Registration Dossier

Administrative data

Description of key information

In an oral 28-day toxicity study (OECD TG 407) in rats with polysulfides, di-tert-dodecyl, the NOAEL for both males and females was higher than 1000 mg/kg bw/day.

An OECD TG 407 study was conducted using male and female Sprague-Dawley rats administered 0, 50, 250, or 1000 mg/kg bw/day of polysulfides, di-tert-dodecyl by daily gavage for 29 days; a satellite group in the control and high-dose groups were monitored for two weeks for recovery (Molinier, 1995). Group sizes were 12/sex for the control and 1000 mg/kg bw/day groups, and 6/sex for 50 and 250 mg/kg bw/day groups. One female given 1000 mg/kg bw/day was found dead on day 5. Prior to death, piloerection, hypokinesia, dyspnea and loud breathing were noted. At macroscopic examination, foamy contents were found in the trachea as well as dilatation and reddish color was noted for the lungs. No relevant findings were noted at microscopic examination. One female given 250 mg/kg bw/day was found dead on day 16; however, no clinical signs were observed prior to death. At macroscopic examination, dilatation with reddish coloration was noted for the lungs. No relevant findings were noted at microscopic examination. The probable cause of death of these two females might be regurgitation or misdosing, consequently these mortalities were notconsidered to be related to test substance toxicity. No deaths occurred during the recovery period. Ptyalism was observed in all animals of both sexes given 1000 mg/kg bw/day just after treatment. This finding was considered to be related to the test substance. During the recovery period, no clinical signs were observed in the high dose group, and no clinical signs were noted in the other groups during the dosing phase of the study. During the treatment and recovery periods, mean body weights and food consumption were similar between treated and control animals. With respect to clinical pathology, on week 4, a slightly higher erythrocyte count and hemoglobin concentration (+5% or +6% for males and females, respectively) was noted in animals of both sexes given 1000 mg/kg bw/day. This was associated with a slightly higher packed cell volume (+7% and +6%, for the males and females, respectively). These differences from controls were not seen after 2 weeks of recovery. These differences were not considered to be of toxicological significance. There were no differences in hematology, blood chemistry and urinalysis measurements that were considered to be of toxicological importance. Higher mean absolute and relative ovary weights were noted in the females, attaining statistical significance for the relative weight in the intermediate dose-level group (absolute: +26%, +5%, respectively for the intermediate and high dose-level groups; relative: +9%, +35%, +13%, respectively, for the low, intermediate and high dose-level groups). Higher mean absolute and relative kidney weights were noted for the females given 1000 mg/kg bw/day (absolute and relative: +8%), when compared to the respective controls. This difference was statistically significant for the relative weight only, and was not considered to be of toxicological importance. Statistically significantly lower mean absolute and relative mandibular lymph node weights were noted in the females given 1000 mg/kg bw/day as compared to the controls. Because this was not observed following the treatment period, it was not considered to be of toxicological importance. Statistically significant lower mean absolute and relative thyroid gland weights were noted in the females given 1000 mg/kg bw/day (absolute: -32%; relative: -37%). As no histological findings were observed and a higher mean thyroid weights were noted after the recovery period, this was not considered to be of toxicological importance. At necropsy, there were no macroscopic findings considered to be of toxicological importance. Microscopically, minimal to moderate acidophilic globules were found in the cortical tubular epithelium of kidneys in 3/6 males given 50 mg/kg bw/day and in 5/6 males given 250 mg/kg bw/day; minimal to slight acidophilic globules were found in all treated males at 1000 mg/kg bw/day. These kidney findings were not observed in any males of the control group. The presence of acidophilic globules in the treated males was considered to be treatment-related. No evidence of reversibility was found after the recovery period, as minimal to moderate acidophilic globules were found in the cortical tubular epithelium of 5/6 treated males given 1000 mg/kg bw/day versus minimal acidophilic globules in 1/6 control males. However it was not associated with any degeneration/necrosis of the cortical tubular epithelium. This was considered to be due to the well-known increase in accumulation of sex-linked protein (a2-µglobuline) in the lysosomes of the cortical tubular cells and this species and sex-related abnormality was considered to be of no toxicological importance (Hard et al., 2009). Few other microscopic findings were noted, and due to their low incidence, the absence of a dose relationship, they were considered to be of no toxicological importance. The NOAEL for both males and females was higher than 1000 mg/kg bw/day

