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Toxicological information

Immunotoxicity

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Description of key information

28-Day Rat Diet NOAEL: >3500 ppm; no humoral immune response. EPA OPPTS 870.7800; Reliability = 1

28-Day Mouse Diet NOAEL: 4800 ppm; no humoral immune response. EPA OPPTS 870.7800; Reliability = 1

Key value for chemical safety assessment

Effect on immunotoxicity: via oral route

Link to relevant study records

Referenceopen allclose all

Endpoint:
immunotoxicity: sub-chronic oral
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.7800
Deviations:
no
GLP compliance:
yes
Specific details on test material used for the study:
99.3% purity
Species:
mouse
Strain:
other: Crl:CD1(ICR)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: 8 weeks
- Weight at study initiation: mean of 29.9-30.7 g (males); mean of 22.4-23.3 g (females
- Housing: Animals were housed singly in stainless steel, wire-mesh cages suspended above cage boards with nestlets as enrichment. Each cage rack contained only animals of one sex.
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-26°C
- Humidity (%): 30-70%
- Air changes (per hr): not reported
- Photoperiod (hrs dark / hrs light): 12 hour light and 12 hour dark
Route of administration:
oral: feed
Vehicle:
other: LLC Certified Rodent LabDiet® 5002
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
A minimum of 2 samples (homogeneity and concentration verification) of all dietary concentrations were collected at the initial diet preparation and analyzed to verify the concentration and homogeneity of the test substance in the diets. Stability in the diet from 100 to 4800 ppm, up to 21-days, refrigerated was established in a concurrent study. Toward the middle of the study, samples were taken to verify concentration.

All diet samples not analyzed immediately were stored frozen until analyzed. At the time of analysis, an appropriate aliquot of each sample was extracted with acetonitrile and the extracts were analyzed by high-performance liquid chromatography (HPLC) with ultraviolet (UV) detection.
Duration of treatment / exposure:
28 days
Frequency of treatment:
Daily
Dose / conc.:
100 ppm
Dose / conc.:
600 ppm
Dose / conc.:
2 400 ppm
Dose / conc.:
4 800 ppm
No. of animals per sex per dose:
10
Control animals:
yes, plain diet
Details on study design:
- Dose selection rationale: Dietary concentrations for this study were selected based on the results of a currently conducted oncogenicity study in mice.
Observations and clinical examinations performed and frequency:
Cage-site examinations to detect moribund or dead mice and abnormal behaviour and/or appearance among mice were conducted at least once daily throughout the study. Abnormal behaviour/appearance was recorded by exception. At every weighing, each mouse was individually handled and examined for abnormal behaviour and appearance. Any abnormal clinical signs noted were recorded. During the test period, all mice were weighed once each week. During the test period, the amount of food consumed by each mouse over the weighing interval was determined and the mean daily food efficiency and mean daily intake of test substance were calculated.
Sacrifice and pathology:
At the end of the exposure period, the animals were euthanized by carbon dioxide anesthesia and exsanguination. The order of sacrifice for scheduled deaths was stratified across groups. Approximately 1 mL of blood was collected at sacrifice from the abdominal vena cava, while the animal was under carbon dioxide anesthesia, for evaluation of humoral immune function. Gross examinations were performed on all mice.
Humoral immunity examinations:
On test day 23, animals were injected intravenously in the lateral tail vein with 0.2 mL of 5 x 10e8 sRBC/mL. One mouse (100 ppm test substance group) was not injected with the appropriate amount of sRBC and the data for this mouse were not analyzed. On test day 28, (5 days after injection), the animals were euthanized by carbon dioxide anesthesia and exsanguination. Serum was collected from each mouse and frozen at ≤-60°C until analyzed. Humoral immune function was evaluated by the quantitative measurement of mouse anti-sRBC IgM levels in serum. The serum from each animal was assayed as 3 serial, 2-fold dilutions with 1 replicate per dilution. The optical density (OD) of the serial dilutions was measured at the 450 nm wavelength. The log2 of the mean result of the serial diluted serum sample was reported. Positive control mouse serum was obtained from mice injected with cyclophosphamide monohydrate.
Positive control:
Yes, cyclophosphamide monohydrate
Statistics:
For body weight, body weight gain, food consumption, food efficiency, humoral immune function data, and organ weights, the preliminary tests were Levene’s test for homogeneity and Shapiro-Wilk test for normality. If the preliminary test was not significant, applied the One-way analysis of variance followed by Dunnett's test. If the preliminary test was significant, applied the Kruskal-Wallis test followed by Dunn's test. Significance was judged at p < 0.05. Separate analyses were performed on the data collected for each sex.
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Description (incidence and severity):
There were no statistically significant or adverse changes in mean body weight and mean body weight gains in male or female mice fed 0, 100, 600, 2400 or 4800 ppm of the test substance. Final (test day 28) group mean body weight for male and female mice fed 4800 ppm was 94% and 101% of the control group, respectively.
Food consumption and compound intake (if feeding study):
effects observed, non-treatment-related
Description (incidence and severity):
There were no adverse changes in food consumption or food efficiency in male or female mice fed 0, 100, 600, 2400 or 4800 ppm of the test substance. Mean overall daily food consumption (test day 0-28) in male mice fed 4800 ppm was 100% of control (not statistically significant). Mean overall daily food consumption (test day 0-28) in female mice fed 4800 ppm was 87% of control (not statistically significant). A statistically significant decrease in mean daily food consumption (78% of control) was observed in female mice fed 4800 ppm during week 2. This decrease was not considered test substance related as it was not associated with a significant difference in overall food consumption.
Food efficiency:
no effects observed
Description (incidence and severity):
There were no adverse changes in food efficiency in male or female mice fed 0, 100, 600, 2400 or 4800 ppm of the test substance. Mean overall daily food efficiency (test day 0-28) in male mice fed 4800 ppm was 69% of control (not statistically significant). Mean overall daily food efficiency (test day 0-28) in female mice fed 4800 ppm was 126% of control (not statistically significant).
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
no effects observed
Description (incidence and severity):
No adverse or statistically significant effects were observed on the humoral immune response for male or female mice at any concentration tested.

