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EC number: 202-625-6 | CAS number: 97-99-4
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
![](https://poisoncentres.echa.europa.eu/o/diss-blank-theme/images/factsheets/A-REACH/factsheet/print_toxicological-information.png)
Endpoint summary
Administrative data
Description of key information
Key value for chemical safety assessment
Repeated dose toxicity: via oral route - systemic effects
Link to relevant study records
- Endpoint:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1992-02-19 to 1993-01-25
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study
- Reason / purpose for cross-reference:
- reference to same study
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
- Principles of method if other than guideline:
- No guideline stated, broadly similar to OECD 408.
- GLP compliance:
- yes
- Limit test:
- no
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Labs, Portage, MI, USA
- Age at study initiation: approx 23 days
- Housing: 1/wire mesh cage
- Diet: standard diet (Purina Certified Rodent Chow #5002
- Water: drinking water ad libitum
- Acclimation period: 20 days, including pretest
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 67-75 deg F
- Humidity (%): 29-88 (said not to have affected results)
- Air changes (per hr): 12h/ 12h
- Photoperiod (hrs dark / hrs light):
IN-LIFE DATES: From: 1992-02-19 To: 1992-05-22 - Route of administration:
- oral: feed
- Vehicle:
- other: standard diet
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
DIET PREPARATION
- Rate of preparation of diet (frequency): diet offered fresh weekly - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Three samples were taken from the 500 and 10,000 ppm diets to determine homogeneity, stability (for 7 and 14 days). Samples were taken from the middle of each control and test diet on the day of preparation during weeks 0, 1, 2, 3, 7 and 12 to determine concentration of test substance.
Individual food consumption was measured weekly and the mean daily dose calculated for each dose group using body weight. - Duration of treatment / exposure:
- 91-93 days
- Frequency of treatment:
- diet ad libitum
- Dose / conc.:
- 35 mg/kg bw/day (actual dose received)
- Remarks:
- males: equivalent to 500ppm
- Dose / conc.:
- 69 mg/kg bw/day (actual dose received)
- Remarks:
- males: equivalent to 1000ppm
- Dose / conc.:
- 339 mg/kg bw/day (actual dose received)
- Remarks:
- males: equivalent to 5000ppm
- Dose / conc.:
- 673 mg/kg bw/day (actual dose received)
- Remarks:
- males: equivalent to 10000ppm
- Dose / conc.:
- 42 mg/kg bw/day (actual dose received)
- Remarks:
- females: equivalent to 500ppm
- Dose / conc.:
- 84 mg/kg bw/day (actual dose received)
- Remarks:
- females: equivalent to 1000ppm
- Dose / conc.:
- 401 mg/kg bw/day (actual dose received)
- Remarks:
- females: equivalent to 5000ppm
- Dose / conc.:
- 781 mg/kg bw/day (actual dose received)
- Remarks:
- females: equivalent to 10000ppm
- No. of animals per sex per dose:
- 20
- Control animals:
- yes, plain diet
- Details on study design:
- - Dose selection rationale:
- Rationale for animal assignment: computer randomized - Positive control:
- no
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly
BODY WEIGHT: Yes
- Time schedule for examinations: weekly (from wk -1)
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: prior to treatment and week 12
- Dose groups that were examined: all groups
HAEMATOLOGY: Yes
- Time schedule for collection of blood: at necropsy (13 wk)
- Anaesthetic used for blood collection: No data
- Animals fasted: Yes
- How many animals: 10/sex/dose
- Parameters checked in table No.1 were examined.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood:
- Animals fasted: Yes
- How many animals: 10/sex/dose
- Parameters checked in table No.1 were examined.
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: No - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes (see table 2) - Statistics:
- All analyses were conducted using 2-tailed tests for minimum significance levels 1% and 5% comparing treated groups with controls by sex. Body weights, food consumption, clinical laboratory parameters, absolute and relative organ weights: 1-way analyis of variance and Dunnett's test.
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- no deaths, rectal mucous exudate.
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- no deaths, rectal mucous exudate.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- significant reduction in final body weight in males at 1000 ppm and above and in females at 5000 ppm and above
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- reduced food consumption at 5000 ppm in males and 10000 ppm in both sexes
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- dose-related effects at 5000 ppm and above in both sexes
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- dose-related effects at 5000 ppm and above in both sexes
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- lower testis, epididimal and prostate weight (5000 and/or 10,000 ppm)
- Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- testis: small and/or soft at 5000 ppm and above
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- testis: dose-related degenerationof germinal epithelium of seminiferous tubules and interstitial oedema at 5000 ppm and above. Adhesions of the spleen at these doses and capsular fibrosis (focal) sporadically in all treated groups.
- Histopathological findings: neoplastic:
- no effects observed
- Details on results:
- CLINICAL SIGNS AND MORTALITY
No deaths.
Rectal mucous exudate sporadically at 5000 ppm and above.