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents)
Deviations:
no
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River, France
- Age at study initiation: six weeks old
- Weight at study initiation: 197g for males and 168 g for females
- Fasting period before study: none
- Housing: 2 rats of same sex in suspended wire-mesh cages
- Diet (ad libitum): A04C pelleted diet (UAR, France)
- Water (ad libitum): filetred tap water
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21+/-2
- Humidity (%): 50+/-20
- Air changes (per hr): 12
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: weekly

VEHICLE
- Justification for use and choice of vehicle (if other than water):
- Concentration in vehicle: 10, 50, 200 mg/ml
- Amount of vehicle (if gavage): 5 ml/kg
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
On week 1 and 4 by HPLC with UV detection
Duration of treatment / exposure:
28 days
Frequency of treatment:
daily
Dose / conc.:
50 mg/kg bw/day (actual dose received)
Dose / conc.:
250 mg/kg bw/day (actual dose received)
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
6 (low and mid dose levels), 12 (control and high dose levels)
Control animals:
yes, concurrent vehicle
Details on study design:
Post-exposure period: 14 days
- Dose selection rationale: based on a 7-day range finding study
- Post-exposure recovery period in satellite groups: 2 weeks
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
Clinical signs were observed for each animal at least once a day. All animals were checked at least twice a day for mortality/morbidity

DETAILED CLINICAL OBSERVATIONS: No

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
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No

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 AND COMPOUND INTAKE (if drinking water study): No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: 24 hours after the administration of the test substance (week 4, and at the end of the recovery period on week 6)
- Anaesthetic used for blood collection: Yes (ether)
- Animals fasted: Yes
- How many animals: all
- Parameters checked in table 7 [attached document] were examined.


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: 24 hours after the administration of the test substance (week 4, and at the end of the recovery period on week 6)
- Animals fasted: Yes
- How many animals: all
- Parameters checked in table 11 [attached document] were examined.

URINALYSIS: Yes
- Time schedule for collection of urine: week 4
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes
- Parameters checked in table 15 [attached document] were examined.

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
A detailed macroscopic examination was performed on all animals including those that died during the study.

ORGAN WEIGHTS: Yes
Adrenals; brain; heart; kidneys; liver; mesenteric lymph nodes; mandibular lymph nodes; ovaries; spleen; testes; epididymides; thymus; thyroids with parathyroids.