The humoral immune response from mice dosed with 25 mg/kg/day cyclophosphamide monohydrate (positive control) for 5 days was lower than the study control group for males and females. Therefore, the SRBC-specific ELISA test system was valid for this feeding study.
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Description (incidence and severity):
There were no test substance related effects on final body weight or mean absolute or relative brain, spleen, and thymus weights at any dietary concentrations in male or female mice. A statistically significant increase in group mean relative brain to final body weight was observed in male mice fed 2400 or 4800 ppm (110% of control, respectively). The difference was attributed to lower final body weight in these groups (not statistically significant).
Gross pathological findings:
no effects observed
Description (incidence and severity):
There were no gross necropsy observations made in male or female mice at any dietary concentration tested.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Cell viabilities:
not examined
Humoral immunity examinations:
no effects observed
Description (incidence and severity):
No adverse or statistically significant effects were observed on the humoral immune response for male or female mice at any concentration tested.

The humoral immune response from mice dosed with 25 mg/kg/day cyclophosphamide monohydrate (positive control) for 5 days was lower than the study control group for males and females. Therefore, the SRBC-specific ELISA test system was valid for this feeding study.
Specific cell-mediated immunity:
not examined
Non-specific cell-mediated immunity:
not examined
Other functional activity assays:
not examined
Other findings:
not examined
Dose descriptor:
NOAEL
Effect level:
4 800 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no adverse effects observed on systemic toxicity or immunotoxicity
Conclusions:
Under the conditions of this study, the no-observed-adverse-effect level (NOAEL) for the test substance was 4800 ppm, the highest concentration tested. This concentration is equivalent to 727 mg/kg/day in male mice and 931 mg/kg/day in female mice. The NOAEL is based on the lack of adverse test substance-related effects on any in-life or anatomic pathology parameter or on the humoral immune response in male or female mice fed up to 4800 ppm of the test substance. The humoral immune response NOAEL of was 4800 ppm. The test substance is not considered to be an immunotoxicant.
Executive summary:

The purpose of this study was to evaluate the potential of the test substance to suppress the primary humoral response to sheep red blood cells (sRBC) when incorporated into nutritionally adequate diet and fed to male and female mice for at least 28 days.

Groups of 10 mice per sex were administered the test substance at dietary levels of 0, 100, 600, 2400 or 4800 ppm. Body weights, food consumption measurements, and clinical observations were recorded during the in-life period. Prior to sacrifice, the immune system was stimulated by injecting sheep red blood cells (sRBC) on test day 23 and blood samples were collected from each mouse on test day 28. The serum samples were assayed for their concentrations of sRBC specific IgM antibodies to provide a quantitative assessment of humoral immune response. Serum from animals similarly challenged with a positive control immunosuppressive agent were analyzed concurrently to provide confirmation that the assay performance was acceptable for detection of immunosupression. At sacrifice, each animal was examined grossly and selected organs were weighed (brain, spleen, and thymus).

