4-chlorobenzophenone

Endpoint summary

Description of key information

Repeated Dose Toxicity: Oral

Based on the available results and applying the weight of evidence approach, the test chemical can be considered to be non-toxic to living organisms when dosed repeatedly via oral route. The No Observed Adverse Effect Level can be considered to be >1000 mg/kgbw/day. Comparing the above annotations with the criteria of CLP Regulation, the test chemical can be classified under the category “Not Classified”.

 

Repeated Dose toxicity: Inhalation

A short-term toxicity study need not be conducted as because exposure of humans via inhalation route in production and/or use is not likely based on the provided thorough and rigorous exposure.

 

Repeated Dose Toxicity: Dermal

A short-term toxicity study need not be conducted as because exposure of humans via dermal route in production and/or use is not likely based on the provided thorough and rigorous exposure assessment.

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

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

Remarks:

Read across data

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Justification for type of information:

Data is from J-check

Qualifier:

according to guideline

Guideline:

other: The study was performed in accordance with Guidelines for 28 Day Repeat Dose Toxicity Testing for Chemicals(Japan)

Principles of method if other than guideline:

A repeat dose oral toxicity test was performed to determine the repeated dose oral toxic nature of the test chemical

GLP compliance:

not specified

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Details on species / strain selection:

SD strain [Crl: CD (SD)] rats

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Japan Charles River (Kanagawa)
- Females (if applicable) nulliparous and non-pregnant: [yes/no] : yes
- Age at study initiation: The age at the start of administration was 5 weeks for both males and females
- Weight at study initiation: body weight range was 165 to 190 g for males and 129 to 153 g for females.
- Housing: Rats are housed individually in wire mesh cages in a breeding room
- Diet (e.g. ad libitum): solid feed (Lab MR stock, Japan Agro-industry), ad libitum
- Water (e.g. ad libitum): water, adlibitum
- Acclimation period: both males and females are acclimated to the test environment for 11 days while being quarantined.

DETAILS OF FOOD AND WATER QUALITY:

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-25 degrees C
- Humidity (%): 40-70%
- Air changes (per hr): the ventilation is about 12 times / hour
- Photoperiod (hrs dark / hrs light): the lighting room was automatically adjusted to 12 hours (7: 00-19: 00)

Route of administration:

oral: gavage

Details on route of administration:

No data available

Vehicle:

other: 0.5% carboxymethylcellulose / sodium solution containing 0.1% Tween80

Details on oral exposure:

REPARATION OF DOSING SOLUTIONS:The dosing solution was prepared by suspending the test substance in 0.5% carboxymethylcellulose / sodium solution containing 0.1% Tween80 and refrigerated. The test substance in the administration solution was stable for at least 8 days under refrigerated storage conditions, and it was confirmed that the used administration solution contained a uniform amount of the test substance.

DIET PREPARATION
- Rate of preparation of diet (frequency): No data available
- Mixing appropriate amounts with (Type of food): No data available
- Storage temperature of food: No data available

VEHICLE
- Justification for use and choice of vehicle (if other than water): 0.5% carboxymethylcellulose / sodium solution containing 0.1% Tween80
- Concentration in vehicle: 0, 20, 140 or 1000 mg/kg/day
- Amount of vehicle (if gavage): The dosing volume was 10 ml / kg and was calculated based on the body weight of the closest measurement day. The solvent was similarly administered to the control group.
- Lot/batch no. (if required): No data available
- Purity: No data available

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

No data available

Duration of treatment / exposure:

28 days

Frequency of treatment:

Daily

Remarks:

0, 20, 140 and 1000 mg / kg / day

No. of animals per sex per dose:

The number of animals in each group was 6 males and 6 females, and for the control and high-dose groups, a recovery group of 14 males and 6 females was established

Control animals:

yes, concurrent vehicle

Details on study design:

Dose selection rationale: As a dose-setting study, the test substance was orally administered at a dose of 0, 30, 100, 300, and 1000 mg / kg for 14 days in 4 males and 4 females per group. Observation of general condition, body weight, and food consumption , Hematology and blood biochemistry, autopsy, and organ weights were measured. As a result, no toxic effects due to administration were observed. Therefore, the maximum dose for this study was 1000 mg / kg / day, and the following three doses of 300 and 100 mg / kg / day and controls were set.
- Rationale for animal assignment (if not random): Prior to the start of treatment, animals were divided into groups by weight-based stratified random sampling.The number of animals in each group was 6 males and 6 males, and for the control and high-dose groups, a recovery group of 14 males and 6 males was established.