BODY WEIGHT AND WEIGHT GAIN
Significant reduction in final body weight in males at 1000 ppm and above and in females at 10,000 ppm (p<0.01 in both cases). Dose-related decreases (statistically significant in some cases) in mean body weights (compared to control) and body weight gains in all treated male groups (500 ppm and above) and in females in the top two dose groups.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
Reduced food consumption at 5000 ppm in males and 10,000 ppm in both sexes. Dose-related decrease in mean food consumption in treated male groups.
OPHTHALMOSCOPIC EXAMINATION
No treatment-related effects.
HAEMATOLOGY
Dose-related effects at 5000 ppm and above in both sexes: decreased haemoglobin, MCH, MCHC and platelet counts. Slightly reduced MCV values in females at 5000 ppm and above.
CLINICAL CHEMISTRY
Dose-related effects at 5000 ppm and above in both sexes: dose-related reduction in total protein and globulin, and increased A/G ratio at 5000 ppm and above in both sexes. Albumin was reduced in females at 10,000 ppm.
ORGAN WEIGHTS
Reduced testis and epididimal weight (mean absolute and relative) at 5000 ppm and above in males, lower prostate weight (mean absolute and relative) at 10,000 ppm (all p<0.01 or 0.05, except mean relative testis weight at 5000 ppm). Absolute seminal vesicle weights were lower at 5000 ppm and above, and absolute prostate weight was lower at 1000 and above. Differences in liver weights were not considered treatment-related due to inconsistency between the responses of the sexes. No other treatment-related differences reported.
GROSS PATHOLOGY
Testis: small and/or soft at 5000 ppm and above
HISTOPATHOLOGY: NON-NEOPLASTIC
Testis: dose-related degeneration of germinal epithelium of seminiferous tubules and interstitial (peritubular) oedema at 5000 ppm and above.
Epididymides: empty or fluid filled tubules with accumulation of cellular debris seen in all 10,000 ppm males and some 5000 ppm males.
Spleen: adhesion to mesentery, abdominal wall or adipose tissue sporadically at 5000 ppm and above (both sexes). Capsular fibrosis (focal) sporadically in all treated groups. The investigators noted that while this effect may have been treatment-related its toxicological significance was not known. - Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 500 ppm
- Based on:
- other: in the diet
- Sex:
- male
- Basis for effect level:
- other: mean measured dose 35 mg/kg bw/day
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 ppm
- Based on:
- other: in the diet
- Sex:
- female
- Basis for effect level:
- other: mean measured dose 84 mg/kg bw/day
- Critical effects observed:
- not specified
- Conclusions:
- A well reported 90-day dietary study, conducted in the main according to the current guideline and in accordance with GLP, identified NOAELs of 500 ppm and 1000 ppm in the diet in male and female rats, respectively. This dietary intake was equivalent to mean measured intakes of 35 and 84 mg THFA/kg bw/day, in males and females. Reduced body weights were reported at the next highest dietary concentration in both cases. The testis was the major target organ.
Reference
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- NOAEL
- 35 mg/kg bw/day
- Study duration:
- subchronic
- Species:
- rat
- Quality of whole database:
- In addition to the key study two further oral studies in the rat (MHLW, 2004a, MHLW, 2004b) provided results that closely support the findings of the key oral study. Both were conducted according to a standard guideline and GLP, meriting a reliability score of 1 (reliable without restriction).
A 28-day oral gavage study (MHLW, 2004a) reported a NOAEL of 40 mg/kg bw/day in both sexes, with effects on the testis, thymus, spleen, kidney, or clinical chemistry and haematology parameters at 150 mg/kg bw/day, and above. A combined repeated-dose and reproductive/developmental toxicity screening test (MHLW, 2004b), in which rats were treated via gavage for around 50 days, identified a NOAEL for both sexes in the parental generation of 50 mg/kg bw/day in both sexes, with effects to the thymus, spleen, testis and body weights at 150 mg/kg bw/day, and above.
