Registration Dossier

Administrative data

Description of key information

Repeated dose toxicity: Oral

Repeated dose chronic/carcinogenicity study was conducted to determine the toxic nature of the test chemical. The study was performed using male and female CD rats for 2 years. The test chemical was mixed with feed and used at dose level of 0, 25, 75 or 250 mg/Kg/day. During the study period, the animals were observed for mortality, clinical signs, body weight and food consumption changes, ophthalmology, hematology, clinical chemistry, urinalysis, gross pathology and histopathology. During the study, no treatment related mortality was noted. No physical observations were noted which could be attributed were to treatment. During 64-86 weeks, there was an overall increase in the number of control and treated males which exhibited varying degrees of emaciation, labored breathing and rales. The mean body weights of 250 mg/Kg/day males and 75 and 250 mg/Kg/day females were lower than the controls during most of the study. However, differences from control never exceeded 9 and 12% in the females and 6% in the males. The mean food consumption displayed normal variability, and was comparable to that of control. No ocular abnormalities attributed to test chemical treatment were noted. Slight decreases were observed in mean hemoglobin, hematocrit and erythrocyte counts in the high-dose males throughout the study. These decreases were associated with an increased mean reticulocyte count at termination. Less marked decreases in mean hemoglobin, hematocrit and erythrocyte counts were noted in the mid-dose males at 6 and l2 months. The mean erythrocyte counts of the low-dose males was also slightly reduced at 12 months. Mean reticulocyte counts were considered unremarkable in the low- and mid-dose males at termination. Mean total leukocyte counts were slightly elevated in the 25 and 75 mg/Kg/day dose males at 6 months, in the 25, 75 and 250 mg/Kg/day dose males at 12 months and in the high-dose males at termination. In the females, mean hemoglobin values and erythrocyte counts were reduced for the 75 and 250 mg/Kg/day dose groups at 6 months and for the 250 mg/Kg/day group at 12 and 20 months and termination. Mean hematocrit values were slightly reduced in the high-dose females at 6 and 20 months and termination. Mean alkaline phosphatase levels were slightly elevated in the 75 and 250 mg/Kg/day dose males at 12 months and at termination. Mean blood urea nitrogen levels were slightly increased in the high-dose males at all study intervals. Mean total bilirubin values were slightly increased in the high-dose females at termination. Mean absolute testes weights, testes/body weight ratios and testes/brain weight ratios were elevated in the high-dose males at 6 and 12 months, but not at termination. Mean absolute and relative (to body and brain weights) spleen weights were elevated in the 75 and 250 mg/Kg/day dose males at all necropsy intervals. Increased Spleen weights were observed in the 75 and 250 mg/Kg/day dose females at 6, 12 and 20 months and at termination and in the 25 mg/Kg/day dose females at termination. Mean liver weights (absolute, liver/body weight and liver/brain weight ratios) were increased in the mid- and high-dose males at 6 and 12 months and in the 25, 75 and 250 mg/Kg/day dose males at termination. Mean liver weight increases were also observed in the 75 and 250 mg/Kg/day dose females at 6 and 12 months and in all treated females at 20 months and termination. Mean absolute and relative adrenal weights were increased in the high-dose females at 12 months, in the 25, 75 and 250 mg/Kg/day dose females at 20 months and termination and in the high-dose males at termination. Mean absolute and relative heart weights were increased in the 250 mg/Kg/day males at 12 months and at termination. Compound-related pathological changes were seen grossly in the 250 mg/Kg/day males only, and microscopically in the 75 and 250 mg/Kg/day dose males and females. Grossly, flaccidity and decrease in size of the testes were shown by a large number of 250 mg/Kg/day dose males. Microscopically significant findings were seen in the testes/epididymides, liver, kidneys, spleen, bone marrow and mesenteric lymph nodes. The microscopic pathological changes consisted of degeneration of seminiferous tubules; enlargement of epididymal secretory epithelium; decrease or absence of sperm in epididymal ducts; hepatocellular hypertrophy; brown pigment in Kupffer‘s cells; cholangiofibrosis; brown pigment in cytoplasm of proximal convoluted tubules; splenic congestion; hypercellularity and congestion of bone marrow. The most common findings in male rats dying at 17-19 months of study were pulmonary consolidation and edema with pus-like material on the pleural surface grossly, and acute multifocal suppurative bronchopneumonia microscopically. No morphologic evidence of the carcinogenic potential of the test chemical was observed. Based on findings of the study, the no observed adverse effect level (NOAEL) is considered to be 25 mg/Kg/day when male and female rats were exposed to the test chemical for 2 years. 

Repeated dose toxicity: Inhalation

The test substance Triclocarban has very low vapor pressure (0.00000000361 mmHg) and high melting point, so the potential for the generation of inhalable vapours of Triclocarban is low. Also the normal conditions of use of this substance will not result in aerosols, particles or droplets of an inhalable size, so exposure to humans via the inhalatory route will be unlikely to occur, and therefore this end point for repeated dose toxicity by inhalation route of exposure was considered for waiver.

