup weight at birth (mean) in gram |
5.54 |
5.69 |
5.45 |
5.74 |
Male Pup weight on LD4 (mean) in gram |
9.54 |
9.84 |
9.56 |
9.74 |
Female Pup weight on LD4 (mean) in gram |
9.10 |
9.25 |
9.03 |
9.61 |
Male Pup weight on LD7 (mean) in gram |
15.10 |
15.25 |
15.06 |
14.97 |
Female Pup weight on LD7 (mean) in gram |
14.83 |
14.86 |
14.82 |
14.91 |
Male Pup weight on LD13 (mean) in gram |
24.85 |
25.43 |
25.23 |
25.07 |
Female Pup weight on LD13 (mean) in gram |
24.80 |
25.23 |
25.19 |
24.84 |
TABLE 1. SUMMARYOF CLINICAL SIGNSOF TOXICITY, DETAILED CLINICAL EXAMINATIONAND MORTALITY RECORD
Refer Appendix 1
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 & F 0 |
12 |
N |
0/12 |
G2, M &F250 |
12 |
N |
0/12 |
G3, M &F500 |
12 |
N |
0/12 |
G4, M &F1000 |
12 |
N |
0/12 |
M: Male; N: Normal
Applicant's summary and conclusion
- Conclusions:
- The reproductive and developmental No-Observed-Adverse-Effect-Level (NOAEL) for the test item was considered to be 1000 mg/kg/day when administered to male SD rats for two weeks pre-mating, during mating and up to the day before sacrifice during post-mating period (total of 37 days), and to female SD rats for two weeks pre-mating, during mating, gestation and up to lactation day 13, under the experimental conditions described.
- Executive summary:
A reproductive and developmental toxicity study of test item was performed on male and female Sprague Dawley rats according to OECDTG 421“Reproduction/Developmental Toxicity Screening Test”.A total of 96 (48 males + 48 females) Sprague Dawley rats were distributed to fourdosegroups, each consisted of 12 males and 12 females.Groups of 12 rats/sex/dose were orally dosed with 0 (vehicle control), 250, 500 and 1000 mg/kg body weight/day. The vehicle and test compound 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 37 days of treatment). The females were treated for two weeks pre-mating period, during mating, pregnancyand up to lactation day 13 after which the pups were sacrificed on lactation day 13 and females were sacrificed on lactation day 14 after overnight fasting.All animals were observed for clinical signs, body weight changes and feed consumption. Blood serum was collected from adult males and one pup per litter on lactation day 13 to determine the T4 hormone level. 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 the mating and fertility indexes were calculated for all adult animals. Gross pathology and organ weighing were performed on day 38 for males and on lactation day 14 for dams. Gross pathology was performed on lactation day 4/13 for pups. The number of corpora lutea and implantation sites for dams were recorded during necropsy. Each litter was examined after delivery (lactation day 1) and the number and sex of pups (litter size), stillbirths and live births were recorded. The pups were observed for clinical signs and external examinations once daily from lactation day 1 to 13.All the tested dose group animals of either sex did not reveal any clinical signs of toxicity and no mortality/morbidity observed. There were no changes observed in mean body weight, percent change in body weight with respect to day 1 and feed consumption at all the tested dose group animals of either sex during the experimental period.No alteration in absolute and relative weight of testes and epididymites were seen, although the weight of prostate and seminal vesicles with coagulating glands (PSC) were significantly reduced at 500 and 1000 mg/kg. No data on ovary and uterus weight was provided in the study.There were no treatment related changes observed in serum T4 levels of adult males and in serum T4 levels of lactation day 13 pups at any of the tested dose groups.Dams did not reveal any treatment related changes in oestrus cyclicity, copulatory interval, gestation length, live birth index, number of pups, sex ratio and pup survival index at all tested dose groups throughout the lactation period. Pups did not reveal any clinical signs or external anomalies throughout the lactation period. No treatment related changes were noted in pup weights and ano-genital distances ratio. The retention of nipples in male pups was unaffected as compared to control. No gross external and internal pathological changes were observed in any tested dose groups both in adults and pups.A detailed qualitative examination of the testes was made, taking into account the tubular stages of the spermatogenic cycle. The examination was conducted in order to identify treatment related effects such as missing germ cell layers or types, retained spermatids, multinucleate or apoptotic germ cells and sloughing of spermatogenic cells into the lumen or any cell or stage specificity of testicular findings. There was no treatment related histopathological findings noticed during the microscopic examination of testes, epididymites and ovaries.In conclusion, the repeated administrationof the test chemical exerted no adverse effects on male and female reproductive functions. In males, the test compound significantly reduced the weight of accessory sex glands (PSC) at middle and high doses, which could affect fertility, but the unchanged mating, fertility and gestation indexes showed no functional impairment. Similarly, the test substancewas not developmentally toxic or teratogenic as measured endpoints of embryo/fetal viability, growth, or development was unaltered at all doses tested.Hence, the reproductive and developmental NOAEL were considered as 1000 mg/kg body weight/day when male and female SD rats were orally treated during the period of pre-mating, mating, gestation and early lactation.
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