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EC number: - | CAS number: 1474044-66-0
- 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
- Toxic effect type:
- dose-dependent
Effects on fertility
Description of key information
An extended one generation reproductive toxicity study has not been performed on this substance. In a 90 -day repeated dose toxicity study and in an extended 14 -day repeated dose range finding study there were no effects noted in reproductive organs related to test item administration at any dose level. On the basis of these studies, the substance is not expected to cause adverse effects on fertility.
A screening test was not performed because a prenatal developmental toxicity study is available for this substance.
Effect on fertility: via oral route
- Endpoint conclusion:
- no study available
Effect on fertility: via inhalation route
- Endpoint conclusion:
- no study available
Effect on fertility: via dermal route
- Endpoint conclusion:
- no study available
Additional information
An extended one generation reproductive toxicity study has not been performed on this substance. In a 90 -day repeated dose toxicity study and in an extended 14 -day repeated dose range finding study there were no effects noted in reproductive organs related to test item administration at any dose level. On the basis of these studies, the substance is not expected to cause adverse effects on fertility.
A screening test was not performed because a prenatal developmental toxicity study is available for this substance.
Effects on developmental toxicity
Description of key information
OECD TG 414 performed using the registered substance, Alkane C6-C8 (even numbered), 1-sulphonic acid, sodium salt
NOAELmaternal toxicity: 1000 mg a.i./kg bw/day, based on no maternal systemic effects at 1000 mg a.i./kg bw/day.
NOAELembryotoxicity: 1000 mg a.i./kg bw/day, based on the lack of any test-item related intra-uterine effect in any treatment group.
NOAELfoetotoxicity: 1000 mg a.i./kg bw/day, based on no effect on runts at 1000 mg a.i./kg bw/day.
NOAELteratogenicity: 1000 mg a.i./kg bw/day, based on the lack of treatment related malformations in any dose group.
Link to relevant study records
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 05 November 2019 - 12 December 2019
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Version / remarks:
- 2018
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
- Specific details on test material used for the study:
- Batch/Lot number: 0008282300
Description: Clear liquid
Purity: 40.9 % in water
Expiry date: 13 July 2021
Storage conditions: Controlled room temperature (15-25 °C, ≤70% relative humidity) - Species:
- rat
- Strain:
- Wistar
- Remarks:
- Hannover Wistar rats CRL:WI (Han)
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH (Sandhofer Weg 7, D-97633 Sulzfeld, Germany) from SPF colony
- Age at study initiation: Young adult female rats, nulliparous and non-pregnant, 13-14 weeks old at mating.
- Weight at study initiation: 218 - 289 g (the variation did not exceed ± 20% of the mean weight).
- Fasting period before study: none
- Housing: Type II polycarbonate cages were used during mating and gestation period and Type III polycarbonate cages were used during the acclimatisation period. Successfully mated animals were housed individually.
- Diet (e.g. ad libitum): ssniff® SM "Autoclavable Complete Diet for Rats/Mice – Breeding and Maintenance" (Ssniff Spezialdiäten GmbH, D-59494 Soest, Germany), ad libitum.
- Water (e.g. ad libitum): tap water (in water bottles) as for human consumption, ad libitum.
- Acclimation period: At least 12 days.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19.8-24.7°C (target: 22 ± 3°C).
- Humidity (%): 22-56% (target: 30-70%).
- Air changes (per hr): 15-20 air exchanges/hour.
- Photoperiod (hrs dark / hrs light): 12 hours daily, from 6.00 a.m. to 6.00 p.m.
IN-LIFE DATES: From: 11 November 2020 To: 12 December 2020 - Route of administration:
- oral: gavage
- Vehicle:
- water
- Remarks:
- distilled
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
The test item was formulated in the vehicle (distilled water) at the appropriate concentrations according to the dose level and volume selected, in the Pharmacy of Charles River Laboratories Hungary Kft.
Formulations were prepared prior to administration to the animals within the stability parameters established via the analytical method development study of the Test Site 1 for analytical work. Based on these results, the test item is stable in the vehicle for at least ten days at room temperature.
Stability of the test item in the vehicle was assessed under the conditions employed on the study (concentration range and storage conditions of the dose formulations pending use, according to Test Site cross-validated method development study).