 

Repeated dose toxicity: Dermal

The acute toxicity value for Triclocarban (as provided in section 7.2.1) is >2000 mg/kg body weight. Thus, it is expected that Triclocarban shall not exhibit 28 day repeated dose toxicity by the dermal route. In addition, there is no data available that suggests that Triclocarban shall exhibit repeated dose toxicity by the dermal route. Hence this end point for repeated dose toxicity by dermal route of exposure was considered for waiver

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:
chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
secondary literature
Justification for type of information:
Data is from secondary source NTRL
Qualifier:
according to
Guideline:
other: Refer below principle
Principles of method if other than guideline:
Repeated dose chronic/carcinogenicity study was conducted to determine the toxic nature of the test chemical
GLP compliance:
not specified
Limit test:
yes
Species:
rat
Strain:
other: CD
Details on species / strain selection:
No data
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc., Wilmington, Massachusetts
- Age at study initiation: 46 days
- Weight at study initiation: No data
- Fasting period before study:
- Housing: The animals were housed individually in elevated stainless steel cages
- Diet (e.g. ad libitum): Standard laboratory diet (Purina Lab Chow R 5001) ad libitum
- Water (e.g. ad libitum): By automated water system ad libitum
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): Monitored twice daily
- Humidity (%): No data
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): 12 hrs light/dark cycle

IN-LIFE DATES: From: To: No data
Route of administration:
oral: feed
Vehicle:
other: Feed
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: Appropriate amounts of test substance and standard laboratory diet were mixed weekly to give dose levels of 0, 25, 75 or 250 mg/Kg/day

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

VEHICLE
- Justification for use and choice of vehicle (if other than water): Feed
- Concentration in vehicle: 0, 25, 75 or 250 mg/Kg/day
- Amount of vehicle (if gavage): No data
- Lot/batch no. (if required): No data
- Purity: No data
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
200g samples of control feed and each dietary level were taken weekly for analysis
Duration of treatment / exposure:
2 years
Frequency of treatment:
Daily
Remarks:
0, 25, 75 or 250 mg/Kg/day
No. of animals per sex per dose:
0 mg/Kg/day: 80 males and 80 females
25 mg/Kg/day: 80 males and 80 females
75 mg/Kg/day: 80 males and 80 females
250 mg/Kg/day: 80 males and 80 females
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: No data
- Rationale for animal assignment (if not random): Random assignment
- Rationale for selecting satellite groups: No data
- Post-exposure recovery period in satellite groups: No data
- Section schedule rationale (if not random): No data
Positive control:
No data
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily for mortality
- Cage side observations checked in table [No.?] were included. Mortality and gross signs of toxicology or pharmacologic effects

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Weekly

BODY WEIGHT: Yes
- Time schedule for examinations: Twice pretest, weekly through 13 weeks, biweekly 14 thourgh 26 weeks and monthly thereafter

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, Twice pretest, weekly through 13 weeks, biweekly 14 through 26 weeks and monthly thereafter
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes, calculated from food consumption 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 AND COMPOUND INTAKE (if drinking water study): No data
- Time schedule for examinations: No data

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Pretest, 6, 12, 18 and 24 months
- Dose groups that were examined: All animals

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at 6 and 12 months for group receiving 0 and 250 mg/kg/day test chemical; 10/sex/group for all groups at 18 (females only) and 24 months
- Anaesthetic used for blood collection: Yes, light ether anaethesia
- Animals fasted: Yes, overnight fasting
- How many animals: Animals were selected randomly; 10/sex/group
- Parameters checked in table [No.?] were examined. Hemoglobin, hematocrit, eryhtocytes, reticulocytes, prothrombin time, total and differential leukocytes, erythrocyte morphology, Heinz bodies and methemoglobin

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at 6 and 12 months for group 0 and 250 mg/kg/day test chemical; 10/sex/group for all groups at 18 (females only) and 24 months
- Animals fasted: Yes, overnight fasting
- How many animals: Animals were selected randomly; 10/sex/group
- Parameters checked in table [No.?] were examined. Serum glutamic pyruvic transminase, alkaline phosphatase, blood urea nitrogen, fasting glucose, total bilirubin

URINALYSIS: Yes
- Time schedule for collection of urine: No data
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters checked in table [No.?] were examined. Gross appearance, specific gravity, pH, protein, glucose, ketones, bilirubin, occult blood, microscopic analysis

NEUROBEHAVIOURAL EXAMINATION: No data
- Time schedule for examinations: No data
- Dose groups that were examined: No data
- Battery of functions tested: sensory activity / grip strength / motor activity / other: No data

OTHER: No data
Sacrifice and pathology:
GROSS PATHOLOGY: Yes, complete gross postmortem examination was performed

Organs weighed: Brains, pituitary, adrenals, testes, ovaries, heart, spleen, kidneys and liver

HISTOPATHOLOGY: Yes, adrenals, bone marrow, blood smear, brain, epididymis, eye, heart with coronary vessels, intestine, cecum, colon, duodenum, ileum, jejunum, kidneys, liver, lungs with mainstem bronchi, lymphnodes, ovary, pancreas, pituitary, prostate/urinary bladder/ seminal vesicles, salivary glands, skeletal muscle, sciatic nerves, spinal cord, spleen, stomach, testis, thymus, thyroid, parathyroid, trachea, uterus, urinary bladder, gross lesions, tissue masses or suspet tumors and regional lymph nodes were examined
Other examinations:
No data
Statistics:
Yes, statistical analysis was performed
Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
No physical observations were noted wich could be attributed week, to treatment. During 64-86 weeks, there was an overall increase in the number of control and treated males which exhibited varying degrees of emaciation , labored breathing and rales.
Mortality:
no mortality observed
Description (incidence):
No test substance related mortality was observed during the study. Almost twice as many animals were classified as moribund or died spontaneously in the control and treated males than in control and treated female groups throught the study.

