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EC number: 270-219-6 | CAS number: 68413-47-8
- 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
Description of key information
Repeated dose toxicity (oral) – 14 day
Administration of Butanedioic acid, (dipropoxyphosphinothioyl)thio]-,1,4-dibutyl ester to male and female Crl:CD(SD) rats was not well tolerated at dosage levels of 250, 500, and 1000 mg/kg/day, as evidenced by moribundity, mortality, and/or adverse clinical observations. All rats in the 1000 mg/kg/day group were found dead or euthanised in extremis by Study Day 2. Lower mean body weight gain was noted for males at 500 mg/kg/day during Study Days 0–4. Beginning on Study Day 5, animals administered 50 or 100 mg/kg/day exhibited no noteworthy clinical observations through Study Day 14. Mean body weights, body weight gains, and food consumption were generally unaffected by test substance administration at 0/50, 250, 500/100 mg/kg/day. Based on these results, dosage levels of 15, 50, and 150 mg/kg/day were selected for a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test (OECD 422) in male and female Crl:CD(SD) rats (Charles River Laboratories, 2017).
Repeated dose toxicity (oral) – 28 day
No test substance-related effects for Butanedioic acid, 2-(dipropoxyphosphinothioyl)thio]-, 1,4-dibutyl esterwere observed on F0 male and female fertility and mating indices, F0 male copulation index, F0 female conception index, gestation length, parturition, or reproductive organs at any dosage level, therefore, dosage levels of 150 mg/kg/day for males and 100 mg/kg/day for females, the highest doses tested, were considered to be the no-observed-adverse-effect levels (NOAEL) for reproductive toxicity. Test substance-related mortality, moribundity, and adverse clinical observations (hypoactivity, tremors, ataxia, clonic convulsions, and thin body) were noted for females at 150 mg/kg/day, resulting in the reduction of the dosage level to 100 mg/kg/day on Study Day 13. Following the reduction in dosage level for females, a single female in the 150/100 mg/kg/day group was euthanised in extremis. There were no adverse test substance-related clinical observations for males at 150 mg/kg/day or effects on body weights and food consumption for males and females at any dosage level. Test substance-related higher heart weights (absolute and relative to brain and body weights) were noted in the 150/100 mg/kg/day group F0 females. There were no adverse effects on clinical pathology parameters, thyroid hormones, or macroscopic/microscopic alterations in F0 males and females at any dosage level. Based on these results, the NOAELs for systemic toxicity were considered to be 150 mg/kg/day for males, the highest dose tested, and 50 mg/kg/day for females. The NOAEL for neonatal toxicity was 100 mg/kg/day, the highest dose tested, based on the absence of effects on F1 offspring at all dosage levels. (Charles River Laboratories, 2018).
Key value for chemical safety assessment
Repeated dose toxicity: via oral route - systemic effects
Link to relevant study records
- Endpoint:
- repeated dose toxicity: oral, other
- Remarks:
- Fourteen day repeated dose oral (gavage) range-finding toxicity study in the rat conducted as part of OECD 422 study, under GLP conditions.
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Study period:
- 22 December 2016 - 10 July 2017
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other:
- Remarks:
- Range find study conducted as part of OECD 422 study, under GLP conditions.
- Qualifier:
- according to guideline
- Guideline:
- other: Range-Finding Toxicity Study in the Rat, to inform dose selection in an OECD Guideline 422 study.
- Principles of method if other than guideline:
- The study described in this report was conducted in a facility which operates in accordance with Good Laboratory Practice principles, however no claim of GLP compliance was intended nor is made for this study.
- GLP compliance:
- no
- Limit test:
- no
- Specific details on test material used for the study:
- - Description: Light yellow, clear liquid
- Storage: Room temperature (18 - 24°C), protected from light - Species:
- rat
- Strain:
- other: Crl:CD(SD)
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories, Inc.
- Age at first dose: Approximately 10 weeks of age at the initiation of dose
administration.
- Weight at first dose: 343 g to 387 g for males and from 221 g to 251 g for females on Study Day 0
- Housing: Clean, solid-bottom cages with bedding material (Bed O’Cobs®)
- Bedding: See above
- Feed: PMI Nutrition International, LLC Certified Rodent LabDiet® 5002 offered ad libitum
- Water: Filtered water was provided ad libitum
- Acclimation period: A minimum of 15 days for acclimation purposes
ENVIRONMENTAL CONDITIONS
- Temperature Range: 20 to 26°C
- Humidity Range: 33.7 to 48.5%
- Light Cycle: 12-hour light/12-hour dark
- Air Changes: Minimum of 10 air changes per hour - Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on oral exposure:
- Test substance formulations and vehicle control were stirred continuously at room temperaturefor the duration of the dosing.
