Registration Dossier

Administrative data

Description of key information

The data base consists of oral studies in rats and dogs of 28 day,  90 day and 2 year duration, together with two unreliable studies in monkeys. Although the chronic studies are relatively old they are well reported and allow a weight of evidence based conclusion on the repeated dose toxicity. However when evaluating the NOAEL levels it is important to consider that the animals suffered from infections and the effects observed consisted of an aggravation of effects also seen in the concurrent control animals. Therefore they are considered rather conservative. The main target organ after subchronic and chronic exposure was the liver in both rat and dog. The effects were observed at comparable dose levels in both species, suggesting that the interspecies differences are low. The 2 year study in dogs included a 7 month recovery period in which most of the effects were reversible at least down to levels that were not considered to impair the function of the liver. The two monkey studies are both old and show no significant toxicological effects in the animals over the test period. Overall, the studies show that no severe organ toxicity was observed and the lowest NOAEL that is used for the assessment of 4 mg/kg w/day in the 2-year rat study is considered conservative.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
chronic toxicity: oral
Remarks:
combined repeated dose and carcinogenicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
1969
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study with acceptable restrictions
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
Deviations:
yes
Remarks:
limited clinical chemistry, no urinalysis, limited data on test substance purity and no report onm analylsis of the diets
GLP compliance:
no
Limit test:
no
Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Lab. Inc. Brookline Mass.
- Age at study initiation: weanling rats
- Weight at study initiation: males 394 - 436 g (av 1. week), females 248 - 269 g (av. week 1)
- Fasting period before study: no
- Housing: 3 males or 4 females per cage
- Diet ad libitum
- Water ad libitum:
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 76 +- 2 deg. F
- Humidity (%): not controlled
Route of administration:
oral: feed
Vehicle:
corn oil
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:

DIET PREPARATION
- Rate of preparation of diet (frequency): 1 kg of corn oil was added to 19 kg of the base diet with or without the test substance. The mixture was stirred for 20 min in a Hobart mixerr (stainless steel). 5 diets with test item were prepared at a concentration of 15, 60, 100, 500, 3000 ppm. The diet was freshly perpared every week.
- Mixing appropriate amounts with (Type of food):special perparation of Rockland Mouse and Rat diet containing no more than 1% of fat. The diet was obtained fresh every month.
- Storage temperature of food: refigerator

VEHICLE
- Justification for use and choice of vehicle (if other than water): for dissolution of at least part of the substance is dissolved in cornoil (6% solubility) to ensure homogenous distribution
- Concentration in vehicle: 300, 1200, 2000, 10000, 60000 mg/kg corn oil
- Purity: Mazola Corn oil free of antioxidants
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
104 weeks
Frequency of treatment:
continuously in diet
Remarks:
Doses / Concentrations:
15, 60, 100, 500, 3000 ppm
Basis:
nominal in diet
No. of animals per sex per dose:
25, 50 controls, 4 males and 4 females were assigned to subgroups for interim kills after 13, 26, 52 and 78 weeks
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: dose selection based on 90-day study
- Rationale for animal assignment (if not random): were randomly assigned
.
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations checked: general appearance and behaviour

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule:
weekly
BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): weekly per cage
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: 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 AND COMPOUND INTAKE (if drinking water study): No data


OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: weekly
- Dose groups that were examined: all for cataracts

HAEMATOLOGY: Yes
- Time schedule for collection of blood: 1 week before dosing, week 13, 26, 52, 78, 104
- Anaesthetic used for blood collection: No data
- Animals fasted: No
- How many animals:10 per dose
- Parameters examined: prothrombin time, hemoglobin, packed cell volume of erythrocytes, total and differential leukocytes

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at scheduled sacrifice
- Animals fasted: No
- How many animals: all allocated to the respective groups
- Parameters examined: total lipids, cholesterol, alkaline phopsphatase