During months 17, 18 and 19, 108 males and 24 female control and treated animals died or were sacrifised as moribund animals. This increase in mortality was attributed to respiratory infection which was present predominantly in the males during this time period.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
The mean body weights of 250 mg/Kg/day males and 75 and 250 mg/Kg/day females were lower than the controls during most of the study. However, differences from control never exceeded 9 and 12% in the females and 6% in the males
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
The mean food consumption displayed normal variability, and was comparable to that of control
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
no effects observed
Description (incidence and severity):
No ocular abnormalities attributed to test chemical treatment were noted
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
Mean hemoglobin and hematocrit values were significantly reduced for 250 mg/Kg/day dose males throughout the study and for 75 mg/Kg/day at 6 and 12 months. Mean erythrocyte counts were significanlt reduced in the 250 mg/Kg/day at 6 and 12 months and in 75 mg/Kg/day males at 12 months. Slight decrease were also observed in the 75 mg/Kg/day at months and in the 250 mg/Kg/day males at termination. The mean erythrocytes count of the 25 mg/Kg/day males was also significantly elevated in the 250 mg/Kg/day males at termination and were considered unremarkable in the 25 and 75 mg/Kg/day males at termination.

The mean leucocytes count was significantly elevates in the 25 and 75 mg/Kg/day males at 6 months and in the 25, 75 and 250 mg/Kg/day at 12 months. Mean total leukocyte counts were slightly elevated in the high dose males at termination.

In the females, mean erythrocyte counts were significanlt reduced in the 75 and 250 mg/Kg/day at 6 months ans in the 250 mg/Kg/day at 12 and 20 months. A slight increase was also observed at termination in the 250 mg/Kg/day group. A slight decrease was also observed at termination in the 250 mg/Kg/day group. Reductions in hemoglobin and hematocrit values for the 250 mg/Kg/day females were statistically significant at 6 and 20 months but not at 12 months and termination. In the 75 mg/Kg/day females, mean hemoglobin values were significantly reduced at 6 months and mean hematocrit values were slightly reduced at termination. Mean total and differential leucocytes at all study intervals and mean reticulocyte counts at termination were considered unremarkable.

Mean methemoglobin levels and mean prothrombin times were unremarkable in the treated males and females throughout the study. Heinz body counts were considered comparable to control in the treated males and females at termination.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
The mean alkanline phosphatase level in 75 mg/Kg/day males was significanlt increased at 12 months and slightly increased at termination. Mean values for the 250 mg/Kg/day males were significantly elevated at both intervals. Mean blood urea nitrogen levels were slightly increased in the 250 mg/Kg/day males at 6 and 12 month. Mean total bilirubin values were slightly but statistically significantly increased for high dose females at all study intervals.
Urinalysis findings:
no effects observed
Description (incidence and severity):
No significant difference in treated and control animals was observed
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Mean absolute and relative testes weights ans testes/brain weight ratios were elevated in the high dose males at 6 and 12 months but not at termination. These increases were statistically significant with theexception of the relative testes weight at 6 months and the testes/brain weight rations at 12 months. Mean absolute spleen weights, spleen/body weight ratios and spleen/brain weight ratios were elevated in the 75 and 250 mg/Kg/day at 6 and 12 months and at termination. These increases were dose related and statistically significant. Increased spleen weights were observed in the 75 and 250 mf/Kg/day females at 6, 12 and 20 months and termination and in 25 mg/Kg/day females at termination. These increases were not as pronounced as those in the males and were not significant statistically.

Mean absolute liver weights, liver/body weight rations and liver/brain weight ratios were significantly increased in the 75 mg/Kg/day males at 6 months and in 250 mg/Kg/day at 6 and 12 months and at termination. Slight increase were observed in the 75 mg/Kg/day males at 12 months and in the 25 and 75 mg/Kg/day males at termination. Mean liver weight increases were also observed in 75 and 250 mg/Kg/day and in the 25, 75 and 250 mg/Kg/day females at 20 months and termination. These increase were statistically significant in the 25 mg/Kg/day at termination and in the 250 mg/Kg/day females at 12 and 20 months and termination. Statistically significance was also noted for liver/body weight rations in the 250 mg/Kg/day females at 6 months and in 75 mg/Kg/day females at 12 and 20 months and termination. Mean absolute and relative adrenal weight increases were also observed in the 75 and 250 mg/Kg/day at 6 and 12 months and in the 25, 75 and 250 mg/Kg/day females at 20 months and termination.

Mean absolute and relative adrenal weights were increased in the 250 mg/Kg/day females at 12 months, in the 25, 75 and 250 mg/Kg/day at 20 months and termination and in the 250 mg/Kg/day males at termination. These were not statistically significant.

Mean absolute heart weight, heart/body weight ratio and heart/brain weight ration were increase in the 250 mg/Kg/day males at 12 months and at termination. These increases were statistically significant with the exception of the heart/brain weight ratio at 12 months and the heart/body weight ratio at termination. These parameters were unremarkable in the treated females at all necropsy intervals.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
The testes of the 250 mg/Kg/day males were frequently observed to be small and flaccid. These findings were considered to be treatment related.

No significant difference was seen in the incidence and number of rats with neoplasms in the control and 250 mg/Kg/day group.

