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EC number: 218-915-0 | CAS number: 2280-49-1
- 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
Endpoint summary
Administrative data
Key value for chemical safety assessment
Effects on fertility
Description of key information
There is no indication of toxicity to fertility based on the available data. The NOEL for systemic effects was 500 mg/kg B.W., the highest dose tested, for both sexes in a sub-actute toxicity study. Local irritation of gastric mucosa was observed in the sub-acute toxicity study at 150 mg/kg B.W. leading to a local NOAEL (no-observed-adverse-effect-level) of 50 mg/kg B.W. for male and female rats for N-Phenyl-N-[(trichloromethyl)thio]benzenesulphonamide after 4-week daily oral treatment by gavage. There is no indication of adverse effects on the reproductive organs in this study. In the developmental toxicity study reported below, there is no indication of maternal or developmental toxicity up to the high dose tested. Overall, there is no trigger to perform a generation study at this tonnage band. No Screening test has to be conducted because a developmental toxicity study according to OECD TG 414 is available.
Effect on fertility: via oral route
- Endpoint conclusion:
- no study available
- Quality of whole database:
- There is no indication of toxicity to fertility based on the available data. The NOEL for systemic effects was 500 mg/kg B.W., the highest dose tested, for both sexes in a sub-actute toxicity study. Local irritation of gastric mucosa was observed in the sub-acute toxicity study at 150 mg/kg B.W. leading to a local NOAEL (no-observed-adverse-effect-level) of 50 mg/kg B.W. for male and female rats for N-Phenyl-N-[(trichloromethyl)thio]benzenesulphonamide after 4-week daily oral treatment by gavage. There is no indication of adverse effects on the reproductive organs in this study. In the developmental toxicity study reported below, there is no indication of maternal or developmental toxicity up to the highs dose tested. Overall, there is no indication of adverse effects on fertility based on all available data.
Effect on fertility: via inhalation route
- Endpoint conclusion:
- no study available
Effect on fertility: via dermal route
- Endpoint conclusion:
- no study available
Effects on developmental toxicity
Description of key information
An OECD TG 414 study was performed to investigate the effects of the test item on embryonic and fetal development following repeated administration by gavage to the pregnant female during gestation including the period of organogenesis. Based on the results of the study, a dosage of 1000 mg/kg bw/day, the highest dosage tested, was considered to be the No Observed Adverse Effect Level (NOAEL) for the pregnant female and the No Observed Effect Level (NOEL) for the developing conceptus.
Link to relevant study records
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- Experimental Starting Date: 15 March 2017 Experimental Completion Date: 10 July 2017
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
- Specific details on test material used for the study:
- Identification: N-Phenyl-N-[(trichloromethyl)thio]benzenesulphonamide
Physical State/Appearance: White solid
Date Received: 04 May 2016
Storage Conditions: Room temperature in the dark (used/formulated in light)
Expiry Date: 18 July 2017 - Species:
- rat
- Strain:
- Sprague-Dawley
- Details on test animals or test system and environmental conditions:
- A total of ninety-six time-mated female Sprague-Dawley Crl:CD (SD) IGS BR strain rats were obtained from Charles River (UK) Limited, Margate, Kent. Animals were delivered in two batches containing females prior to Day 3 of gestation. The day that positive evidence of mating was observed was designated Day 0 of gestation. At the start of treatment (Day 5) the females weighed 197 to 319g.
Animal Care and Husbandry
The animals were housed individually in solid-floor polypropylene cages with stainless steel mesh lids furnished with softwood flakes (Datesand Ltd., Cheshire, UK). The animals were allowed free access to food and water. A pelleted diet (Rodent 2018C Teklad Global Certified Diet, Envigo RMS (UK) Limited, Oxon, UK) was used. Mains drinking water was supplied from polycarbonate bottles attached to the cage. Environmental enrichment was provided in the form of wooden chew blocks and cardboard fun tunnels (Datesand Ltd., Cheshire, UK). The diet, drinking water, bedding and environmental enrichment was considered not to contain any contaminant at a level that might have affected the purpose or integrity of the study.
The animals were housed in a single air-conditioned room within the Envigo Research Limited, Shardlow, UK Barrier Maintained Rodent Facility. The rate of air exchange was at least fifteen air changes per hour and the low intensity fluorescent lighting was controlled to give twelve hours continuous light and twelve hours darkness. Environmental conditions were continuously monitored by a computerized system, and print-outs of hourly mean temperatures and humidity are included in the study records. The Study Plan target ranges for temperature and relative humidity were 22 ± 3 ºC and 50 ± 20% respectively; there were no deviations from these targets.
The animals were randomly allocated to treatment groups using a randomization procedure based on stratified body weight to ensure similarity between the treatment groups. The animals were uniquely identified within the study by an ear punching system routinely used in these laboratories. - Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
For the purpose of the study the test item was prepared at the appropriate concentrations as a solution/suspension in Corn Oil. The stability and homogeneity of the test item formulations were determined by Envigo Research Limited, Shardlow, UK Analytical Services as part of Envigo Study Number YJ86PP. These investigations showed that test item formulations were stable for at least twenty one days when stored refrigerated (approximately 4 °C in the dark). Bulk formulations were therefore prepared for the study, divided into daily aliquots and stored at approximately +4 °C in the dark. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Samples were taken of each test item formulation and were analyzed for concentration of N Phenyl N [(trichloromethyl)thio]benzenesulphonamide at Envigo Analytical Laboratory, Shardlow. The results indicate that the prepared formulations were within 103-108% of the nominal concentration, confirming accurate formulation.
The test item concetration in the test samples was determined by high performance liquid chromatography with UV detection (HPLC/UV) using an external standard technique. The test item gave a chromatographic profile consisting of a single peak.
The analytical procedure was previously successfully validated with respect to specificity of chromatographic analysis, linearity of detector response, method accuracy and precision during studies YJ86PP and HL74FW. The homogeneity and stability of the test item in corn oil was also confirmed in study YJ86PP. - Details on mating procedure:
- Time-mated female Sprague-Dawley Crl:CD (SD) IGS BR strain rats were obtained from Charles River (UK) Limited, Margate, Kent. Animals were delivered in two batches containing females prior to Day 3 of gestation. The day that positive evidence of mating was observed was designated Day 0 of gestation.
- Duration of treatment / exposure:
- The test item was administered from Day 5 to Day 19 of gestation, by gavage. Control animals were treated in an identical manner with the vehicle alone.
- Frequency of treatment:
- Daily
- Duration of test:
- 15 days from day 1 of treatment to day 19.
