Registration Dossier

Diss Factsheets

Administrative data

Description of key information

Maleic anhydride was tested in a chronic study (equivalent to OECD 451). The only test item related effects observed during this study were the reduced body weights in male and female rats at mid (32 mg/kg bw/day) and high (100 mg/kg bw/day) doses. At the doses tested, there was not a treatment related increase in tumor incidence when compared to controls. Based on the results, the NOAEL for carcinogenicity is considered to be higher or equal to 100 mg/kg bw/day.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records
Reference
Endpoint:
carcinogenicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1978-01-24 to 1980-03-15
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Reason / purpose for cross-reference:
reference to same study
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 451 (Carcinogenicity Studies)
Deviations:
yes
Remarks:
Diets were not analyzed for maleic anhydride until 2-4 years after the study ended. Maleic anhydride may have converted to maleic acid when mixed in the feed.
GLP compliance:
not specified
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River
- Age at study initiation: 7 weeks
- Weight at study initiation: weight range males: 130 - 169 g; weight range females: 105 - 129 g
- Housing: in groups of three animals per cage; control animals were housed separately in an adjacent room
- Diet: Wayne Laboratory powdered meal (No . 86-04, Supplied by Locke-Erickson, Melrose Pk, IL), ad libitum
- Water: tap water ad libitum


ENVIRONMENTAL CONDITIONS
- Photoperiod (hrs dark / hrs light): 12/12. However, there is a possibility that the animals were exposed to continuous light during an undefined period of the study.
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on exposure:
The basal laboratory diet consisted of Wayne Laboratory powdered meal (No. 86-04, Supplied by Locke-Erickson, Melrose Pk, IL). The maleic anhydride bricks (approximately 2ft x lR X In) were placed in a plastic bag and broken into a powder with a mallet. The powder was then passed through a sieve (Size SO, 0.297 sq mm openings) before weighing. The various quantities of maleic anhydride, depending on the dietary levels, were first added to 500 grams of the basal diet and premixed by hand by stirring with a large spatula. The premix was then added to a twin-shell blender (Patterson-Kelly) and mixed for at least one minute per kilogram of meal to provide the appropriate dose level. The diets, based on body weight and food consumption data for each group, were prepared weekly to ensure the maintenance of a constant intake on a mg/kg body weight basis. The mean maleic anhydride consumed by each level and sex was calculated based on target dose levels (weekly from Week I through Week 13, bi-weekly through Week 25, and monthly thereafter).
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The analysis of the diet for maleic anhydride was conducted 2 to 4 years after completion of the in-life phase of the study. A sample of each diet was removed, refrigerated or frozen for future chemical determination of the concentration of maleic anhydride. The GC-MS measurements were (on average of random samples) 69-75% of the expected for male and female diets, respectively.
Duration of treatment / exposure:
2 years
Frequency of treatment:
daily
Dose / conc.:
0 mg/kg bw/day (nominal)
Dose / conc.:
10 mg/kg bw/day (nominal)
Remarks:
Low dose
Dose / conc.:
32 mg/kg bw/day (nominal)
Remarks:
Mid dose
Dose / conc.:
100 mg/kg bw/day (nominal)
Remarks:
High dose
No. of animals per sex per dose:
126 animals per sex per dose (besides the females which got 10 mg/kg bw: 123 animals).
Control animals:
yes, concurrent no treatment
Details on study design:
- Fasting period before blood sampling for clinical biochemistry:16 hours
Positive control:
no
Observations and examinations performed and frequency:
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice daily (7 days/week)

BODY WEIGHT: Yes
- Time schedule for examinations: weekly for the first 13 weeks, bi-weekly the succeeding 12 weeks, and monthly thereafter

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption : Yes

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: prior to the 6, 12, and 18-month and terminal sacrifices.
- Dose groups that were examined: both eyes of each animal to be sacrificed

HAEMATOLOGY: Yes
- Time schedule for collection of blood:6, 12, 18 and 24 months
- Anaesthetic used for blood collection: pentobarbital injection at the 6-month sacrifice and by exposure to carbon dioxide gas thereafter.
- Animals fasted: 16 hrs
- How many animals: 5 animals of each sex from the control and each test group at 6 and 12 months and on approximately 20 animals from
each group at 18 and 24 months.
- Parameters examined were: hemoglobin, hematocrit, and erythrocyte, leukocyte (total and differential) and reticulocyte counts.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood:6, 12, 18 and 24 months
- Animals fasted: 16 hrs
- How many animals: 5 animals of each sex from the control and each test group at 6 and 12 months and on approximately 20 animals from
each group at 18 and 24 months.
- Parameters examined were:Serum samples for clinical chemistry analyzed for glucose, urea nitrogen (BUN), glutamic pyruvic transaminase (SGPT), and alkaline phosphatase (AP).

URINALYSIS: Yes
- Time schedule for collection of urine: 6, 12, 18 and 24 months
- Metabolism cages used for collection of urine: yes
- Animals fasted: 16 hrs

NEUROBEHAVIOURAL EXAMINATION: Yes
- Dose groups that were examined: animals which were sacrificed at the 6, 12, and 18 month intervals and animals that survived to the terminal sacrifice
- Battery of functions tested: sensory activity / grip strength / motor activity
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
At 6 and 12 months five animals from each group, and at 18 months, 20 animals from each group, were anesthe,ized, sacrificed by exsanguination, and necropsied. Surviving animals were sacrificed and necropsied after 24 months on test. Anesthesia was induced by pentobarbital injection at the 6-month sacrifice and by exposure to carbon dioxide gas thereafter. Necropsies were performed under the supervision of the Project Officer and a pathologist. For animals sacrificed at 6, 12, and 18 months and for 20-22 per group of those sacrificed at study termination, fresh unstained impression smears of liver were examined microscopically for porphyrin fluorescence by exposure to ultra-violet light.