A unusually large number of male rats died during months 17-19 of the study. The most common gross findings in these studies were consolidation and edema of the lungs with creamy pus-like material on the pleura. Proteus mirabilis was identified to be the causative agent behind the effects observed.
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
The 75 and 250 mg/Kg/day males and females exhibited microscopic changes considered to be compound related in the testes/epididymides, liver, spleen, kidneys, bone marrow and mesenteric lymph nodes. The tissue alterations were evident in rats in killed at scheduled necrospies, killed in extremis or dying spontaneously. No significant testicular or epididymal lesions were seen in treated male rats at 6 months. 250 mg/Kg/day male rats killed at the 12 month interim exhibited marked multifocal degeneration of the seminiferous tubules with mild to marked interstitial edema. Spermatocytic spermatidic giant cells were found only in 1 case of tubular degenaration. Similar gonadal lesions were seen in the 75 and 250 mg/Kg/day males killed at termination. The multi-focal tubular degeneration was judged mild to marked and the interstitial edema, moderate to marked. At terminal sacrifice, a fes 250 mg/Kg/day rats with an apparent intact tubular lining showed a mild to moderate decrease in the number of sperm. 250 mg/Kg/day rats which were killed moribund or found dead demonstrated focal to diffuse tubular degeneration with a high incidence of giant cell formation.

The changes in testes were reflected in epididymides. The sperm was either decreased in number mildly or moderately, or absent in the epididymal ducts of 250 mg/kg/day males that died spontanesouly or were sacrificed at 12 months and termination. On these occasions, the ductal lumens were occupied either by a mixture of sperm and cell debris or filled entirely with cell debris. Enlargement of secretory epithelium was first observed in 250 mg/Kg/day males at 12 months. This change persisted at termination but the degree of change was reduced from mild/moderate to minimal/mild.

Mild hepatocellular hypertrophy, centrilobular to midzonal was observed in 25, 75 and 250 mg/Kg/day males and females at 6 and 12 months. An increase incidence of mild hepatocellular hypertrophy was observed in 75 and 250 mg/Kg/day males and females during last 12 months of the study. Brown pigment in kupffer cells was noted as early as 6 months in the 75 and 250 mg/Kg/day in males and females was observed continuously throughout the study. The amount of pigment increased slightly with age as more animals manifested moderate to marked pigmentation. The overall incidence of bile duct hyperplasia and cholangiofibrosis was increased significantly for the 75 and 250 mg/Kg/day males.

No significant difference was noted in the intensity of splenic hemosiderosis among females at 6 and 12 months. Among 250 mg/Kg/day males, the frequency of mild hemosiderosis was increased when compared to control males. Hemosiderosis ceased to be significant at 20 months and termination. Congestion of the spleen was significant for the 25 mg/Kg/day females and 75 and 250 mg/Kg/day males and females at 6 and 12 months. During the last half of the study, an increased incidence of congestion was observed for males and females at all dose levels. The degree of congestion changed from minimal to moderate at 6 months, to mild to moderate at 12 months. Extramedullary hematopoiesis was increased in the high dose males and females at 6 and 12 months, but not at 20 months and termination for the females. The overall incidence of extramedullary hematopoiesis was significantly increased in the 250 mg/Kg/day males and females.

Brown pigment in the cytoplasm of the proximal convulted tubules was present in the 75 and 250 mg/Kg/day males at 6, but not at 12 months. The dgree of pigmentation was slightly increased at 12 months when a few rats exhibited a moderate amount of pigment. Similar pigment was noted in 75 and 250 mg/Kg/day at 20 months and on 75 and 250 mg/Kg/day and 250 mg/Kg/day females at termination.

Hypercellularity of the bone marrow, judged minimal to mild, was seen in males and females at 75 and 250 mg/Kg/day at 6 and 12 months. 250 mg/Kg/day males and females at 12 months also exhibited minimal to mild congestion of the bob=ne marrow. No difference in the cellularity of the female bone marrow was discernible at 20 months. Increase in cellularity and marrow congestion became apparent in the 75 and 250 mg/Kg/day males and females and 250 mg/Kg/day males and females respectively at termination.

Increased brown pigment-laden macrophages in the mesentic lymph nodes was demonstrated by mild and high dose males at 6 and 12 months and high dose females at 12 months, a few affected males and females exhibited a moderate increase in pigment cells at 12 months. This change was not apparent at the 20 month and terminal sacrifice. When a total incidence for each group was examined, the incidence in 75 and 250 mg/Kg/day males was significant.

No other microscopic findings are considered treatment related. The other changes noted represent spontaneous or common incidental histological findings. No morphologic evidence of the carcinogenic potential of the test chemical was observed.
Histopathological findings: neoplastic:
not specified
Description (incidence and severity):
No significant difference was seen in the incidence and number of rats with neoplasm, both benign and malignant, in the control and high dose groups.

