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EC number: 944-482-9 | CAS number: -
- 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
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- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
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- Additional physico-chemical information
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- Endpoint summary
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- 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
Extended OECD TG 422 (>90-day): NOAEL 700 ppm (equivalent to 42 mg/kg bw)
Key value for chemical safety assessment
Repeated dose toxicity: via oral route - systemic effects
Link to relevant study records
- Endpoint:
- sub-chronic toxicity: oral
- Remarks:
- with reproduction/developmental toxicity sceening
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- October 2015 - March 2016
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Reason / purpose for cross-reference:
- reference to same study
- Remarks:
- endpoints 7.8.1 and 7.8.2
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
- Version / remarks:
- September 1998
- Deviations:
- no
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- GLP compliance:
- yes
- Limit test:
- no
- Species:
- rat
- Strain:
- other: Crl:WI(Han)
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Females nulliparous and non-pregnant: yes
- Age at study initiation: Approximately 6 weeks
- Weight at study initiation: males 142-184 grams, females 112-139 grams
- Fasting period before study: no
- Housing: during premating in groups of 5 animals/sex/cage in Macrolon plastic cages; during mating females were caged together with males on a one-to-one-basis in Macrolon plastic cages; during post-mating males were housed in their home cage with a maximum of 5 animals/cage, females were individually housed in Macrolon plastic cages; during lactation pups were kept with the dam until termination in Macrolon plastic cages
- Diet: Free access to prepared diets. During the acclimatization period, animals had free access to standard powder rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany). During motor activity measurements, animals did not have access to food for a maximum of 2 hours.
- Water: Free access to tap-water
- Acclimation period: At least 5 days prior to start of treatment
DETAILS OF FOOD AND WATER QUALITY:
The diet was provided in stainless steel containers, covered by a stainless steel grid to prevent spillage. The same diets remained in the food hopper for a maximum of one week. On the day of weighing the remaining food in the food hopper, remaining diet was replaced with new diet retained from the freezer acclimated to room temperature conditions for at least 1 hour prior to opening the diet bag.
ENVIRONMENTAL CONDITIONS (set to maintain)
- Temperature (°C): 18 to 24
- Humidity (%): 40 to 70
- Air changes (per hr): at least 10
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: 18 November 2015 To: 11 March 2016 - Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Details on oral exposure:
- DIET PREPARATION
- Rate of preparation of diet (frequency): Diets were prepared up to 3 weeks in advance of first use.
- Mixing appropriate amounts with (Type of food): Standard powder rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany).
- Storage temperature of food: Diets were kept in the freezer (≤-15°C) until use, if not used on the day of preparation. Any remaining food left after filling the food hoppers was stored at room temperature for a maximum of 8 days for supplementing food during the respective food consumption measurement interval.
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Analyses were conducted on diet samples taken on a single occasion during the treatment phase, according to a validated method. Samples of diet preparations were analyzed for homogeneity (highest and lowest concentration) and accuracy of preparation (all concentrations). Stability in diet over 8 days at room temperature and 3 weeks in the freezer were also determined for 250 ppm diets. Stability in rat diet (powder, SM R/M-Z; supplier SSNIFF®) over the concentration range 500 to 15,000 ppm was previously confirmed for at least 3 weeks in the freezer (≤-15°C) and for at least 8 days at room temperature (method development and validation study). The accuracy of preparation was considered acceptable if the mean measured concentrations were 80-120% of the target concentration. Homogeneity was demonstrated if the coefficient of variation was ≤ 10%. Diet preparations were considered stable if the relative difference before and after storage was maximally 10%.
- Duration of treatment / exposure:
- Males were exposed for 91 days, i.e. 10 weeks prior to mating, during mating, and up to termination. Females were exposed for 103 - 114 days, i.e. during 10 weeks prior to mating, during mating, during post-coitum, and during at least 4 days of lactation (up to the day prior to scheduled necropsy for selected females and until the day of necropsy for non-selected females).