- Dose / conc.:
- 250 mg/kg bw/day (nominal)
- Remarks:
- Low
- Dose / conc.:
- 500 mg/kg bw/day (nominal)
- Remarks:
- Intermediate
- Dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- Remarks:
- High
- No. of animals per sex per dose:
- 24 time mated females per dose
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- Dose selection rationale:
The dose levels were chosen based on previous toxicity data, including the N-Phenyl-N-[(trichloromethyl)thio]benzene -sulphonamide: Preliminary Oral (Gavage) Pre-Natal Development Toxicity Study in the Rat (Envigo Study number YJ86PP). The oral route was selected as the most appropriate route of exposure, based on the physical properties of the test item, and the results of the study are believed to be of value in predicting the likely toxicity of the test item to man. - Maternal examinations:
- Clinical Observations
Following arrival, all animals were examined for overt signs of toxicity, ill-health or behavioral changes once daily during the gestation period. Additionally, during the dosing period, observations were recorded immediately before and soon after dosing and one hour post dosing. All observations were recorded.
Body Weight
Individual body weights were recorded on Day 3 (before the start of treatment) and on Days 5, 6, 7, 8, 11, 14 and 17 of gestation. Body weights were also recorded for animals at terminal kill (Day 20).
Food Consumption
Food consumption was recorded for each individual animal at Day 3, 5, 8, 11, 14, 17 and 20 of gestation.
Water Consumption
Water intake was observed daily by visual inspection of the water bottles for any overt changes.
Terminal Investigation
Necropsy
All animals were killed by carbon dioxide asphyxiation followed by cervical dislocation on Day 20 of gestation. All animals were subjected to a full external and internal examination and any macroscopic abnormalities were recorded - Ovaries and uterine content:
- The ovaries and uteri of pregnant females were removed, examined and the following data recorded:
i) Number of corpora lutea
ii) Number, position and type of intrauterine implantation
iii) Fetal sex
iv) External fetal appearance
v) Fetal weight
vi) Placental weight
vii) Gravid uterus weight
The uteri of any apparently non-pregnant females were immersed in 0.5% ammonium polysulphide solution to reveal evidence of implantation.
Implantation types were divided into:
Early Death: No visible distinction between placental/decidual tissue and embryonic tissue
Late Death: Separate embryonic/fetal and placental tissue visible
Dead Fetus: A fetus that had died shortly before necropsy. These were included in the calculation of late deaths for reporting purposes
All implantations and viable fetuses were numbered according to their intrauterine position as follows (as an example):
Left Horn Cervix Right Horn
L1 L2 L3 L4 L5 L6 L7 L8 R1 R2 R3 R4 R5 R6 R7 R8
V1 V2 V3 V4 V5 V6 V7 V8 V9 V10 V11 V12 V13 V14 V15 V16
V = viable fetus - Fetal examinations:
- The fetuses were killed by subcutaneous injection of sodium pentobarbitone. Fetuses from each litter were divided into two groups and examined for skeletal alterations and soft tissue alterations. Alternate fetuses were identified using an indelible marker and placed in Bouin’s fixative. Fetuses were subsequently transferred to distilled water and examined for visceral anomalies under a low power binocular microscope and then stored in 10% Buffered Formalin. The remaining fetuses were identified using cardboard tags marked with chinagraph pencil and placed into 70% IMS in distilled water. The fetuses were subsequently eviscerated, processed and the skeletons stained with alizarin red S before being transferred to 50% glycerol for examination of skeletal development and anomalies and storage.
- Statistics:
- The following parameters were analyzed statistically, where appropriate, using the test methods outlined below:
Body weight and body weight change (including adjustment for the contribution of the gravid uterus), food consumption, gravid uterus weight, litter data and fetal, litter and placental weights and external, visceral and skeletal observations.
Data were first analysed using Shapiro Wilk normality test and Bartlett’s test for homogeneity of variance. Where there was no significance, parametric methodology was applied using one way analysis of variance and, if significant, Dunnett’s multiple comparison test. Where statistical significance was observed, non parametric methodology was applied using Kruskal-Wallis nonparametric analysis of variance; and, if significant, pairwise analysis of control values against treated values using the Mann-Whitney ‘U’ test. Due to the non-normal distribution of the data, external, visceral and skeletal observations were generally analyzed using non-parametric methodology.
Probability values (p) are presented as follows:
p<0.001 ***
p<0.01 **
p<0.05 *
p≥0.05 (not significant) - Indices:
- Pre and Post Implantation Loss
Percentage pre-implantation loss was calculated as:
(number of corporalutea - number of implantations / number of corporalutea) x 100
Percentage post-implantation loss was calculated as:
(number of implantations - number of live fetuses / number of implantations) x 100
Sex Ratio
Sex ratio was calculated as:
% male fetuses (sex ratio) = (number of male fetuses / total number of fetuses) x 100 - Clinical signs:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Neither the type, incidence nor distribution of clinical signs observed during the study indicated any systemic effect of treatment at 250, 500 or 1000 mg/kg bw/day.
At 1000 mg/kg bw/day, occasional incidences of transient increased post-dosing salivation were apparent for the majority of females; this clinical sign was first apparent from Day 13 of gestation. Increased post-dosing salivation is frequently observed when animals are dosed via the oral gavage route and, at the incidence observed, was considered to reflect distaste or slight irritancy of the test item formulations rather than any systemic effect of treatment. - Dermal irritation (if dermal study):
- not examined
- Mortality:
- no mortality observed
- Description (incidence):
- There were no unscheduled deaths during the study.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- At 1000 mg/kg bw/day, mean cumulative body weight gain was statistically significantly lower than control from Day 17 of gestation, although there were no statistically significant differences in mean body weight gains apparent for any particular phase of gestation. This lower cumulative body weight gain was supported by lower mean overall body weight gain when adjusted for the weight of the gravid uterus, compared to control, indicating that the observed differences in cumulative body weight gains were not attributable to differences in litter size/weight. Despite the lower cumulative body weight gain, there were no statistically significant differences from control apparent for mean body weight throughout the study.
There was no effect of treatment on body weight or body weight gain during gestation, including when adjustment of final body weight and overall body weight gain was made for the contribution of the gravid uterus, at 250 or 500 mg/kg bw/day. - Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- At 1000 mg/kg bw/day, mean food consumption was statistically significantly lower than control between Days 5 to 8 of gestation. Food consumption was also slightly lower than control from Day 11 of gestation, although differences from control did not attain statistical significance.
There was no effect of treatment on food consumption during gestation at 250 or 500 mg/kg bw/day. - Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- no effects observed
- Description (incidence and severity):
- Daily visual inspection of water bottles did not reveal any overt intergroup differences.