Samples of the test diets were chemically analyzed and the results indicated that the test substance was at the targeted concentrations and homogeneously mixed. Stability in the diet up to 21-days, refrigerated was established in a concurrent study.

In male mice, the overall mean daily intake in the 0, 100, 600, 2400 or 4800 ppm groups was calculated to be 0, 16, 95, 358 and 727 mg/kg/day, respectively. In female mice, the overall mean daily intake of test substance was calculated to be 0, 20, 127, 449 and 931 mg/kg/day, respectively.

There were no statistically significant or adverse effects on mean body weight, mean body weight gain, or nutritional parameters in male or female mice at any dose level. No clinical signs of systemic toxicity were observed. No adverse effects were observed on 1) gross pathology; 2) absolute and relative brain, spleen, and thymus weights; or 3) humoral immune response.

Under the conditions of this study, the no-observed-adverse-effect level (NOAEL) was 4800 ppm, the highest concentration tested. This concentration is equivalent to 727 mg/kg/day in male mice and 931 mg/kg/day in female mice. The NOAEL is based on the lack of adverse test substance-related effects on any in-life or anatomic pathology parameter or on the humoral immune response in male or female mice fed up to 4800 ppm picoxystrobin. The humoral immune response NOAEL was 4800 ppm. The test substance is not considered to be an immunotoxicant.

Endpoint:
immunotoxicity: sub-chronic oral
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.7800
Deviations:
no
GLP compliance:
yes
Specific details on test material used for the study:
99.3% purity
Species:
rat
Strain:
other: Crl:CD(SD)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: 8 weeks
- Weight at study initiation: mean of 244.3-246.2 g (males); mean of 188.5-190.3 g (females
- Housing: Animals were housed singly in stainless steel, wire-mesh cages suspended above cage boards with nestlets as enrichment. Each cage rack contained only animals of one sex.
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-26°C (64-79°F)
- Humidity (%): 30-70%
- Air changes (per hr): not reported
- Photoperiod (hrs dark / hrs light): 12 hour light and 12 hour dark
Route of administration:
oral: feed
Vehicle:
other: LLC Certified Rodent LabDiet® 5002
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
A minimum of 2 samples (homogeneity and concentration verification) of all dietary concentrations was collected at the initial diet preparation and analyzed to verify the concentration and homogeneity of test substance in the diets. Twenty-one-day stability from 100 to 4800 ppm in the diets was established from a previous study. In order to verify stability at 50 ppm, a minimum of 2 samples of the 50 ppm dietary concentration were collected at the initial diet preparation and analyzed at 24 days to verify stability. Toward the middle of the study, diet samples were taken from the 50, 200, 1000 and 3500 ppm groups to verify concentration. All diet samples not analyzed immediately were stored frozen until analyzed. At the time of analysis, an appropriate aliquot of each sample was extracted with acetonitrile and the extracts were analyzed by high-performance liquid chromatography (HPLC) with ultraviolet (UV) detection.
Duration of treatment / exposure:
28 days
Frequency of treatment:
Daily
Dose / conc.:
50 ppm
Dose / conc.:
200 ppm
Dose / conc.:
1 000 ppm
Dose / conc.:
3 500 ppm
No. of animals per sex per dose:
10
Control animals:
yes, plain diet
Details on study design:
- Dose selection rationale: Dietary concentrations for this study were selected based on the results of a currently conducted chronic study in rats.
Observations and clinical examinations performed and frequency:
At every weighing, each rat was individually handled and examined for abnormal behavior and appearance. Any abnormal clinical signs noted were recorded.

Cage-site examinations to detect moribund or dead rats and abnormal behavior and/or appearance among rats were conducted at least once daily throughout the study. Abnormal behavior/appearance was recorded by exception.
Sacrifice and pathology:
On test day 28, the animals were euthanized by carbon dioxide anesthesia and exsanguination. Gross examinations were performed on all rats. Spleen, thymus and brain from all animals were weighed and discarded without further evaluation. Relative organ weights (relative to final body weight; relative to brain weight) for weighed organs were calculated. Final body weights determined just prior to necropsy were used in the assessment of organ weight changes.
Humoral immunity examinations:
Serum was collected from each rat and frozen at ≤-60°C until analyzed. Humoral immune function was evaluated by the quantitative measurement of rat anti-sRBC IgM levels in serum.
Positive control:
yes. cyclophosphamide monohydrate
Statistics:
For body weight, body weight gain, food consumption, food efficiency, humoral immune function data, and organ weights, the preliminary tests were Levene’s test for homogeneity and Shapiro-Wilk test for normality.