Rats with malignant neoplasms wer enot diagnosed in the 250 mg/Kg/day males and females. The incidence of neoplasm at the 25 and 75 mg/Kg/day levels were comparable to or lower than control and 250 mg/Kg/day dosed animals.
Other effects:
not specified
Dose descriptor:
NOAEL
Effect level:
25 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Significant effects were observed at the dose levels of 75 or 250 mg/Kg/day
Critical effects observed:
not specified
Conclusions:
The no observed adverse effect level (NOAEL) is considered to be 25 mg/Kg/day when male and female rats were exposed to the test chemical for 2 years.
Executive summary:

Repeated dose chronic/carcinogenicity study was conducted to determine the toxic nature of the test chemical. The study was performed using male and female CD rats for 2 years. The test chemical was mixed with feed and used at dose level of 0, 25, 75 or 250 mg/Kg/day. During the study period, the animals were observed for mortality, clinical signs, body weight and food consumption changes, ophthalmology, hematology, clinical chemistry, urinalysis, gross pathology and histopathology. During the study, no treatment related mortality was noted. No physical observations were noted which could be attributed were to treatment. During 64-86 weeks, there was an overall increase in the number of control and treated males which exhibited varying degrees of emaciation, labored breathing and rales. The mean body weights of 250 mg/Kg/day males and 75 and 250 mg/Kg/day females were lower than the controls during most of the study. However, differences from control never exceeded 9 and 12% in the females and 6% in the males. The mean food consumption displayed normal variability, and was comparable to that of control. No ocular abnormalities attributed to test chemical treatment were noted. Slight decreases were observed in mean hemoglobin, hematocrit and erythrocyte counts in the high-dose males throughout the study. These decreases were associated with an increased mean reticulocyte count at termination. Less marked decreases in mean hemoglobin, hematocrit and erythrocyte counts were noted in the mid-dose males at 6 and l2 months. The mean erythrocyte counts of the low-dose males was also slightly reduced at 12 months. Mean reticulocyte counts were considered unremarkable in the low- and mid-dose males at termination. Mean total leukocyte counts were slightly elevated in the 25 and 75 mg/Kg/day dose males at 6 months, in the 25, 75 and 250 mg/Kg/day dose males at 12 months and in the high-dose males at termination. In the females, mean hemoglobin values and erythrocyte counts were reduced for the 75 and 250 mg/Kg/day dose groups at 6 months and for the 250 mg/Kg/day group at 12 and 20 months and termination. Mean hematocrit values were slightly reduced in the high-dose females at 6 and 20 months and termination. Mean alkaline phosphatase levels were slightly elevated in the 75 and 250 mg/Kg/day dose males at 12 months and at termination. Mean blood urea nitrogen levels were slightly increased in the high-dose males at all study intervals. Mean total bilirubin values were slightly increased in the high-dose females at termination. Mean absolute testes weights, testes/body weight ratios and testes/brain weight ratios were elevated in the high-dose males at 6 and 12 months, but not at termination. Mean absolute and relative (to body and brain weights) spleen weights were elevated in the 75 and 250 mg/Kg/day dose males at all necropsy intervals. Increased Spleen weights were observed in the 75 and 250 mg/Kg/day dose females at 6, 12 and 20 months and at termination and in the 25 mg/Kg/day dose females at termination. Mean liver weights (absolute, liver/body weight and liver/brain weight ratios) were increased in the mid- and high-dose males at 6 and 12 months and in the 25, 75 and 250 mg/Kg/day dose males at termination. Mean liver weight increases were also observed in the 75 and 250 mg/Kg/day dose females at 6 and 12 months and in all treated females at 20 months and termination. Mean absolute and relative adrenal weights were increased in the high-dose females at 12 months, in the 25, 75 and 250 mg/Kg/day dose females at 20 months and termination and in the high-dose males at termination. Mean absolute and relative heart weights were increased in the 250 mg/Kg/day males at 12 months and at termination. Compound-related pathological changes were seen grossly in the 250 mg/Kg/day males only, and microscopically in the 75 and 250 mg/Kg/day dose males and females. Grossly, flaccidity and decrease in size of the testes were shown by a large number of 250 mg/Kg/day dose males. Microscopically significant findings were seen in the testes/epididymides, liver, kidneys, spleen, bone marrow and mesenteric lymph nodes. The microscopic pathological changes consisted of degeneration of seminiferous tubules; enlargement of epididymal secretory epithelium; decrease or absence of sperm in epididymal ducts; hepatocellular hypertrophy; brown pigment in Kupffer‘s cells; cholangiofibrosis; brown pigment in cytoplasm of proximal convoluted tubules; splenic congestion; hypercellularity and congestion of bone marrow. The most common findings in male rats dying at 17-19 months of study were pulmonary consolidation and edema with pus-like material on the pleural surface grossly, and acute multifocal suppurative bronchopneumonia microscopically. No morphologic evidence of the carcinogenic potential of the test chemical was observed. Based on findings of the study, the no observed adverse effect level (NOAEL) is considered to be 25 mg/Kg/day when male and female rats were exposed to the test chemical for 2 years. 

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
25 mg/kg bw/day
Study duration:
chronic
Species:
rat
Quality of whole database:
Data is from K4 but detailed source

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
Endpoint:
repeated dose toxicity: inhalation
Data waiving:
other justification
Justification for data waiving:
other:
Critical effects observed:
not specified
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:
repeated dose toxicity: dermal
Data waiving:
other justification
Justification for data waiving:
other:
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no study available
Quality of whole database:
Waiver

Repeated dose toxicity: dermal - local effects

Link to relevant study records
Reference
Endpoint:
repeated dose toxicity: dermal
Data waiving:
other justification
Justification for data waiving:
other:
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Repeated dose toxicity (Oral):

 

Various data available for the test chemical was reviewed to determine the toxic nature of the test chemical. The studies are as mentioned below:

 