HISTOPATHOLOGY: Yes
Preserved tissues: adrenals; aorta*; brain including medulla/pons, cerebellar and cerebral cortex; cecum*; colon; duodenum; eyes with Harderian glands*; femoral bone with articulation*; heart; ileum; jejunum; kidneys; liver; lungs with bronchi; lymph nodes (mandibular and mesenteric); mammary glands*; esophagus; ovaries; pancreas*; pituitary gland*; prostate*; rectum*; sciatic nerve; seminal vesicle*; skeletal muscle*; skin; spinal cord (cervical, thoracic and lumbar); spleen; sternum with bone marrow; stomach with forestomach; salivary glands* (sublingual and submaxillary); testes and epididymides; thymus; thyroids with parathyroids; trachea; tongue*; urinary bladder; uterus (horns and cervix); vagina*. Microscopic examination was performed on all macroscopic lesions and tissue listed above, except those marked by *, in animals of the high dose and control groups killed at the end of the treatment period, and those that died. Microscopic examination was also performed on all macroscopic lesions, lungs, liver and kidneys of all animals of the low and intermediate dose groups, all macroscopic lesions of all animals of the high dose and control groups killed at the end of the recovery period, and kidneys of the males of the high dose and control groups killed at the end of the recovery period.
Statistics:
The following sequence was used for the statistical analysis of body weight, food consumption, haematology, blood biochemistry, urinalysis and organ weight data:
The normality of the distribution of the values in each group was checked by Kolmogorov-Smirnov's test (1948).
If the distribution was normal, the homogeneity of variances between the groups was assessed by Bartlett's test (1937) (more than 2 groups) or Fisher's test (1934) (2 groups).
If no significant heterogeneity of the variances was established, the comparison between treated and control groups was performed by Dunnett's test (1955).
If the variances were heterogeneous, the comparison between treated and control groups was performed by Dunn's test (1964) (more than 2 groups) or by Mann Whitney's test (1947) (2 groups).
If the distribution of values in the groups was not normal, the analysis was repeated after logarithmic transformation of the values (except for organ weights).
If this logarithmic transformation failed to normalise the distribution of the values, comparison of treated and control groups was performed by Dunn's test using original values.
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Ptyalism was observed in all animals of both sexes given 1000 mg/kg bw/day just after treatment. This finding was considered to be related to the test substance. During the recovery period, no clinical signs were observed. No clinical signs were noted in the other groups.
Mortality:
mortality observed, non-treatment-related
Description (incidence):
One female given 250 mg/kg bw/day was found dead on day 16. No clinical signs were observed prior to death. At macroscopic examination, dilatation with reddish coloration was noted for the lungs. No relevant findings were noted at microscopic examination. One female given 1000 mg/kg bw/day was found dead on day 5. Prior to death, piloerection, hypokinesia, dyspnea and loud breathing were noted. At macroscopic examination, foamy contents were found in the trachea as well as dilatation and reddish color was noted for the lungs. No relevant findings were noted at microscopic examination. Neither death was considered to be treatment related. No deaths occurred during the recovery period.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
During the treatment period and the recovery period, the mean body weight gain was similar between treated and control animals.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
During the treatment and recovery periods, the mean food consumption was similar between treated and control animals.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
effects observed, non-treatment-related
Description (incidence and severity):
On week 4, a slightly higher erythrocyte count and hemoglobin concentration (+5% or +6% for males and females, respectively) was noted in animals of both sexes given 1000 mg/kg bw/day. This was associated with a slightly higher packed cell volume (+7% and +6%, for the males and females, respectively). These differences from controls were not seen after 2 weeks of recovery. Since these differences were minor and the individual values were within the range of the background historical data, this was considered not to be of toxicological importance. The other differences from controls noted among haematological parameters (including lymphocyte and neutrophil counts) were minor and lacked a dose-relationship. Accordingly, they were considered to be of no toxicological significance.
Clinical biochemistry findings:
effects observed, non-treatment-related
Description (incidence and severity):
In week 4, the differences from controls noted among blood biochemical parameters (including: sodium, chloride and calcium levels, albumin level, triglyceride and glucose) were minor, without similar trend in both sexes, lacked a dose-relationship and the individual values were within or close to the normal range of the historical data. Consequently, they were considered not to be of toxicological importance.
Urinalysis findings:
no effects observed
Description (incidence and severity):
No differences from controls were noted at the end of the treatment period.
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Description (incidence and severity):
At the end of the treatment period:
Lower mean absolute and relative mandibular lymph node weights were noted in the males (absolute: -29%,-22%,-36%; relative: -27%,-18%,-31%). This was not statistically significant, not dose-related and almost all the individual values were within the range of the control values. Thus, this was considered not to be of toxicological importance. Moreover, this could be explained, at least in part, by a very high absolute and relative mandibular lymph node weight in 1/6 control males (L29587).

Lower mean absolute and relative thymus weights were noted in the males and females (absolute: -2%,-8%,-15% respectively for the males given 50, 250 or 1000 mg/kg/day; -8%, -4%,-13% respectively for the females; relative: -1%,-4%,-9% respectively for the males; -1%,+3%,-7% respectively for the females). These differences were minor, not statistically significant, not dose-related in the females and all the individual values of the treated males, except 1/6 absolute value in the high dose-level group, were within the range of the control values. In the females, 2/6 absolute and 1/6 relative thymus weights were lower than the lowest respective control weight in the low and intermediate dose-level groups and 3/5 absolute and relative thymus weights were lower than the lowest respective control weights in the high dose level group, whereas 1/5 absolute and 1/5 relative values were higher than the highest respective control values. Moreover no relevant macroscopic or microscopic findings were noted. Thus, this was considered not to be of toxicological importance.