- Ophthalmological findings:
- not specified
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not specified
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- Neither the type, incidence nor distribution of macroscopic necropsy findings for adult animals at Day 20 of gestation indicated any effect of treatment at 250, 500 or 1000 mg/kg bw/day.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- not examined
- Number of abortions:
- not examined
- Pre- and post-implantation loss:
- effects observed, non-treatment-related
- Description (incidence and severity):
- See Table 8 in section 'Any other information on results' for Pre and Post implantantion loss %.
- Total litter losses by resorption:
- effects observed, non-treatment-related
- Description (incidence and severity):
- See Table 8 in section 'Any other information on results' for number of embryonic/fetal deaths.
- Early or late resorptions:
- effects observed, non-treatment-related
- Description (incidence and severity):
- See Table 8 in section 'Any other information on results' for early and late numbers of embryonic/ fetal deaths
- Dead fetuses:
- effects observed, non-treatment-related
- Description (incidence and severity):
- See Table 8 in section 'Any other information on results' for number of late embryonic/ fetal deaths
- Changes in pregnancy duration:
- not examined
- Description (incidence and severity):
- Not applicable as animals killed on day 20 of gestation
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not examined
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.DescriptionIncidenceAndSeverityEffectsOnPregnancyDuration): Not applicable, animals killed on day 20 of gestation - Changes in number of pregnant:
- effects observed, non-treatment-related
- Description (incidence and severity):
- See Table 1 in section 'Any other information on results' for number of pregnant females.
- Other effects:
- no effects observed
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Basis for effect level:
- other: No adverse effect observed ate the highest dose tested.
- Abnormalities:
- no effects observed
- Fetal body weight changes:
- no effects observed
- Description (incidence and severity):
- There were no effects of maternal treatment on mean fetal, litter or placental weights at 250, 500 or 1000 mg/kg bw/day.
At 500 mg/kg bw/day, mean placental weight was statistically significantly higher than control but, in the absence of any statistically significant difference at 1000 mg/kg bw/day, this finding was considered to reflect normal biological variation and was unrelated to maternal treatment.
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.DescriptionIncidenceAndSeverityFetalPupBodyWeightChanges): See Table 8 in section 'Any other information on results' for mean fetal weights. - Reduction in number of live offspring:
- effects observed, non-treatment-related
- Description (incidence and severity):
- See Table 8 in section 'Any other information on results' for number of live implants
- Changes in sex ratio:
- effects observed, non-treatment-related
- Description (incidence and severity):
- There was no effect of maternal treatment on litter data as assessed by numbers of implantations, in-utero offspring survival (as assessed by the mean numbers of early or late resorptions), live litter size and sex ratio at 250, 500 or 1000 mg/kg bw/day.
At 500 mg/kg bw/day, sex ratio (percentage male) was statistically significantly higher than control but, in the absence of any statistically significant difference at 1000 mg/kg bw/day, this finding was considered to reflect normal biological variation and was unrelated to maternal treatment. - Changes in litter size and weights:
- no effects observed
- Description (incidence and severity):
- See Table 8 in section 'Any other information on results' for mean litter data values.
- Changes in postnatal survival:
- not examined
- Description (incidence and severity):
- Not applicable as animals killed on day 20 of gestation.
- External malformations:
- no effects observed
- Description (incidence and severity):
- Neither the type, incidence nor distribution of findings apparent during external examination of fetuses on Day 20 of gestation indicated any obvious effect of maternal treatment on fetal development at 250, 500 or 1000 mg/kg bw/day.
- Skeletal malformations:
- no effects observed
- Description (incidence and severity):
- Neither the type, incidence nor distribution of findings apparent during detailed skeletal examination of fetuses on Day 20 of gestation indicated any obvious effect of maternal treatment on fetal development at 250, 500 or 1000 mg/kg bw/day.
- Visceral malformations:
- no effects observed
- Description (incidence and severity):
- Neither the type, incidence nor distribution of findings apparent during detailed visceral examination of fetuses on Day 20 of gestation indicated any obvious effect of maternal treatment on fetal development at 250, 500 or 1000 mg/kg bw/day.
- Other effects:
- not examined
- Dose descriptor:
- NOEL
- Effect level:
- 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: no effect observed at the highest dose tested
- Abnormalities:
- no effects observed
- Developmental effects observed:
- no
- Conclusions:
- Based on the results of the study, a dosage of 1000 mg/kg bw/day, the highest dosage tested, was considered to be the No Observed Adverse Effect Level (NOAEL) for the pregnant female and the No Observed Effect Level (NOEL) for the developing conceptus.
- Executive summary:
Introduction
The study was performed to investigate the effects of the test item on embryonic and fetal development following repeated administration by gavage to the pregnant female during gestation including the period of organogenesis.
The study was designed to comply with the following guidelines:
· US EPA Health Effects Test Guideline OPPTS 870.3700, ‘Prenatal Developmental Toxicity Study’ (August 1998)
· Japanese Ministry of Agriculture, Forestry and Fisheries Testing guidelines for Toxicology studies, 12 NohSan No 8147, (24 November 2000)
· OECD Guidelines for Testing of Chemicals, No 414, ‘Prenatal Developmental Toxicity Study’ (adopted 22 January 2001)
· Commission Regulation (EC) No 440/2008 of 30 May 2008 test methods pursuant to Regulations (EC) No 1907/2006 of the European Parliament and of the Council on the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH)
Methods
The test item was administered by gavage to three groups each of twenty-four time mated Sprague-Dawley Crl:CD®(SD) IGS BR strain rats, between Days 5 and 19 of gestation inclusive at dose levels of 250, 500 and 1000 mg/kg bw/day. A further group of twenty-four time mated females was exposed to the vehicle only (Corn oil) to serve as a control.
Clinical signs, body weight change, food and water consumptions were monitored during the study.
All females were terminated on Day 20 of gestation and subjected to gross necropsy including examination of the uterine contents. The number of corpora lutea, number, position and type of implantation, placental weights, fetal weight, sex and external and internal macroscopic appearance were recorded. Half of each litter were examined for detailed skeletal development and the remaining half were subjected to detailed visceral examination.
Results
Adult Responses
Mortality
There were no unscheduled deaths during the study.
Clinical Observations
Clinical signs were generally restricted to occasional incidences of transient increased post-dosing salivation for the majority of females at 1000 mg/kg bw/day and did not indicate any systemic effect of treatment.
Body Weight
At 1000 mg/kg bw/day, mean cumulative body weight gain was statistically significantly lower than control from Day 17 of gestation and overall body weight gain remained statistically significantly lower than control, when adjusted for the contribution of the gravid uterus.
