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EC number: 411-370-1 | CAS number: 82857-68-9 GM 102 E
- 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
![](https://echa.europa.eu/o/diss-blank-theme/images/factsheets/A-REACH/factsheet/print_toxicological-information.png)
Endpoint summary
Administrative data
Key value for chemical safety assessment
Effects on fertility
Link to relevant study records
- Endpoint:
- screening for reproductive / developmental toxicity
- Remarks:
- based on test type (migrated information)
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- September 2015 - To be completed
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: GLP- and OECD-test guideline compliant study.
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Janvier, Le Genest-Saint-Isle, France
- Age at study initiation: Males: 10 weeks; Females: 9 weeks
- Weight at study initiation: Males: approx. 400 g; Females: approx. 220 g
- Fasting period before study: No
- Housing: individually (except during mating and lactation) in cages (TEcniplast 2154: 940 cm², polycarbonate with stainless steel lid) containing autoclaved sawdust
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: at least 5 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 2
- Humidity (%): 50 +/- 20
- Air changes (per hr): 8 to 15
- Photoperiod (hrs dark / hrs light): 12 / 12
IN-LIFE DATES: From: 08 September 2015 To: 15 November 2015 - Route of administration:
- oral: gavage
- Vehicle:
- other: Drinking water tretead by reverse osmosis
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS: test item weighed and mixed with required amount of vehicle in accordance with internal procedures
VEHICLE
- Concentration in vehicle: 0, 2.5, 5, 8 or 10 mg/mL
- Amount of vehicle (if gavage): 10 mL/kg - Details on mating procedure:
- Females were paired with males at the same dose-level. One female was placed with one male, in the latter's cage, overnight.
Mating was confirmed in the morning by checking for the presence of a vaginal plug or for sperm in a vaginal lavage.
The day of confirmed mating was designated Day 0 p.c.
Each female was placed with the same male until mating occurs or 7 days have elapsed. Any pair with no evidence of mating after 7 days was separated and the female was placed for a further 7 days with a different male (at the same dose-level) that had already mated.
The pre-coital time was calculated for each female.
Any female with no evidence of mating after 7 days with the second male would have been sacrificed 24 to 26 days after the end of the mating period (unless delivery occurs). - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- - Analytical technique: High Performance Liquid Chromatography with UV detection (HPLC/UV).
- Principle and validation of the method: Analytical method was validated at CiToxLAB France (CiToxLAB France/Study No. 42844 VAA) before dose formulation analysis. Checked parameters, acceptance criteria and obtained results are described in the validation report.
- Determination of test item concentrations in dose formulations: Once in Weeks 1, 3/4 and 5/6 (three occasions). Samples of control and test item dose formulations were analyzed using the validated method. Acceptance criterion: Measured concentration = nominal concentration ± 10%. - Duration of treatment / exposure:
- The dose formulations will be administered daily according to the following schedule:
Males:
- 2 weeks before mating,
- during the mating period (up to 2 weeks),
- until sacrifice (at least 4 weeks in total),
Females:
- at least 2 weeks before mating,
- during the mating period (up to 2 weeks),
- during gestation,
- during lactation until Day 4 p.p. (post partum) inclusive,
- until sacrifice for females with no evidence of mating or no delivery.
Day 1 corresponds to the first day of the treatment period. - Frequency of treatment:
- See above
- Details on study schedule:
- See above
- Remarks:
- Doses / Concentrations:
0, 25, 50 and 100 mg/kg bw/day
Basis:
nominal in water
From Study Day 1 to 18 - Remarks:
- Doses / Concentrations:
0, 25, 50 and 80 mg/kg bw/day
Basis:
nominal in water
From Study Day 19 on (due to mortality in high-dose group) - No. of animals per sex per dose:
- 10
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- Rationale for dose-level selection:
The initial dose-levels were based on the results of the following previous studies:
a) 4-week toxicity study (1991): GM 102 E was administered daily by oral gavage to Sprague Dawley rats (5 rats/sex/group) at dose-levels of 6.25, 12.5, 25 and 50 mg/kg/day. The formulations were administered as solutions in water (10 mL/kg/day). Ptyalism (hypersalivation) was observed immediately after dosing. From study Week 3 onwards, there were no noteworthy findings. Under the condition of this study the No Observed Effect Level (NOEL) was considered to be 50 mg/kg/day.
b) Acute toxicity studies (1983 and 1994): two studies were conducted by the oral route (gavage) in two different strains of rats. The LD50 values were the following:
- 160 mg/kg, 95% confidence interval: [123-208], Wistar rats (1983),
- 123 mg/kg, 95% confidence interval: [100-150], Sprague-Dawley rats (1994).