- Analytical verification of doses or concentrations:
- no
- Details on analytical verification of doses or concentrations:
- Homogeneity, stability, and concentration of the test substance formulations were not assessed on this non-GLP study.
- Duration of treatment / exposure:
- 14 days
- Frequency of treatment:
- Once daily during Study Days 0–2 at dosage levels of 0, 250, 500, and 1000 mg/kg/day
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Dose / conc.:
- 50 mg/kg bw/day (nominal)
- Dose / conc.:
- 250 mg/kg bw/day (nominal)
- Dose / conc.:
- 500 mg/kg bw/day (nominal)
- Remarks:
- Only dosed at this level on day 0 - 2
- Dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- Remarks:
- Only dosed at this level for day 0 - 2
- Dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- Remarks:
- Group 4
- Dose / conc.:
- 100 mg/kg bw/day (nominal)
- Remarks:
- Added dose on days 5 - 14
- No. of animals per sex per dose:
- 5
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- The dosage levels were selected following consultation between the Charles River Study Director and the Study Monitor for the Sponsor, with consideration given to the results of a single-dose acute oral toxicity study in which a single dose of undiluted test substance was orally
given to female rats at 2000 mg/kg 1. Hunched posture, diuresis, diarrhea and dehydration were noted in some rats. No mortality and other abnormality were observed. The high dose for this range-finding study will be 1,000 mg/kg/day, as this is the maximum dose level required for the
subsequent combined repeated dose toxicity and reproductive/developmental toxicity screening study in the rat (OECD 422). - Observations and examinations performed and frequency:
- All animals were observed twice daily for mortality and moribundity. Clinical observations, body weights, and food consumption were recorded at the intervals specified in the study protocol. Complete necropsies were conducted on all surviving animals on Study Day 14, and
selected organs were weighed. - Sacrifice and pathology:
- A gross necropsy was conducted on all surviving animals at the scheduled euthanasia on Study Day 14.
All animals were euthanized by carbon dioxide inhalation. Necropsy included examination of the external body surface, all orifices, the cranial cavity, the external surface of the brain, and the abdominal, pelvic, and thoracic cavities, including viscera. Tissues were preserved in 10% neutral-buffered formalin only as indicated by the gross findings. - Statistics:
- All statistical tests were performed using WTDMS™ unless otherwise noted. Analyses were conducted using two-tailed tests (except as noted otherwise) for minimum significance levels of 1% and 5%, comparing each test substance-treated group to the control group. Each mean was presented with the standard deviation (S.D.), standard error (S.E.), and the number of animals(N) used to calculate the mean. Statistical analyses were not conducted if the number of animals was 2 or less. Due to the use of significant figures and the different rounding conventions inherent in the types of software used, the means, standard deviations, and standard errors on the summary and individual tables may differ slightly. Therefore, the use of reported individual values to calculate subsequent parameters or means will, in some instances, yield minor variations from those listed in the report data tables. Body weights, body weight changes, and absolute and relative organ weights were subjected to a parametric one-way ANOVA3 to determine intergroup differences. If the ANOVA revealed significant (p < 0.05) intergroup variance, Dunnett's test was used to compare the test substance-treated groups to the control group.
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Clinical observations noted 1.5 hours after dosing in the 500 and 1000 mg/kgday included tremors, hypoactivity, ataxia, piloerection, decreased respiration rate, labored respiration, red material around the eyes and/or nose, clear material around the mouth, exophthalmia, and/or yellow material around the anogenital area.
There were no remarkable clinical observations noted for surviving animals when the test substance was administered to the 250 mg/kg/day group.
Clinical observations noted for surviving animals at the daily examinations, including scabbing, hair loss, and/or red material on various body surfaces, occurred infrequently and/or in a manner that was not dose-related. - Mortality:
- mortality observed, treatment-related
- Description (incidence):
- During Study Days 0–2, 5 males and 5 females in the 1000 mg/kg/day group were found dead or euthanized in extremis following 1–3 doses of test substance.