There was no effect of treatment on body weight or body weight gain during gestation, including when adjustment of final body weight and overall body weight gain was made for the contribution of the gravid uterus, at 250 or 500 mg/kg bw/day.
Food Consumption
At 1000 mg/kg bw/day, mean food consumption was statistically significantly lower than control between Days 5 to 8 of gestation.
There was no effect of treatment on food consumption during gestation at 250 or 500 mg/kg bw/day.
Post Mortem Studies
Macroscopic necropsy findings for adult animals at Day 20 of gestation did not indicate any effect of treatment at 250, 500 or 1000 mg/kg bw/day.
Litter Responses
Litter Data
There was no effect of maternal treatment on litter data as assessed by numbers of implantations, in-utero offspring survival (as assessed by the mean numbers of early or late resorptions), live litter size and sex ratio at 250, 500 or 1000 mg/kg bw/day.
Litter, Placental and Fetal Weights
There were no effects of maternal treatment on mean fetal, litter or placental weights at 250, 500 or 1000 mg/kg bw/day.
Fetal Evaluation
External Examinations
External examination of fetuses at Day 20 of gestation did not indicate any effect of maternal treatment at 250, 500 or 1000 mg/kg bw/day.
Detailed Visceral Examinations
Detailed visceral examinations of fetuses at Day 20 of gestation did not indicate any effect of maternal treatment at 250, 500 or 1000 mg/kg bw/day.
Detailed Skeletal Examinations
Detailed skeletal examinations of fetuses at Day 20 of gestation did not indicate any effect of maternal treatment at 250, 500 or 1000 mg/kg bw/day.
Conclusion
Based on the results of the study, a dosage of 1000 mg/kg bw/day, the highest dosage tested, was considered to be the No Observed Adverse Effect Level (NOAEL) for the pregnant female and the No Observed Effect Level (NOEL) for the developing conceptus.
Reference
Table1 Summary of Female Performance
Category |
Number of Females at Dose Level (mg/kg bw/day) |
|||
0 (Control) |
250 |
500 |
1000 |
|
Initial Group Size |
24 |
24 |
24 |
24 |
Non-pregnant |
2 |
0 |
0 |
1 |
Pregnant |
22 |
24 |
24 |
23 |
With live young on Day 20 of gestation |
22 |
24 |
24 |
23 |
Table2 Summary Incidence of Daily Clinical Observations
|
Dose Level (mg/kg bw/day) |
|||
0 (Control) |
250 |
500 |
1000 |
|
Number of animals |
24 |
24 |
24 |
24 |
|
|
|
|
|
Increased post-dosing salivation |
0 |
0 |
0 |
19 |
|
|
|
|
|
Mass on right side of thoracic region |
0 |
1 |
0 |
0 |
|
|
|
|
|
Scab on dorsal region |
0 |
0 |
1 |
0 |
|
|
|
|
|
No abnormalities detected |
24 |
23 |
23 |
5 |
Table 3 Group Mean Body Weight Values
Dose Level (mg/kg bw/day) |
|
Body Weight (g) on Day of Gestation |
||||||||
3 |
5 |
6 |
7 |
8 |
11 |
14 |
17 |
20 |
||
0 (Control) |
mean |
249.3 |
263.1 |
265.3 |
271.8 |
275.5 |
299.8 |
316.5 |
345.0 |
390.4 |
sd |
27.6 |
28.0 |
28.5 |
28.0 |
28.6 |
30.7 |
32.0 |
33.8 |
39.1 |
|
n |
22 |
22 |
22 |
22 |
22 |
22 |
22 |
22 |
22 |
|
250 |
mean |
251.5 |
266.0 |
269.0 |
274.4 |
279.5 |
303.6 |
319.8 |
350.0 |
393.0 |
sd |
23.6 |
23.9 |
23.2 |
24.2 |
24.2 |
26.3 |
25.7 |
29.8 |
32.0 |
|
n |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
|
500 |
mean |
250.5 |
264.8 |
268.3 |
273.7 |
278.8 |
301.0 |
317.1 |
343.0 |
385.4 |
sd |
20.9 |
21.3 |
21.4 |
21.7 |
22.0 |
23.8 |
25.3 |
25.8 |
31.0 |
|
n |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
23 |
|
1000 |
mean |
251.3 |
266.3 |
269.0 |
273.7 |
278.5 |
300.8 |
309.6 |
334.6 |
378.5 |
sd |
22.1 |
22.9 |
21.9 |
22.1 |
22.3 |
22.6 |
23.6 |
21.2 |
28.8 |
|
n |
23 |
23 |
23 |
23 |
23 |
23 |
23 |
23 |
23 |
Table 4 Group Mean Body Weight Change Values
Dose Level (mg/kg bw/day) |
|
Body Weight Change (g) during Days of Gestation |
||||||||
3 to 5 |
5 to 6 | 6 to 7 |
7 to 8 | 8 to 11 |
11 to 14 | 14 to 17 |
17 to 20 | |||
0 (Control) |
mean |
13.8 |
2.2 |
6.5 |
3.7 |
24.3 |
16.8 |
28.4 |
45.5 |
|
sd |
4.3 |
2.7 |
3.5 |
4.5 |
5.2 |
4.9 |
3.4 |
6.9 |
||
n |
22 |
22 |
22 |
22 |
22 |
22 |
22 |
22 |
||
250 |
mean |
14.5 |
3.0 |
5.4 |
5.1 |
24.1 |
16.1 |
30.3 |
43.0 |
|
sd |
4.0 |
2.7 |
2.7 |
3.2 |
3.8 |
5.8 |
7.4 |
10.2 |
||
n |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
||
500 |
mean |
14.3 |
3.5 |
5.4 |
5.1 |
22.3 |
16.1 |
25.8 |
40.7 |
|
sd |
4.1 |
2.5 |
4.0 |
2.8 |
4.7 |
7.9 |
8.7 |
11.4 |
||
n |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
23 |
||
1000 |
mean |
15.0 |
2.7 |
4.7 |
4.9 |
22.3 |
8.8 |
25.0 |
43.9 |
|
sd |
3.7 |
4.3 |
3.5 |
3.4 |