- Frequency of treatment:
- ad libitum
- Dose / conc.:
- 250 ppm
- Dose / conc.:
- 700 ppm
- Dose / conc.:
- 2 000 ppm
- No. of animals per sex per dose:
- 10
- Control animals:
- yes
- Details on study design:
- Dose levels were based on results of a 14-day dose range finding study.
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: at least twice daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: at least once daily
BODY WEIGHT: Yes
- Time schedule for examinations: males and females were weighed on the first day of exposure and weekly thereafter; mated females were weighed on Days 0, 4, 7, 11, 14, 17 and 20 post-coitum and during lactation on Days 1 and 4.
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
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: Yes
- Subjective appraisal was maintained during the study, but no quantitative investigation was introduced as no treatment related effect was suspected.
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: Yes
- Time schedule for collection of blood: at the end of the treatment period on the day of scheduled necropsy
- Anaesthetic used for blood collection: Yes (isoflurane)
- Animals fasted: Yes
- How many animals: 5 animals/sex/group
- Parameters checked according to guidelines.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at the end of the treatment period on the day of scheduled necropsy
- Animals fasted: Yes
- How many animals: 5 animals/sex/group
- Parameters checked according to guidelines.
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: selected males were tested during Week 13 of treatment and the selected females were tested towards the end of the scheduled lactation period from lactation Day 4 onwards (all before blood sampling)
- Dose groups that were examined: all
- Battery of functions tested: hearing ability, pupillary reflex, static righting reflex, fore- and hind-limb grip strength, locomotor activity
IMMUNOLOGY: No
OTHER: General reproduction data, litter and pup examination. - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes, according to Guidelines
HISTOPATHOLOGY: Yes, according to Guidelines - Other examinations:
- the following organ weights from 5 animals/group were recorded:
Adrenal glands, Brain -cerebellum, midbrain, cortex, Epididymides, Heart, Kidneys, Liver, Ovaries, Spleen, Testes, Thymus, Uterus (including cervix), Prostate, Seminal vesicles including coagulating glands, Thyroid including parathyroid
from all remaining males; epididymides and testes - Statistics:
- The following statistical methods were used to analyze the data:
- If the variables could be assumed to follow a normal distribution, the Dunnett-test (many-to-one t-test) based on a pooled variance estimate was applied for the comparison of the treated groups and the control groups for each sex.
- The Steel-test (many-to-one rank test) was applied if the data could not be assumed to follow a normal distribution.
- The Fisher Exact-test was applied to frequency data.
- The Kruskal-Wallis nonparametric ANOVA test was applied to motor activity data to determine intergroup differences.
All tests were two-sided and in all cases p < 0.05 was accepted as the lowest level of significance. - Clinical signs:
- effects observed, non-treatment-related
- Description (incidence and severity):
- The only clinical finding noted consisted of scabs on the back in a single female at 250 ppm. This incidental finding was not related to treatment and within the range of background findings expected for rats of this age and strain.
- Mortality:
- no mortality observed
- Description (incidence):
- One female at 250 ppm was sacrificed due to total litter loss.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Pre-mating body weight gain of females at 2000 ppm was slightly lower compared to controls (percentual difference in mean body weight gain was about 10% in most weeks, being statistically significant at Days 50 and 71).
Throughout the post-coitum and lactation periods, mean body weights of females at 2000 ppm were statistically significantly lower compared to controls (relative differences from controls were about 10%). However, body weight gain values during the post-coitum and lactation periods at 2000 ppm were considered similar to controls.
No treatment-related changes in body weights or body weight gain were noted up to 2000 ppm in males and up to 700 ppm in females.