If the preliminary test was not significant, applied the One-way analysis of variance followed by Dunnett's test. If the preliminary test was significant, applied the Kruskal-Wallis test followed by Dunn's test. Significance was judged at p < 0.05. Separate analyses were performed on the data collected for each sex.
Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
There were no clinical signs of systemic toxicity observed for male or female rats at any concentration tested. The clinical signs observed were discharge of the eye, hair loss, stained cage board and a superficial wound. These signs are common findings in rats and were not considered to be test substance related.
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
There were no statistically significant or test substance related differences in mean body weight or body weight gain in male or female rats fed 50, 200 or 1000 ppm; however, decreases in mean body weight and body weight gain in male or female rats fed 3500 ppm were considered to be adverse.

Statistically significant lower mean body weight was observed in the 3500 ppm dose group on test days 7, 14, 21 and 28 in male rats and on test days 7, 14 and 28 in female rats. Mean body weights ranged from 91% to 94% of the respective control group. Although minimal in nature, the decrease in body weight throughout the study, correlated to decreased body weight gain, food consumption and food efficiency. Therefore, these variably statistically significant decreases were considered to be test substance related and adverse.

Statistically significant decreases in mean body weight gain was observed in male and female rats fed 3500 ppm on test day 0-7 (47% and 6% of control, respectively). All male rats fed 3500 ppm gained weight between test days 0-7; however, 3 female rats had a weight loss of 3%, 5% and 11%, respectively, between test days 0-7. These 3 female rats gained weight throughout the remainder of the study; however, the decrease in body weight gain at test day 0-7 was considered to be test substance related and adverse in both male and female rats fed 3500 ppm.

The overall body weight gain for male and female rats fed 3500 ppm was statistically significantly decreased (78% and 60% of control, respectively). The overall body weight gain for male rats fed 1000, 200 or 50 ppm, was 97%, 108% and 110% of control, respectively. The overall body weight gain for females fed the same concentrations of test substance was 94%, 105% and 95% of control, respectively. Therefore the statistically significant decrease in overall body weight gain in male and female rats fed 3500 ppm was considered to be test substance related and adverse.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Statistically significant decreased food consumption was observed at all time points in female rats fed 3500 ppm. The percent of control ranged from 62-89%. Mean overall daily food consumption and food efficiency (test day 0-28) in the female 3500 ppm group were 79% and 76% of control, respectively (both statistically significant).

The overall mean daily intake of test substance for male rats in the 0, 50, 200, 1000, 3500 ppm groups was calculated to be 0, 3.5, 15, 68, and 231 mg/kg/day, respectively.

The overall mean daily intake of test substance for female rats in the same groups was calculated to be 0, 3.9, 16, 75, and 229 mg/kg/day, respectively.
Food efficiency:
no effects observed
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
no effects observed
Description (incidence and severity):
No adverse or statistically significant effects were observed on the humoral immune response for male or female rats at any concentration tested.
The humoral immune response from rats dosed with 25 mg/kg/day cyclophosphamide monohydrate (positive control) for 6 days was lower than the study control group for males and females. Therefore, the SRBC-specific ELISA test system was valid for this feeding study.
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Cell viabilities:
not examined
Humoral immunity examinations:
no effects observed
Specific cell-mediated immunity:
not examined
Non-specific cell-mediated immunity:
not examined
Dose descriptor:
other: NOAEL (systemic)
Effect level:
1 000 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
food consumption and compound intake
food efficiency
Dose descriptor:
other: NOAEL (immunotoxicity)
Effect level:
3 500 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no effect on humoral immune response at highest dose tested
Conclusions:
Under the conditions of this study, the no-observed-adverse-effect level (NOAEL) was 1000 ppm. This concentration is equivalent to 68 mg/kg/day in male rats and 75 mg/kg/day in female rats. The NOAEL is based on lower body weight, body weight gain, food consumption or food efficiency in male or female rats fed 3500 ppm of the test substance. The humoral immune response NOAEL was 3500 ppm. The test substance is not considered to be an immunotoxicant.
Executive summary:

The purpose of this study was to evaluate the potential of the test substance to suppress the primary humoral response to sheep red blood cells (sRBC) when incorporated into nutritionally adequate diet and fed to male and female rats for at least 28 days. Groups of 10 rats per sex were administered the test substance at dietary levels of 0, 50, 200, 1000 or 3500 ppm. Body weights, food consumption measurements, and clinical observations were recorded during the in-life period. Prior to sacrifice, the immune system was stimulated by injecting sheep red blood cells (sRBC) on test day 23 and blood samples were collected from each rat on test day 28. The serum samples were assayed for their concentrations of sRBC-specific IgM antibodies to provide a quantitative assessment of humoral immune response. Serum from animals similarly challenged with a positive control immunosuppressive agent were analyzed concurrently to provide confirmation that the assay performance was acceptable for detection of immunosupression. At sacrifice, each animal was examined grossly and selected organs were weighed (brain, spleen, and thymus).