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes: liver, heart, lungs, kidneys, spleen, brain, gonads, pituitary, adrenals, thyroid
HISTOPATHOLOGY: Yes : Heart, Aorta, lungs, liver, spleen , kidney, stomach, duodenum, pylorus, small intestine (ileum), large intestine (colon), mesenteric lymph nodes, urinary bladder, prostate, testes, ovaries and uterus, pancreas, thyroids, thymus, adrenals, pituitary, brain, spinal cord, eye, bone marrow, bone, skeletal muscle, skin.
Statistics:
Performed, but no data on methods
Clinical signs:
no effects observed
Description (incidence and severity):
no test substance realted effects observed
Mortality:
no mortality observed
Description (incidence):
no test substance realted effects observed
Body weight and weight changes:
no effects observed
Description (incidence and severity):
no test substance realted effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
no test substance realted effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Description (incidence and severity):
no test substance realted effects observed
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
no test substance realted effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
increase in liver weight at the highest dose tested
Gross pathological findings:
no effects observed
Description (incidence and severity):
no test substance realted effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
liver increased fatty degenaration and bile duct proliferation at 3000 and 500 ppm, but similar lesions also in controls
Histopathological findings: neoplastic:
no effects observed
Description (incidence and severity):
no test substance realted effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY
Throughout the study several rats had various infectious diseases and died in the course of the illness. The incidence and severity of these diseases were unrelated to the content of the test substance in the diets and occurred equally in the control rats. The mortality in the different groups was comparable to controls. (see Table 1). The only test substance related clinicall sign was a greenish-yellow discoloration of the fur of the high dose rats commencing after 6 motnhs and in rats receiving 500 ppm after one year. Occasional discoloration was seen some the rats receiving 100 ppm after 15 months.
BODY WEIGHT AND WEIGHT GAIN
No test substance realted changes in body weight or body weight gain were observed in the study. Variations in body weight and body weight gain of individual animals during the cours of the study were attributed to infectious diseases or spontaneous tumors that occurred at comparable incidence in the treated and control groups and were accompanied by respective changes in food consumption.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
Food consumption was comaprable between treated and control animals and only influenced by diseases as mentioned above. The average test substance intake during the study was calculated for males and females (see table 2).
FOOD EFFICIENCY
Food efficiency was reported to be comparable between treated and control animals.
OPHTHALMOSCOPIC EXAMINATION
No findings were reported from the ophthalmologic examinations
HAEMATOLOGY
Mild to moderate leukopenia was reported in some females at week 52 and 78, but not after 104 weeks of feeding. The incidence in treated and control animals was comparable. Single cases of some degree of anaemia or polychromasia wer occaisonally seen during week 78 and 104 in males and females of all groups including controls with no relationship to treatment. Prothrombin time was statisitcally significantly different from controls in males of the 15 and 500 ppm group in the week before treatment started, and in the 15, 100 and 3000 ppm groups at 13 weeks. In females statistically significant differences to controls were observed in the 60, 100, 500 and 3000 ppm groups one week before treatment started and in the 500 ppm group on week 26. No statistically significant differences to control values were observed at the 26, 52, 78 and 104 week observation times. As the finding was not dose related and did not persist throughout the course of the study, it was not considered treatment related. All other haematological parameters were comparable between treated and control animals.
CLINICAL CHEMISTRY
Alkaline phosphatase levels varied widely within the groups and the only statistically significant finding was an increased level in the high dose group males in week 104. Due to the major fluctuations in the measurements this finding was not considered treatment related by the authors. No consistent treatment related effect was observed on the serum cholesterol anmd total lipid levels
ORGAN WEIGHTS
All relative organ weightsand most absolute organ weights in the treated groups were comparable to the respective control values. Single rats receiving 3000 ppm of the test substance were reproted to have enlarged livers, but the group avaerages did not reach statisitcal significance, with the exeption of females killed aftter week 13 and males killed after week 78. In females fed for 104 weeks at 15 ppm a relative liver weight statistically significantly lower than control values was reported. This is an isolated finding and in the higher dose groups no significant changes in liver weight were observed. Therefore this finding is not considered treatment related by the authors.
GROSS PATHOLOGY
No test substance related macroscopic organ changes were observed in the study.
HISTOPATHOLOGY: NON-NEOPLASTIC
All animals (treatment and control) killed at 24 months had pneumonia or interstitial nephritis or both. A total of 183 rats died during the cours of the study. Fior 52 no postmortem pathology could be done due to autolysis. For 131 postmortem pathology revealed in most instances massive pulmonary infection as the cause of death. Liver lesions were the most prominent findings and consisted of fatty degeneration of the hepatic sells and a proliferation of the bile ducts. Fatty degeneration reached from small fat vacuoles to a fatty liver. There was no special localization of the degeneated cells in the liver lobe. The incidence and severity in the different groups is given below (table 3). Two types of proliferation of the bile ducts coudl be distinguished morphologically: 1. multiplication of the bile ducts with retainment of their normal stucture occurred in small clusters. 2. A dilatation and multiplication of the bile ducts with fibrotic walls without epithelium. In some of the dilated bile ducts mucous plaques were observed. No inflammatory reaction was present. Up to 3 months of feeding no alterations in the livers were observed. Both lesions invcreased in control and treated rats from 18 months of treatment. After 24 more severe lesions were observed in the 500 and 3000 ppm dose groups. Incidence and severity was more pronounced in males than in females.
HISTOPATHOLOGY: NEOPLASTIC (if applicable)
Neoplastic lesions observed in the study were subcutaneous or in females mammary gland adenofribroma, pituitary adenoma, one adenoma in the parathyroid, thyroid adenoma, adrenal adenoma, liver angioma that wer all benign tumors. Leukemia, Seminoma and ovary carcinoma were single findings in control animals only. No test substance related increased incidence of any tumour was observed and it can be concluded that the test substance did not induce neoplastic lesions under the conditions of this study. The findings are summarized in chapter 7.7.

