Registration Dossier

Administrative data

Description of key information

Repeated dose studies with the test substance are available. 
A 16 -day oral range finding study in rats (NTP, 1990): no effects were found upto doses of 400 mg/kg bw/day.
A 16 -day oral range finding study in mice (NTP, 1990): no effects were found upto doses of 400 mg/kg bw/day.
A 13 -week oral range finding study in rats (Kluwe, 1982): no effects were found at 400 m/kg bw/day (effects at 800 mg/kg bw/day).
A 13 -week oral range finding study in mice (Kluwe, 1982): no effects were found at 300 mg/kg bw/day (effects at 600 mg/kg bw/day) for males and 600-1200 mg/kg bw/day (effects at 1200 mg/kg bw/day) for females.
In a 16 -week oral toxicity study in rats (Hagan, 1966), a NOAEL of 500 mg/kg bw/day was established.
A chronic (carcinogenicity) study in rats (NTP, 1990) with a NOAEL of 400 mg/kg bw.
A chronic (carcinogenicity) study in mice (NTP, 1990): effects at 300 mg/kg bw (LOAEL).
LOAEL converted to NOAEL using an assessment factor of 3.
Based on route-to-route extrapolation from the oral LOAEL assuming an oral and dermal absorption of 100%, the NOAEL for dermal toxicity will be 100 mg/kg bw/day.
In a subacute inhalation study in rats (Lahan, 1991), a NOAEC could not be derived, since effects of the test substance were noted in all treatment groups. Clinical observations (indicative of neurotoxicity), hypothermia and goblet cell metaplasia were noted at concentrations of 500 ppm and above. Therefore, the LOAEC is established at 500 ppm (equivalent to 2.2 mg/L and 2200 mg/m3).

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Reliable study summary (NTP), however, no full OECD compliant chronic study (no haematology and clinical biochemistry).
Qualifier:
no guideline followed
Principles of method if other than guideline:
Fischer 344/N rats and B6C3F1 mice were used in this study. Groups of 50 rats of each sex and groups of 50 male mice were administered 0, 200, or 400 mg/kg the test substance in corn oil by gavage, 5 days per week for 103 (rats) or 104 (male mice) weeks. Groups of 50 female mice were administered 0, 300, or 600 mg/kg, 5 days per week for 103 weeks.
GLP compliance:
yes
Limit test:
no
Species:
other: rat and mouse
Strain:
other: Fischer 344/N rats and B6C3F1 mice
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Frederick Cancer Research Facility
- Age at study initiation: Rats: 8 wk; Mice: male: 8 wk, female: 9 wk
- Housing: five per cage, Polycarbonate cages with reemay spun-bonded polyester filters
- Diet (e.g. ad libitum): NIH 07 Rat and Mouse Ration; available ad libitum
- Water (e.g. ad libitum): available ad libitum
- Acclimation period: Rats: 20 d; Mice: 19 d

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 16.7-31.7
- Humidity (%): 25%-86%
- Air changes (per hr): 15 room air changes/h
- Photoperiod (hrs dark / hrs light): fluorescent light 12 h/d

IN-LIFE DATES:
Rats: From: 18 January 1982 To: 20 January 1984;
Male mice: From: 19 January 1982 To: 26 January 1984;
Female mice: From: 2 March 1982 To: 1 March 1984

No additional data
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
VEHICLE
- Amount of vehicle (if gavage): rats: 5 mL/kg; mice: 10 mL/kg

No additional data
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The test substance in corn oil was found to be stable at room temperature in the dark for 14 days when stored in sealed vials. A small (5%) loss occurred when the test substance in corn oil was exposed to air and light for 3 hours at room temperature under simulated dosing conditions. Dose formulations were prepared once a week and were stored in the dark at room temperature under nitrogen for a maximum of 14 days.
Duration of treatment / exposure:
103 weeks for rats and female mice, 104 weeks for male mice
Frequency of treatment:
5 days per week
Remarks:
Doses / Concentrations:
0, 200 or 400 mg/kg for rats and male mice; 0, 300 or 600 mg/kg for female mice
Basis:
actual ingested
No. of animals per sex per dose:
50 males and 50 females of each species per dose
Control animals:
yes, concurrent vehicle
Details on study design:
None stated
- Dose selection rationale: Rats: Because of the various lesions observed at 800 mg/kg but not at 400 mg/kg, doses selected for rats for the 2-year studies were 200 and 400 mg/kg the test substance, administered in corn oil by gavage, 5 days per week.
Mice: Doses of the test substance selected for male mice for the 2-year studies were 200 and 400 mg/kg, based on renal lesions in one male mouse given 600 mg/kg and in all of the male mice given 1200 mg/kg for 13 weeks. Doses selected for female mice for the 2-year studies were 300 and 600 mg/kg because of the steep dose-response curve for mortality demonstrated in the 16-day and 13-week studies (survival-16-day study: 1600 mg/kg, 0/5; 13-week study: 1200 mg/kg, 9/10).