Higher mean absolute and relative ovary weights were noted in the females; this attained statistical significance for the relative weight in the intermediate dose-level group (absolute: +26%,+5% respectively for the intermediate and high dose-level groups; relative: +9%,+35%,+13% respectively for the low, intermediate and high dose-level groups). As this lacked a dose-relationship it was considered to be of no toxicological importance and most probably related to the differences in the phases of oestrous cycle.

Higher mean absolute and relative thyroid gland weights were noted in the females given 1000 mg/kg/day, when compared with the controls (absolute: +12%; relative: +29%). This was not statistically significant and was not observed in the two lower dose-level groups, where lower mean absolute values were noted. Only 1/6 individual absolute and relative values were higher than the highest control value. Thus, this was considered not to be of toxicological importance.
Some other differences were noted between treated males and females and their respective controls: they were minor, not statistically significant, not dose-related and thus, they were considered not to be of toxicological importance.

At the end of the recovery period:
Higher mean absolute and relative kidney weights were noted for the females given 1000 mg/kg/day (absolute and relative:+8%), when compared to the respective controls. This was statistically significant only for the relative weight. In addition, only 2/6 individual absolute and 1/6 individual relative values were higher than the highest respective control values. As this minor difference was not seen after the treatment period, it was not considered to be of toxicological importance.

Higher mean absolute and relative mesenteric lymph node weights were noted for the males and females given 1000 mg/kg/day (absolute: +13%,+18% respectively; relative: +22%,+19% respectively), when compared to the respective controls. This was not statistically significant, except for the relative weight in the females, and the individual absolute and relative values, for the males, were within the range of the respective controls. In the females, 4/6 individual absolute and only 1/6 individual relative values were higher than the highest respective control values. In addition, this was not observed after the treatment period. Consequently, this was not considered to be of toxicological importance.

Statistically significant lower mean absolute and relative mandibular lymph node weights were noted in the females given 1000 mg/kg/day, when compared with their respective controls (absolute and relative:-21%). This was not seen after the treatment period. In addition, only 3/6 individual absolute and 2/6 individual relative values were lower than the lowest respective control values. Consequently, this was not considered to be of toxicological importance.

Lower mean absolute and relative ovary weights were noted in the females given 1000 mg/kg/day (-12% for both absolute and relative weights). This was not statistically significant. Only 2/6 individual absolute or relative values were lower than the lowest respective control values; moreover, higher mean weights were recorded after the treatment period. Thus, this was not considered to be of toxicological importance.

Higher mean absolute and relative spleen weights were noted for the females given 1000 mg/kg/day, when compared to the respective controls (absolute: +19%; relative: +17%). This was not statistically significant. In addition, only 3/6 individual absolute values were higher than the highest respective control value and all the individual relative values were within the range of the controls. Moreover, this was not seen after the treatment period. Thus, this was not considered to be of toxicological importance.