Positive control:

No data available

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes / No / Not specified : yes
- Time schedule: daily
- Cage side observations checked in table [No.?] were included. : All rats were observed daily for general condition.

DETAILED CLINICAL OBSERVATIONS: Yes / No / Not specified; yes
- Time schedule: daily

BODY WEIGHT: Yes / No / Not specified : yes
- Time schedule for examinations: Body weight was measured on the first day of administration and once a week thereafter

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes / No / Not specified : yes, Food intake was measured on the first day of administration and once a week thereafter, and the average daily food intake per animal was calculated for each period

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: Yes / No / Not specified ; not specified

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes / No / Not specified : not specified
- Time schedule for examinations: not specified

OPHTHALMOSCOPIC EXAMINATION: Yes / No / Not specified : no


HAEMATOLOGY: Yes / No / Not specified : yes
- Time schedule for collection of blood: At the time of each planned autopsy, blood was collected from the posterior vena cava under anesthesia by intraperitoneal administration of thiopental sodium
- Anaesthetic used for blood collection: Yes (identity) / No / Not specified: thiopental sodium
- Animals fasted: Yes / No / Not specified : no data available
- How many animals: all the test and control animals
- Parameters checked in table [No.?] were examined.: red blood cell count (sheath flow DC impedance detection method), white blood cell count (RF/ DC impedance detection method), platelet count (Sheath flow DC impedance detection method), hemoglobin concentration (SLS hemoglobin method), hematocrit value (red blood cell pulse peak detection method) multi-item automatic blood cell analyzer, white blood cell percentage ( Wright stained smear) automatic blood cell analyzer, reticulocyte count (flow cytometry method using argon laser), automatic reticulocyte analyzer, Prothrombin time (PT: Quick one-step method), activated partial thromboplastin time (APTT: activated cephaloplastin method) blood coagulation automatic measuring device (KC 10A: Amerung) were measured. The mean red blood cell volume (MCV), average red blood cell pigment content (MCH), and average red blood cell pigment concentration (MCHC) were calculated from the results of the tests. As a coagulation inhibitor, 3.13% sodium citrate aqueous solution was used to measure prothrombin time and activated partial thromboplastin time, and EDTA-2K was used to measure other parameters

CLINICAL CHEMISTRY: Yes / No / Not specified : yes
- Time schedule for collection of blood: At the time of each planned autopsy, blood was collected from the posterior vena cava under anesthesia by intraperitoneal administration of thiopental sodium
- Animals fasted: Yes / No / Not specified : not specified
- How many animals: all the test and control animals
- Parameters checked in table [No.?] were examined.: The collected blood is allowed to stand at room temperature for about 30 minutes and then centrifuged at 3000 rpm for 10 minutes.
Using the obtained serum, total protein (Biuret method), albumin (BCG method), A / G ratio (total protein and Calculated from albumin), glucose (GK-G6PDH method), triglyceride (LPL-GK-G3PO-POD method), total cholesterol (CES-CO-POD method), urea nitrogen (Urease-GLDH method), creatinine (Jaff method) , Calcium (O-CPC method), inorganic phosphorus (UV method), GOT (SSCC improved method), GPT (SSCC improved method), γ-GTP (SSCC improved method), ALP (GSCC improved method), sodium, potassium, Crawl (ion selective electrode method) was measured with an automatic analyzer .