No additional data
Positive control:
No stated
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice per day

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice per day

BODY WEIGHT: Yes
- Time schedule for examinations: on day 1, once a week for 13 weeks and once a month thereafter

OPHTHALMOSCOPIC EXAMINATION: No data

HAEMATOLOGY: No data

CLINICAL CHEMISTRY: No data

URINALYSIS: No data

NEUROBEHAVIOURAL EXAMINATION: No data

No additional data
Sacrifice and pathology:
GROSS PATHOLOGY: yes. Number of animals receiving complete necropsy examination; all gross lesions including masses examined microscopically.
HISTOPATHOLOGY: Yes. The following tissues examined histologically for all vehicle control and high dose animals, low dose male rats, and all animals dying before the end of the studies: adrenal glands, brain, cecum, colon, duodenum, epididymis/prostate/testes or ovaries/uterus, esophagus, eyes (rats), femur including marrow, gallbladder (mice), gross lesions and tissue masses, heart, ileum, jejunum, kidneys, liver, lungs and mainstem bronchi, mammary gland, mandibular or mesenteric lymph nodes, nasal cavity and turbinates, pancreas, parathyroid glands, pituitary gland, preputial or clitoral gland (rats), rectum, salivary glands, sciatic nerve, skin, spinal cord (rats), spleen, stomach, thymus, thyroid gland, trachea, and urinary bladder. Tissues examined for low dose groups include adrenal glands, bone, brain, clitoral gland, eyes, gross lesions, heart, kidneys, liver, lungs, pituitary gland, spinal cord, spleen, and stomach for female rats and gross lesions and stomach for mice.
Other examinations:
None stated
Statistics:
Survival analyses: The probability of survival was estimated by the product-limit procedure of Kaplan and Meier (1958) and is presented in the form of graphs. Statistical analyses for a possible dose-related effect on survival used the method of Cox (1972) for testing two groups for equality and Tarone's (1975) life table test for a dose-related trend. When significant survival differences were detected, additional analyses using these procedures were carried out to determine the time point at which significant differences in the survival curves were first detected. All reported P values for the survival analysis are two-sided.
Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food efficiency:
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
effects observed, treatment-related
Details on results:
CLINICAL SIGNS AND MORTALITY
Rats: The survival of the high dose group of male rats was significantly lower than that of the vehicle controls after day 373; no other significant differences were observed between any groups of either sex.
Mice: No significant differences were observed between any groups of either sex in mortality. No compound-related clinical signs were observed in clnical signs.

BODY WEIGHT AND WEIGHT GAIN
Rats: Mean body weights of dosed and vehicle control rats were similar throughout the studies.
Mice: Mean body weights of dosed and vehicle control mice were similar throughout the studies. No compound-related clinical signs were observed.

GROSS PATHOLOGY (Neoplastic effects)
Rats
Pancreas: Hyperplasia and adenomas of the exocrine pancreas were marginally increased in high dose male rats; the incidence of adenomas in the high dose group was significantly greater than that in the vehicle controls. The incidence of adenomas in the high dose group, however, was well within the range of historical corn oil vehicle control incidences of pancreatic acinar cell neoplasms at the study laboratory (0/49-11/50, 22%) and only slightly greater than the mean historical control incidence at the study laboratory (36/397, 9%).
Mesothelium: Malignant mesotheliomas of the tunica vaginalis and/or peritoneum (mesentery) were marginally increased in dosed male rats. The incidence of 5/50 in the low dose group slightly exceeded the highest incidence observed in a corn oil vehicle control group (4/50, 8%) at the study laboratory. Because there was no significant increase in the high dose group and because the incidence in the low dose group was only marginally increased relative to the mean historical corn oil vehicle control incidence at the study laboratory (15/450, 3%), the malignant mesotheliomas were considered to be unrelated to the administration of the test substance.
Hematopoietic System: Mononuclear cell leukemia in male rats occurred with a significant positive trend; the incidences in the dosed groups were significantly greater than that in the vehicle controls.
Forestomach: Squamous papillomas were seen in two high dose female rats; the historical incidence of forestomach neoplasms in corn oil vehicle control female F344/N rats is 9/2,085 (0.4%), and the highest observed incidence is 2/49. Hyperplasia of the mucosa was seen in 5/50 vehicle control, 2/50 low dose, and 3/50 high dose female rats.