Two further studies involving 90-day adminsitration of THFA in the diet to rats and dogs (Industrial Biotest, 1970) were considered unreliable and not considered. - System:
- male reproductive system
- Organ:
- testes
Repeated dose toxicity: inhalation - systemic effects
Link to relevant study records
- Endpoint:
- sub-chronic toxicity: inhalation
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1994-10-03 to 1995-01-26
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Reason / purpose for cross-reference:
- reference to same study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Labs, Portage, MI, USA
- Age at study initiation: 6 wk
- Weight at study initiation: 155-203 (m); 129-159 (f) g
- Fasting period before study: no data
- Housing: 1/wire mesh cage
- Diet: standard diet at libitum
- Water: drinking water ad libitum
- Acclimation period: 12 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 72 +/- 4 deg F
- Humidity (%): 30-70
- Photoperiod (hrs dark / hrs light): 12 h/12 h
IN-LIFE DATES: From: To: 1994-10-03 to around 1995-01-03 - Route of administration:
- inhalation: vapour
- Type of inhalation exposure:
- whole body
- Vehicle:
- clean air
- Details on inhalation exposure:
- GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 0.5 m3 stainless steel and glass inhalation chambers, dynamic operation
- Source and rate of air: filtered air, 12-15 chamber volumes/hr
- Temperature, humidity, pressure in air chamber: 19.7-25.8 deg C; 19-85 % RH
- Air change rate: 12-15 chamber volumes/hr
TEST ATMOSPHERE
- Brief description of analytical method used: infrared spectoscopic method , examination 3 times daily (no findings given in Volumer 1 of report) - Analytical verification of doses or concentrations:
- not specified
- Duration of treatment / exposure:
- 6 hr/day, 5 days/wk, at least 65 exposures (equivalent to 13 weeks)
- Frequency of treatment:
- daily on weekdays
- Dose / conc.:
- 50 ppm (nominal)
- Dose / conc.:
- 150 ppm (nominal)
- Dose / conc.:
- 500 ppm (nominal)
- No. of animals per sex per dose:
- 10, with a further 4 males per concentration to examine spermatogenic effects
- Control animals:
- yes, concurrent vehicle
- Positive control:
- no
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice per day
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once/week
BODY WEIGHT: Yes
- Time schedule for examinations: weekly
FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes, weekly
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: weeks 0 and 12
HAEMATOLOGY: Yes
- Time schedule for collection of blood: weeks 3, 13
- Anaesthetic used for blood collection:No data
- Animals fasted: Yes
- How many animals: all survivors from main groups (10/sex/concentration)
- Parameters checked in table 1 were examined.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood:
- Animals fasted: Yes
- How many animals: all survivors from main groups (10/sex/concentration)
- Parameters checked in table 1 were examined.
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: No
OTHER: examination of groups of 4 males at week 6 and 10 males at week 13, at each concentration, for effects on spermatogenic endpoints - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes see table 2
HISTOPATHOLOGY: Yes see table 2 - Statistics:
- 2-tailed tests for minimum significance levels of 1% and 5%, comparing treatment groups to the vehicle control. Body weight, weight change, food consumption, clinical laboratory, spermatogenic and organ weight data were subjected to a 1-way analysis of variance and Dunnett’s test.
- Clinical signs:
- effects observed, treatment-related
- Mortality:
- mortality observed, treatment-related
- Body weight and weight changes:
- effects observed, treatment-related
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- effects observed, treatment-related
- Clinical biochemistry findings:
- no effects observed
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- testis
- Details on results:
- CLINICAL SIGNS AND MORTALITY
1/10 females died in at 50 ppm during week 0, the cause of death was not found to be treatment-related. The predominant clinical finding was intermittent whole-body spasms in all treated groups that were frequent and exposure-related. Hypoactivity and excessive grooming were occasionally observed in males and females at 500 ppm. One hour after exposure, concentration-related hyperactivity was reported in all treated groups, and yellow urogenital matting and salivation at 500 ppm.
BODY WEIGHT AND WEIGHT GAIN
Mean body weight gains were lower than controls in males at 150 and 500 ppm (9.2% and 13.3%, respectively).
FOOD CONSUMPTION
Mean food consumption was generally lower in mid and high exposure males throughout the study
OPHTHALMOSCOPIC EXAMINATION
No treatment-related observations.
HAEMATOLOGY
Several statistically significant treatment-related changes were reported after exposure to 500 ppm. Platelet and haemoglobin means were significantly reduced in both sexes (study weeks 3 and/or 13). MCH (mean cell haemoglobin) was reduced in males (weeks 3 and 13) and females (week 13); MCHC (mean corpuscular haemoglobin concentration) was reduced in males (week 13) and females (week 3).
CLINICAL CHEMISTRY
No treatment-related effect.
ORGAN WEIGHTS
Prostate weight (absolute and relative) were lower than controls in 150 and 500 ppm groups. The weights of seminal vesicles (absolute) and epididymides (absolute and relative) were lower at 500 ppm.
GROSS PATHOLOGY
No macroscopic lesions in any exposure group.
HISTOPATHOLOGY: NON-NEOPLASTIC
Spermatogenic findings: reduced epididymal sperm numbers and motility, and a higher incidence of morphological abnormalities were seen in 500 ppm males at weeks 6 and 13. Multifocal atrophy of the testes was reported in a single male at 500 ppm. - Dose descriptor:
- NOAEC
- Effect level:
- 50 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: whole body spasm and hyperactivity, and other effects.
- Remarks on result:
- not determinable
- Remarks:
- no NOAEC identified
- Dose descriptor:
- LOAEC
- Effect level:
- 50 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: around 0.2 mg/l
- Critical effects observed:
- not specified
- Conclusions:
- A well reported 90-day rat inhalation study, conducted according to the current guideline and in accordance with GLP, did not identify a NOAEC value. Clinical observations (including spasm) were evident at the lowest tested nominal concentration of 50 ppm (around 0.2 mg/l).