Overall the decrease in body weight (gain) can be attibuted to decreased food consumption and without any other signs, these were not considered adverse. - Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- Throughout the post-coitum and lactation period, females at 2000 ppm had an approximately 30-40% lower food intake than controls. Food consumption after allowance for body weight showed a similar pattern, but was not statistically significantly lower during lactation. During premating, food consumption before and after allowance for body weight was similar to control levels.
No treatment-related changes in food consumption before or after allowance for body weight were noted up to and including 2000 ppm in males and up to and including 700 ppm in females.
The mean daily intake of the test item per kg body weight during the different phases of the study:
Mean test item intake (mg test item/kg bw/day)
250 ppm 700 ppm 2000 ppm
Males
Pre-mating 19 52 153
Mating 16 42 137
Females
Pre-mating 21 59 168
Post-coitum 32 87 184
Lactation 44 129 280 - Food efficiency:
- not examined
- Description (incidence and severity):
- Effects on food consumption are observed, which are likely due to the palatability of the substance, which is not considered an adverse effect.
- Water consumption and compound intake (if drinking water study):
- no effects observed
- Ophthalmological findings:
- not examined
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Description (incidence and severity):
- Statistically significant variations noted in clinical biochemistry parameters were unrelated to treatment or not toxicologically relevant due to the slight magnitude of the change (values in treated rats remained within normal limits), low control values and/or absence of a doserelated response.
- Urinalysis findings:
- no effects observed
- Behaviour (functional findings):
- no effects observed
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- Test item-related higher liver weights were noted in the 2000 ppm treated males (absolute and relative to body weight). Mean relative weight was approximately 13% higher than controls.
Test item-related higher kidneys weights were noted in the 700 and 2000 ppm treated males (relative to body weight at 700 ppm and both absolute and relative to body weight at 2000 ppm). Mean relative weight was approximately 13% and 15% higher than controls at 700 and 2000 ppm, respectively.
Test item-related higher kidneys weights were also noted in the 250, 700 and 2000 ppm treated females (relative to body weight at 250 and 2000 ppm and both absolute and relative to body weight at 700 ppm). Mean relative weights were approximately 13%, 21% and 16% higher than controls at 250, 700 and 2000 ppm, respectively. No dose-related trend was apparent.
There were no other test item-related organ weight changes. All other organ weight differences observed, including those that reached statistical significance, were considered incidental and unrelated to the administration of the test item. - Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Enlargement of the liver was noted in 2/10 males at 2000 ppm. This macroscopic finding was considered to be test item-related.
The remainder of the recorded macroscopic findings were within the range of background findings encountered in rats of this age and strain, and did not show a dose-related incidence trend. These necropsy findings were therefore considered to be unrelated to treatment. - Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- - Liver: hepatocellular hypertrophy in 4/5 males and 4/5 females at 2000 ppm up to slight degree.
- Kidneys: increased incidence and severity of hyaline droplet accumulation in males at 2000 ppm up to moderate degree, accompanied by an increased incidence and severity of tubular basophilia up to slight degree at 2000 ppm and tubular granular casts in a single male treated at 2000 ppm at minimal degree.
- Urinary bladder: Minimal to slight hypertrophy of the urothelium in females at 2000 ppm.
The remainder of the recorded microscopic findings were within the range of background pathology encountered in rats of this age and strain. There was no test item-related alteration in the prevalence, severity, or histologic character of those incidental tissue alterations. - Histopathological findings: neoplastic:
- no effects observed
- Other effects:
- no effects observed
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- parental
- Effect level:
- 42 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Remarks:
- 700 ppm diet
- Sex:
- male/female
- Basis for effect level:
- histopathology: non-neoplastic
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 137 mg/kg bw/day (actual dose received)
- System:
- urinary
- Organ:
- bladder
- Treatment related:
- yes
- Dose response relationship:
- no
- Relevant for humans:
- yes
- Conclusions:
- At the high and sometimes mid dose treatment related effects were noted on body weight (gain) food consumption (both decreased), adaptive liver changes were seen. In males hydrocarbon nephropathy in kidneys was seen and related granular casts. These effects were not considered adverse or not relevant for humans. The toxicological relevance of the slight to mild hypertrophy in urine bladder in females at 2000 ppm (actual, 137 mg/kg bw) was discussed and it was decided to use this effect for the overall parental NOAEL for systemic effects of 700 ppm (actual 42 mg/kg bw).