Mice: Forestomach: Focal hyperplasia and squamous cell papillomas were increased in dosed male and female mice; the incidences of squamous cell papillomas in low and high dose female mice were significantly greater than that in vehicle controls.
Focal hyperplasia of the forestomach was characterized by a localized region of increased thickness of the stratified squamous epithelium. In the less severe lesions the surface of the epithelium was irregular or slightly folded, whereas in the more advanced lesions the epithelium was more extensively folded, producing short papillary projections with a narrow core of connective tissue. The squamous cell papillomas exhibited greater complexity of the papillae and the formation of a stalk .
A squamous cell carcinoma was diagnosed in a single high dose female mouse by the pathologist at the study laboratory.

HISTOPATHOLOGY: NON-NEOPLASTIC
Incidences of lesions were not related to the test substance or showed a dose response relationship in rats
In mice the incidence of forestomach hyperplasia was increased at 200 and 400 mg/kg bw

HISTOPATHOLOGY: NEOPLASTIC (if applicable)
The only effects of the test substance were those seen in the forestomach of mice. The incidences of uncommonly occurring squamous cell papillomas of the forestomach in both exposure groups were significantly greater than those in vehicle controls (male: vehicle control, 1/50; low dose, 2/50; high dose, 5/50; female: 0/50; 5/50; 6/50). The increased incidences of papillomas were accompanied by dose-related increases in the incidences in forestomach hyperplasia (male: 7/50; 8/50; 16/50; female: 12/50; 23/50; 39/50).

No additional data
Dose descriptor:
NOAEL
Effect level:
400 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Rat; no effects observed
Dose descriptor:
LOAEL
Effect level:
300 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Mouse: forestomach hyperplasia
Dose descriptor:
NOAEL
Effect level:
< 300 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Mouse
Critical effects observed:
not specified
Conclusions:
Under the conditions of these 2-year gavage studies, there was no evidence of carcinogenic activity or other effects as investigated in this study of the test substance for male or female F344/N rats receiving 200 or 400 mg/kg per day. There was some evidence of carcinogenic activity of the test substance for male or female B6C3F1 mice, as indicated by increased incidences of squamous cell papillomas and hyperplasia of the forestomach at both doses tested. Female rats and male and female mice might have been able to tolerate higher doses.
Executive summary:

Fischer 344/N rats and B6C3F1 mice were used in this study.Groups of 50 rats of each sex and groups of 50 male mice were administered 0, 200, or 400 mg/kg the test substance in corn oil by gavage, 5 days per week for 103 (rats) or 104 (male mice) weeks. Groups of 50 female mice were administered 0, 300, or 600 mg/kg, 5 days per week for 103 weeks.

 

Under the conditions of these 2-year gavage studies, there was no evidence of carcinogenic activity or other effects as investigated in this study of the test substance for male or female F344/N rats receiving 200 or 400 mg/kg per day. There was some evidence of carcinogenic activity of the test substance for male or female B6C3F1 mice, as indicated by increased incidences of squamous cell papillomas and hyperplasia of the forestomach at both doses tested. Female rats and male and female mice might have been able to tolerate higher doses.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEL
300 mg/kg bw/day
Study duration:
chronic
Species:
mouse
Quality of whole database:
2 (reliable with restrictions)

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study performed in accordance with OECD guideline 412. However, summary in public literature available, no summary and individual data of all results available.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)
Deviations:
yes
Remarks:
No analytical results available, however, analysis of test concentrations was performed.
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Sprague-Dawley (SD)
- Weight at study initiation: 184±2 g for females and 240±2 g for males
- Housing: Animals were individually identified with ear notches and randomly assigned by a computer-assisted method that provided homogeneity of variance and equality of initial body weights for all groups.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±1°C
- Humidity (%): 50%±15%