Reference
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- LOAEC
- 209 mg/m³
- Study duration:
- subchronic
- Species:
- rat
- Quality of whole database:
- No other inhalation studies were identified.
- System:
- male reproductive system
- Organ:
- testes
Repeated dose toxicity: inhalation - local effects
Link to relevant study records
- Endpoint:
- sub-chronic toxicity: inhalation
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1994-10-03 to 1995-01-26
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Reason / purpose for cross-reference:
- reference to same study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Labs, Portage, MI, USA
- Age at study initiation: 6 wk
- Weight at study initiation: 155-203 (m); 129-159 (f) g
- Fasting period before study: no data
- Housing: 1/wire mesh cage
- Diet: standard diet at libitum
- Water: drinking water ad libitum
- Acclimation period: 12 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 72 +/- 4 deg F
- Humidity (%): 30-70
- Photoperiod (hrs dark / hrs light): 12 h/12 h
IN-LIFE DATES: From: To: 1994-10-03 to around 1995-01-03 - Route of administration:
- inhalation: vapour
- Type of inhalation exposure:
- whole body
- Vehicle:
- clean air
- Details on inhalation exposure:
- GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 0.5 m3 stainless steel and glass inhalation chambers, dynamic operation
- Source and rate of air: filtered air, 12-15 chamber volumes/hr
- Temperature, humidity, pressure in air chamber: 19.7-25.8 deg C; 19-85 % RH
- Air change rate: 12-15 chamber volumes/hr
TEST ATMOSPHERE
- Brief description of analytical method used: infrared spectoscopic method , examination 3 times daily (no findings given in Volumer 1 of report) - Analytical verification of doses or concentrations:
- not specified
- Duration of treatment / exposure:
- 6 hr/day, 5 days/wk, at least 65 exposures (equivalent to 13 weeks)
- Frequency of treatment:
- daily on weekdays
- Dose / conc.:
- 50 ppm (nominal)
- Dose / conc.:
- 150 ppm (nominal)
- Dose / conc.:
- 500 ppm (nominal)
- No. of animals per sex per dose:
- 10, with a further 4 males per concentration to examine spermatogenic effects
- Control animals:
- yes, concurrent vehicle
- Positive control:
- no
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice per day
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once/week
BODY WEIGHT: Yes
- Time schedule for examinations: weekly
FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes, weekly
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: weeks 0 and 12
HAEMATOLOGY: Yes
- Time schedule for collection of blood: weeks 3, 13
- Anaesthetic used for blood collection:No data
- Animals fasted: Yes
- How many animals: all survivors from main groups (10/sex/concentration)
- Parameters checked in table 1 were examined.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood:
- Animals fasted: Yes
- How many animals: all survivors from main groups (10/sex/concentration)
- Parameters checked in table 1 were examined.
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: No
OTHER: examination of groups of 4 males at week 6 and 10 males at week 13, at each concentration, for effects on spermatogenic endpoints - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes see table 2
HISTOPATHOLOGY: Yes see table 2 - Statistics:
- 2-tailed tests for minimum significance levels of 1% and 5%, comparing treatment groups to the vehicle control. Body weight, weight change, food consumption, clinical laboratory, spermatogenic and organ weight data were subjected to a 1-way analysis of variance and Dunnett’s test.
- Clinical signs:
- effects observed, treatment-related
- Mortality:
- mortality observed, treatment-related
- Body weight and weight changes:
- effects observed, treatment-related
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- effects observed, treatment-related
- Clinical biochemistry findings:
- no effects observed
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- testis
- Details on results:
- CLINICAL SIGNS AND MORTALITY
1/10 females died in at 50 ppm during week 0, the cause of death was not found to be treatment-related. The predominant clinical finding was intermittent whole-body spasms in all treated groups that were frequent and exposure-related. Hypoactivity and excessive grooming were occasionally observed in males and females at 500 ppm. One hour after exposure, concentration-related hyperactivity was reported in all treated groups, and yellow urogenital matting and salivation at 500 ppm.
BODY WEIGHT AND WEIGHT GAIN
Mean body weight gains were lower than controls in males at 150 and 500 ppm (9.2% and 13.3%, respectively).
FOOD CONSUMPTION
Mean food consumption was generally lower in mid and high exposure males throughout the study
OPHTHALMOSCOPIC EXAMINATION
No treatment-related observations.
HAEMATOLOGY
Several statistically significant treatment-related changes were reported after exposure to 500 ppm. Platelet and haemoglobin means were significantly reduced in both sexes (study weeks 3 and/or 13). MCH (mean cell haemoglobin) was reduced in males (weeks 3 and 13) and females (week 13); MCHC (mean corpuscular haemoglobin concentration) was reduced in males (week 13) and females (week 3).