A correction factor of 2.45 was used at dose formulation preparation to take account of the active substance content in the test material.
VEHICLE
- Justification for use and choice of vehicle (if other than water): Based on the available information provided by the Sponsor and the results of a trial formulation as well as a Dose Range Finding (DRF) study, distilled water was selected as a suitable vehicle for this study
- Lot/batch no. (if required): Supplier: Magilab Kft.; Lot No.: 201909057; Expiry date: 20 March 2020; Storage conditions: Room temperature
- Dose volume: 5 mL/kg body weight - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Analysis of test item formulations for concentration was performed at the Test Site 1 for analytical work using a developed analytical method (19/211-901ANE). The test item concentration was analysed By Fumoprep Kft. using a HPLC-MS method. Duplicate samples were taken from the test item formulations at least on 2 occasions during the study (13 November 2019 and 04 December 2019) one set for analysis and one set as a back-up, if required for any confirmatory analyses. Duplicate samples were similarly taken from the vehicle control formulation for analysis.
Acceptance criterion of the concentration analysis was set according to the analytical method validation, expected to be at 100 ± 15% of the nominal concentration. Formulation samples were kept at room temperature until shipment. Samples to be analysed were shipped to the Principal Investigator 1 (PI 1) as soon as practical after collection for concentration measurements.
A summary of the analysis results obtained are presented in the results section below (Table 1).
Detailed results from each sampling point are attached. - Details on mating procedure:
- - Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1male:1 female
- Length of cohabitation: Daily for 2-3 hours until 24 sperm positive females/group were attained
- Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as [day 0] of pregnancy - Duration of treatment / exposure:
- gestation day 6 (GD 6) to gestation day 19 (GD 19)
- Frequency of treatment:
- Daily
- Duration of test:
- GD 0 - GD 20
- Dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- Remarks:
- based on active ingredient
- Dose / conc.:
- 300 mg/kg bw/day (nominal)
- Remarks:
- based on active ingredient
- Dose / conc.:
- 100 mg/kg bw/day (nominal)
- Remarks:
- based on active ingredient
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Remarks:
- vehicle control
- No. of animals per sex per dose:
- 24 mated females/group
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale:
- Rationale for animal assignment (if not random): The sperm-positive, assumed pregnant females were allocated to the experimental groups (on each mating day) in such a way that the group averages of the body weight were as similar as possible. A computer software program (Provantis v9) was used to verify homogeneity/variation among/within groups.
- Fasting period before blood sampling for (rat) dam thyroid hormones: For thyroid hormone analysis, blood samples were taken from all dams at termination by venepuncture into tubes containing K3-EDTA as anticoagulant - Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily
- Cage side observations checked in table [No.?] were included.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: GD 6, then weekly
BODY WEIGHT: Yes
- Time schedule for examinations: GD 0, 3, 6, 8, 10, 12, 14, 16, 18 and 20
- Body weight gains were calculated for each interval, including GD 0-6, GD 6-20, GD 0-20
FOOD CONSUMPTION: Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No
- Food was measured on GD 0, 3, 6, 8, 10, 12, 14, 16, 18 and 20
- Food consumtpion was calculated for each interval, including GD 0-6, GD 6-8, GD 8-10, GD 6-20 and GD 0-20
WATER CONSUMPTION: No
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: The dams’ viscera were examined macroscopically for any structural abnormalities or pathological changes
OTHER: The weight of the thyroid gland with parathyroid glands for all dams were measured with a precision of at least 0.001g (as a paired organ, they were weighed together). Absolute organ weights were measured, and organ weights relative to the body weights were calculated and reported. If any significant difference in size is noted between paired organs, an individual weight of each organ was recorded. - Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other: - Blood sampling:
- - Plasma: Yes
- Serum: No
- Volume collected : 125 μL for the first aliquot and at least 75 μL for the second aliquot - Fetal examinations:
- - External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: Yes: half per litter
- Anogenital distance of all live rodent pups: yes - Statistics:
- Statistical evaluation of data was performed with SAS v9.2 in case of Provantis v.9, or SPSS PC+4.0 for data tabulated in Excel.