4.4 |
15.1 |
11.8 |
13.0 |
||
n |
23 |
23 |
23 |
23 |
23 |
23 |
23 |
23 |
Dose Level (mg/kg bw/day) |
|
Cumulative Body Weight Change (g) from Day 5 of Gestation |
|||||||
5 |
6 |
7 |
8 |
11 |
14 |
17 |
20 |
||
0 (Control) |
mean |
13.8 |
2.2 |
8.7 |
12.4 |
36.7 |
53.5 |
81.9 |
127.3 |
sd |
4.3 |
2.7 |
3.0 |
5.3 |
6.1 |
9.2 |
10.3 |
14.9 |
|
n |
22 |
22 |
22 |
22 |
22 |
22 |
22 |
22 |
|
250 |
mean |
14.5 |
3.0 |
8.4 |
13.5 |
37.6 |
53.7 |
84.0 |
127.0 |
sd |
4.0 |
2.7 |
2.9 |
2.9 |
4.9 |
7.1 |
11.0 |
13.6 |
|
n |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
|
500 |
mean |
14.3 |
3.5 |
8.9 |
14.0 |
36.3 |
52.4 |
78.2 |
120.1 |
sd |
4.1 |
2.5 |
4.2 |
4.3 |
7.6 |
11.5 |
15.6 |
21.0 |
|
n |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
23 |
|
1000 |
mean |
15.0 |
2.7 |
7.3 |
12.2 |
34.5 |
43.3 |
68.3** |
112.2** |
sd |
3.7 |
4.3 |
3.6 |
5.1 |
5.5 |
17.2 |
13.9 |
18.5 |
|
n |
23 |
23 |
23 |
23 |
23 |
23 |
23 |
23 |
Table 5 Group Mean Gravid Uterus Weight and Adjusted Body Weight and Body Weight Change Values
Dose Level (mg/kg bw/day) |
|
Body Weight (g) on Days of Gestation |
Body Weight Change (g) during Days of Gestation |
Gravid Uterus Weight |
Adjusted |
Adjusted |
|
5 |
20 |
5-20 |
|||||
0 (Control) |
mean |
263.9 |
392.0 |
128.1 |
83.765 |
308.2 |
44.3 |
sd |
28.5 |
39.3 |
14.8 |
12.017 |
32.7 |
10.3 |
|
n |
21 |
21 |
21 |
21 |
21 |
21 |
|
250 |
mean |
265.0 |
391.6 |
126.7 |
84.550 |
307.1 |
42.1 |
sd |
23.8 |
31.9 |
13.8 |
15.509 |
27.3 |
12.4 |
|
n |
23 |
23 |
23 |
23 |
23 |
23 |
|
500 |
mean |
265.3 |
385.4 |
120.1 |
79.373 |
306.1 |
40.7 |
sd |
21.6 |
31.0 |
21.0 |
18.763 |
24.8 |
11.8 |
|
n |
23 |
23 |
23 |
23 |
23 |
23 |
|
1000 |
mean |
265.5 |
376.6 |
111.1** |
85.787 |
290.8 |
25.3*** |
sd |
23.2 |
28.1 |
18.2 |
11.368 |
24.5 |
17.0 |
|
n |
22 |
22 |
22 |
22 |
22 |
22 |
Table 6 Group Mean Food Consumption Values
Dose Level (mg/kg bw/day) |
|
Food Consumption (g/rat/day) between Days of Gestation |
|||||
3 - 5 |
5 - 8 |
8 - 11 |
11 - 14 |
14 - 17 |
17 - 20 |
||
0 (Control) |
mean |
23.5 |
21.1 |
22.4 |
23.4 |
25.7 |
26.0 |
sd |
3.1 |
2.1 |
2.6 |
2.6 |
2.9 |
3.2 |
|
n |
22 |
22 |
22 |
22 |
22 |
22 |
|
250 |
mean |
24.5 |
21.1 |
22.5 |
24.3 |
25.9 |
26.6 |
sd |
2.3 |
2.1 |
3.0 |
4.5 |
3.0 |
3.3 |
|
n |
24 |
24 |
24 |
24 |
24 |
24 |
|
500 |
mean |
24.5 |
20.3 |
22.7 |
22.8 |
23.6 |
27.5 |
sd |
2.3 |
1.7 |
2.3 |
3.4 |
4.4 |
4.6 |
|
n |
24 |
24 |
24 |
24 |
24 |
24 |
|
1000 |
mean |
23.3 |
19.5** |
23.1 |
21.1 |
23.6 |
24.5 |
sd |
6.0 |
1.7 |
2.2 |
5.0 |
3.3 |
3.8 |
|
n |
23 |
23 |
23 |
23 |
23 |
23 |
Table 7 Summary Incidence of Necropsy Findings
|
Dose Level (mg/kg bw/day) |
|||
0 (Control) |
250 |
500 |
1000 |
|
Number of animals examined |
24 |
24 |
24 |
24 |
|
|
|
|
|
Mammary tissue:Solid mass attached, located under right forelimb |
0 |
1 |
0 |
0 |
|
|
|
|
|
Stomach:Gaseous distension |
0 |
1 |
0 |
0 |
|
|
|
|
|
No abnormalities detected |
24 |
22 |
24 |
24 |
Table 8 Group Mean Litter DataValues
Dose Level (mg/kg bw/day) |
|
Number of Corpora Lutea |
Number of Implants |
Number of Embryonic/Fetal Deaths |
Implantation Loss |
Number of Live Implants |
% |
Mean Male Fetal Weight (g) |
Mean Female Fetal Weight (g) |
Mean Fetal Weight (g) |
MeanPlacentalWeight |
Litter Weight (g) |
TotalPlacentalWeight |
|||||
Early |
Late |
Total |
Pre |
Post |
Male |
Female |
Total |
|||||||||||
0 (Control) |
mean |
16.5 |
13.9 |
0.1 |
0.1 |
0.3 |
15.6 |
2.8 |
6.1 |
7.3 |
13.5 |
45.2 |
4.072 |
3.886 |
3.971 |
0.557 |
53.415 |
7.475 |
sd |
3.0 |
2.1 |
0.4 |
0.4 |
0.5 |
13.4 |
4.6 |
1.9 |
1.5 |
2.1 |
10.1 |
0.218 |
0.195 |
0.197 |
0.048 |
8.520 |
1.170 |
|
n |
22 |
22 |
22 |
22 |
22 |
21 |
22 |
22 |
22 |
22 |
22 |
22 |
22 |
22 |
22 |
22 |
22 |
|
250 |
mean |
16.4 |
14.0 |
0.1 |
0.1 |
0.2 |
14.2 |
3.1 |
6.6 |
6.9 |
13.5 |
49.0 |
4.141 |
3.890 |
4.015 |
0.566 |
54.040 |
7.620 |
sd |
2.7 |
2.7 |
0.3 |
0.4 |
0.5 |
14.9 |
6.2 |
2.4 |
2.3 |
2.8 |
13.5 |
0.405 |
0.349 |
0.357 |
0.062 |
10.806 |
1.676 |
|
n |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
|
500 |
mean |
16.1 |
12.8 |
0.1 |
0.1 |
0.2 |
20.0 |
1.8 |
7.0 |
5.6 |
12.6 |
55.4* |
4.250 |
3.980 |
4.123 |
0.610* |
51.786 |
7.499 |
sd |
3.0 |
3.3 |
0.3 |
0.3 |
0.4 |
20.1 |
4.1 |
2.4 |
2.5 |
3.3 |
14.3 |
0.311 |
0.340 |
0.320 |
0.087 |
13.580 |
1.817 |
|
n |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
24 |
|
1000 |
mean |
16.7 |
14.3 |
0.1 |
0.0 |
0.1 |
13.1 |
0.9 |
7.6 |
6.5 |
14.1 |
54.3 |
4.020 |
3.775 |
3.907 |
0.593 |
55.136 |