Effects on survival were also noted for males and females in the 500 mg/kg/day group, as 2 males and 4 females in this group were found dead or euthanized in extremis on Study Day 2 following 2 doses of test substance.
In the 250 mg/kg/day group, 1 male was found dead on Study Day 11 following a lower body weight gain during Study Days 0–4. Two females in the 250 mg/kg/day group were found dead on Study Days 6 and 14, respectively. There were no remarkable clinical observations noted for the animals in the 250 mg/kg/day group that were found dead. There were no remarkable macroscopic findings for the 250 mg/kg/day group animals that were found dead. - Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Body weights not measure in 1000 mg/kg/day.
A significant (p < 0.05) mean body weight loss was noted in the 500 mg/kg/day group male and females for days 0 - 2. This group recovered when dosing was adjusted to 100 mg/kg/day.
Mean body weights and body weight gains were comparable between the 0/50 and 250 mg/kg/day group males and females. - Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- Evaluation of food consumption not measured in 1000 mg/kg/day group.
Mean food consumption, evaluated as g/animal/day, was comparable between the 0 and 250 mg/kg/day group males and females during Study Days 0–4.
During Study Days 7–14, mean food consumption was comparable between the 0/50, 250, and 500/100 mg/kg/day group males and females. - Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- effects observed, treatment-related
- Description (incidence and severity):
- Tremors, hypoactivity and ataxia were observed in the 500 mg/kg/day dose group.
Tremors, hypoactivity, ataxia, and poloerection were observed in the 1000 mg/kg/day dose group. - Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Description (incidence and severity):
- Mean organ weights (absolute and relative to body final body weight and brain weight) were comparable across the dose groups that were measured.
- Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- At necropsy, remarkable macroscopic findings noted in the males and females found dead or euthanized in extremis in the 1000 mg/kg/day group included dark red discoloration of the adrenal glands, lungs, and pancreas, a pale spleen, and cystic ovaries.
At necropsy, findings for the found dead or euthanized in extremis animals in the 500 mg/kg/day group included dark red discoloration or areas on the adrenal glands, kidneys, lungs, and/or thymus, cystic ovaries, and/or small thyroid gland(s).
There were no remarkable macroscopic findings for the 250 mg/kg/day group animals. - Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- not examined
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 100 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- clinical signs
- Key result
- Critical effects observed:
- not specified
- Conclusions:
- Based on the results, dosage levels of 15, 50, and 150 mg/kg/day were selected for a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test (OECD 422) in male and female Crl:CD(SD) rats.
- Executive summary:
The objective of the study was to determine dosage levels of the test material, to be evaluated in a potential combined repeated dose toxicity study with the reproduction/developmental toxicity screening test (OECD 422) in rats.
The test material in the vehicle (corn oil) was to be administered orally by gavage to 3 groups of 5 Crl:CD(SD) rats, each group consisting of 5 males and 5 females, once daily for 14 consecutive days at dosage levels of 250, 500, and 1000 mg/kg/day. However, due to excessive toxicity noted in the 1000 mg/kg/day group, all animals in this group were found dead or euthanized in extremis by Study Day 2. Mortality and moribundity were also noted in the 500 mg/kg/day group during the first 3 days (Study Days 0–2) of dosing; therefore, an additional
2 males and 4 females were assigned to the 500 mg/kg/day group. The surviving animals in the 500 mg/kg/day group were placed on a dosing holiday for 2 days (Study Days 3 and 4), and then subsequently dosed at a lower dosage level of 100 mg/kg/day during Study Days 5–13. Animals assigned to the 250 mg/kg/day group received the test substance at this dosage level throughout the treatment period (Study Days 0–13). A concurrent control group composed of 5 males and 5 females received the vehicle during Study Days 0–4 and were administered the test substance at a dosage level of 50 mg/kg/day during Study Days 5–13. The dosage volume was 5 mL/kg for all groups. The animals were approximately 10 weeks of age at the initiation of dose administration.
All animals were observed twice daily for mortality and moribundity. Clinical observations, body weights, and food consumption were recorded at the intervals specified in the study protocol. Complete necropsies were conducted on all surviving animals on Study Day 14, and
selected organs were weighed.