For SAS v9.2 (within the validated Provantis system) the following decision tree was applied automatically for statistical evaluation of numeric data. The normality and heterogeneity of variance between groups were checked by Shapiro-Wilk and Levene tests using the most appropriate data format (log-transformed when justified). Where both tests showed no significant heterogeneity, an Anova /Ancova (one-way analysis of variance) test was carried out. If the result was positive, Dunnett’s (Multiple Range) test was used to assess the significance of intergroup differences; identifying differences of <0.05 or <0.01 as appropriate. This parametric analysis was the better option when the normality and heterogeneity assumptions implicit in the tests were adequate.
If either of the Shapiro-Wilk or Levene tests showed significance on the data, then a non-parametric analysis was used. A Kruskal-Wallis analysis of variance was used after Rank Transformation. If there was a positive result, the inter-group comparisons were performed using Dunn test; identifying differences of <0.05 or <0.01 as appropriate. For non-continuous data, the Cochran-Amitage test for trend was applied and the Chisquared test was used for statistical differences relative to control.
Non-pregnant females, females with no implantation or ≤ 5 implantation sites, and females showing signs of abnormal pathology and/or mis-dosing were excluded from selected statistical analysis; in-life individual data was reported as applicable.
The limit for growth-retarded foetuses was calculated from the average body weight of the vehicle control foetuses. A foetus was considered as growth retarded (runt) if the deviation from the mean control values was greater than minus two-fold standard deviation of all control foetuses (2.915 g for males and 2.869 g for females.). - Historical control data:
- Attached (Appendix 9).
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- One High dose female (4521) was found dead on Day 10. Decreased activity, piloerection, hunched back, tremor, red left eye/nose were clinically recorded for this female. This death was considered to be the result of a local effect of the test item. Occasional deaths, due to reflux or similar respiratory exposure, after oral dosing with surfactants may be anticipated.
Thin fur was observed in 1 out of 23 animals in the High dose group.
Piloerection was present in 1 out of 24 animals in the Mid dose group, and 3 out of 23 animals in the High dose group. The finding appeared from Day 9 until Day 16, the symptom persisted for a maximum of six days.
Laboured respiration was observed in 1 out of 23 animals in the High dose group.
Slight noisy respiration was present in 4 out of 23 animals in the High dose group. The finding appeared from Day 8 until Day 19.
Noisy respiration is a common local effect with surfactants because even a very small amount entering the trachea (e.g. from reflux) may cause local irritation.
All other changes were considered incidental, and not thought to be test item related effects.
Summary tables from the study report are attached. - Mortality:
- mortality observed, treatment-related
- Description (incidence):
- One High dose female (4521) was found dead on Day 10. Decreased activity, piloerection, hunched back, tremor, red left eye/nose were clinically recorded for this female. This death was considered to be the result of a local effect of the test item. Occasional deaths, due to reflux or similar respiratory exposure, after oral dosing with surfactants may be anticipated.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- No test item related body weight effects were observed in any of the dose groups.
No significant dose-related effects on corrected body weight, corrected body weight gain, and net body weight gain were observed.
Selected body weight data are shown in Table 2.
Detailed body weight data of the evaluated animals are attached. - Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- A transient decrease of food consumption in the High dose group was observed at the start of the treatment.
Food consumption data of the evaluated animals are attached. - Endocrine findings:
- no effects observed
- Description (incidence and severity):
- Blood samples were taken from all dams at termination and 95 blood samples were successfully analysed. There were no statistically significant changes in the concentration of the T3, T4 and TSH level between the Control and the Dose groups.
Summary tables are attached. - Organ weight findings including organ / body weight ratios:
- no effects observed
- Description (incidence and severity):
- During the macroscopic examination of dams, the thyroid gland with parathyroid glands were retained from all animals and the organ weights recorded. There were no statistical differences in the organ weight between the Control and the Dose groups.
Summary data are attached. - Gross pathological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Dark/red discoloration of the non-collapsed lungs, seen in the one found dead female, (4521) may have been treatment related although it is a common agonal/post-mortem change; enlarged adrenal glands were also observed macroscopically. There was no evidence for clear systemic toxicity in the dead animal.
For pregnant females, no evidence of test item-related macroscopic and microscopic changes were observed in animals dosed at 100, 300 and 1000 mg a.i./kg bw/day on necropsy Day 20.
There were no gross changes observed in the one non-pregnant Low dose female (2506) on necropsy Day 20.