URINALYSIS: Yes / No / Not specified : yes
- Time schedule for collection of urine: fresh urine was collected from all surviving animals 2 days before dissection at the end of administration
- Metabolism cages used for collection of urine: Yes / No / Not specified : no
- Animals fasted: Yes / No / Not specified: no
- Parameters checked in table [No.?] were examined. : pH, occult blood, protein, sugar, ketone bodies, bilirubin, urobilinogen (test paper method, Marti Sticks: Miles Sankyo Co., Ltd.) was measured. As a result, changes were observed in females in the 1000 mg / kg group, so the collected urine was further collected for 21 hours only for females, the urine volume was measured with a graduated cylinder, and the specific gravity (refractive method) was measured with a urine hydrometer Atago Co., Ltd., sodium and potassium (flame photometric method) with a fully automatic flame photometer (FLAME-30C / AD-3: JASCO Medical Co., Ltd.) and chlor (coulometric titration method) with a chloride meter (Model 925: Corning Medical Co., Ltd.) Similar examinations were performed on females with changes during the treatment period 2 days before dissection at the end of the recovery period.

Sacrifice and pathology:

GROSS PATHOLOGY: Yes, At the time of each planned killing, all animals were bled and the abdominal aorta was severed, exsanguinated and necropsied, and the brain, liver, kidney, adrenal gland, thymus, spleen, testis and ovary were weighed. In addition to these organs, the pituitary gland, eyeball (including accessory glands), lung, stomach, thyroid (including parathyroid bodies), heart, bladder, and bone marrow (femur) were collected and 10% neutral phosphorus was collected. After fixation with acid-buffered formalin solution (Davidson solution for eyeball and Harder's gland), these organs were stored.
HISTOPATHOLOGY: Yes, At the end of administration, hematoxylin and eosin-stained specimens were prepared and examined microscopically in the control of anatomical animals and in the 1000 mg / kg group of male and female hearts, liver, spleen, kidney, and adrenal gland. In addition, the testis of 1 male in the 20 mg / kg group and 2 males in the 140 mg / kg group and the testis of 1 male in the 1000 mg / kg group and recovery period at the end of the administration period, which had undergone macroscopic changes A similar study was performed on the lungs of one male in the control group and the thymus of one male in the 1000 mg / kg group at the end.

Other examinations:

No data available

Statistics:

The metric data were tested for equal variances using the Bartlett method, and if the variance was uniform, a one-way analysis of variance was performed, followed by a mean comparison test using the Dunnett or Scheff method. When the variance was not uniform, the Kruskal-Wallis test was performed, and the Dunnett or Scheff type rank sum test was performed. For counting data obtained from urinalysis, Armitage's χ ^ 2 test was used. The significance level was 5% or less.

Clinical signs:

no effects observed

Description (incidence and severity):

There were no abnormal findings throughout the study

Mortality:

no mortality observed

Description (incidence):

There were no deaths throughout the study

Body weight and weight changes:

no effects observed

Description (incidence and severity):

Body weight remained the same in all test substance-administered groups as well as in the control group

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

food consumption remained the same in all test substance-administered groups as well as in the control group

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

no effects observed

Description (incidence and severity):

At the end of the treatment period, males in the 20 mg / kg group showed low MCHC, but not in the 140 and 1000 mg / kg groups, indicating changes not related to test substance administration. In addition, at the end of the recovery period, a high monocyte ratio was observed in females in the 1000 mg / kg group, but not at the end of the administration period

Clinical biochemistry findings:

no effects observed

Description (incidence and severity):

There were no changes in the test at the end of the treatment period. In the test at the end of the recovery period, a low level of urea nitrogen was observed in females in the 1000 mg / kg group, but this was not observed at the end of the administration period

Urinalysis findings:

no effects observed

Description (incidence and severity):

In the examination of the administration period, the pH of the 1000 mg / kg group showed a change to the alkaline side. Although bilirubin was elevated in males in the 20 mg / kg group but not in the 140 and 1000 mg / kg groups, it was judged that the change was not related to test substance administration.No changes in pH were observed in the recovery period tests performed on females only. In addition, a low potassium level was observed in the 1000 mg / kg group, but it was not observed during the administration period. Therefore, the change was not related to the test substance administration

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

At the end of the dosing period, females in the 140 mg / kg group showed a low relative weight of the adrenal gland but not in the 1000 mg / kg group, which is not related to test substance administration. In the test at the end of the recovery period, the relative weight of the ovary was observed in females in the 1000 mg / kg group, but this was not observed at the end of the administration period, so it was not related to test substance administration

Gross pathological findings:

no effects observed

Description (incidence and severity):

There were no changes due to the administration of the test substance. Spontaneous changes included mild discoloration of the kidneys, kidney cysts, adrenal enlargement, testicular miniaturization, pulmonary hemorrhage, and thymic bleeding.