8.333 |
sd |
2.9 |
2.0 |
0.3 |
0.0 |
0.3 |
11.7 |
2.5 |
1.9 |
2.2 |
2.0 |
13.0 |
0.321 |
0.293 |
0.290 |
0.066 |
8.360 |
1.228 |
|
n |
23 |
23 |
23 |
23 |
23 |
23 |
23 |
23 |
23 |
23 |
23 |
23 |
23 |
23 |
23 |
23 |
23 |
Table 9 Summary Incidence of Fetal External Findings
External Findings |
Dose level (mg/kg bw/day) |
|||||||||||
0 (Control) |
250 |
500 |
1000 |
|||||||||
Number of fetuses (litters) examined |
||||||||||||
296 (22) |
325 (24) |
303 (24) |
325 (23) |
|||||||||
NF |
NL |
%† |
NF |
NL |
%† |
NF |
NL |
%† |
NF |
NL |
%† |
|
Total Number Affected |
3 |
3 |
1.2 |
1 |
1 |
0.3 |
10 |
6 |
6.4 |
6 |
4 |
1.9 |
Small |
2 | 2 |
0.8 | 1 |
1 | 0.3 |
4 | 2 |
1.3 | 6 |
4 | 1.9 |
Pale |
1 | 1 |
0.3 | 0 |
0 | 0.0 |
1 |
1 |
0.3 |
0 |
0 |
0.0 |
Swollen abdomen |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
1 |
1 |
0.3 |
0 |
0 |
0.0 |
Placenta small |
0 |
0 |
0.0 |
1 |
1 |
0.3 |
1 |
1 |
0.3 |
1 |
1 |
0.3 |
Placenta large |
1 |
1 |
0.4 |
0 |
0 |
0.0 |
4 |
2 |
4.5 |
0 |
0 |
0.0 |
Table 10 Summary Incidence of Fetal Visceral Findings
Visceral Findings |
Dose Level (mg/kg bw/day) |
|||||||||||
0 (Control) |
250 |
500 |
1000 |
|||||||||
Number of Fetuses (litters) Examined |
||||||||||||
155 (22) |
169 (24) |
159 (24) |
169 (23) |
|||||||||
NF |
NL |
%† |
NF |
NL |
%† |
NF |
NL |
%† |
NF |
NL |
%† |
|
HEAD |
|
|
|
|
|
|
|
|
|
|
|
|
Rugae - non-uniform patterning |
13 |
11 |
9.1 |
10 |
9 |
5.6 |
10 |
8 |
8.2 |
7 |
5 |
4.8 |
ABDOMEN |
|
|
|
|
|
|
|
|
|
|
|
|
Liver - additional lobe between right and left median |
0 |
0 |
0.0 |
1 |
1 |
0.5 |
1 |
1 |
0.6 |
1 |
1 |
0.5 |
Spleen - reduced in size |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
1 |
1 |
0.5 |
Umbilical artery - left-sided |
1 |
1 |
0.5 |
1 |
1 |
0.6 |
0 |
0 |
0.0 |
1 |
1 |
0.5 |
Urinary bladder - distended with fluid or gas |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
1 |
1 |
0.6 |
Testis - partially undescended |
0 |
0 |
0.0 |
1 |
1 |
1.0 |
1 |
1 |
0.7 |
1 |
1 |
0.9 |
Ureter - kinked |
15 |
10 |
9.8 |
6 |
6 |
3.2 |
8 |
7 |
6.1 |
10 |
8 |
5.7 |
Ureter - dilated - Slight/Severe |
11 |
7 |
6.5 |
4 |
4 |
2.2 |
6 |
6 |
3.3 |
7 |
6 |
4.1 |
Renal pelvic cavitation - increased - Slight/Severe |
6 |
4 |
4.1 |
0 |
0 |
0.0 |
5 |
4 |
4.5 |
1 |
1 |
0.6 |
Renal papilla - absent |
2 |
2 |
1.3 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
THORAX |
|
|
|
|
|
|
|
|
|
|
|
|
Thymus - lobe partially undescended |
2 |
2 |
1.3 |
6 |
6 |
3.4 |
5 |
5 |
4.2 |
3 |
3 |
1.6 |
Innominate artery - absent |
0 |
0 |
0.0 |
1 |
1 |
0.6 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
Atrium - enlarged |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
1 |
1 |
0.6 |
0 |
0 |
0.0 |
Total |
31 |
19 |
20.6 |
25 |
15 |
13.9 |
22 |
15 |
16.4 |
23 |
14 |
13.8 |
Table 11 Summary Incidence of Fetal Skeletal Findings
Skeletal Findings |
Dose Level (mg/kg bw/day) |
|||||||||||
0 (Control) |
250 |
500 |
1000 |
|||||||||
Number of Fetuses (litters) Examined |
||||||||||||
141 (22) |
156 (24) |
144 (24) |
156 (23) |
|||||||||
NF |
NL |
%† |
NF |
NL |
%† |
NF |
NL |
%† |
NF |
NL |
%† |
|
SKULL |
|
|
|
|
|
|
|
|
|
|
|
|
Fontanelle (anterior) - large |
1 |
1 |
0.8 |
0 |
0 |
0.0 |
2 |
2 |
1.4 |
3 |
3 |
2.0 |
Nasal - incomplete ossification |
8 |
6 |
6.4 |
14 |
9 |
8.0 |
3 |
2 |
1.9 |
6 |
5 |
3.9 |
Frontal - incomplete ossification |
0 |
0 |
0.0 |
2 |
2 |
1.1 |
2 |
2 |
1.3 |
1 |
1 |
0.6 |
Frontal - unossified area |
1 |
1 |
0.6 |
2 |
1 |
1.2 |
0 |
0 |
0.0 |
3 |
3 |
1.8 |
Frontal - sutural line |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
1 |
1 |
0.5 |
Parietal - incomplete ossification |
6 |
5 |
4.8 |
5 |
5 |
3.1 |
4 |
4 |
2.6 |
4 |
3 |
2.5 |
Parietal/Interparietal - sutural bone |
1 |
1 |
0.6 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
1 |
1 |
0.6 |
Interparietal - incomplete ossification |
15 |
8 |
11.8 |
14 |
10 |
8.3 |
6 |
3 |
4.2 |
12 |
10 |
7.9 |
Interparietal - unossified area(s) |
1 |
1 |
0.8 |
1 |
1 |
0.5 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
Occipital (Supra-occipital) - incomplete ossification |
3 |
3 |
2.7 |
9 |
9 |
5.2 |
2 |
2 |
1.4 |
8 |
6 |
5.1 |
Occipital (Supra-occipital) - unossified area(s) |
2 |
2 |
1.6 |
3 |
3 |
1.6 |
6 |
5 |
5.6 |
4 |
4 |
2.5 |
Squamosal - incomplete ossification |
9 |
6 |
6.0 |
8 |
7 |
4.6 |
6 |
6 |
3.9 |
7 |
6 |
4.3 |
Squamosal - unossified area(s) |
1 |
1 |
0.6 |
5 |
3 |
2.7 |
5 |
4 |
2.9 |
0 |
0 |
0.0 |
Jugal - incomplete ossification |
4 |
3 |
3.3 |
3 |
3 |
1.7 |
2 |
2 |
1.4 |
1 |