Repeated dose chronic/carcinogenicity study was conducted to determine the toxic nature of the test chemical. The study was performed using male and female CD rats for 2 years. The test chemical was mixed with feed and used at dose level of 0, 25, 75 or 250 mg/Kg/day. During the study period, the animals were observed for mortality, clinical signs, body weight and food consumption changes, ophthalmology, hematology, clinical chemistry, urinalysis, gross pathology and histopathology. During the study, no treatment related mortality was noted. No physical observations were noted which could be attributed were to treatment. During 64-86 weeks, there was an overall increase in the number of control and treated males which exhibited varying degrees of emaciation, labored breathing and rales. The mean body weights of 250 mg/Kg/day males and 75 and 250 mg/Kg/day females were lower than the controls during most of the study. However, differences from control never exceeded 9 and 12% in the females and 6% in the males. The mean food consumption displayed normal variability, and was comparable to that of control. No ocular abnormalities attributed to test chemical treatment were noted. Slight decreases were observed in mean hemoglobin, hematocrit and erythrocyte counts in the high-dose males throughout the study. These decreases were associated with an increased mean reticulocyte count at termination. Less marked decreases in mean hemoglobin, hematocrit and erythrocyte counts were noted in the mid-dose males at 6 and l2 months. The mean erythrocyte counts of the low-dose males was also slightly reduced at 12 months. Mean reticulocyte counts were considered unremarkable in the low- and mid-dose males at termination. Mean total leukocyte counts were slightly elevated in the 25 and 75 mg/Kg/day dose males at 6 months, in the 25, 75 and 250 mg/Kg/day dose males at 12 months and in the high-dose males at termination. In the females, mean hemoglobin values and erythrocyte counts were reduced for the 75 and 250 mg/Kg/day dose groups at 6 months and for the 250 mg/Kg/day group at 12 and 20 months and termination. Mean hematocrit values were slightly reduced in the high-dose females at 6 and 20 months and termination. Mean alkaline phosphatase levels were slightly elevated in the 75 and 250 mg/Kg/day dose males at 12 months and at termination. Mean blood urea nitrogen levels were slightly increased in the high-dose males at all study intervals. Mean total bilirubin values were slightly increased in the high-dose females at termination. Mean absolute testes weights, testes/body weight ratios and testes/brain weight ratios were elevated in the high-dose males at 6 and 12 months, but not at termination. Mean absolute and relative (to body and brain weights) spleen weights were elevated in the 75 and 250 mg/Kg/day dose males at all necropsy intervals. Increased Spleen weights were observed in the 75 and 250 mg/Kg/day dose females at 6, 12 and 20 months and at termination and in the 25 mg/Kg/day dose females at termination. Mean liver weights (absolute, liver/body weight and liver/brain weight ratios) were increased in the mid- and high-dose males at 6 and 12 months and in the 25, 75 and 250 mg/Kg/day dose males at termination. Mean liver weight increases were also observed in the 75 and 250 mg/Kg/day dose females at 6 and 12 months and in all treated females at 20 months and termination. Mean absolute and relative adrenal weights were increased in the high-dose females at 12 months, in the 25, 75 and 250 mg/Kg/day dose females at 20 months and termination and in the high-dose males at termination. Mean absolute and relative heart weights were increased in the 250 mg/Kg/day males at 12 months and at termination. Compound-related pathological changes were seen grossly in the 250 mg/Kg/day males only, and microscopically in the 75 and 250 mg/Kg/day dose males and females. Grossly, flaccidity and decrease in size of the testes were shown by a large number of 250 mg/Kg/day dose males. Microscopically significant findings were seen in the testes/epididymides, liver, kidneys, spleen, bone marrow and mesenteric lymph nodes. The microscopic pathological changes consisted of degeneration of seminiferous tubules; enlargement of epididymal secretory epithelium; decrease or absence of sperm in epididymal ducts; hepatocellular hypertrophy; brown pigment in Kupffer‘s cells; cholangiofibrosis; brown pigment in cytoplasm of proximal convoluted tubules; splenic congestion; hypercellularity and congestion of bone marrow. The most common findings in male rats dying at 17-19 months of study were pulmonary consolidation and edema with pus-like material on the pleural surface grossly, and acute multifocal suppurative bronchopneumonia microscopically. No morphologic evidence of the carcinogenic potential of the test chemical was observed. Based on findings of the study, the no observed adverse effect level (NOAEL) is considered to be 25 mg/Kg/day when male and female rats were exposed to the test chemical for 2 years. 

 

The above study is further supported by the data from various other test chemicals

 

The test chemical was administered to three groups of 35 Sprague-Dawley rats in their diet at concentrations equivalent to 25, 75 and 250 mg/kg bw/d for 8 weeks. No control group was included in the study. Animals were observed twice daily for morbidity and mortality and once daily for clinical signs. Body weight, food consumption and detailed clinical signs were recorded weekly. Blood samples were taken from 5 animals per group every two weeks for evaluation of blood levels. No necropsy was performed at the end of the study. There were no signs of toxicity or treatment related mortalities throughout the study. Mean body weight and food consumption were lower in the highest dose group, however the statistical significance of this difference could not be evaluated due to the absence of a control group. No compound-related pathological or histopathological findings were noted. Based on the findings, the no observed adverse effect level (NOAEL) for the test chemical in rats over an exposure period of 8 weeks was considered to be 75 mg/Kg body weight & the Low observed adverse effect level (LOAEL) was considered to be 250 mg/Kg body weight.