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

There were no changes due to the administration of the test substance. Accidental changes in liver microgranulomas, basal changes in renal tubular epithelium, cystic expansion of renal tubules, renal mononuclear cell infiltration, hypotubule formation, lung bleeding, thymic bleeding was observed.

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No effects attributable to the test chemical were noted at the mentioned dose level

Critical effects observed:

no

Conclusions:

There were no deaths throughout the study period, there was no change in general condition, body weight, food consumption, and toxicological changes due to test substance administration were not observed in hematology, blood biochemistry, urinalysis, and pathology result. In the urinalysis, the pH of the 1000 mg / kg / day group of females showed an alkaline change during the administration period. Alkaline urine is generally found in metabolic and respiratory alkalosis, renal H + excretion due to renal failure and pyelonephritis. However, this change was within the range of the laboratory's background data, and no pathological changes were observed suggesting renal damage.Therefore, the NOAEL after repeated oral administration to rats was concluded to be at least 1000 mg / kg / day for both males and females.

Executive summary:

A 28 day repeated dose oral toxicity of the test chemical was determined in Sprague Dawley rats. The study was performed in accordance with Guidelines for 28 Day Repeat Dose Toxicity Testing for Chemicals (Japan). Male and female SD rats (Crj: CD, SPF) obtained from Charles River Japan Co., Ltd. were quarantined and acclimatized for 8 days and used for the test. Prior to the start of treatment, animals were divided into groups by weight-based stratified random sampling. The number of animals in each group was 6 males and 6 females, and for the control and high-dose groups, a recovery group of 14 males and 6 females was established. The age at the start of administration was 5 weeks for both males and females, and the body weight range was 165 to 190 g for males and 129 to 153 g for females. The dosing solution was prepared by suspending the test substance in 0.5% carboxymethylcellulose / sodium solution containing 0.1% Tween80 and refrigerated. The test substance in the administration solution was stable for at least 8 days under refrigerated storage conditions. As a result of repeated oral administration of the test substance to SD rats at doses of 500 and 1000 mg / kg for 7 days, no change in toxicity was observed in the 1000 mg / kg group. Therefore, in this study, the high dose was set at 1000 mg / kg, the upper limit of the guideline, and the medium dose was set at 140 mg / kg and the low dose was set at 20 mg / kg. The test substance was orally administered by gavage once a day for 28 days using a stomach tube. The dosing volume was 10 ml/kg and was calculated based on the body weight of the closest measurement day. The solvent was similarly administered to the control group. The treated and control animals were observed for changes in General condition observation, detailed clinical observation, body weight, food intake, urinalysis (male only), hematology examination, blood biochemistry examination, autopsy, organ examination. There were no deaths throughout the study period, there was no change in general condition, body weight, food consumption, and toxicological changes due to test substance administration were not observed in hematology, blood biochemistry, urinalysis, and pathology result. In the urinalysis, the pH of the 1000 mg / kg / day group of females showed an alkaline change during the administration period. Alkaline urine is generally found in metabolic and respiratory alkalosis, renal H + excretion due to renal failure and pyelonephritis. However, this change was within the range of the laboratory's background data, and no pathological changes were observed suggesting renal damage.Therefore, the NOAEL after repeated oral administration to rats was concluded to be at least 1000 mg / kg / day for both males and females.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subchronic

Experimental exposure time per week (hours/week):

168

Species:

rat

Quality of whole database:

Klimisch rating 2

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: inhalation

Data waiving:

exposure considerations

Justification for data waiving:

a short-term toxicity study does not need to be conducted because exposure of humans via inhalation in production and/or use is not likely as based on the provided thorough and rigorous exposure assessment

Endpoint conclusion

Endpoint conclusion:

no study available

Quality of whole database:

waiver

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: dermal

Data waiving:

exposure considerations

Justification for data waiving:

a short-term toxicity study does not need to be conducted because exposure of humans via the dermal route in production and/or use is not likely as based on the provided thorough and rigorous exposure assessment

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Repeated Dose Oral Toxicity:

Various studies have been reviewed to determine the exact toxic dose of the test chemical when dosed repeatedly to test animals. These include in vivo experimental studies performed on rats for the test chemicals.