The high dose-level was set at 100 mg/kg/day. The low and intermediate dose-levels were selected using a ratio representing a 2-fold interval (i.e. 25 and 50 mg/kg/day). Due to elevated mortality in the high-dose group, the dose of 100 mg/kg/day was reduced to 80 mg/kg/day from Study Day 19 on. - Positive control:
- No
- Parental animals: Observations and examinations:
- - Morbidity and mortality:
Each animal was checked for mortality and morbidity at least once a day before the treatment period and at least twice a day during the treatment period, including weekends and public holidays. Any animal showing signs of poor clinical condition, especially if death appeared imminent, was humanely sacrificed. A macroscopic post-mortem examination was performed on any animals found dead or prematurely sacrificed.
- Clinical signs:
From arrival, each animal was observed at least once a day as part of routine examinations. From the start of the treatment period, each animal was observed at least once a day, at approximately the same time of day, for the recording of clinical signs.
- Body weight:
The body weight of each male was recorded on the first day of treatment (Day 1), then once a week until sacrifice. The body weight of each female was recorded on the first day of treatment (Day 1), once a week until mated (or until sacrifice for females with no evidence of mating), then on Days 0, 7, 14 and 20 p.c. (post-coitum) and on Days 1 and 5 p.p.
- Food consumption:
The quantity of food consumed by each male was measured once a week, over 7-day periods, from the first day of treatment until the start of the mating period. The quantity of food consumed by each female was measured once a week, over 7-day periods, from the first day of treatment until the start of the mating period, then during gestation over 7 day periods (Days 0-7, 8-14 and 15-20 p.c.), and during lactation (Days 1-5 p.p.). During the mating period, food consumption was not measured for males or females. Food intake per animal and per day was calculated by noting the difference between the food given and that remaining in the food-hopper at the next distribution. - Oestrous cyclicity (parental animals):
- The estrous cycle stage was determined from a fresh vaginal lavage (stained with methylene blue), each morning during the mating period until the females were mated.
- Litter observations:
- Each live pup was individually identified on Day 1 post-partum (morning of complete parturition), by subcutaneous injection of indian ink.
- Litter size:
The total litter size and the sex of each pup was recorded as soon as possible after birth. Any gross external malformations in pups was noted. Litters were observed daily to note the number of live, dead and cannibalized pups.
- Clinical signs:
The pups were observed daily for clinical signs, abnormal behavior and external abnormalities.
- Body weight:
The body weight of each pup was recorded on Days 1 and 5 p.p. - Postmortem examinations (parental animals):
- On completion of the treatment period, all surviving F0 animals were deeply anesthetized by intraperitoneal injection of sodium pentobarbital and sacrificed by exsanguination:
- Males: after the end of the mating period (at least 4 weeks of treatment in total),
- Females: on Day 5 p.p.,
- Females which did not deliver: on Day 24-26 p.c. (after a body weight recording to check for a possible un-noticed delivery; sacrifice by inhalation of carbon dioxide gas followed by cervical dislocation was used if gestation was suspected),
- Females with no evidence of mating: 24-26 days after the end of the mating period if no delivery occurred (sacrifice by inhalation of carbon dioxide gas followed by cervical dislocation was used if gestation was suspected),
- Females with total litter loss: as appropriate.
--> Animals prematurely sacrificed or found dead
- F0 Males:
Prematurely sacrificed males were deeply anesthetized by intraperitoneal injection of sodium pentobarbital and euthanized by exsanguination. A complete macroscopic post mortem examination was performed on any males found dead or prematurely sacrificed.
- F0 Females:
During the pre-mating period: Prematurely sacrificed females were deeply anesthetized by intraperitoneal injection of sodium pentobarbital and euthanized by exsanguination. A complete macroscopic post mortem examination was performed on any females found dead or prematurely sacrificed.