The histopathology findings were confirmed in a second reading of the data with independent pathologists and reported in a supplementary report of the same laboratory dated July 9, 1971.
Dose descriptor:
NOAEL
Effect level:
ca. 100 mg/kg diet
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Increased incidence and severity of hepatic lesions compared to controls at 3000 and 500 ppm
Critical effects observed:
not specified

Table 1 Mortality in the different groups

Level of TS in the diet (mg/kg diet)

Mortality males %

Motality females %

Mortality malea and females combined %

0

54.9

52.9

53.9

15

46.2

40.0

43.1

60

57.1

44.0

50.9

100

44.0

68.0

56.0

500

61.5

38.5

50.0

3000

46.2

52.0

49.0

Table 2: Average Test substance intake over the study period

Dose group mg/kg in diet

TS intake males mg/kg bw/day

TS intake female mg/kg bw/day

0

0.55

0

15

2.14

0.67

60

3.56

2.63

100

18.13

4.35

500

107.25

22.23

3000

0.55

138.43

Table 3 incidence and severity of liver lesions

Table 3.1 Fatty degeneration males

Dose group

No of months

Number of rats With no change

(%)

No rats (%)

Grade 1 severity (marginal)

No rats (%)

Grade 2 severity

slight

No rats (%)

Grade 3 severity

modrate

No rats (%)

Grade4

Severity

Severe

0

6

4 (100)

0

0

0

0

 

12

4 (100)

0

0

0

0

 

18

4 (100)

0

0

0

0

 

24

14 (62)

4 (17)

3 (13)

1 (4)

0

15

6

4 (100)

0

0

0

0

 

12

3 (75)

1 (25)

0

0

0

 

18

4 (100)

0

0

0

0

 

24

6 (43)

5 (36)

0

1 (7)

2 (14)

60

6

3 (75)