CLINICAL CHEMISTRY
No treatment-related effect.
ORGAN WEIGHTS
Prostate weight (absolute and relative) were lower than controls in 150 and 500 ppm groups. The weights of seminal vesicles (absolute) and epididymides (absolute and relative) were lower at 500 ppm.
GROSS PATHOLOGY
No macroscopic lesions in any exposure group.
HISTOPATHOLOGY: NON-NEOPLASTIC
Spermatogenic findings: reduced epididymal sperm numbers and motility, and a higher incidence of morphological abnormalities were seen in 500 ppm males at weeks 6 and 13. Multifocal atrophy of the testes was reported in a single male at 500 ppm. - Dose descriptor:
- NOAEC
- Effect level:
- 50 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: whole body spasm and hyperactivity, and other effects.
- Remarks on result:
- not determinable
- Remarks:
- no NOAEC identified
- Dose descriptor:
- LOAEC
- Effect level:
- 50 ppm
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: around 0.2 mg/l
- Critical effects observed:
- not specified
- Conclusions:
- A well reported 90-day rat inhalation study, conducted according to the current guideline and in accordance with GLP, did not identify a NOAEC value. Clinical observations (including spasm) were evident at the lowest tested nominal concentration of 50 ppm (around 0.2 mg/l).
Reference
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
Repeated dose toxicity: dermal - systemic effects
Link to relevant study records
- Endpoint:
- sub-chronic toxicity: dermal
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1994-09-08 to 1994-12-15
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Reason / purpose for cross-reference:
- reference to same study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 411 (Subchronic Dermal Toxicity: 90-Day Study)
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Labs, Portage, MI, USA
- Weight at study initiation g: 168-209 (m); 137-164 (f)
-age: 6 weeks
- Housing: 1/ wire mesh cage
- Diet: standard diet ad libitum
- Water: drinking water ad libitum
- Acclimation period: 14 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 70-76 deg F
- Humidity (%): 37-66
- Photoperiod (hrs dark / hrs light): 12 h/12 h
IN-LIFE DATES: From: To: 1994-09-15 to 1994-12-15 - Type of coverage:
- occlusive
- Vehicle:
- unchanged (no vehicle)
- Details on exposure:
- TEST SITE
- Area of exposure:
- % coverage: 20-25% shaved; coverage (maximum possible) 1.7-4.1% and 1.6-4.2% coverage of body for males, and females, respectively
- Type of wrap if used: gauze binder, impervious plastic wrap, dermiform tape
- Time intervals for shavings or clipplings: day prior to dosing and weekly
REMOVAL OF TEST SUBSTANCE
- Washing (if done): wiped with wet paper towel moistened with tepid tap water
- Time after start of exposure: 6h
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.095, 0.29, 0.96 ml/kg bw/day; 100, 300, 1000 mg/kg bw/day
- Concentration: neat
- Constant volume or concentration used: no
VEHICLE
Control: 0.9% saline, 0.95 ml/kg bw/day
USE OF RESTRAINERS FOR PREVENTING INGESTION: yes (Elizabethan restraint collars) - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- application neat; purity reported
- Duration of treatment / exposure:
- 6h/day, 5 days/week, 13 weeks
- Frequency of treatment:
- daily (weekdays)
- Dose / conc.:
- 100 mg/kg bw/day
- Remarks:
- analytical per unit body weight
- Dose / conc.:
- 300 mg/kg bw/day
- Remarks:
- analytical per unit body weight
- Dose / conc.:
- 1 000 mg/kg bw/day
- Remarks:
- analytical per unit body weight
- No. of animals per sex per dose:
- 17 males, 12 females (5 males terminated at 7 weeks for examination of spermatogenic endpoints)
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale:
- Rationale for animal assignment (if not random): computer randomization - Positive control:
- no
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily
DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: weekly
BODY WEIGHT: Yes
- Time schedule for examinations: weekly
FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes, weekly
FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No
WATER CONSUMPTION: No
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule: week 12
- slit lamp and indirect ophthalmoscope
HAEMATOLOGY: Yes
- Time schedule for collection of blood: weeks 4, 13
- Anaesthetic used for blood collection: /No data
- Animals fasted: Yes
- How many animals: 12/sex/dose
- Parameters checked in table 1 were examined.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: weeks 4, 13
- Animals fasted: Yes
- How many animals: 12/sex/dose
- Parameters checked in table 1 were examined.
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: No
OTHER:
Spermatogenic endpoints: 5 males/dose; terminated at week 7: sperm motility, morphology - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes (see table 2)
HISTOPATHOLOGY: Yes (see table2) - Statistics:
- All analyses were conducted using two-tailed tests for significance levels of 5 % and 1%.