- Executive summary:
The substance was administered via the diet to male and female Wistar Han rats at dietary concentrations of 250, 700 and 2000 ppm (10 rats/sex/dose level) according to OECD 422 Guideline (nominal doses were 17, 47, 133, mg/kg bw). The mid and high dose actual doses were 42, and 137 mg/kg bw, respectively, using the most conservative intake and intake period). The concurrent controls (10 rats/sex) received basal diet without test item. Males were exposed for 10 weeks prior to mating, during mating, and up to termination (for 91 days). The females were exposed for 10 weeks prior to mating, during mating, during post-coitum, and at least 4 days of lactation (for 103 - 114 days). Analysis of diet preparations showed that the diets were prepared accurately and homogenously, and were stable during storage at room temperature under normal laboratory light conditions in an open container for at least 8 days and in a freezer (≤-15°C) for at least 3 weeks.
The food and test substance intake of 250, 700 and 2000 ppm resulted in 16, 42 and 137 mg/kg bw, using the lower and thus most conservative values of males and females.
Results: There were no adverse changes in in-life parameters (body weight, food consumption, clinical signs and functional observations) across the dose groups.
A lower body weight and food consumptionwas recorded for females treated at 2000 ppm throughout the post-coitum and lactation periods, and for body weight also during the premating period. Compared to controls, mean body weights were about 10% lower than controls, whereas the differences in food consumption were more marked (approximately 30-40% lower than controls throughout the post-coitum and lactation period). This lower food intake was not considered adverse in nature since it occurred in absence of any adverse changes in body weight or clinical appearance, or treatment-related changes in pup body weights.
Organ effects:
Relativeliverweight was increased in males and females with 13% and macroscopic liver enlargement was seen at the high dose in some males. Microscopically a treatment-related but non-adverse hepatocellular hypertrophy was recorded in the liver of males and females treated at 2000 ppm up to slight degree. In the absence of any other indicators of hepatocellular toxicity, these liver changes were not considered to be adverse.
Kidney: Inmalesat 2000 ppm had kidney weights that were approximately 15% higher than controls and were considered to be related to the microscopic renal changes. Higher kidney weights were also recorded for males at 700 ppm (approximately 13% higher than controls), and for females at 250, 700 and 2000 ppm (approximately 13%, 21% and 16% higher, respectively). There were neither corroborative microscopic changes nor clinical biochemical alterations indicative of renal toxicity. Furthermore, kidney weights remained within the range considered normal for this strain of rats of similar age. Therefore, the higher kidney weights for males at 700 ppm and for females at 250 ppm and higher were not considered adverse in nature.
At 2000 ppm an adverse histopathological lesion was recorded in the kidneys of males treated at 2000 ppm. In these males, an increased incidence and severity (up to moderate) of hyaline droplet accumulation was noted. The hyaline droplet accumulation was considered to represent alpha-2u-globulin, a normal protein in male rats which undergoes reabsorption in the proximal cortical tubules. A range of chemicals is known to increase hyaline droplet formation leading ultimately to proximal cortical tubule cell injury as manifested by formation of granular casts and increased tubular basophilia. This male rat specific protein is not present in female rats and not in higher mammals, including man (Ref. 6, see end of section). In this study the increased hyaline droplet accumulation in males treated at 2000 ppm was accompanied by indicators of renal tubular damage in the form of granular casts at minimal degree and increased tubular basophilia up to slight degree. The granular casts and the increase in tubular basophilia are considered adverse for male rats but need not to be considered for humans.