No additional data
Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
clean air
Remarks on MMAD:
MMAD / GSD: Not applicable. Animals were exposed to vapour.
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Sage Instrument co. syringe pump (model 220).
- Method of holding animals in test chamber: Animals were exposed in 2.50 m3 stainless steel chambers.
- Air flow rate: 500 L/min

TEST ATMOSPHERE
- Brief description of analytical method used: gas chromatography
- Samples taken from breathing zone: yes

No additional data
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The inhalation chambers were continuously monitored throughout the exposure by gas chromatography. Concentration of the test substance in air was deteremined for each chamber every 6 minutes by using an automatic sampling system and a Bendix gas chromatograph. The monitory was conducted by comparion with a standard sample chromatographed on a CSP-20M stainless steel column under the following conditions: injector and electron capture detector temperature, 175°C, oven temperature, 100°C, flow rate for the carrier gas nitrogen, 120mL/min, hydrogen, 32.3 mL/min, and air: 300 mL/min. The retention time of the test substance was found to be 260 seconds.
Duration of treatment / exposure:
Animals were exposed for 6 hours/day for 14 days.
Frequency of treatment:
Animals were exposed for 14 consecutive days.
Remarks:
Doses / Concentrations:
0, 500, 750 and 1000 ppm
Basis:
no data
No. of animals per sex per dose:
14 animals/sex/concentration
Control animals:
yes
Details on study design:
The study was performed in accordance with OECD guideline 412.
Rats from the control and each test substance exposure group were necropsied 72 hours after the last exposure.
Positive control:
No positive control was included.
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: after 2, 8 and 14 exposures

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data

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 data

WATER CONSUMPTION: No data

OPHTHALMOSCOPIC EXAMINATION: No data

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Blood samples were taken at necropsy from the vena cava.
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: 6

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Blood samples were taken at necropsy from the vena cava.
- Animals fasted: No data
- How many animals: 6

URINALYSIS: No data

NEUROBEHAVIOURAL EXAMINATION: No data

OTHER:

No additional data
Sacrifice and pathology:
At necropsy, a gross pathological examination was performed on all animals. The rats found moribund after exposure were immediately necropsied to prevent autolysis of tissues. Seven animals/sex/dose were necropsied 72 hours after the last exposure, the remaining animals were subjected to whole body perfusion and prepared for future electron microscopy examination.
The following tissues were excised and collected for histopathological examination: adrenals, brain, heart, kidneys, liver, lungs, small and large intestines, larynx, rhinopharynx, spleen, stomach, trachea, testes or ovaries, thyroid and urinary bladder. The following organs were weighed prior to perfusion: brain, heart, kidneys, livers, lungs and spleen.
During necropsy, special care was taken to avoid damage to the brain and nasal tissues. Tisses were fixed, processed, and embedded in paraffin, sectionated at 6 µm, stained with hematoxy and eosin, and examined by light microscopy.
Nasal tissues of 7 animals of the control, 500 and 1000 ppm groups were first declacified in a formin acid-sodium citrate solution before processing and embedding. Sections were cut to illustrate the respiratory, olfactory and stratified squamous eptihelia.
Other examinations:
Heamatology and clinical biochemistry was performed in 6 animals of the control, 500 and 750 ppm groups and 4 animals of the 1000 ppm group. Blood was taken at necropsy (no time after last exposure indicated).
The following haematological parameters were determined: red blood cell count, white blood cell count, hematocrit, mean corpuscular volume, hemoglobin, mean corpuscular hemoglobin and mean corpuscular hemoglobin concentration.
Acetylcholinesterase was determined in red cells, and the following biochemical parameters were determined in serum: albumin, bilirubin, blood urea nitrogen, cholesterol, glucose, inorganic phosphorus, total protein, triglycerides, calcium, chloride, magnesium, potassium, sodium, amylase, cholinesterase, creatine phophokinase, gamma-glutamyl transferase, aspartate aminotransferase, alanine aminotransferase, alpha-hydroxybutyrate dehydrogenase and alkaline phosphatase.
Statistics:
Body and tissue weights and hematology, biochemistry and physiological data were analyzed using a one-way analysis of variance, Duncan's multiple range test, and a modified least significant difference procedure. For parameters fuond to be significantly different (p≤0.05). Student's t-test was used to determine levels of significance between groups.
Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
not specified
Behaviour (functional findings):
effects observed, treatment-related
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY
Clinical signs (incl. signs of neurotoxicity e.g. reduced motor activity) and hypothermia in all test substance exposed groups. Mortality at 750 and 1000 ppm. Nasal and ocular irritatation in all test substance exposed groups.