Oral administration of the test material to male and female Crl:CD(SD) rats was not well tolerated at dosage levels of 250, 500, and 1000 mg/kg/day as evidenced by moribundity, mortality, and/or adverse clinical observations. All rats in the 1000 mg/kg/day group were found dead or euthanized in extremis by Study Day 2. Lower mean body weight gain was noted for males at 500 mg/kg/day during Study Days 0–4. Beginning on Study Day 5, animals administered 50 or 100 mg/kg/day exhibited no noteworthy clinical observations through Study Day 14. Mean body weights, body weight gains, and food consumption were generally unaffected by test substance administration at 0/50, 250, 500/100 mg/kg/day. Based on these results, dosage levels of 15, 50, and 150 mg/kg/day were selected for a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test (OECD 422) in male and female Crl:CD(SD) rats.
Reference
The following table presents the individual animal data for males and females found dead or euthanized in extremis during the study.
Summary of Individual Findings for Animals Found Dead or Euthanized in Extremis
AnimalNo. |
Dosage Level(mg/kg/day) |
Sex |
Study Day of Death or Euthanasia |
No. of DosesReceived |
Clinical Observations |
Macroscopic Findings |
1959 |
1000 |
M |
EE SD 2 |
3 |
Clear material around mouth |
Dark red discoloration of the adrenal glands |
1971 |
1000 |
M |
FD SD 2 |
2 |
NA |
Dark red discoloration of the adrenal glands, dark red discoloration of the lungs, pale spleen, red matting on the skin in the ocular, nasal, and urogenital areas |
1974 |
1000 |
M |
FD SD 1 |
1 |
NA |
NA |
1977 |
1000 |
M |
FD SD 2 |
2 |
NA |
Dark red discoloration of the adrenal glands, dark red discoloration of the lungs, pale spleen, red matting on the skin in the ocular and nasal areas |
1978 |
1000 |
M |
FD SD 2 |
2 |
NA |
Dark red discoloration of the lungs, pale spleen |
1983 |
1000 |
F |
EE SD 1 |
2 |
NA |
Red matting on the skin in the ocular area |
1989 |
1000 |
F |
EE SD 1 |
2 |
Decreased respiration rate, labored respiration, red material around eyes and nose, yellow material around anogenital area, hypoactivity, red discharge from eye |
Red matting on the skin in the ocular area |
1992 |
1000 |
F |
EE SD 1 |
2 |
Tremors, decreased respiration rate, red discharge from eyes, red material around eyes, clear material around mouth |
Cystic ovary, dark red discoloration of the pancreas, red matting on the skin in theocular area |
1998 |
1000 |
F |
FD SD 1 |
2 |
Hypoactivity, ataxia, tremors, decreased respiration rate, redmaterial around eyes, yellow material around urogenital area, clear materialaround mouth |
Yellow matting of the skin in buccal area and ventral neck, Red matting on the skin ocular area |
FD = Found dead EE = Euthanized in extremis SD = Study Day
NA = Not applicable; no remarkable clinical or macroscopic observations were noted
Summary of Individual Findings for Animals Found Dead or Euthanized in Extremis (Continued)
AnimalNo. |
Dosage Level(mg/kg/day) |
Sex |
Study Day of Death or Euthanasia |
No. of DosesReceived |
Clinical Observations |
Macroscopic Findings |
2001 |
1000 |
F |
FD SD 1 |
2 |
Piloerection, ataxia, decreased respiration rate, red material around eye, exophthalmus (bilateral), yellow material around the urogenital area, broken tail, clear material around mouth, tremors |
Yellow matting on the skin in nasal and buccal and ventral neck, red matting of the skin ocular area |
1965 |
500 |
M |
FD SD 2 |
2 |
NA |
Dark red discoloration of the adrenal glands, renal pelvis, lungs, and thymus, red matting on the skin in the ocular and nasal areas |
1981 |
500 |
M |
FD SD 2 |
2 |
NA |
Dark red discoloration of the lungs, red matting on the skin in the nasal area, dark red areas on the thymus |
1991 |
500 |
F |
FD SD 2 |
2 |
NA |
Dark red discoloration of the lungs, red matting on the skin in the ocular area |
1993 |
500 |
F |
FD SD 2 |
2 |
NA |
Dark red discoloration of the adrenal glands, red matting on theskin in the ocular and nasal areas, small thyroids |
1997 |
500 |
F |
EE SD 2 |
2 |
Tremors, ataxia, decreased respiration rate, red material around eyes |
Red matting on the skin in the ocular area |
2000 |
500 |
F |
EE SD 2 |
2 |
Tremors, hypoactivity, ataxia, decreased respiration rate, clear or red discharge from eyes, red material around eyes |
Dark red discoloration of the adrenal glands, red matting of the skin in the ocular area |
1963 |
250 |
M |
FD SD 11 |
11 |
NA |
NA |
1990 |
250 |
F |
FD SD 6 |
6 |
NA |
NA |
2005 |
250 |
F |
FD SD 14 |
14 |
NA |
NA |
FD = Found dead EE = Euthanized in extremis SD = Study Day
NA = Not applicable; no remarkable clinical or macroscopic observations were noted
All other animals survived to the scheduled necropsy.