1 (25)

0

0

0

 

12

4(100)

0

0

0

0

 

18

1 (100)

0

0

0

0

 

24

7 (58)

2 (17)

2 (17)

1 (8)

0

100

6

4(100)

0

0

0

0

 

12

4(100)

0

0

0

0

 

18

4(100)

0

0

0

0

 

24

6 (43)

5 (36)

1 (7)

2 (14)

0

500

6

4(100)

0

0

0

0

 

12

0

0

0

3 (75)

1 (25)

 

18

0

0

1 (33)

2 (67)

0

 

24

5 (45)

2 (18)

1 (9)

3 (18)

0

3000

6

1 (25))

2 (50)

0

1 (25)

0

 

12

0

0

1 (25)

2 (50)

1 (25)

 

18

1 (33)

0

1 (33)

1 (33)

0

 

24

0

2 (14)

4 (29)

6 (43)0

2 (14)

Table 3.2 Fatty degeneration females

Dose group

No of months

Number of rats With no change

(%)

No rats (%)

Grade 1 severity (marginal)

No rats (%)

Grade 2 severity

slight

No rats (%)

Grade 3 severity

modrate

No rats (%)

Grade4

Severity

Severe

0

6

4 (100)

0

0

0

0

 

12

4 (100)

0

0

0

0

 

18

4 (100)

0

0

0

0

 

24

20 (84)

1 (4)

1 (4)

2 (8)

0

15

6

4(100)

0

0

0

0

 

12

4(100)

0

0

0

0

 

18

4(100)

0

0

0

0

 

24

11(73)

 

2 (13)

1(7)

 

60

6

4(100)

0

0

0

0

 

12

4(100)

0

0

0

0

 

18

3(75)

0

0

1 (25)

0

 

24

10(72)

0

3 (21)

1 (7)

0

100

6

4(100)

0

0

0

0

 

12

4(100)

0

0

0

0

 

18

4(100)

0

0

0

0

 

24

6(76)

0

1 (12)

1 (12)

0

500

6

4(100)

0

0

0

0

 

12

3(75)

0

1 (25)

0

0

 

18

1(25)

0

3 (75)

0

0

 

24

10 (63)

0

4 (25)

2 (12)

 

3000

6

4(100)

0

0

0

0

 

12

1(25)

0

1 (25)

2 (50)

 

 

18

0

1(25)

0

2 (50)

0

 

24

4 (33)

3(25)

4(33)

0

1 (9)

 Table 3.3 Bile duct multiplication males

Dose group

No of months

Number of rats With no change

(%)

No rats (%)

Grade 1 severity (marginal)

No rats (%)

Grade 2 severity

slight

No rats (%)

Grade 3 severity

modrate

No rats (%)

Grade4

Severity

Severe

0

6

4 (100)

0

0

0

0

 

12

4 (100)

0

0

0

0

 

18

4 (100)

0

0

0

0

 

24

18 (78)

3 (13)

1 (4)

0

1 (4)

15

6

4 (100)

0

0

0

0

 

12

3 (75)

1 (25)

0

0

0

 

18

4 (100)

0

0

0

0

 

24

11 (79)

3 (21)

0

0)

0

60

6

4 (100)

0

0

0

0

 

12

3 (75)

0

0

1 (25)

0

 

18

1 (100)

0

0

0

0

 

24

10 (83)

1 (8)

1 (8)

0

0

100

6

3 (75)

0

0

1 (25)

0

 

12

2 (50)

1 (25)

0

1 (25)

0

 

18

4(100)

0

0

0

0

 

24

9 (64)

1 (7)

2 (14)

2 (14)

0

500

6

4(100)

0

0

0

0

 

12

1 (25)0

2 (50)0

0

1 (25)

0

 

18

0

1 (33)0

2 (67)

0

0

 

24

6 (55)

2 (18)

2 (18)

1 (9)

0

3000

6

1 (25))