 

Study 1: A 28 day repeated dose oral toxicity of the test chemical was determined in Sprague Dawley rats. The study was performed in accordance with Guidelines for 28 Day Repeat Dose Toxicity Testing for Chemicals (Japan). Male and female SD rats (Crj: CD, SPF) obtained from Charles River Japan Co., Ltd. were quarantined and acclimatized for 8 days and used for the test. Prior to the start of treatment, animals were divided into groups by weight-based stratified random sampling. The number of animals in each group was 6 males and 6 males, and for the control and high-dose groups, a recovery group of 14 males and 6 males was established. The age at the start of administration was 5 weeks for both males and females, and the body weight range was 165 to 190 g for males and 129 to 153 g for females. The dosing solution was prepared by suspending the test substance in 0.5% carboxymethylcellulose / sodium solution containing 0.1% Tween80 and refrigerated. The test substance in the administration solution was stable for at least 8 days under refrigerated storage conditions. As a result of repeated oral administration of the test substance to SD rats at doses of 500 and 1000 mg / kg for 7 days, no change in toxicity was observed in the 1000 mg / kg group. Therefore, in this study, the high dose was set at 1000 mg / kg, the upper limit of the guideline, and the medium dose was set at 140 mg / kg and the low dose was set at 20 mg / kg. The test substance was orally administered by gavage once a day for 28 days using a stomach tube. The dosing volume was 10 ml/kg and was calculated based on the body weight of the closest measurement day. The solvent was similarly administered to the control group. The treated and control animals were observed for changes in General condition observation, detailed clinical observation, body weight, food intake, urinalysis (male only), hematology examination, blood biochemistry examination, autopsy, organ examination. There were no deaths throughout the study period, there was no change in general condition, body weight, food consumption, and toxicological changes due to test substance administration were not observed in hematology, blood biochemistry, urinalysis, and pathology result. In the urinalysis, the pH of the 1000 mg / kg / day group of females showed an alkaline change during the administration period. Alkaline urine is generally found in metabolic and respiratory alkalosis, renal H + excretion due to renal failure and pyelonephritis. However, this change was within the range of the laboratory's background data, and no pathological changes were observed suggesting renal damage.Therefore, the NOAEL after repeated oral administration to rats was concluded to be at least 1000 mg / kg / day for both males and females.

 