Summary tables are attached. - Histopathological findings: non-neoplastic:
- no effects observed
- Description (incidence and severity):
- Tissue sections were stained with haematoxylin-eosin/phloxine and examined by light microscope. There were no statistical differences between the Control and the Dose groups.
Summary data are attached. - Histopathological findings: neoplastic:
- no effects observed
- Number of abortions:
- no effects observed
- Pre- and post-implantation loss:
- no effects observed
- Description (incidence and severity):
- There were no statistically significant differences in the pre- and post-implantation loss in the test item treated animals when compared to the control.
- Total litter losses by resorption:
- no effects observed
- Early or late resorptions:
- no effects observed
- Description (incidence and severity):
- There were no significant differences in early or late embyronic loss between controls and any test item group.
- Dead fetuses:
- no effects observed
- Description (incidence and severity):
- There were no dead fetuses observed in any group.
- Changes in number of pregnant:
- no effects observed
- Description (incidence and severity):
- Ninety-six females (24 each for the Control, the Low, Mid, and High dose group, respectively) were mated in the study. The number of confirmed pregnant, evaluated dams was: 24 in the Control and the Mid dose group and 23 each in the Low and High dose groups. See table 3 below.
- Other effects:
- no effects observed
- Description (incidence and severity):
- No placental abnormalities were observed in any of the control or test group animals.
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (nominal)
- Based on:
- act. ingr.
- Basis for effect level:
- other: no maternal systemic effects at the high dose
- Fetal body weight changes:
- no effects observed
- Description (incidence and severity):
- No significant change in the body weights were observed in animals in the Low, Mid, and High dose groups. All values were within the historical control range (mean ± SD: 3.407 ± 0.225).
There was no significant change in the number of foetuses with retarded body weight in any of the dose groups - Reduction in number of live offspring:
- no effects observed
- Changes in sex ratio:
- no effects observed
- Description (incidence and severity):
- There were no significant differences in the sex distribution (%males/females) between controls and any of the test groups.
- Changes in litter size and weights:
- no effects observed
- Description (incidence and severity):
- There were no significant differences in the mean litter size between controls and any of the test groups.
- Anogenital distance of all rodent fetuses:
- no effects observed
- Description (incidence and severity):
- There were no significant differences in anogenital difference for males, females or combined males/females between the controls and any of the test groups.
- External malformations:
- no effects observed
- Description (incidence and severity):
- No external variations or malformations were seen in the test item treated groups. Refer to table 6 below.
- Skeletal malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- The observed skeletal abnormalities are summarized in Table 9 below. Most of the skeletal findings were within the current historical control range or the concurrent study control data or were considered to be incidental findings without dose response (see table 10, attached, for detailed data).
Analysis of the skeletal findings showed the numbers of malformed / intact foetuses were comparable with the control in the Low, Mid and High dose groups. The number of variations were higher in all test item treated groups.
For the majority of the skeletal variations, the foetal or litter based incidence in the test item treated groups was comparable with the current study control or historical control values. Therefore, they were considered as not biologically significant and not related to test item treatment.
Most of the findings were within the study control data ranges or had isolated occurrences that were considered incidental and ascribed to individual variability. - Visceral malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- The observed visceral abnormalities are summarized in Table 7. Most of the findings were within the current historical control ranges or the study control data or had an isolated occurrence that was considered incidental, ascribed to individual variability and therefore not related to treatment. (see table 8 attached for detailed data)
- Dose descriptor:
- NOAEL
- Remarks:
- embryotoxicity
- Effect level:
- 1 000 mg/kg bw/day (nominal)
- Based on:
- act. ingr.
- Sex:
- male/female
- Basis for effect level:
- other: no test-item related intra-uterine effect in any treatment group
- Dose descriptor:
- NOAEL
- Remarks:
- foetotoxicity
- Effect level:
- 1 000 mg/kg bw/day (nominal)
- Based on:
- act. ingr.
- Sex:
- male/female
- Basis for effect level:
- other: no effect on runts at 1000 mg/kg bw/day
- Dose descriptor:
- NOAEL
- Remarks:
- teratogenicity
- Effect level:
- 1 000 mg/kg bw/day (nominal)
- Based on:
- act. ingr.