During the mating and gestation periods: During the mating period, prematurely sacrificed females were deeply anesthetized by intraperitoneal injection of sodium pentobarbital and euthanized by exsanguination, except if gestation was suspected (see below). During the gestation period, prematurely sacrificed females were euthanized by inhalation of carbon dioxide gas followed by cervical dislocation. A complete macroscopic post mortem examination was performed on any females found dead or prematurely sacrificed.
The pregnancy status was determined and, if appropriate and possible, the numbers of corpora lutea and implantation sites was recorded and classified as live or dead concepti, early or late resorptions or scars. For apparently non-pregnant (mated or apparently unmated) females, the presence of implantation scars on the uterus was checked using the ammonium sulphide staining technique (Salewski, 1964), except between Days 0 and 5 p.c. inclusive.
During the lactation period: Prematurely sacrificed females were deeply anesthetized by intraperitoneal injection of sodium pentobarbital and euthanized by exsanguination. A complete macroscopic post mortem examination was performed on any females found dead or prematurely sacrificed. In addition, the number of corpora lutea and implantation sites was recorded.
The body weight of each F0 animal sacrificed as scheduled (after the end of the mating period for males or on Day 5 p.p. for females) was recorded before sacrifice. The organs selected for microscopic examination were weighed wet as soon as possible after dissection. The ratio of organ weight to body weight (recorded immediately before sacrifice) was calculated.
A macroscopic post-mortem examination of the principal thoracic and abdominal organs was performed on all F0 animals, including any that died during the study or were sacrificed prematurely. Particular attention was accorded to the reproductive organs. The number of corpora lutea and implantation sites was recorded for females sacrificed as scheduled on Day 5 p.p. and, if possible, for any females sacrificed 24 to 26 days after the end of the mating period with no evidence of mating and for any females sacrificed on Day 24-26 p.c. due to no delivery. For apparently non-pregnant females the presence of implantation scars on the uterus was checked using the ammonium sulphide staining technique.
The following tissues were preserved in 10% buffered formalin (except for the testes and epididymides which were fixed in Modified Davidson's Fixative): Macroscopic lesions, Epididymides, Mammary gland area, Ovaries (with oviducts), Prostate, Seminal vesicles (with coagulating glands), Testes, Uterus (horns and cervix), Vagina. All tissues required for microscopic examination were trimmed according to the RITA guidelines, when applicable (Ruehl-Fehlert et al., 2003; Kittel et al., 2004; Morawietz et al., 2004), embedded in paraffin wax, sectioned at a thickness of approximately 4 microns and stained with hematoxylin-eosin (except testes and epididymides which were stained with hematoxylin/PAS).
Microscopic examination was performed on the reproductive organs from control, mid- and high-dose males and females at terminal sacrifice and from premature decedents, and on all macroscopic observations in all groups. Particular attention was accorded to stages of spermatogenesis in male gonads and histopathology of interstitial testicular cell structure. - Postmortem examinations (offspring):
- Pups were sacrificed by intraperitoneal injection of sodium pentobarbital:
- Pups whose mother dies: as soon as possible,
- Surviving pups: on Day 5 p.p.
Moribund pups and pups prematurely sacrificed because their dam died were sacrificed by intraperitoneal injection of sodium pentobarbital. A macroscopic post-mortem examination of the principal thoracic and abdominal organs was performed on all found dead and prematurely sacrificed pups. Particular attention was accorded to the reproductive organs and to whether the pup had fed (e.g. presence of milk in the stomach). No tissues were preserved.
A macroscopic post-mortem examination of the principal thoracic and abdominal organs was performed on all pups sacrificed on Day 5 p.p. No tissues were preserved. - Statistics:
- - Body weight, food consumption and reproductive data:
Data were compared by one-way analysis of variances and the Dunnett test (where mean values are considered as normally distributed, and variances are considered as homogenous) or by Fisher’s exact probability test (proportions).
- Organ weights:
PathData software (version 6.2d2) was used to perform the statistical analysis of organ weight data (level of significance of 0.05 or 0.01). - Reproductive indices:
- - Pre-implantation loss: (Number of corpora lutea - Number of implantation sites) / Number of corpora lutea x 100
- Post-implantation loss (calculated manually): (Number of implantation sites - Number of live pups) / Number of implantation sites x 100 - Mating index: Number of mated animals / Number of paired animals x 100
- Fertility index: Number of pregnant female partners / Number of mated pairs x 100
- Gestation index: Number of females with live born pups / Number of pregnant females x 100 - Offspring viability indices:
- - Live birth index: Number of live born pups / Number of delivered pups x 100
- Viability index on Day 4 p.p.: Number of surviving pups on Day 4 p.p. / Number of live born pups x 100 - Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Mortality in high-dose group. Severe clinical signs in mid- and high-dose groups.