 

 

In another repeated dose oral toxicity study, the test was performed to determine the toxic nature of the test chemical. The study was performed using rats. The test chemical was mixed with feed and used at dose level of 100, 300 or 1000 mg/Kg/day. The test chemical resulted in degeneration of the germinal epithelium lining the seminiferous tubules, atrophy of the tubules, and oligospermia after 6 months at dose level of 300 or 1000 mg/Kg/day. No testicular lesions were present in rats fed 1000 ppm (100 mg/kg/day). Based on the data available, the no observed adverse effect level for the test chemical is considered to be 100 mg/Kg/day when rats were exposed to the test chemical for 6 months by oral feed route of exposure.

 

 

 

In yet another supporting repeated dose toxicity, the toxic effect of the test chemical was evaluated in male Sprague-Dawley rats. For 10 days, animals in group 1 (controls) received sham treatments of sesame oil (no androgen support) and normal diet (no test chemical supplement). Animals in group 2 were treated with TP injection (0.2 mg/kg, sc in sesame oil) and received a normal diet. Animals in group 3 received vehicle control injections (no androgen support) and test chemical-supplemented diet, and animals in Group 4 received TP injection (0.2 mg/kg, sc in sesame oil) and test chemical- supplemented diet. At the end of treatment, the animals were sacrificed and the liver, kidney, levator anibulbocavernosus muscle (LABC), glans penis, ventral prostate, seminal vesicles, and Cowper’s gland were removed and weighed. In the study, testosterone propionate (TP) was used as the positive control due to its superior pharmacokinetic properties and enhanced efficacy both in humans and animal models. A suboptimal dose of 0.2 mg/kg TP was selected for use to ensure the ability to observe an amplification effect of TCC. No significant differences were observed for the weights of the seminal vesicles, Cowper’s gland, LABC muscle, and glans penis between sham-treated rats and rats receiving TCC only in the diet. However, an increase in ventral prostate weight was observed in rats treated with TCC only as compared with sham-treated rats. TP-treatment alone significantly increased the weights of accessory sex organs, compared with controls and the test chemical alone. The co-treatment of TP with the test chemical revealed a substantial and significant increase in the weights of all accessory sex organs, compared with TP treatment alone, indicating a synergism between TP and test chemical in vivo. Therefore, the low observed adverse effect level (LOAEL) for the test chemical was considered to be 0.25% (wt/wt) i.e. 250 mg/Kg/day when male Sprague-Dawley rats were exposed to the test chemical for 10 days.

 

 

In a repeated dose toxicity, the toxic effect of the test chemical was evaluated in male Sprague-Dawley rats. The rats were treated orally in diet with the test chemical at a dosage of 0 or 0.25% (wt/wt) for 10 days. At time of sacrifice, animals were anesthetized and blood was collected by cardiac puncture prior to euthanasia. Necropsies and blood sample collections were conducted at the same time of the day for both treated and control groups. Liver, kidney, adrenal glands, testes, levator ani-bulbocavernosus muscle (LABC), glans penis, ventral prostate, and seminal vesicles were surgically removed and weighed. Organs of half of the animals from each group were fixed and assessed histologically. Pretreatment body weights were comparable in both groups. However, during the 10-day course of the study, animals exposed to the test chemical gained significantly more weight than control animals, resulting in an average of 5.1% greater terminal weight in the treated group. At the end of the treatment, livers in the treated group were also bigger, weighing on average 13.3% more than in the control group. Kidneys, adrenals, and testes in both groups had comparable weight. All accessory sex organs were significantly enlarged in treated test chemical group, with seminal vesicles weighing 42% more, ventral prostate 37% more, LABC 136% more, and glans penis 35% more. No visible abnormalities of any of the accessory sex glands, penis or testes, in treated animals and no histologically distinguishable difference were observed between specimens from the control and treated animals. All tissues were histologically normal and there were no consistent histological differences among any animals examined from treated and control groups. Therefore, the low observed adverse effect level (LOAEL) for the test chemical was considered to be 0.25% (wt/wt) i.e. 250 mg/Kg/day when male Sprague-Dawley rats were exposed to the test chemical for 10 days.

 

 