- Sex:
- male/female
- Basis for effect level:
- other: no treatment related malformations in any dose group
- Developmental effects observed:
- no
- Executive summary:
A developmental toxicity study (OECD TG 414) was performed to assess the effects of the test item on the embryonic and foetal development (including the organogenesis period) of Hannover Wistar rats in their first pregnancy. The dams (one control and three test item treated groups) were treated daily by oral (gavage) administration, from gestation day 6 (GD 6) up to and including gestation day 19 (GD 19), where sperm positive day was counted as day 0 of pregnancy (GD 0). Control dams were treated with the vehicle (distilled water) only. Caesarean sections, necropsy of dams and examination of uterine contents were performed on GD 20.
The dose levels were set based on the available data and information from previous experimental work, including the results of an Oral (gavage) Dose Range Finding Toxicity Study in Pregnant Hannover Wistar Rats. Based on the results from the Dose Range Finding study, doses of 1000, 300 and 100 mg a.i./kg bw/day were selected for the main study (designated High, Mid and Low dose respectively). The aim was to use the highest dose of 1000 mg a.i./kg bw/day to induce toxic effects, but ideally no death or suffering, and to obtain a NOAEL at the lowest
dose level.
Test item formulations were analysed for concentration twice during the treatment period using a validated HPLC-MS method. Simultaneously, vehicle control formulations were also analysed for the test item.
Parameters monitored during the study included mortality and clinical observations, body weight, body weight gain and individual food consumption. Maternal reproductive parameters associated with uterine examination were evaluated, and the foetuses were weighed and examined for external, visceral and skeletal abnormalities. Placentas were examined macroscopically.
The number of confirmed pregnant, evaluated dams was 24 in the Control and in the Mid dose group, and 23 in the Low and in the High dose groups.
Results
All test item formulations were within the range of 93.4-107.3% of nominal concentration, were stable (at least 10 days at 20°C) and were found to be homogenous. No test item was detected in the vehicle control samples. Based on these results, test item formulations were considered suitable for the study purposes.
One High dose female (4521) was found dead on Day 10. Decreased activity, piloerection, hunched back, tremor, red left eye/nose were clinically recorded for this female. The death was considered to be the result of a local effect of the test item.
Thin fur was observed in 1 out of 23 animals in the High dose group.
Piloerection was present in 1 out of 24 animals in the Mid group, and 3 out of 23 animals in the High dose group. It was apparent from Day 9 until Day 16, and occurred for up to six days.
Laboured respiration was observed in 1 out of 23 animals in the High dose group. Slight noisy respiration was present in 4 out of 23 animals in the High dose group. The finding appeared from Day 8 until Day 19. Noisy respiration can be a common local effect with surfactants. This may result from exceedingly small amounts entering the trachea (e.g. from reflux, after oral dosing) causing local irritation. Occasional deaths, due to reflux or similar respiratory exposure, after oral dosing with surfactants may be anticipated.
No test item related body weight decrease was observed in any of the dose groups.
A transient decrease of food consumption in the High dose group was observed at the start of the treatment.
Dark/red discoloration, of the non-collapsed lungs, seen in the female found dead (4521) may have been treatment related although this is a common agonal/post mortem incidental change. Enlarged adrenal glands were also observed macroscopically in this animal. There was no evidence for overt systemic toxicity in this animal.
No test item related macroscopic or microscopic findings were present at necropsy in the surviving females.
There were no statistically significant differences in the intra-uterine parameters in the test item treated animals when compared to the controls.
There was no toxicologically significant difference in the sex distribution of foetuses between the control and treatment groups.
There was no difference in the number of runts between the control and treated groups.
There were no test item related effects on the external or visceral development of the foetuses in this study. The number of skeletal variations was higher in the test item treated groups when compared to the controls. Foetal malformations observed in the study were all considered to be incidental. They showed no dose dependency and constituted the common range of background changes. They were, therefore, not regarded as a test item related.
In conclusion, the test item, when administered daily by oral gavage to pregnant Hannover Wistar rats from gestation days GD 6 to GD 19 at 1000 mg a.i./kg bw/day induced no maternal systemic toxicity with no effects on body weight or growth. There was some evidence for local respiratory irritation at the High dose, which is considered as a common finding with orally dosed surfactants. No embryotoxicity or foetotoxicity was observed in this study following developmental and foetal examinations. There were no malformations considered attributable to the test item at any dose level.