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Other effects:
- no effects observed
- Reproductive function: oestrous cycle:
- not specified
- Reproductive function: sperm measures:
- not examined
- Reproductive performance:
- effects observed, treatment-related
- Description (incidence and severity):
- Lower mating and fertility indexes in high-dose group.
- Dose descriptor:
- NOAEL
- Remarks:
- Parental toxicity
- Effect level:
- 50 mg/kg bw/day (nominal)
- Based on:
- act. ingr.
- Sex:
- male/female
- Basis for effect level:
- other: clinical signs; mortality
- Dose descriptor:
- NOAEL
- Remarks:
- Reproductive performance (mating, fertility and delivery data)
- Effect level:
- 25 mg/kg bw/day (nominal)
- Based on:
- act. ingr.
- Sex:
- male/female
- Basis for effect level:
- other: lower number of pups delivered
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Marked increase in pups cold to the touch and with a few milk in the stomach as well as in the incidence of litters affected in high-dose group.
- Mortality / viability:
- mortality observed, treatment-related
- Description (incidence and severity):
- Marked increase in the number of found dead, moribund and cannibalized pups as well as in the incidence of litters affected in high-dose group.
- Body weight and weight changes:
- no effects observed
- Sexual maturation:
- no effects observed
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- no effects observed
- Histopathological findings:
- not examined
- Dose descriptor:
- NOAEL
- Remarks:
- Toxic effects on progeny
- Generation:
- F1
- Effect level:
- 50 mg/kg bw/day (nominal)
- Based on:
- act. ingr.
- Sex:
- male/female
- Basis for effect level:
- other: low pup viability
- Reproductive effects observed:
- not specified
- Conclusions:
- - The No Observed Adverse Effect Level (NOAEL) for parental toxicity was considered to be 50 mg/kg/day (based on mortality and clinical recorded for both sexes at 100/80 mg/kg/day),
- The NOAEL for reproductive performance (mating, fertility and delivery data) was considered to be 25 mg/kg/day (based on the lower number of pups delivered from 50 mg/kg/day),
- The NOAEL for toxic effects on progeny was considered to be 50 mg/kg/day (on the low pup viability at 100/80 mg/kg/day). - Executive summary:
GM 102 E (batch No. 180020) was administered daily by oral gavage to male and female Sprague‑Dawley rats, for 2 weeks before mating, during mating, and until sacrifice (for males) or throughout gestation and until day 4post-partum(for females), at dose-levels of 25, 50 or 100/80 mg/kg/day.
Animals were checked daily for clinical signs and mortality. Body weights and food consumption were recorded weekly until mating and then at designated intervals throughout gestation and lactation. The animals were paired for mating after 2 weeks of treatment and the dams were allowed to litter and rear their progeny until day 5p.p.. The total litter sizes and numbers of pups of each sex were recorded after birth. The pups were observed daily for clinical signs of toxicity and pup body weights were recorded on days 1 and 5p.p.. The males were sacrificed after completion of the mating period. Dams were sacrificed on day 5 p.p.. Body weights and selected organs weights were recorded and a complete macroscopicpost-mortemexamination performed, with particular attention paid to the reproductive organs. Microscopic examination was performed on the reproductive organs from control, mid- and high-dose males and females at terminal sacrifice and from premature decedents, and on all macroscopic observations in all groups. Pups, including those found dead before study termination, were also submitted for a macroscopic post-mortem examination.