Study 2: This is supported by another study whose objective was to provide evaluations of general and reproduction/ developmental toxicity endpoints associated with administration of repeated doses of the test chemical. The study was performed according to OECD Guideline for the Testing of Chemicals No. 422 “Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test”; adopted: 29thJuly, 2016.A total of 124 Wistar rats (62 males and 62 females) were randomly allocated to six different dose groups for Main study. Each group consisted of 13 animals/sex for main group and 5 animals/sex for recovery group. The animals allocated to Group G2, G3, and G4/G4-R received 750, 1000 and 1250 mg/kg body weight of the test chemical respectively, whereas the animals of Group G1/G1-R received vehicle alone (Corn oil) for each day during the dosing period by oral route. Dose formulations were prepared daily. Male rats were treated two weeks before mating and thereafter for a total of 48 dosing days. Female rats were treated two weeks before mating, during mating, during gestation and during lactation, for a total of approx. 63 dosing days. Recovery groups of male and female rats (5/sex/dose) were treated at 0 or 1250 mg/kg bw/day for 66 days in total. Animals in the recovery groups were allowed to recover for two weeks after the final dose was given. No morbidity was observed during the study period. No mortality was observed other than two deaths due to gavage error (one male at 750 and one male and 1000 mg/kg). Clinical findings were sporadic and of no biological significance. Body weight changes were restricted to a significant decrease in % body weight change in the recovery group of male rats treated at 1250 mg/kg from day 1 – 22 as compared to the control group. This effect was considered incidental and therefore not attributed to the test chemical. Food consumption was unaffected by treatment. Changes in motor activity and behaviour were restricted to a significant increase in grip strength in male rats treated at 1000 mg/kg bw/day as compared to control. This effect was considered incidental and therefore not attributed to the test chemical. Oestrous cyclicity was unaffected by treatment. All female rats showed evidence of copulation after the cohabitation/mating period. Pregnancy rates were 77, 62, 77 and 77% at 0, 750, 1000 and 1250 mg/kg, respectively. No significant effects were observed on gestation length or litter size. Likewise, no significant effects were observed on the number of live births, pup survival, pup weight or sex ratio. Four pups were cannibalized at the 750 mg/kg treatment group. All other pups at 0, 750, 1000 and 1250 mg/kg were normal externally. The internal examination of the pups revealed no abnormalities attributed to the test chemical. Microscopic examination of the pups’ thyroid and parathyroid glands in the 0 and 1250 mg/kg treatment groups revealed no abnormalities. Changes in haematology in the adult rats included a significant decrease in activated partial thromboplastin time in male rats treated at 1250 mg/kg compared to controls; a significant increase in red blood cell levels in the recovery group of male rats treated at 1250 mg/kg compared to controls; a significant increase in platelet levels in the recovery group of male rats treated at 1250 mg/kg compared to controls; and a significant increase in prothrombin time in the recovery group of male rats treated at 1250 mg/kg compared to controls. Changes in clinical chemistry included decreased creatinine levels in male rats treated at ≥1000 mg/kg compared to controls; increased sodium levels in the recovery group of male rats treated at 1250 mg/kg compared to controls; decreased phosphorus levels in the recovery group of male rats treated at 1250 mg/kg compared to controls; decreased aspartate transaminase levels in the recovery groups of male and female rats treated at 1250 mg/kg compared to controls. The changes in haematology and clinical chemistry were not consistent between groups and lacked histological correlates. Therefore, the changes in haematology and clinical chemistry were not considered to be of toxicological importance. Hormonal data showed no significant effects on the concentrations of T4 or TSH (male and females), testosterone (males) or oestradiol (females). There were no significant effects on either the absolute or the relative weight of the brain, adrenals, heart, liver, kidneys, spleen, thymus, thyroid with parathyroid, testes, or epididymides. All adult animals were normal externally. Visceral findings included a case of mild splenic enlargement at 1000 mg/kg and one case of mild testicular shrinkage at 1250 mg/kg. Microscopic examination revealed no treatment-related effects, that is, the incidences and types of lesions observed at 1250 mg/kg were comparable to that of the concurrent control groups. Ophthalmological examination was not performed, however, detailed clinical examinations and microscopic examination of the eyes with optic nerve (at 0 and 1250 mg/kg) did not reveal any abnormalities. NOAEL for the test chemical was established at 1250 mg/kg bw/day in male and female rats after oral gavage treatment for a period of 48 to 66 days.

 

Based on the available results and applying the weight of evidence approach, the test chemical can be considered to be non-toxic to living organisms when dosed repeatedly via oral route. The No Observed Adverse Effect Level can be considered to be >1000 mg/kgbw/day. Comparing the above annotations with the criteria of

CLP Regulation, the test chemical can be classified under the category “Not Classified”.

 

Repeated Dose toxicity: Inhalation

A short-term toxicity study need not be conducted as because exposure of humans via inhalation route in production and/or use is not likely based on the provided thorough and rigorous exposure.

 

Repeated Dose Toxicity: Dermal

A short-term toxicity study need not be conducted as because exposure of humans via dermal route in production and/or use is not likely based on the provided thorough and rigorous exposure assessment.

Justification for classification or non-classification

Available studies indicate that the test chemical lacks the potential to cause any toxicity when exposed repeatedly to living organisms via oral, dermal, inhalation route of exposure. Hence,comparing the above annotations with the criteria of CLP Regulations, the test chemical can be classified under the category “Not Classified”.