The following no-observed-adverse-effect (NOAEL) levels were derived:
NOAELmaternal toxicity: 1000 mg a.i./kg bw/day
Based on no maternal systemic effects at 1000 mg a.i./kg bw/day.
NOAELembryotoxicity: 1000 mg a.i./kg bw/day
Based on the lack of any test-item related intra-uterine effect in any treatment group.
NOAELfoetotoxicity: 1000 mg a.i./kg bw/day
Based on no effect on runts at 1000 mg a.i./kg bw/day.
NOAELteratogenecity: 1000 mg a.i./kg bw/day
Based on the lack of treatment related malformations in any dose group.
Reference
Table 1: Summary of the dose formulation analysis
Formulation | 13 November 2019 | 04 December 2019 | ||
Mean measured concentration (mg/L) | Relative to the nominal concentration (%) | Mean measured concentration (mg/L) | Relative to the nominal concentration (%) | |
Control | not detected | - | not detected | - |
20 mg a.i./mL | 20.64 ± 0.39 | 103.0 | 19.16 ± 0.2 | 95.6 |
60 mg a.i./mL | 64.52 ± 1.76 | 107.3 | 58.11 ± 0.98 | 96.6 |
200 mg a.i./mL | 215.0 ± 3.41 | 107.3 | 187.3 ± 1.89 | 93.4 |
Note: Samples were collected freshly on the days indicated in the header of the table.
Samples for test item concentration determination of the dosing formulations were collected twice during the treatment period. Formulation stability was established before
this study. The test item concentration was analysed By Fumoprep Kft. using a HPLCMS method.
The mean concentration of all formulations was found to be in the range of 93.4-107.3% of their nominal concentrations (20, 60, and 200 mg/mL) and were found
to be homogenous.
No test item was detected in the vehicle control formulations.
Based on these results, test item formulations were considered suitable for the study purposes.
Table 2: Selected body weight parameters
Parameters | Historical control | Dose (mg a.i./kg bw/day) | |||
0 | 100 | 300 | 1000 | ||
Number of evaluated dams | 507 | 24 | 23 | 24 | 23 |
Body weight gain GD0 -3 (g) | 10.9±4.2 | 10.4 | 9.5 | 12.9## | 9.9 |
Notes: Historical control data is mean ± 1SD. Body weight data were rounded to one decimal place.
Corrected and net weight / weight gains refer to body weight values minus the weight of the gravid uterus.
##= p<0.05; Dunnett two sided test
Table 3: Summary of pregnancy data
Parameters | Dose (mg a.i./kg bw/day) | |||
0 | 100 | 300 | 1000 | |
Number of mated females | 24 | 24 | 24 | 24 |
Pre-terminal death or euthanasia | 0 | 0 | 0 | 1 |
Number of non-pregnant females | 0 | 1 | 0 | 0 |
Number of females with ≤ 5 implantation sites | 0 | 0 | 0 | 0 |
Number of evaluated females on GD20 (Caesarean section) |
24 |
23 |
24 |
23 |
Table 4: Summary of the intra-uterine evaluation
Parameter |
Dose (mg a.i./kg bw/day) |
|||
|
0 |
100 |
300 |
1000 |
Number of evaluated dams |
24 |
23 |
24 |
23 |
Mean number of corpora lutea |
12.08 |
11.75 |
11.75 |
12.04 |
Pre-implantation loss, mean |
1.21 |
1.74 |
1.04 |
1.35 |
Pre-implantation loss (%), mean |
9.19 |
13.93 |
8.64 |
10.26 |
Mean number of implantations |
10.88 |
10.52 |
10.71 |
10.70 |
Early embryonic loss, mean |
0.50 |
0.43 |
0.38 |
0.65 |
Early embryonic loss (%), mean |
4.53 |
3.55 |
3.25 |
5.93 |
Late embryonic loss, mean |
0.08 |
0.09 |
0.17 |
0.04 |
Late embryonic loss (%), mean |
0.67 |
0.87 |
1.60 |
0.33 |
Dead foetuses, mean |
0.00 |
0.00 |
0.00 |
0.00 |
Dead foetuses (%), mean |
0.00 |
0.00 |
0.00 |
0.00 |
Post-implantation loss, mean |
0.52 |
0.58 |
0.54 |