0

1 (25)

2 (50)

0

 

12

0

0

1 (25)

2 (50)

1 (25)

 

18

0

0

2 (67)

1 (33)

0

 

24

4 (35)

0

5 (28)

4 (35)

1 (17)

Table 3.4 Bile duct multiplication females

Dose group

No of months

Number of rats With no change

(%)

No rats (%)

Grade 1 severity (marginal)

No rats (%)

Grade 2 severity

slight

No rats (%)

Grade 3 severity

modrate

No rats (%)

Grade4

Severity

Severe

0

6

4 (100)

0

0

0

0

 

12

4 (100)

0

0

0

0

 

18

3 (75)

0

1 (25)

0

0

 

24

22 (92)

0

2 (8)

0

0

15

6

4 (100)

0

0

0

0

 

12

4 (100)

0

0

0

0

 

18

4 (100)

0

0

0

0

 

24

12 (80)

1 (7)

2 (13)

0)

0

60

6

4 (100)

0

0

0

0

 

12

3 (75)

0

0

1 (25)

0

 

18

1 (25)

0

2 (50)

0

1 (25)

 

24

10 (71)

2 (14)

2 (14)

0

0

100

6

4 (100)

0

0

0

0

 

12

3 (75)

0

0

1 (25)

0

 

18

4(100)

0

0

0

0

 

24

4 (50)

1 (12.5)

1 (12.5)

2 (25)

0

500

6

3 (75)

0

0

1 (25)

0

 

12

3 (75)0

1 (25)`

0

0

0

 

18

1 (25)

0

3 (75)

0

0

 

24

5 (31)

3 (19)

3 (19)

4 (25)

1 (6)

3000

6

2 (50)

0

2 (50)

0

0

 

12

1 (25)

0

0

2 (50)

1 (25)

 

18

0

1 (25)

0

3 (75)

0

 

24

4 (33)

1 (8)

2 (17)

3 (25)

2 (17)

Tumor incidences: see chapter 7.7. Carcinogenicity

 

 

Conclusions:
In a 2-year combined repeated dose-carcinogenicity dietary study in rats the test substance related effects were confined to a dose related aggravation of liver lesions identified as fatty degeneration and bile duct multiplication that were also present to a lesser extend and severity in control animals. The incidence and severity of the changes at 500 and 1000 ppm was regarded to represent an adverse effect. Therefore the NOAEL in this study is 100 mg/kg diet which corresponds to approximately 3.56 mg/kg bw in males and 4.35 mg/kg bw in females. The onset of the lesions occurred from 18 to 24 months of study duration. With regard to carcinogenicity it can be concluded that under the conditions of this study the test substance did not lead to an increased tumour incidence up to the highest dose level tested of 3000 mg/kg diet corresponding to appr. 107 mg/kg bw/day in males and 138 mg/kg bw/day in female rats.
Executive summary:

Groups of male and female CD-1 rats (25 per sex per dose, with 50 controls per sex) were fed diets containing 0 (control), 15, 60, 100, 500, and 3000 ppm (mg/Kg diet) of 4'4'-methylene bis(2,6 -di-tert. butylphenol) for a period of 2 years. This corresponded to approximate dose levels of 0, 0.55 (m)/0.67 (f); 2.14 (m)/2.63 (f), 3.56 (m)/ 4.35 (f), 18.1 (m)/22.2 (f); 107 (m) and 138 (f) mg/kg bw/day. Mortality was comparable to controls in all dose groups. No test substance related clinical signs, body weight changes, haematological or clinical chemical changes were observed during the study. A discoloration of the fur was observed among animals of the 500 and 3000 ppm dose group and single animals in the 100 ppm dose group. No clearly test substance related changes in organ weights and gross pathology were observed at all dose levels.