Body weight, body weight change, food consumption, clinical laboratory, spermatogenic and absolute and relative organ weight data were subjected to a one-way analysis of variance followed by Dunnett's Test. Clinical laboratory values for white blood cell types that occur at a low incidence (i.e. monocytes, eosinophils, basophils and unsegmented neutrophils) were not subjected to statistical analysis. - Clinical signs:
- no effects observed
- Dermal irritation:
- effects observed, treatment-related
- Description (incidence and severity):
- very minimal dermal irritation
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- reduced mean body weight in both sexes at 1000 mg/kg bw/day
- Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- not examined
- Details on results:
- CLINICAL SIGNS AND MORTALITY
No mortatily or treatment-related clinical signs.
BODY WEIGHT AND WEIGHT GAIN
8-10% lower weight gain in 1000 mg/kg bw/day males comapred to controls (p<0.05 or 0.1; weeks 9-13). 7% lower weight gain in 1000 mg/kg bw/day females compared to controls (p<0.05; weeks 12, 13).
FOOD CONSUMPTION
No effect.
OPHTHALMOSCOPIC EXAMINATION
No treatment-related effects at week 12 examination.
HAEMATOLOGY
No treatment-related effect on haematological parameters. Mean white blood cell counts and absolute numbers of lymphocytes were lower (p<0.01 or 0.05) in 1000 mg/kg bw/day males at weeks 4 and 13 examinations, No similar effects were seen in females and the white cell counts were within WIL Research Laboratories historic control ranges for this species, strain and age. Statistically significant differences in red blood cell parameters did not show trends to indicate they were treatment-related.
CLINICAL CHEMISTRY
No treatment-related effect on serum chemistry parameters. Statistically significant differences (p<0.01 or <0.05) in serum protein parameters were seen in both sexes at 1000 mg/kg bw/day at weeks 4 or 13 but these were small, their means within the normal range of biologic variation and without trend to indicate an association with treatment. Other statistically significant differences were limited to one sex at a single evaluation, showed no dose-response or were not considered toxicologically significant.
ORGAN WEIGHTS
No treatment-related effect.
GROSS PATHOLOGY
No treatment-related observations.
HISTOPATHOLOGY: NON-NEOPLASTIC
No treatment-related effects at any dose including effects on skin and male reproductive organs
OTHER FINDINGS
dermal: very limited dermal irritation - single occasions of very slight erythema for one, two and one males in the 100, 300 and 1000 mg/kg bw/day groups, respectively, and or one female in the 100 mg/kg bw/day group. Desquamation was observed on one day for single females in the control and 100 mg/kg bw/day group and thus was apparently not test article-related. No other dermal irritation was observed.
Spermatogenic endpoints:
Administration of up to 1000 mg THFA/kg bw/day for 7 weeks (interim necropsy) had no effect on spermatogenic endpoints (testicular epididymal sperm numbers, sperm production rate, sperm motility, sperm morphology).
Mean numbers of sperm present in testicular homogenates and mean sperm production rate were lower than controls in 300 and 1000 mg/kg bw/day males after 13 weeks treatment (p<0.01). One male in the 1000 mg/kg bw/day group had markedly lower values for these parameters but the the group mean was still significantly reduced (p<0.01) when the values for this male were omitted. Sperm motility was reduced at 1000 mg/kg bw/day (p<0.05). - Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 100 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- other: spermatogenesis
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 300 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- other: lower body weight gain
- Critical effects observed:
- not specified
- Conclusions:
- A 90-day dermal study, conducted according to the current guideline (OECD 411) and GLP, identified NOAEL values of 100 mg/kg bw/day in male rats and 300 mg/kg bw/day female rats. Effects on body weight were evident at 1000 mg/kg bw/day in both sexes and spermatogenic effects were reported in males at 300 mg/kg bw/day.