0.70 |
Post-implantation loss (%), mean |
5.19 |
4.42 |
4.85 |
6.26 |
Total intra-uterine mortality, mean |
1.79 |
2.26 |
1.58 |
2.04 |
Total intra-uterine mortality (%), mean |
13.86 |
17.83 |
13.06 |
15.91 |
Viable foetuses, mean |
10.29 |
10.00 |
10.17 |
10.00 |
Table 5: Examination of viable foetuses
Parameter |
Dose (mg a.i./kg bw/day) |
|||
|
0 |
100 |
300 |
1000 |
Number of examined litters |
24 |
23 |
24 |
23 |
Viable foetuses, mean |
10.19 |
10.00 |
10.27 |
10.00 |
Male foetuses, mean |
5.50 |
4.91 |
4.83 |
4.70 |
Female foetuses, mean |
4.70 |
5.09 |
5.33 |
5.30 |
Total number of foetuses |
247 |
230 |
244 |
230 |
Total number of male foetuses |
132 |
113 |
116 |
108 |
Total number of female foetuses |
115 |
117 |
128 |
122 |
Sex distribution (% of males / females) |
53/47 |
49/51 |
48/52 |
47/53 |
Mean foetal weight / litter (g) |
3.449 |
3.457 |
3.453 |
3.390 |
Number of foetuses with retarded body weight |
7 |
10 |
7 |
11 |
Number of affected litters (with runts) |
6 |
4 |
6 |
7 |
Table 6: Summary table of the external abnormalities
Parameter | Dose (mg a.i./kg bw/day) | |||
0 | 100 | 300 | 1000 | |
Total number of examined litters | 24 | 23 | 24 | 23 |
Total number of examined foetuses | 247 | 230 | 234 |
230 |
Total number of intact (normal) foetuses | 230 | 211 | 220 | 213 |
Total number of foetuses / litters with malformation |
0/0 |
0/0 |
0/0 |
0/0 |
Total number of foetuses / litters with variation |
0/0 |
0/0 |
0/0 |
0/0 |
Notes: Numbers represent the number of abnormalities / number of affected litters.
Table 7: Summary table of the visceral abnormalities
Parameter
|
Dose (mg a.i./kg bw/day) |
|||
0 |
100 |
300 |
1000 |
|
Total number of examined litters |
24 |
23 |
24 |
23 |
Total number of examined foetuses |
124 |
115 |
121 |
116 |
Total number of intact (normal) foetuses |
118 |
110 |
116 |
112 |
Total number of foetuses/litters with malformations |
2/2 |
0/0 |
2/2 |
3/3 |
Total number of foetuses/litters with variation |
4/4 |
5/5 |
3/3 |
1/1 |
Notes: Numbers represent the number of abnormalities / number of affected litters.
Table 9: Summary table of the skeletal abnormalities
Parameter |
Dose (mg a.i./kg bw/day) |
|||
|
0 |
100 |
300 |
1000 |
Total number of examined litters |
24 |
23 |
24 |
23 |
Total number of examined foetuses |
123 |
115 |
123 |
114 |
Total number of intact (normal) foetuses |
112 |
101 |
114 |
101 |
Total number of foetuses/litters with malformations |
5/5 |
4/3 |
0/0 |
1/1 |
Total number of foetuses/litters with variation |
6/5 |
10/8 |
9/7 |
12/7 |
Effect on developmental toxicity: via oral route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 1 000 mg/kg bw/day
- Study duration:
- subchronic
- Species:
- rat
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
A developmental toxicity study (OECD TG 414) was performed to assess the effects of the test item on the embryonic and foetal development (including the organogenesis period) of Hannover Wistar rats in their first pregnancy. The dams (one control and three test item treated groups) were treated daily by oral (gavage) administration, from gestation day 6 (GD 6) up to and including gestation day 19 (GD 19), where sperm positive day was counted as day 0 of pregnancy (GD 0). Control dams were treated with the vehicle (distilled water) only. Caesarean sections, necropsy of dams and examination of uterine contents were performed on GD 20.