1 |
0.6 |
Zygomatic process of maxilla - incomplete ossification |
7 |
5 |
4.8 |
5 |
5 |
3.2 |
3 |
3 |
2.0 |
3 |
3 |
1.8 |
Zygomatic process of squamosal - incomplete ossification |
1 |
1 |
0.9 |
1 |
1 |
0.6 |
1 |
1 |
0.7 |
1 |
1 |
0.6 |
Premaxilla - incomplete ossification |
1 |
1 |
0.9 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
1 |
1 |
0.6 |
Table11(continued) Summary Incidence of Fetal Skeletal Findings
Skeletal Findings |
Dose Level (mg/kg bw/day) |
|||||||||||
0 (Control) |
250 |
500 |
1000 |
|||||||||
Number of Fetuses (litters) Examined |
||||||||||||
141 (22) |
156 (24) |
144 (24) |
156 (23) |
|||||||||
NF |
NL |
%† |
NF |
NL |
%† |
NF |
NL |
%† |
NF |
NL |
%† |
|
SKULL |
|
|
|
|
|
|
|
|
|
|
|
|
Hyoid - incomplete ossification |
8 |
5 |
6.0 |
8 |
6 |
4.6 |
6 |
5 |
4.0 |
4 |
4 |
2.5 |
Hyoid - not ossified |
4 |
4 |
2.4 |
6 |
4 |
3.3 |
4 |
4 |
2.7 |
10 |
4 |
6.3 |
Presphenoid - incomplete ossification |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
1 |
1 |
0.7 |
0 |
0 |
0.0 |
Presphenoid - not ossified |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
1 |
1 |
0.6 |
Basisphenoid - incomplete ossification |
1 |
1 |
0.9 |
2 |
2 |
1.6 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
VERTEBRAL COLUMN |
|
|
|
|
|
|
|
|
|
|
|
|
Odontoid - ossification present |
0 |
0 |
0.0 |
1 |
1 |
0.6 |
2 |
1 |
1.4 |
0 |
0 |
0.0 |
Ventral arch of vertebra 1 - ossification present |
52 |
19 |
36.1 |
59 |
19 |
36.0 |
64 |
19 |
47.5 |
64 |
21 |
40.8 |
Cervical (neural) arch - incomplete ossification |
1 |
1 |
0.9 |
2 |
2 |
1.1 |
6 |
6 |
3.8 |
9 |
5 |
5.7 |
Thoracic centrum - incomplete ossification |
1 |
1 |
0.8 |
8 |
5 |
4.5 |
11 |
6 |
8.3 |
4 |
3 |
2.6 |
Thoracic centrum - not ossified |
0 |
0 |
0.0 |
2 |
1 |
1.0 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
Thoracic centrum - bipartite ossification |
2 |
2 |
1.5 |
2 |
2 |
1.2 |
5 |
4 |
3.3 |
2 |
2 |
1.3 |
Thoracic centrum - dumb-bell-shaped |
11 |
8 |
7.2 |
12 |
10 |
7.0 |
21 |
11 |
14.7 |
7 |
5 |
4.4 |
Thoracic centrum - asymmetrically ossified |
1 |
1 |
0.6 |
2 |
2 |
1.3 |
4 |
3 |
2.6 |
1 |
1 |
0.7 |
Lumbar centrum - dumb-bell-shaped |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
1 |
1 |
0.7 |
0 |
0 |
0.0 |
Lumbar centrum - asymmetrically ossified |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
1 |
1 |
0.7 |
0 |
0 |
0.0 |
Sacral (neural) arch - incomplete ossification |
4 |
4 |
3.0 |
8 |
5 |
4.8 |
7 |
5 |
4.6 |
13 |
7 |
8.6 |
Sacral (neural) arch - not ossified |
0 |
0 |
0.0 |
1 |
1 |
0.5 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
Caudal vertebrae - less than 4 ossified |
12 |
5 |
8.5 |
18 |
8 |
10.1 |
14 |
8 |
8.7 |
14 |
7 |
9.2 |
Table11(continued) Summary Incidence of Fetal Skeletal Findings
Skeletal Findings |
Dose Level (mg/kg bw/day) |
|||||||||||
0 (Control) |
250 |
500 |
1000 |
|||||||||
Number of Fetuses (litters) Examined |
||||||||||||
141 (22) |
156 (24) |
144 (24) |
156 (23) |
|||||||||
NF |
NL |
%† |
NF |
NL |
%† |
NF |
NL |
%† |
NF |
NL |
%† |
|
RIBS |
|
|
|
|
|
|
|
|
|
|
|
|
Ossification centre - associated with 7th cervical vertebra |
0 |
0 |
0.0 |
1 |
1 |
0.5 |
1 |
1 |
0.7 |
3 |
3 |
1.9 |
Ossification centre - associated with 1st lumbar vertebra |
3 |
2 |
1.8 |
6 |
5 |
4.0 |
12 |
7 |
7.8 |
11 |
6 |
7.1 |
One or more ribs - thickened |
1 |
1 |
0.9 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
1 |
1 |
0.6 |
Rib - short |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
1 |
1 |
0.6 |
0 |
0 |
0.0 |
Rib - rudimentary |
1 |
1 |
0.9 |
2 |
2 |
1.3 |
0 |
0 |
0.0 |
1 |
1 |
0.5 |
Rib - misshapen |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
1 |
1 |
0.5 |
0 |
0 |
0.0 |
Costal cartilage - misaligned |
1 |
1 |
0.6 |
3 |
3 |
1.6 |
3 |
3 |
2.0 |
8 |
6 |
4.8 |
Costal cartilage - not fused to sternebra |
12 |
7 |
9.6 |
14 |
10 |
9.4 |
9 |
6 |
5.7 |
7 |
5 |
4.2 |
STERNEBRAE |
|
|
|
|
|
|
|
|
|
|
|
|
Sternebra - incomplete ossification |
0 |
0 |
0.0 |
2 |
2 |
1.0 |
1 |
1 |
0.6 |
1 |
1 |
0.6 |
Sternebra - not ossified |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
1 |
1 |
0.6 |
Sternebra - bipartite ossification |
1 |
1 |
0.9 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
2 |
2 |
1.2 |
Sternebra - misaligned |
5 |
4 |
3.4 |
5 |
4 |
3.3 |
5 |
5 |
3.3 |
5 |
4 |
3.3 |
Sternum - split |
0 |
0 |
0.0 |
1 |
1 |
1.0 |
1 |
1 |
0.5 |
1 |
1 |
0.6 |
Sternum - split - cartilage only |
0 |
0 |
0.0 |
1 |
1 |
1.0 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
Xiphoid cartilage - split |