Microscopic examination infemale urinary bladderrevealed minimal to slight hypertrophy of the urothelium treated at 2000 ppm. This test item-related change was considered to be adverse in this 90-day study because it was seen in three out of five females, none in the control and it is an effect which does not typically occur as background finding. It does not seem to be a secondary response to irritation by calculi, lower urinary tract obstruction or in association with renal papillary necrosis as these effects were not observed. Therefore the bladder effects are possibly a primary effect of the test item. The mode of action for this effect is unclear and therefore the effect is used for deriving the NOAEL. There are, however, no indications that the kidney function in females was impaired based on other kidney (related) findings. In addition, there were no related findings seen such as morphological lesions (e.g. inflammation or cell death) and it was not seen in males.
In conclusion: Based on the hypertrophy of the urothelium of the urinary bladder in females at 2000 ppm (corresponding to 137 mg/kg bw) renal changes (granular casts and basophilia) in males at 2000 ppm a parental NOAEL for systemic effects of 700 ppm was derived for rats. The latter effect is not considered relevant for humans. The overall parental NOAEL is based on the bladder effects, this NOAEL is 700 ppm in diet, which corresponding to 42 mg/kg bw.
Reference
Accuracy of preparation: The concentrations analysed in the diets at 250, 700 and 2000 ppm were in agreement with target concentrations, with mean accuracies between 87% and 114%. No test item was detected in the Group 1 diets.
Homogeneity: The diets at 250 and 2000 ppm were homogeneous with coefficient of variation of 2.0% and 5.4%, respectively.
Stability: Diets at 250 ppm were stable when stored at room temperature under normal laboratory light conditions in an open container for at least 8 days, with difference between the stored and freshly taken samples was -7.7%. The relative difference of diet samples at low level 250 ppm for 3 weeks in the freezer (≤ -15°C) stability test was slightly above the criterion (- 13%). The decrease was considered not to be due to instability of the samples since the mean accuracy of the stability samples was comparable to the accuracy of the quality control samples at the same concentration level which were analysed together with the 3-week stability samples. Furthermore, since the deviations were considered small and accuracies after storage were within the range of 80 and 120%, the diets were considered stable. Based on this, the diets from 250 ppm to 15000 ppm were found to be stable during storage at room temperature under normal laboratory light conditions with open container for at least 8 days and in a freezer (≤ -15°C) for at least 3 weeks.
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- NOAEL
- 42 mg/kg bw/day
- Study duration:
- subchronic
- Species:
- rat
- Quality of whole database:
- For repeated dose toxicity there is one oral study extended OECD TG 422 in compliance with GLP, resulting in adquate information for the endpoint.
Additional information
The substance was administered via the diet to male and female Wistar Han rats at dietary concentrations of 250, 700 and 2000 ppm (10 rats/sex/dose level) according to OECD 422 Guideline (nominal doses were 17, 47, 133, mg/kg bw). The mid and high dose actual doses were 42, and 137 mg/kg bw, respectively, using the most conservative intake and intake period). The concurrent controls (10 rats/sex) received basal diet without test item. Males were exposed for 10 weeks prior to mating, during mating, and up to termination (for 91 days). The females were exposed for 10 weeks prior to mating, during mating, during post-coitum, and at least 4 days of lactation (for 103 - 114 days). Analysis of diet preparations showed that the diets were prepared accurately and homogenously, and were stable during storage at room temperature under normal laboratory light conditions in an open container for at least 8 days and in a freezer (≤-15°C) for at least 3 weeks.
The food and test substance intake of 250, 700 and 2000 ppm resulted in 16, 42 and 137 mg/kg bw, using the lower and thus most conservative values of males and females.
Results: There were no adverse changes in in-life parameters (body weight, food consumption, clinical signs and functional observations) across the dose groups.