Reference
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- NOAEL
- 100 mg/kg bw/day
- Study duration:
- subchronic
- Species:
- rat
- Quality of whole database:
- No other relevant studies were identified
- System:
- male reproductive system
- Organ:
- testes
Repeated dose toxicity: dermal - local effects
Link to relevant study records
- Endpoint:
- sub-chronic toxicity: dermal
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1994-09-08 to 1994-12-15
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Reason / purpose for cross-reference:
- reference to same study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 411 (Subchronic Dermal Toxicity: 90-Day Study)
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Labs, Portage, MI, USA
- Weight at study initiation g: 168-209 (m); 137-164 (f)
-age: 6 weeks
- Housing: 1/ wire mesh cage
- Diet: standard diet ad libitum
- Water: drinking water ad libitum
- Acclimation period: 14 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 70-76 deg F
- Humidity (%): 37-66
- Photoperiod (hrs dark / hrs light): 12 h/12 h
IN-LIFE DATES: From: To: 1994-09-15 to 1994-12-15 - Type of coverage:
- occlusive
- Vehicle:
- unchanged (no vehicle)
- Details on exposure:
- TEST SITE
- Area of exposure:
- % coverage: 20-25% shaved; coverage (maximum possible) 1.7-4.1% and 1.6-4.2% coverage of body for males, and females, respectively
- Type of wrap if used: gauze binder, impervious plastic wrap, dermiform tape
- Time intervals for shavings or clipplings: day prior to dosing and weekly
REMOVAL OF TEST SUBSTANCE
- Washing (if done): wiped with wet paper towel moistened with tepid tap water
- Time after start of exposure: 6h
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.095, 0.29, 0.96 ml/kg bw/day; 100, 300, 1000 mg/kg bw/day
- Concentration: neat
- Constant volume or concentration used: no
VEHICLE
Control: 0.9% saline, 0.95 ml/kg bw/day
USE OF RESTRAINERS FOR PREVENTING INGESTION: yes (Elizabethan restraint collars) - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- application neat; purity reported
- Duration of treatment / exposure:
- 6h/day, 5 days/week, 13 weeks
- Frequency of treatment:
- daily (weekdays)
- Dose / conc.:
- 100 mg/kg bw/day
- Remarks:
- analytical per unit body weight
- Dose / conc.:
- 300 mg/kg bw/day
- Remarks:
- analytical per unit body weight
- Dose / conc.:
- 1 000 mg/kg bw/day
- Remarks:
- analytical per unit body weight
- No. of animals per sex per dose:
- 17 males, 12 females (5 males terminated at 7 weeks for examination of spermatogenic endpoints)
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale:
- Rationale for animal assignment (if not random): computer randomization - Positive control:
- no
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily
DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: weekly
BODY WEIGHT: Yes
- Time schedule for examinations: weekly
FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes, weekly
FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No
WATER CONSUMPTION: No
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule: week 12
- slit lamp and indirect ophthalmoscope
HAEMATOLOGY: Yes
- Time schedule for collection of blood: weeks 4, 13
- Anaesthetic used for blood collection: /No data
- Animals fasted: Yes
- How many animals: 12/sex/dose
- Parameters checked in table 1 were examined.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: weeks 4, 13
- Animals fasted: Yes
- How many animals: 12/sex/dose
- Parameters checked in table 1 were examined.
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: No
OTHER:
Spermatogenic endpoints: 5 males/dose; terminated at week 7: sperm motility, morphology - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes (see table 2)
HISTOPATHOLOGY: Yes (see table2) - Statistics:
- All analyses were conducted using two-tailed tests for significance levels of 5 % and 1%.
Body weight, body weight change, food consumption, clinical laboratory, spermatogenic and absolute and relative organ weight data were subjected to a one-way analysis of variance followed by Dunnett's Test. Clinical laboratory values for white blood cell types that occur at a low incidence (i.e. monocytes, eosinophils, basophils and unsegmented neutrophils) were not subjected to statistical analysis. - Clinical signs:
- no effects observed
- Dermal irritation:
- effects observed, treatment-related
- Description (incidence and severity):
- very minimal dermal irritation
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- reduced mean body weight in both sexes at 1000 mg/kg bw/day
- Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- not examined
- Details on results:
- CLINICAL SIGNS AND MORTALITY
No mortatily or treatment-related clinical signs.
BODY WEIGHT AND WEIGHT GAIN
8-10% lower weight gain in 1000 mg/kg bw/day males comapred to controls (p<0.05 or 0.1; weeks 9-13). 7% lower weight gain in 1000 mg/kg bw/day females compared to controls (p<0.05; weeks 12, 13).
FOOD CONSUMPTION
No effect.
OPHTHALMOSCOPIC EXAMINATION
No treatment-related effects at week 12 examination.
HAEMATOLOGY
No treatment-related effect on haematological parameters. Mean white blood cell counts and absolute numbers of lymphocytes were lower (p<0.01 or 0.05) in 1000 mg/kg bw/day males at weeks 4 and 13 examinations, No similar effects were seen in females and the white cell counts were within WIL Research Laboratories historic control ranges for this species, strain and age. Statistically significant differences in red blood cell parameters did not show trends to indicate they were treatment-related.
CLINICAL CHEMISTRY
No treatment-related effect on serum chemistry parameters. Statistically significant differences (p<0.01 or <0.05) in serum protein parameters were seen in both sexes at 1000 mg/kg bw/day at weeks 4 or 13 but these were small, their means within the normal range of biologic variation and without trend to indicate an association with treatment. Other statistically significant differences were limited to one sex at a single evaluation, showed no dose-response or were not considered toxicologically significant.
ORGAN WEIGHTS
No treatment-related effect.
GROSS PATHOLOGY
No treatment-related observations.
HISTOPATHOLOGY: NON-NEOPLASTIC
No treatment-related effects at any dose including effects on skin and male reproductive organs
OTHER FINDINGS
dermal: very limited dermal irritation - single occasions of very slight erythema for one, two and one males in the 100, 300 and 1000 mg/kg bw/day groups, respectively, and or one female in the 100 mg/kg bw/day group. Desquamation was observed on one day for single females in the control and 100 mg/kg bw/day group and thus was apparently not test article-related. No other dermal irritation was observed.