Samples of the test diets were analyzed and the results indicated that the test substance was at the targeted concentrations and homogeneously mixed. Twenty-one day stability from 100 to 4800 ppm was established from a previous study. Stability of the 50 ppm was determined in the current study.

In male rats, the overall mean daily intake in the 0, 50, 200, 1000 and 3500 ppm groups was calculated to be 0, 3.5, 15, 68 and 231 mg/kg/day, respectively. In female rats, the overall mean daily intake of test substance was calculated to be 0, 3.9, 16, 75 and 229 mg/kg/day for the same respective concentrations.

There were no statistically significant or adverse effects on body weight, body weight gain, food consumption or food efficiency in male or female rats fed 0, 50, 200 or 1000 ppm of the test substance. Lower mean body weight, body weight gain, food consumption and food efficiency were observed in male and female rats fed 3500 ppm (variable statistical significance), and were considered to be adverse. No clinical signs of systemic toxicity were observed. No adverse effects were observed on 1) gross pathology; 2) absolute and relative brain, spleen, and thymus weights; or 3) humoral immune response.

Under the conditions of this study, the no-observed-adverse-effect level (NOAEL) for the test substance was 1000 ppm. This concentration is equivalent to 68 mg/kg/day in male rats and 75 mg/kg/day in female rats. The NOAEL is based on lower body weight, body weight gain, food consumption or food efficiency in male or female rats fed 3500 ppm of the test substance. The humoral immune response NOAEL of the test substance was 3500 ppm. The test substance is not considered to be an immunotoxicant.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Effect on immunotoxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Effect on immunotoxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

In a 28-day immunotoxicity study in rats, the test substance was incorporated into the diet for at least 28 days. Groups of 10 rats per sex were administered the test substance at dietary levels of 0, 50, 200, 1000 or 3500 ppm. Body weights, food consumption measurements, and clinical observations were recorded during the in-life period. Prior to sacrifice, the immune system was stimulated by injecting sheep red blood cells on test day 23 and blood samples were collected from each rat on test day 28. The serum samples were assayed to provide a quantitative assessment of humoral immune response. There were no statistically significant or adverse effects on body weight, body weight gain, food consumption or food efficiency in male or female rats fed 0, 50, 200 or 1000 ppm test substance. Lower mean body weight, body weight gain, food consumption and food efficiency were observed in male and female rats fed 3500 ppm, and were considered to be adverse. No clinical signs of systemic toxicity were observed. No adverse effects were observed on gross pathology; absolute and relative brain, spleen, and thymus weights; or humoral immune response. The systemic toxicity NOAEL fort he test substance was 1000 ppm, equivalent to 68 mg/kg bw/day in male rats and 75 mg/kg bw/day in female rats. The humoral immune response NOAEL was 3500 ppm, the highest concentration tested.

 

In a 28-day immunotoxicity study in mice, the test substance was incorporated into the diet for at least 28 days. Groups of 10 mice per sex were administered the test substance at dietary levels of 0, 100, 600, 2400 or 4800 ppm. Body weights, food consumption measurements, and clinical observations were recorded during the in-life period. Prior to sacrifice, the immune system was stimulated by injecting sheep red blood cells on test day 23 and blood samples were collected from each mouse on test day 28. The serum samples were assayed to provide a quantitative assessment of humoral immune response. There were no statistically significant or adverse effects on mean body weight, mean body weight gain, or nutritional parameters in male or female mice at any dose level. No clinical signs of systemic toxicity were observed. No adverse effects were observed on gross pathology; absolute and relative brain, spleen, and thymus weights; or humoral immune response. The NOAEL for systemic toxicity and immunotoxicity was 4800 ppm, or 727 mg/kg bw/day in male mice and 931 mg/kg bw/day in female mice, the highest concentration tested.

Justification for classification or non-classification

The test substance did not produce a humoral response in rats or mice in immunotoxicity studies. Therefore, the substance does not need to be classified for mutagenicity according to EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.