There were no remarkable clinical observations noted for surviving animals when the test substance was only administered to the 250 mg/kg/day group (dosing holiday for Group 3) during Study Days 3 and 4. Following the adjustment of dosage levels on Study Day 5, clinical observations noted approximately 1.5 hours following dose administration were limited to clear or red material around the nose or mouth for 2 males in the 250 mg/kg/day group and 1 female inthe 0/50 mg/kg/day group. Clinical observations noted for surviving animals at the daily examinations, including scabbing, hair loss, and/or red material on arious body surfaces, occurred infrequently and/or in a manner that was not dose-related.
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- NOAEL
- 50 mg/kg bw/day
- Study duration:
- subchronic
- Species:
- rat
- Quality of whole database:
- 1
Repeated dose toxicity: inhalation - systemic effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: inhalation - local effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: dermal - systemic effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: dermal - local effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Additional information
Repeated dose toxicity (oral) – 14 day
Key study:
In an OECD Guideline 422 Study (14 day), conducted according to GLP, oral administration of Butanedioic acid, (dipropoxyphosphinothioyl)thio]-,1,4-dibutyl ester to male and female Crl:CD(SD) rats was not well tolerated at dosage levels of 250, 500, and 1000 mg/kg/day, as evidenced by moribundity, mortality, and/or adverse clinical observations. All rats in the 1000 mg/kg/day group were found dead or euthanised in extremis by Study Day 2. Lower mean body weight gain was noted for males at 500 mg/kg/day during Study Days 0–4. Beginning on Study Day 5, animals administered 50 or 100 mg/kg/day exhibited no noteworthy clinical observations through Study Day 14. Mean body weights, body weight gains, and food consumption were generally unaffected by test substance administration at 0/50, 250, 500/100 mg/kg/day. Based on these results, dosage levels of 15, 50, and 150 mg/kg/day were selected for a combined repeated dose toxicity study with the reproduction/developmental toxicity screening test (OECD 422) in male and female Crl:CD(SD) rats (Charles River Laboratories, 2017).
Repeated dose toxicity (oral) - 28 day
Key study:
In an OECD Guideline 422 Study (28 day screening study), no test substance-related effects forButanedioic acid, 2-[(dipropoxyphosphinothioyl)thio]-, 1,4-dibutyl esterwere observed on F0 male and female fertility and mating indices, F0 male copulation index, F0 female conception index, gestation length, parturition, or reproductive organs at any dosage level, therefore, dosage levels of 150 mg/kg/day for males and 100 mg/kg/day for females, the highest doses tested, were considered to be the no-observed-adverse-effect levels (NOAEL) for reproductive toxicity. Test substance-related mortality, moribundity, and adverse clinical observations (hypoactivity, tremors, ataxia, clonic convulsions, and thin body) were noted for females at 150 mg/kg/day, resulting in the reduction of the dosage level to 100 mg/kg/day on Study Day 13. Following the reduction in dosage level for females, a single female in the 150/100 mg/kg/day group was euthanised in extremis. There were no adverse test substance-related clinical observations for males at 150 mg/kg/day or effects on body weights and food consumption for males and females at any dosage level. Test substance-related higher heart weights (absolute and relative to brain and body weights) were noted in the 150/100 mg/kg/day group F0 females. There were no adverse effects on clinical pathology parameters, thyroid hormones, or macroscopic/microscopic alterations in F0 males and females at any dosage level. Based on these results, the NOAELs for systemic toxicity were considered to be 150 mg/kg/day for males, the highest dose tested, and 50 mg/kg/day for females. The NOAEL for neonatal toxicity was 100 mg/kg/day, the highest dose tested, based on the absence of effects on F1 offspring at all dosage levels.(Charles River Laboratories, 2018).
Justification for classification or non-classification
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