Test substance related effects were confined to histopathological findings of a dose related aggravation of liver lesions identified as fatty degeneration and bile duct multiplication that were also present to a lesser extend and severity in control animals. The incidence and severity of the changes at 500 and 1000 ppm was regarded to represent an adverse effect. Therefore the NOAEL in this study is 100 mg/kg diet which corresponds to approximately 3.56 mg/kg bw in males and 4.35 mg/kg bw in females. The onset of the lesions occurred from 18 to 24 months of study duration. With regard to carcinogenicity it can be concluded that under the conditions of this study the test substance did not lead to an increased tumour incidence up to the highest dose level tested of 3000 mg/kg diet corresponding to appr. 107 mg/kg bw/day in males and 138 mg/kg bw/day in female rats.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
4 mg/kg bw/day
Study duration:
chronic
Species:
rat
Quality of whole database:
The lowest NOAEL of the chronic studies is chosen. The NOAEL of the 2 year dog study was comparable at 7 mg/kg bw/day. The 90-day studies had NOAEL levels of 700-800 mg/kg bw/day in male and female rats respectively and 810 to 840 mg/kg bw in male and female dogs. In both species liver was the target organ. However, infections in the animals in the longer duration studies may have led to an aggravation of the effect.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

The data base consists of dietary chronic and subchronic studies in rats and dogs, a 28-day oral gavage study in rats and two oral studies in monkeys. Although the chronic and subchronic studies are relatively old, they are well reported and allow a weight of evidence based conclusion on the repeated dose toxicity. However when evaluation the NOAEL levels it is important to consider that the animals suffered from infections and the effects observed consisted in an aggravation of effects also seen in the concurrent control animals. Therefore they are considered rather conservative.

In the 28-day study the most sensitive target organ with regard to histopathological changes was the thyroid. The changes were mild and consisted of slightly increased thyroid weights in the 200 and 1000 mg/kg dose groups and slight diffuse hyperplasia of the follicular epithelial cells. Increased liver weights without any histopathological changes were also observed in these dose groups. The effects were reversible in the recovery animals. 

The main target organ in the subchronic and chronic toxicity studies in rats and dogs was the liver for both species and the effects were observed at comparable dose levels in both species, suggesting that the interspecies differences are low. Interestingly no effects on the thyroid were reported in these studies, although this organ was examined as well. This indicates that the effects in the thyroid observed in the 28 day study may have been an reversible adaptive change that is not observed after longer exposures. The additional two monkey studies are unreliable but showed no significant effects throughout the test period.

The 2 year study in dogs included a 7 month recovery period in which most of the effects were reversible at least down to levels that were not considered to impair the function of the liver. This indicates that no severe organ toxicity was observed and the lowest NOAEL that is used for the assessment of 4 mg/kg w/day in the 2-year rat study is considered conservative. The NOAEL values of the 90 day studies were 700 to 800 mg/kg bw in rats and 810 to 840 mg/kg bw in dogs.

In order to reinvestigate previous findings and to address certain specific concerns, an enhanced Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test (OECD 422) is proposed. The proposed study would be substantially augmented with additional parameters in order to investigate any potential endocrine effects.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
The selection should encompass all repeated dose studies in a weight of evidence approach, but IUCLID only allows to select one study. One subacute study in the rat is available together with subchronic and chronic toxicity studies in 2 species. The latter give comaparable results with regard to target organs and effects.

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

Justification for classification or non-classification

The NOAEL values in the 90 day rat and dog repeated dose dietary toxicity studies are above 700 mg/kg bw. Effects observed in the chronic and subchronic studies are confined to the liver and were indicative of an aggravation of existing infective diseases in the test animals. Furthermore the adverse effects showed signs of reversibility in a 2 year dog study that included a recovery period. It can therefore be concluded that the weight of evidence suggests that exposure to the substance did not cause significant toxic effects in experimental animals at dose levels and conditions that would warrant a classification for repeated dose toxicity. Consequently the substance is not classified for repeated dose target organ toxicity according to Regulation EC 1272/2008 and amendments.