Spermatogenic endpoints:
Administration of up to 1000 mg THFA/kg bw/day for 7 weeks (interim necropsy) had no effect on spermatogenic endpoints (testicular epididymal sperm numbers, sperm production rate, sperm motility, sperm morphology).
Mean numbers of sperm present in testicular homogenates and mean sperm production rate were lower than controls in 300 and 1000 mg/kg bw/day males after 13 weeks treatment (p<0.01). One male in the 1000 mg/kg bw/day group had markedly lower values for these parameters but the the group mean was still significantly reduced (p<0.01) when the values for this male were omitted. Sperm motility was reduced at 1000 mg/kg bw/day (p<0.05). - Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 100 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- other: spermatogenesis
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 300 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- other: lower body weight gain
- Critical effects observed:
- not specified
- Conclusions:
- A 90-day dermal study, conducted according to the current guideline (OECD 411) and GLP, identified NOAEL values of 100 mg/kg bw/day in male rats and 300 mg/kg bw/day female rats. Effects on body weight were evident at 1000 mg/kg bw/day in both sexes and spermatogenic effects were reported in males at 300 mg/kg bw/day.
Reference
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
Additional information
In a 90-day oral study, THFA was administered to rats via the dietary route at 0, 500, 1000, 5000 or 10000 ppm. All animals survived the study period and there were no remarkable clinical signs. Lower body weight gain and food consumption were noted in all treated groups and were generally dose-related, the effects being considered adverse at concentrations of 1000 ppm and above in males and at 10 000 ppm at females. The other notable effects of treatment were recorded at 5000 and or 10000 ppm and included lower red cell parameters and total protein and albumin levels. At necropsy lower testes and epididimal, prostate and seminal vesicle weights were recorded for males and the testes were noted to be small and/or soft at these doses. Dose-related degeneration of germinal epithelium of seminiferous tubules and interstitial (peritubular) oedema in the testes and empty or fluid filled tubules with accumulation of cellular debris in the epididymides were noted. In the spleen, adhesions and focal capsular fibrosis were noted. The No-Observed-Adverse-Effect-Level was considered to be 500 ppm (corresponding to 35 mg/kg/day) in males and 1000 ppm (corresponding to 84 mg/kg/day) in females.
In a 28-day oral study, THFA was administered to rats by oral gavage at doses of 0, 10, 40, 150 or 600 mg/kg/day. Similar effects were noted generally at the high dose to those seen in the 90-day dietary study with histopathological changes, including necrosis of the seminiferous epithelium, again noted in the testes and capsular inflammatory cell infiltrate or fibrosis in the spleen. Based on these effects the No-Observed-Adverse-Effect-Level was considered to be 40 mg/kg/day.
A 90-day inhalation study was conducted in which THFA was administered to rats at 0, 50, 150 or 500 ppm. The predominant clinical finding was intermittent whole-body spasms in all treated groups that were frequent and exposure-related with hyperactivity noted 1 hour after dosing. Hypoactivity and excessive grooming were occasionally observed in males and females at 500 ppm. Body weight gain and food consumption were generally lower at the mid and high doses throughout the study. Lower red cell parameters were recorded at the high dose. At necropsy prostate and epididymides weight were lower at 150 and/or 500 ppm. Microscopically, reduced epididymal sperm numbers and motility and multifocal atrophy of the testes were recorded at 500 ppm. Based on the effects on the male reproductive organs and the clinical findings which were noted at all doses, a No-Observed-Adverse-Effect-Level was not established and the Lowest-Observed-Adverse-Effect-Level was considered to be 50 ppm.
A 90-day dermal study was conducted in which THFA was administered to rats at 0, 100, 300 or 1000 mg/kg/day. All animals survived and there were no remarkable clinical signs or effects on food consumption, haematology or clinical chemistry parameters or organ weight. Body weight gain was lower at the high dose. Mean numbers of sperm present in testicular homogenates and mean sperm production rate were lower than controls in 300 and 1000 mg/kg/day males and sperm motility was reduced at 1000 mg/kg/day. Based on the spermatogenic effects the No-Observed-Adverse-Effect-Level was considered to be 100 mg/kg/day.
.
Justification for classification or non-classification
All five studies (three key, two supporting) suggest that the testes are the main target organ. In accordance with Section 3.7.2.5.3 of Regulation (EC) 1272/2008, adverse effects seen in repeated dose toxicity studies which are judged likely to impair reproductive function and which occur in the absence of significant generalised toxicity may be used as a basis for classification for reproductive toxicity.
The observed effects on testes are considered as likely to impair reproductive function and, as such, the substance is classified for reproductive toxicity (Section 5.9). There is no need to include a separate classification for specific target organ toxicity following repeated exposures, in the absence of other significant adverse effects.
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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