A lower body weight and food consumptionwas recorded for females treated at 2000 ppm throughout the post-coitum and lactation periods, and for body weight also during the premating period. Compared to controls, mean body weights were about 10% lower than controls, whereas the differences in food consumption were more marked (approximately 30-40% lower than controls throughout the post-coitum and lactation period). This lower food intake was not considered adverse in nature since it occurred in absence of any adverse changes in body weight or clinical appearance, or treatment-related changes in pup body weights.
Organ effects:
Relativeliverweight was increased in males and females with 13% and macroscopic liver enlargement was seen at the high dose in some males. Microscopically a treatment-related but non-adverse hepatocellular hypertrophy was recorded in the liver of males and females treated at 2000 ppm up to slight degree. In the absence of any other indicators of hepatocellular toxicity, these liver changes were not considered to be adverse.
Kidney: Inmalesat 2000 ppm had kidney weights that were approximately 15% higher than controls and were considered to be related to the microscopic renal changes. Higher kidney weights were also recorded for males at 700 ppm (approximately 13% higher than controls), and for females at 250, 700 and 2000 ppm (approximately 13%, 21% and 16% higher, respectively). There were neither corroborative microscopic changes nor clinical biochemical alterations indicative of renal toxicity. Furthermore, kidney weights remained within the range considered normal for this strain of rats of similar age. Therefore, the higher kidney weights for males at 700 ppm and for females at 250 ppm and higher were not considered adverse in nature.
At 2000 ppm an adverse histopathological lesion was recorded in the kidneys of males treated at 2000 ppm. In these males, an increased incidence and severity (up to moderate) of hyaline droplet accumulation was noted. The hyaline droplet accumulation was considered to represent alpha-2u-globulin, a normal protein in male rats which undergoes reabsorption in the proximal cortical tubules. A range of chemicals is known to increase hyaline droplet formation leading ultimately to proximal cortical tubule cell injury as manifested by formation of granular casts and increased tubular basophilia. This male rat specific protein is not present in female rats and not in higher mammals, including man (Ref. 6, see end of section). In this study the increased hyaline droplet accumulation in males treated at 2000 ppm was accompanied by indicators of renal tubular damage in the form of granular casts at minimal degree and increased tubular basophilia up to slight degree. The granular casts and the increase in tubular basophilia are considered adverse for male rats but need not to be considered for humans.
Microscopic examination infemale urinary bladderrevealed minimal to slight hypertrophy of the urothelium treated at 2000 ppm. This test item-related change was considered to be adverse in this 90-day study because it was seen in three out of five females, none in the control and it is an effect which does not typically occur as background finding. It does not seem to be a secondary response to irritation by calculi, lower urinary tract obstruction or in association with renal papillary necrosis as these effects were not observed. Therefore the bladder effects are possibly a primary effect of the test item. The mode of action for this effect is unclear and therefore the effect is used for deriving the NOAEL. There are, however, no indications that the kidney function in females was impaired based on other kidney (related) findings. In addition, there were no related findings seen such as morphological lesions (e.g. inflammation or cell death) and it was not seen in males.
In conclusion: Based on the hypertrophy of the urothelium of the urinary bladder in females at 2000 ppm (corresponding to 137 mg/kg bw) renal changes (granular casts and basophilia) in males at 2000 ppm a parental NOAEL for systemic effects of 700 ppm was derived for rats. The latter effect is not considered relevant for humans. The overall parental NOAEL is based on the bladder effects, this NOAEL is 700 ppm in diet, which corresponding to 42 mg/kg bw.
Justification for classification or non-classification
The NOAEL of the substance is 700 ppm (equivalent to 42 mg/kg bw/day) and the LOAEL is 700 ppm (equivalent to 137 mg/kg bw), of which the latter is above the classification and labelling limits. In addition, the effects seen (slight hypertrophy of the urothelium of the urinary bladder in females are insufficiently severe for classification and labelling. Therefore, classification of the substance is not warranted according to EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008 and its amendments.
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