Repeated dose oral toxicity study was also performed to determine the toxic nature of the test chemical. The study was performed using CD strain male albino rats for 30 or 60 days. The test chemical was dissolved in 35% w/v corn oil at dose level of 0, 2500 or 5000 mg/Kg/day. 90 animals were used in the study and the duration of study was 30 days (T-I-A), for 60 days (T-I-B), for 30 days followed by 30 recovery days (no treatment, T-I-C), or for 30 days followed by 60 recovery days (T-I-D). During the study, the treated and control animals were observed for clinical signs, mortality, bodyweight changes, hemaotology, clinical chemistry and urinanalysis, the treated and control animals were also subjected to gross pathology and histopathology. 5 animals died during the study and these were considered to be not treatment related. Animals showed signs of gastric distress after each dose.These were observed both when the animals were treated with corn oil containing TCC and with corn oil alone. Animals treated with 2500 mg/kg/day showed slightly reduced weight gain during the exposure period. During the 30 days of recovery period (Test Days 30 to 60) animals in this group gained more weight than the corresponding control animals (68 g compared to 62 g). Animals allowed 60 days of recovery showed total weight gains comparable to those of the controls, although a slight weight depression (3%) was observed at the end of the 30-day exposure period. Animals treated with 5000 mg/kg/day showed reduced weight gains during the exposure period (approximately 10% reduction in total body weight. 30 to 55% reduction in weight gain). During the recovery period, these animals gained 65 g as compared to 62 g by the concurrent control group. Food consumption was reduced in all animals receiving oral doses of either the test chemical in corn oil or corn oil alone. This is best illustrated by the food consumption values in the Control (B) group in which g/rat/7 days was approximately 180 during weeks 1 through 4 (animals not treated with corn oil) and was approximately 100 during weeks 5 through 9 (animals treated with corn oil). Growth inhibitions observed in the treated animals reflect this lowered food consumption. Some slightly significant differences between test chemical treated and control animals were observed for the hematological parameters. All mean values were however in the normal range for male albino rats of this age. It is concluded that the test chemical treatment did not affect the red or white cell counts, hemoglobin concentration or packed cell volume. Statistically significant differences in BUN and SAP values were observed but since the variation among the 3 control groups was great, they are not considered to be related to treatment with the test chemical. All of the values were within the normal range for albino rats of this age and sex. Lower blood glucose concentrations in T-I-B (60 days treatment with 2500 mg/kg) and T-II-A (30 days at 5000 mg/kg) groups may be related to lower food consumption and interference with normal digestion brought about by large doses of corn oil and the test chemical. The values in the T-I-B group were marginally depressed (119 compared to 126 mg %) and values in the T-ll-A group were moderately depressed (103 mg %). SGPT activity was not affected by treatment. No significant differences among any of the groups was observed for the urinalaysis parameters. Liver weights of animals receiving the test chemical were elevated after both 30 and 60 days of treatment with 2500 mg/Kg and after 30 days with 5000 mg/Kg. Values for all animals allowed 30 days of recovery were normal. No statistically significant differences between treated and untreated animals were observed in the kidneys, heart, or brain. Absolute spleen weights were mildly elevated in a number of groups but all values were within the normal range expected for these animals. Testicular weights were lower in animals treated with 5000 mg/kg. This was not observed in the 2500 mg/kg animals or was this seen in animals treated for 30 days with 5000 mg/Kg which were allowed to recover for 30 days. Elevation in seminal vesicle weight was not observed following 30 days of testing. Statistically significant differences were observed at 60 days in 2 groups both in groups allowed 30 days of recovery following 2500 or 5000 g test chemical/kg treatment. The lack of elevation in animals continuously exposed to 2500 mg/Kg for 60 day makes the significance of this finding doubtful. At each sacrifice, changes were noted in gross pathology of all groups that had received the test chemical. The most frequent findings included yellow nodules in the epididymis and reduced testicular size (sometimes associated by bluish color suggesting necrosis). None of these changes were observed in any of the control animals. The treatment related lesions involved the testes and epididymis. These changes are characterized by impaired spermatogenesis, degeneration of the germinal epithelillm of the seminiferous tubules and inflammatory responses of seminiferous tubules and epididymal ducts to cellular debris and non-viable spermatozoa. These changes were found in animals treated for 30 days with 2500 or 5000 g test chemical/kg for 60 days with 2500 g test chemical/kg and in animals allowed 30 or 60 days of recovery. The severity of the lesions diminished following cessation of exposure to the test material as indicated by the findings in the T-I-D group. In these animals treated for 30 days with 2500 test chemical/kg and allowed 60 recovery days changes attributable to treatment were seen in only 3 of 10 animals and the degree of involvement was graded as mild to moderate. Based on the observations of the study, the low observed adverse effect level for the test chemical is considered to be 2500 mg/Kg/day when CD strain albino rats were exposed to the test chemical for 30 or 60 days by oral route of exposure.

 

In another repeated dose oral toxicity study, the test was performed to determine the toxic nature of the test chemical. Sprague-Dawley rats (10 animals/sex /group) were dosed with a 25% aqueous solution of the test chemical at 0 (controls), 500 or 1000 mg/kg bw by intubation 5 days a week during 30 days. Food consumption and body weights were recorded weekly and observations were made for signs of toxicity. After 30 days, representative animals from each group were sacrificed for necropsy. The viscera of the 1000 mg/kg bw and control groups were examined microscopically. The viscera of the 500 mg/kg bw group were held for potential further examination. Based on food consumption, growth data and tissue examination, the no observed adverse effect level (NOAEL) of the test chemical in male and female Sprague Dawley rats over an exposure period of 30 days was considered to be >1000 mg/Kg body weight.

Repeated dose toxicity: Inhalation

The test substance Triclocarban has very low vapor pressure (0.00000000361 mmHg) and high melting point, so the potential for the generation of inhalable vapours of Triclocarban is low. Also the normal conditions of use of this substance will not result in aerosols, particles or droplets of an inhalable size, so exposure to humans via the inhalatory route will be unlikely to occur, and therefore this end point for repeated dose toxicity by inhalation route of exposure was considered for waiver.

 

Repeated dose toxicity: Dermal

The acute toxicity value for Triclocarban (as provided in section 7.2.1) is >2000 mg/kg body weight. Thus, it is expected that Triclocarban shall not exhibit 28 day repeated dose toxicity by the dermal route. In addition, there is no data available that suggests that Triclocarban shall exhibit repeated dose toxicity by the dermal route. Hence this end point for repeated dose toxicity by dermal route of exposure was considered for waiver

Considering all the above mentioned studies, no gross vital organ toxicity due to target chemical is noted for repeated dose oral toxicity. Based on the presented data, triclocarban is regarded as Not Classified for STOT RE by the oral route. 

Justification for classification or non-classification

Considering all the above mentioned studies, no gross vital organ toxicity due to target chemical is noted for repeated dose oral toxicity. Based on the presented data, triclocarban is regarded as Not Classified for STOT RE by the oral route.