In the parental generation, there were no unscheduled deaths in the control, 25 or 50 mg/kg/day groups. Test item treatment related deaths were recorded in 2/10 males and 8/10 females from the 100/80 mg/kg/day group. Before sacrifice for ethical reason or in the found dead rats, piloerection, round back, emaciated appearance, hypoactivity, loud breathing, abdominal breathing, dyspnea, ptyalism, half closed eyes and/or chromorhinorrhea were observed in most animals. Changes were observed in the lungs, spleen, stomach, ileum, cecum and/or vagina and these findings were considered to be agonal and/or to have contributed to the death or the moribund status of these animals, but the cause of death could not be ascertained. In the 100/80 mg/kg/day group, piloerection and round back were considered to be test-item treatment related and adverse. In the 50 mg/kg/day, round back was considered to be test-item treatment related and adverse. At 25 mg/kg/day, there were no adverse findings. Ptyalism was considered to be related to the treatment with the test item but of minor toxicological significance.
There were no effects on the mean number of days taken to mate (i.e.pre-coital time). When compared with control, there were lower mating and fertility indexes at 100/80 mg/kg/day. At these dose-levels, mating and/or fertility indexes were below the lower limit of the Historical Control Data. Therefore these findings were considered to be test-item treatment related and toxicologically significant. There were no adverse effects at 25 and 50 mg/kg/day. When compared with controls, there were no effects on mean duration of gestation and no adverse effects at 25 mg/kg/day on gestation and delivery data. At 100/80 mg/kg/day, the severe mortality and the limited number of dams makes hazardous any comparison with the control group and Historical Control Data. At 50 mg/kg/day and when compared with controls, there was a low mean number of pups delivered at birth (10.9 vs. 14.0, p<0.05). At this dose-level the mean number of pups delivered was also below the lower limit of the Historical Control Data. This finding was considered to be related to the test-item treatment and adverse.
In the offspring, at 100/80 mg/kg/day and when compared with controls there was a marked increased in the number of found dead, moribund and cannibalized pups as well as in the incidence of litters affected (5/6 vs. 3/10). These findings were considered to be test item treatment related and adverse. At 100/80 mg/kg/day and when compared with controls there was a marked increase in pups cold to the touch and with a few milk in the stomach as well as in the incidence of litters affected (3/6 vs. 2/10). These findings were considered to be the consequence of abnormal maternal behavior, to be test item treatment related and adverse. There were no external abnormalities.
Based on the experimental conditions of this study:
- The No Observed Adverse Effect Level (NOAEL) for parental toxicity was considered to be 50 mg/kg/day (based on mortality and clinical recorded for both sexes at 100/80 mg/kg/day),
- The NOAEL for reproductive performance (mating, fertility and delivery data) was considered to be 25 mg/kg/day (based on the lower number of pups delivered from 50 mg/kg/day),
- The NOAEL for toxic effects on progeny was considered to be 50 mg/kg/day (on the low pup viability at 100/80 mg/kg/day).
Reference
There were no unscheduled deaths in the control, 25 or 50 mg/kg/day groups. Test item treatment related deaths were recorded in 2/10 males and 8/10 females from the 100/80 mg/kg/day group. Before sacrifice for ethical reason or in the found dead rats, piloerection, round back, emaciated appearance, hypoactivity, loud breathing, abdominal breathing, dyspnea, ptyalism, half closed eyes and/or chromorhinorrhea were observed in most animals. Changes were observed in the lungs, spleen, stomach, ileum, cecum and/or vagina and these findings were considered to be agonal and/or to have contributed to the death or the moribund status of these animals, but the cause of death could not be ascertained.
- Clinical signs:
In the 100/80 mg/kg/day group, piloerection and round back were considered to be test-item treatment related and adverse. In the 50 mg/kg/day, round back was considered to be test-item treatment related and adverse. At 25 mg/kg/day, there were no adverse findings. Ptyalism was considered to be related to the treatment with the test item but of minor toxicological significance.
- Body weight and mean body weight change:
When compared with controls, there were no adverse effects on mean body weight or mean body weight change, both in males and females.
- Food consumption:
When compared with controls, there were no adverse effects on mean food consumption.
- Mating and fertility data:
There were no effects on the mean number of days taken to mate (i.e. pre-coital time). When compared with control, there were lower mating and fertility indexes at 100/80 mg/kg/day. At these dose-levels, mating and/or fertility indexes were below the lower limit of the Historical Control Data. Therefore these findings were considered to be test-item treatment related and toxicologically significant. There were no adverse effects at 25 and 50 mg/kg/day.