BODY WEIGHT AND WEIGHT GAIN
Reduced weight gain in all test substance exposed males and 1000 ppm females.

HAEMATOLOGY
Increase in monocytes in all test females, slightly reduced red blood cell count, hemoglobin and hematocrit in 1000 ppm females. Increased white blood cell count and neurophils in males at 1000 ppm, a slightly reduced hemaglobin and hematocrit in males at 1000 ppm. A decrease in lymphocytes, mean corpuscular hemoglobin and mean corpuscular hemoglobin concentration at 750 and 1000 ppm.

CLINICAL CHEMISTRY
Reduced serum ChE in all test females. An increased in ASAT in all test males and females. A decrease in albumin and total protein in all test females.

NEUROBEHAVIOUR
Tremors, piloerection, diuresis, reduction of breathing rate in all test groups. Animals at 750 and 1000 ppm were extreme sensitive to noise in the room and displayed aggressive behaviour.

ORGAN WEIGHTS
Increase in absolute and relative liver weight in all female test groups.

GROSS PATHOLOGY
No findings.

HISTOPATHOLOGY: NON-NEOPLASTIC
Goblet cell metaplasia was seen in all treated males: 4/7 at 500, 750 and 1000 ppm. The goblet cell metaplasia was extensive in the respiratory epithelial lining of the septum, but was minimal in the epithelial lining of the turbinates. The overall change in males was considered mild. Similar, less frequent changes were observed in females. Besides the goblet cell metaplasia, no inflammatory, degenerative, or other alterations were observed in the nasal tissues. Findings in other organs were infrequent and appeared to be incidental background changes regularly observed in this strain of rat.

No additional data
Dose descriptor:
LOAEC
Effect level:
500 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Physiological monitoring, clinical observations, organ weights.
Critical effects observed:
not specified
Conclusions:
In a subacute inhalation study in rats, a NOAEC could not be derived, since effects of the test substance were noted in all treatment groups. Clinical observations (indicative of neurotoxicity), hypothermia and goblet cell metaplasia were noted at concentrations of 500 ppm and above. Therefore, the LOAEC for systemic and local effects is established at 500 ppm (equivalent to 2.2 mg/L).
Executive summary:

This study was run according to a guideline which is equivalent or similar to OECD Guideline 412 with Sprague-Dawley rat. The clinical signs, mortality, body weight, haematology, clinical chemistry, neurobehaviour,organ weights, gross pathology and non-neoplastic histopathology were observed.

In a subacute inhalation study in rats, a NOAEC could not be derived, since effects of the test substance were noted in all treatment groups. Clinical observations (indicative of neurotoxicity), hypothermia and goblet cell metaplasia were noted at concentrations of 500 ppm and above. Therefore, the LOAEC for systemic and local effects is established at 500 ppm (equivalent to 2.2 mg/L).

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEC
2 200 mg/m³
Study duration:
subacute
Species:
rat
Quality of whole database:
2 (reliable with restrictions)

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

The LOAEL from the chronic mouse study will be taken as the starting point for the risk assessment. This study is a carcinogenicity study (NTP 1990) and lacks data on haematology and clinical chemistry.

In addition the 14-day inhalation study (Lahan 1991) will taken as starting point for risk assessment. This study shows signs of respiratory irritation at all concentrations tested (nasal Goblet cell hyperplasia).

The NOAEL for dermal toxicity will be based on route-to-route extrapolation from the oral LOAEL assuming an oral and dermal absorption of 100%.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
This study is a chronic study using mice.

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
This study was carried out according to a reliable method which similar to OECD Guideline 412 using rats.

Repeated dose toxicity: via oral route - systemic effects (target organ) digestive: stomach

Repeated dose toxicity: inhalation - systemic effects (target organ) respiratory: nose

Justification for classification or non-classification

Based on the NOAEL of 100 mg/kg bw/day in a chronic study (extrapolation from LOAEL with assessment factor 3), the test substance needs no classification for target organ toxicity or for danger of serious damage to health after prolonged exposure (DSD and CLP).