0 |
0 |
0.0 |
1 |
1 |
1.0 |
1 |
1 |
0.5 |
0 |
0 |
0.0 |
Xiphoid cartilage - partially split |
4 |
4 |
2.9 |
14 |
11 |
9.4 |
9 |
5 |
5.8 |
7 |
6 |
4.6 |
Table11(continued) Summary Incidence of Fetal Skeletal Findings
Skeletal Findings |
Dose Level (mg/kg bw/day) |
|||||||||||
0 (Control) |
250 |
500 |
1000 |
|||||||||
Number of Fetuses (litters) Examined |
||||||||||||
141 (22) |
156 (24) |
144 (24) |
156 (23) |
|||||||||
NF |
NL |
%† |
NF |
NL |
%† |
NF |
NL |
%† |
NF |
NL |
%† |
|
PECTORAL GIRDLE |
|
|
|
|
|
|
|
|
|
|
|
|
Scapula - misshapen |
8 |
5 |
5.7 |
2 |
2 |
1.3 |
6 |
5 |
3.8 |
5 |
3 |
3.2 |
PELVIC GIRDLE |
|
|
|
|
|
|
|
|
|
|
|
|
Ischium - incomplete ossification |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
1 |
1 |
0.6 |
Pubis - not ossified |
0 |
0 |
0.0 |
1 |
1 |
0.5 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
Pubis - incomplete ossification |
2 |
1 |
1.5 |
1 |
1 |
0.6 |
2 |
2 |
1.3 |
6 |
3 |
3.7 |
FORELIMBS |
|
|
|
|
|
|
|
|
|
|
|
|
Metacarpal - not ossified |
16 |
11 |
11.7 |
17 |
11 |
10.2 |
21 |
10 |
13.3 |
27 |
11 |
17.2 |
Metacarpal - incomplete ossification |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
2 |
2 |
1.2 |
Forepaw phalanges - 1 or more - ossified |
26 |
11 |
18.6 |
46 |
17 |
30.5 |
41 |
18 |
31.7 |
53 |
14 |
32.1 |
Humerus - incomplete ossification |
3 |
3 |
2.0 |
0 |
0 |
0.0 |
1 |
1 |
0.7 |
1 |
1 |
0.6 |
Humerus - hole |
2 |
2 |
1.4 |
0 |
0 |
0.0 |
2 |
2 |
2.0 |
0 |
0 |
0.0 |
HINDLIMBS |
|
|
|
|
|
|
|
|
|
|
|
|
Metatarsal - 1st - ossified |
4 |
3 |
2.8 |
3 |
3 |
1.8 |
4 |
3 |
2.7 |
6 |
3 |
3.5 |
Metatarsal - incomplete ossification |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
2 |
2 |
1.4 |
0 |
0 |
0.0 |
Femur - incomplete ossification |
7 |
4 |
5.2 |
5 |
4 |
3.0 |
6 |
5 |
6.8 |
11 |
4 |
6.8 |
Tarsal flexure - cartilage – severe |
0 |
0 |
0.0 |
1 |
1 |
0.6 |
0 |
0 |
0.0 |
0 |
0 |
0.0 |
Total |
111 |
22 |
79.1 |
134 |
24 |
84.2 |
120 |
23 |
85.3 |
129 |
23 |
82.0 |
NOTE: a fetus may appear in more than one category
Effect on developmental toxicity: via oral route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 1 000 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rat
- Quality of whole database:
- An OECD TG 414 study was performed to investigate the effects of the test item on embryonic and fetal development following repeated administration by gavage to the pregnant female during gestation including the period of organogenesis.
Effect on developmental toxicity: via inhalation route
- Endpoint conclusion:
- no study available
Effect on developmental toxicity: via dermal route
- Endpoint conclusion:
- no study available
Additional information
An OECD TG 414 study was performed to investigate the effects of the test item on embryonic and fetal development following repeated administration by gavage to the pregnant female during gestation including the period of organogenesis.
Methods
The test item was administered by gavage to three groups each of twenty-four time mated Sprague-Dawley Crl:CD®(SD) IGS BR strain rats, between Days 5 and 19 of gestation inclusive at dose levels of 250, 500 and 1000 mg/kg bw/day. A further group of twenty-four time mated females was exposed to the vehicle only (Corn oil) to serve as a control.
Clinical signs, body weight change, food and water consumptions were monitored during the study.
All females were terminated on Day 20 of gestation and subjected to gross necropsy including examination of the uterine contents. The number of corpora lutea, number, position and type of implantation, placental weights, fetal weight, sex and external and internal macroscopic appearance were recorded. Half of each litter were examined for detailed skeletal development and the remaining half were subjected to detailed visceral examination.
Conclusion
Based on the results of the study, a dosage of 1000 mg/kg bw/day, the highest dosage tested, was considered to be the No Observed Adverse Effect Level (NOAEL) for the pregnant female and the No Observed Effect Level (NOEL) for the developing conceptus.
Justification for classification or non-classification
No classification is warranted; based on the results of the study, a dosage of 1000 mg/kg bw/day, the highest dosage tested, was considered to be the No Observed Adverse Effect Level (NOAEL) for the pregnant female and the No Observed Effect Level (NOEL) for the developing conceptus.
Additional information
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