- Gestation and Delivery data:
When compared with controls, there were no effects on mean duration of gestation and no adverse effects at 25 mg/kg/day on gestation and delivery data. At 100/80 mg/kg/day, the severe mortality and the limited number of dams makes irrelevant any comparison with the control group and Historical Control Data. At 50 mg/kg/day and when compared with controls, there was a low mean number of pups delivered at birth (10.9 vs. 14.0, p<0.05). At this dose-level the mean number of pups delivered was also below the lower limit of the Historical Control Data. This finding was considered to be related to the test-item treatment and adverse.
- Pathology:
There were no organ weights changes related to the test item. There were no macroscopic or microscopic changes noted in the testes, epididymides and ovaries in animals treated at 100/80 mg/kg/day or at 50 mg/kg/day.
At 100/80 mg/kg/day and when compared with controls there was a marked increased in the number of found dead, moribund and cannibalized pups as well as in the incidence of litters affected (5/6 vs. 3/10). These findings were considered to be test item treatment related and adverse.
- Pups clinical signs and external abnormalities:
At 100/80 mg/kg/day and when compared with controls there was a marked increase in pups cold to the touch and with a few milk in the stomach as well as in the incidence of litters affected (3/6 vs. 2/10). These findings were considered to be the consequence of abnormal maternal behavior, to be test item treatment related and adverse. There were no external abnormalities.
- Pup viability:
There were no effects on the live birth, viability and lactation indexes up to 50 mg/kg/day.
- Pup body weight:
There were no adverse effect on mean pup body weight and mean pup body weight change.
- Pup sex ratio:
There were no effects on the mean percentage of male fetuses (sex-ratio).
- Test item concentrations:
Dose formulations analyzed in weeks 1, 3 and 6 remained within an acceptable range of -6.1% to +5.3% when compared to the nominal values ( ± 10% of the nominal concentrations).
On weeks 1 and 3, no test item was observed in the control dose formulation. On week 6, a peak was observed at the test item retention time. However, it was below the limit of quantification (< 0.0001 mg/mL) and was considered as negligible.
Effect on fertility: via oral route
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- NOAEL
- 25 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rat
- Quality of whole database:
- GLP OECD 421-compliant study
Effect on fertility: via inhalation route
- Endpoint conclusion:
- no study available
Effect on fertility: via dermal route
- Endpoint conclusion:
- no study available
Additional information
GM 102 E was tested in an OECD 421 -compliant study and administered daily by oral gavage to male and female Sprague‑Dawley rats, for 2 weeks before mating, during mating, and until sacrifice (for males) or throughout gestation and until day 4post-partum(for females), at dose-levels of 25, 50 or 100/80 mg/kg/day.
In the offspring, at 100/80 mg/kg/day and when compared with controls there was a marked increased in the number of found dead, moribund and cannibalized pups as well as in the incidence of litters affected (5/6 vs. 3/10). These findings were considered to be test item treatment related and adverse.At 100/80 mg/kg/day and when compared with controls there was a marked increase in pups cold to the touch and with a few milk in the stomach as well as in the incidence of litters affected (3/6 vs. 2/10). These findings were considered to be the consequence of abnormal maternal behavior, to be test item treatment related and adverse. There were no external abnormalities.
Based on the experimental conditions of this study, the NOAEL for reproductive performance (mating, fertility and delivery data) was considered to be 25 mg/kg/day (based on the lower number of pups delivered from 50 mg/kg/day).
Short description of key information:
In an OECD 421-compliant study, the NOAEL for reproductive performance (mating, fertility and delivery data) was considered to be 25 mg/kg/day, based on the lower number of pups delivered from 50 mg/kg/day on.
Justification for selection of Effect on fertility via oral route:
Only one study available
Effects on developmental toxicity
Effect on developmental toxicity: via oral route
- Endpoint conclusion:
- no study available
Effect on developmental toxicity: via inhalation route
- Endpoint conclusion:
- no study available
Effect on developmental toxicity: via dermal route
- Endpoint conclusion:
- no study available
Justification for classification or non-classification
Decrease in the number of pups delivered has been observed in an OECD 421 -compliant screening test in rats administered GM 102E by oral route, in accordance with REACH Annex VIII test requirements. The NOAEL for these effects was set at 25 mg/kg bw/day. The derivation of DNELs was based on this source study to protect workers from potential effects on reproduction. However, no classification is warranted as long as such findings have not been confirmed through a full and reliable reproductive and developmental toxicity study.
Additional information
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
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