The dose levels were set based on the available data and information from previous experimental work, including the results of an Oral (gavage) Dose Range Finding Toxicity Study in Pregnant Hannover Wistar Rats. Based on the results from the Dose Range Finding study, doses of 1000, 300 and 100 mg a.i./kg bw/day were selected for the main study (designated High, Mid and Low dose respectively). The aim was to use the highest dose of 1000 mg a.i./kg bw/day to induce toxic effects, but ideally no death or suffering, and to obtain a NOAEL at the lowest dose level.
Test item formulations were analysed for concentration twice during the treatment period using a validated HPLC-MS method. Simultaneously, vehicle control formulations were also analysed for the test item.
Parameters monitored during the study included mortality and clinical observations, body weight, body weight gain and individual food consumption. Maternal reproductive parameters associated with uterine examination were evaluated, and the foetuses were weighed and examined for external, visceral and skeletal abnormalities. Placentas were examined macroscopically.
The number of confirmed pregnant, evaluated dams was 24 in the Control and in the Mid dose group, and 23 in the Low and in the High dose groups.
Results
All test item formulations were within the range of 93.4-107.3% of nominal concentration, were stable (at least 10 days at 20°C) and were found to be homogenous. No test item was detected in the vehicle control samples. Based on these results, test item formulations were considered suitable for the study purposes.
One High dose female (4521) was found dead on Day 10. Decreased activity, piloerection, hunched back, tremor, red left eye/nose were clinically recorded for this female. The death was considered to be the result of a local effect of the test item.
Thin fur was observed in 1 out of 23 animals in the High dose group.
Piloerection was present in 1 out of 24 animals in the Mid group, and 3 out of 23 animals in the High dose group. It was apparent from Day 9 until Day 16, and occurred for up to six days.
Laboured respiration was observed in 1 out of 23 animals in the High dose group. Slight noisy respiration was present in 4 out of 23 animals in the High dose group. The finding appeared from Day 8 until Day 19. Noisy respiration can be a common local effect with surfactants. This may result from exceedingly small amounts entering the trachea (e.g. from reflux, after oral dosing) causing local irritation. Occasional deaths, due to reflux or similar respiratory exposure, after oral dosing with surfactants may be anticipated.
No test item related body weight decrease was observed in any of the dose groups.
A transient decrease of food consumption in the High dose group was observed at the start of the treatment.
Dark/red discoloration, of the non-collapsed lungs, seen in the female found dead (4521) may have been treatment related although this is a common agonal/post mortem incidental change. Enlarged adrenal glands were also observed macroscopically in this animal. There was no evidence for overt systemic toxicity in this animal.
No test item related macroscopic or microscopic findings were present at necropsy in the surviving females.
There were no statistically significant differences in the intra-uterine parameters in the test item treated animals when compared to the controls.
There was no toxicologically significant difference in the sex distribution of foetuses between the control and treatment groups.
There was no difference in the number of runts between the control and treated groups.
There were no test item related effects on the external or visceral development of the foetuses in this study. The number of skeletal variations was higher in the test item treated groups when compared to the controls. Foetal malformations observed in the study were all considered to be incidental. They showed no dose dependency and constituted the common range of background changes. They were, therefore, not regarded as a test item related.
In conclusion, the test item, when administered daily by oral gavage to pregnant Hannover Wistar rats from gestation days GD 6 to GD 19 at 1000 mg a.i./kg bw/day induced no maternal systemic toxicity with no effects on body weight or growth. There was some evidence for local respiratory irritation at the High dose, which is considered as a common finding with orally dosed surfactants. No embryotoxicity or foetotoxicity was observed in this study following developmental and foetal examinations. There were no malformations considered attributable to the test item at any dose level.
The following no-observed-adverse-effect (NOAEL) levels were derived:
NOAELmaternal toxicity: 1000 mg a.i./kg bw/day, based on no maternal systemic effects at 1000 mg a.i./kg bw/day.
NOAELembryotoxicity: 1000 mg a.i./kg bw/day, based on the lack of any test-item related intra-uterine effect in any treatment group.
NOAELfoetotoxicity: 1000 mg a.i./kg bw/day, based on no effect on runts at 1000 mg a.i./kg bw/day.
NOAELteratogenicity: 1000 mg a.i./kg bw/day, based on the lack of treatment related malformations in any dose group.
Justification for classification or non-classification
Based on the available data for the registered substance, classification for reproductive toxicity is not required.
Additional information
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