Statistically significant lower mean absolute and relative thyroid gland weights were noted in the females given 1000 mg/kg/day (absolute:-32%; relative:-37%). Only 3/6 individual absolute and 1/6 individual relative values were lower than the lowest respective control values. As higher mean thyroid gland weights were noted after the four week treatment period, this was not considered to be of toxicological importance.
Gross pathological findings:
no effects observed
Description (incidence and severity):
At the end of the treatment and recovery periods:
The few macroscopic findings encountered were those which are commonly recorded spontaneous changes in the untreated laboratory rat of this strain and age and thus were not considered to be of toxicological importance.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
At the end of the treatment period:
Minimal to moderate acidophilic globules were found in the cortical tubular epithelium of the kidneys in 3/6 males given 50 mg/kg/day and in 5/6 males given 250 mg/kg/day; minimal to slight acidophilic globules were found in all treated males at 1000 mg/kg/day. This was not found in any male of the control group. The presence of acidophilic globules in the treated males was considered to be treatment-related. However it was not associated with any degeneration/necrosis of the cortical tubular epithelium. This was considered to be due to the well-known increase in accumulation of the sex-linked protein (alpha-2}µglobuline) in the lysosomes of the cortical tubular cells, following absorption of some chemicals and this species and sex-related abnormality was considered to be of no toxicological importance.
No evidence of reversibility was found after the recovery period, as minimal to moderate acidophilic globules were found in the cortical tubular epithelium of 5/6 treated males given 1000 mg/kg/day versus minimal acidophilic globules in 1/6 control males.

Few other microscopic findings were found in the surviving treated animais and not in the controls; due to their low incidence (1/6 or 1/5 or 2/6 animals), the absence of dose-relationship and the fact that they are commonly observed spontaneously in the untreated rat of this strain and age, they were considered to be of no toxicological importance.
These findings included:
. heart: minimal cardiomyopathy in 1/6 males given 1000 mg/kg/day,
. urinary bladder: slight cystitis and slight epithelial cell hyperplasia noted in one female given 1000 mg/kg/day,
. liver: minimal hepatocellular degeneration in 1/6 females given 50 mg/kg/day; slight haemorrhage in 1/6 females given 250 mg/kg/day; minimal tension lipidosis in 1/6 females given 50 mg/kg/day; minimal steatosis in 1/6 females given 250 mg/kg/day; minimal focal coagulative hepatocellular necrosis in 1/6 males given 50 mg/kg/day and slight focal coagulative hepatocellular necrosis in 1/6 males given 250 mg/kg/day; moderate multifocal hepatocellular degeneration/necrosis in 1/6 females given 250 mg/kg/day,
. adrenals: slight vacuolated cortical cells in 1/6 males given 1000 mg/kg/day,
. kidneys: slight leucohistiocytic pyelitis and slight urothelial cell hyperplasia in 1/5 females given 1000 mg/kg/day (the same female which showed cystitis, as above-mentioned); minimal dilated pelvis in 1/6 males given 250 mg/kg/day; slight dilated pelvis in 1/6 males given 250 mg/kg/day; moderate dilated pelvis in 1/6 males given 1000 mg/kg/day; minimal mineralization in 1/6 males and 1/5 females given 1000 mg/kg/day,
. lungs: minimal perivascular haemorrhage in 1/6 males given 50 mg/kg/day; minimal chronic interstitial pneumonia in 1/6 males given 1000 mg/kg/day; slight chronic interstitial pneumonia in 1/6 males and 1/6 females given 50 mg/kg/day and in 1/6 males given 250 mg/kg/day; moderate chronic interstitial pneumonia in 1/6 males given 50 mg/kg/day and in 1/5 females given 250 mg/kg/day.

All the other microscopic findings noted in control and treated animals were those which are commonly recorded spontaneous changes in the untreated laboratory rat of this strain and age and thus, considered to be of no toxicological importance.
Histopathological findings: neoplastic:
not examined
Other effects:
not specified
Key result
Dose descriptor:
NOAEL
Effect level:
> 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Remarks on result:
not determinable due to absence of adverse toxic effects
Critical effects observed:
no

see attached document for heamatology, blood chemistry and urinalysis

Conclusions:
The oral (gavage) administration of TPS 32 to Sprague-Dawley rats for four weeks at 50 or 250 mg/kg/day was well-tolerated. At 1000 mg/kg/day, ptyalism was noted only during the treatment period and not during the recovery period. Consequently, under the conditions of this study, the No Observable Adverse Effect Level (NOAEL) is 1000 mg/kg/day.
Executive summary:

An OECD TG 407 study was conducted using male and female Sprague-Dawley rats administered 0, 50, 250, or 1000 mg/kg bw/day of di-t-dodecyl polysulfides by daily gavage for 29 days; a satellite group in the control and high-dose groups were monitored for two weeks for recovery. Group sizes were 12/sex for the control and 1000 mg/kg bw/day groups, and 6/sex for 50 and 250 mg/kg bw/day groups. One female given 1000 mg/kg bw/day was found dead on day 5. Prior to death, piloerection, hypokinesia, dyspnea and loud breathing were noted. At macroscopic examination, foamy contents were found in the trachea as well as dilatation and reddish color was noted for the lungs. No relevant findings were noted at microscopic examination. One female given 250 mg/kg bw/day was found dead on day 16; however, no clinical signs were observed prior to death. At macroscopic examination, dilatation with reddish coloration was noted for the lungs. No relevant findings were noted at microscopic examination.  The probable cause of death of these two females might be regurgitation or misdosing, consequently these mortalities were not considered to be related to test substance toxicity. No deaths occurred during the recovery period. Ptyalism was observed in all animals of both sexes given 1000 mg/kg bw/day just after treatment. This finding was considered to be related to the test substance. During the recovery period, no clinical signs were observed in the high dose group, and no clinical signs were noted in the other groups during the dosing phase of the study. During the treatment and recovery periods, mean body weights and food consumption were similar between treated and control animals. With respect to clinical pathology, on week 4, a slightly higher erythrocyte count and hemoglobin concentration (+5% or +6% for males and females, respectively) was noted in animals of both sexes given 1000 mg/kg bw/day. This was associated with a slightly higher packed cell volume (+7% and +6%, for the males and females, respectively). These differences from controls were not seen after 2 weeks of recovery. These differences were not considered to be of toxicological significance. There were no differences in hematology, blood chemistry and urinalysis measurements that were considered to be of toxicological importance. Higher mean absolute and relative ovary weights were noted in the females, attaining statistical significance for the relative weight in the intermediate dose-level group (absolute: +26%, +5%, respectively for the intermediate and high dose-level groups; relative: +9%, +35%, +13%, respectively, for the low, intermediate and high dose-level groups). Higher mean absolute and relative kidney weights were noted for the females given 1000 mg/kg bw/day (absolute and relative: +8%), when compared to the respective controls. This difference was statistically significant for the relative weight only, and was not considered to be of toxicological importance. Statistically significantly lower mean absolute and relative mandibular lymph node weights were noted in the females given 1000 mg/kg bw/day as compared to the controls. Because this was not observed following the treatment period, it was not considered to be of toxicological importance. Statistically significant lower mean absolute and relative thyroid gland weights were noted in the females given 1000 mg/kg bw/day (absolute: -32%; relative: -37%). As higher mean thyroid weights were noted after the recovery period, this was not considered to be of toxicological importance. At necropsy, there were no macroscopic findings considered to be of toxicological importance. Microscopically, minimal to moderate acidophilic globules were found in the cortical tubular epithelium of kidneys in 3/6 males given 50 mg/kg bw/day and in 5/6 males given 250 mg/kg bw/day; minimal to slight acidophilic globules were found in all treated males at 1000 mg/kg bw/day. These kidney findings were not observed in any males of the control group. The presence of acidophilic globules in the treated males was considered to be treatment-related. No evidence of reversibility was found after the recovery period, as minimal to moderate acidophilic globules were found in the cortical tubular epithelium of 5/6 treated males given 1000 mg/kg bw/day versus minimal acidophilic globules in 1/6 control males.  However it was not associated with any degeneration/necrosis of the cortical tubular epithelium. This was considered to be due to the well-known increase in accumulation of sex-linked protein (a2-µglobuline) in the lysosomes of the cortical tubular cells and this species and sex-related abnormality was considered to be of no toxicological importance (Hard et al., 2009). Few other microscopic findings were noted, and due to their low incidence, the absence of a dose relationship, they were considered to be of no toxicological importance. The NOAEL for both males and females was 1000 mg/kg bw/day

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat

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

Justification for classification or non-classification

According to the available data and criteria of Regulation no. 1272/2008, no classification is warranted for repeated dose toxicity.