The following organs of each rat sacrificed at 6, 12, and 18 months and at study termination were excised, trimmed of fascia, blotted dry, and weighed prior to fixation: brain, heart, liver, kidneys, lungs, and testes or ovaries. Organ/body weight ratios were determined for these organs.

HISTOPATHOLOGY: Yes
The following tissues from each rat were preserved in 10% neutral buffered formalin: brain (including optic nerves), peripheral nerves (sciatic and anterior tibial), pituitary, thyroid, parathyroid, SUbmaxillary salivary glands, heart, lungs, spleen, liver, pancreas, adrenals, lymph nodes (mesenteric, thoracic, and mandibular), kidneys, urinary bladder, ovaries, uterus, oviducts, stomach, small intestine (3 levels), large intestine (3 levels), skeletal muscle, skin, mammary glands, bone marrow (smear and section), aorta, ear canal, nasal turbinate, trachea, spinal cord and ganglia (thoracic and lumbar), esophagus, thymus, prostate, seminal vesicles, epididymis, and any gross lesions.
The testes were fixed in Bouin's solution. The eyes were fixed in Bouin's solution if collected during the first 16 months of the study and in 3% gluteraldehyde if collected thereafter. Testes and eyes were SUbsequently stored in 70% ethanol.

All fixed tissues from the scheduled sacrifice animals in the control and high dose groups were stained with hematoxylin and eosin and examined microscopically. In addition, tissues from all animals from the control and high dose group that died spontaneously or were sacrificed due to a moribund state or large masses were processed through histopathologic examination. For animals in the low and middle dose groups that died or were sacrificed during the first 18 months of the study, histopathologic evaluation was performed if selected gross lesions were present. The basis for selection was a mass or organ enlargements that might have been indicative of a mass.
Tissues from the remaining animals were held for possible future consideration.
Statistics:
All data obtained by quantitative methods were statistically evaluated by the analysis of variance. All comparisons were limited to within-sex analysis. A "two-tail" distribution was used for evaluation of mean differences. If significant differences (p < 0.05) occurred -in the preliminary analysis, Tukey's procedure was employed to determine the differences between control and treated groups.
Clinical signs:
effects observed, non-treatment-related
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, non-treatment-related
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
For further details, see section below "Details on results".
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
For further details, see section below "Details on results".
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
effects observed, non-treatment-related
Description (incidence and severity):
For further details, see section below "Details on results".
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
For further details, see section below "Details on results".
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
For further details, see section below "Details on results".
Urinalysis findings:
effects observed, treatment-related
Description (incidence and severity):
For further details, see section below "Details on results".
Behaviour (functional findings):
no effects observed
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
For further details, see section below "Details on results".
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
For further details, see section below "Details on results".
Histopathological findings: neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
For further details, see section below "Details on results".
Details on results:
CLINICAL SIGNS: No distinct treatment-related clinical signs at any of the periods considered:
- at 12 months: the overall incidence of signs was low with only five males and nine females evidencing signs of any kind (not further specified);
- at 18 months:
males: 80-90% of male animals in each group were normal; external or subcutaneous masses were the most frequently occurring abnormal signs in males and were approximately equally distributed across all groups of males (6-9%); 8 males: eye opacities; matter crusted around the eyes (6 % of the males in the high dose group and not in control males) but other "eyelid lesions" such as matted fur were recorded for control males as well as other groups;
females: Incidence of clinical signs was higher in females than in males as indicated by the lower percentage of normal females (58%-65%), but the different treatment groups were comparable; external or subcutaneous masses (14-21% of the abnormal females in the different groups); often masses in the inguinal region and for this region the masses were slightly more frequent in females fed maleic anhydride (11-16%) than in control females (5%); according to the authors such masses, based on location, were probably lesions in mammary tissue which are often seen in aging rats (Goodman et al., 1979); the histopathology evaluations for the subsequent period (when these animals died or were sacrificed) indicate that mammary gland lesions, both neoplastic and nonneoplastic, were if anything more common in control females than in those treated with the high dose of maleic anhydride. Further, by the 23-month clinical examination, masses in the inguinal region were seen at comparable frequencies in all groups (9-12%); other abnormal signs in both control and treated females: matter crusted around the eyes (10-14%) and skin lesions (5-7%); females with eye opacities: 1%-7%, with the high dose group having the lowest percentage;
- at 23 months:
males: The percentage of normal males in each group ranged from 3% in the low dose group to 18% in controls with the percentage for both high and middle dose groups being 8%; eye opacities were the most frequently occurring abnormal signs and were present in 81-89% of the males in each group; all groups of males: increase in the frequency of occurrence of external or subcutaneous masses between 18 and 23 months (24-29% in the different groups);
females: The inguinal region was frequently the site of the mass but relatively large masses on the lateral surface of the body were also common to all groups; of the females examined at 23 months, 20 to 26% of the animals in each group were normal; females with eye opacity: in slightly more than half of the animals in the control and each treated group; external or subcutaneous masses (in 16 to 27% of the females in the different groups with the percentage being the highest in the control group);

MORTALITY: At 12 months: 5 males and 27 females had died or were sacrificed in extremis. For males one death or sacrifice in each of the dose groups except the middle dose group where there were two. For females the distribution was controls 3, high dose 7, middle dose 11 and low dose: 6.
During this period two males were sacrificed due to large subcutaneous masses and one male due to apparent paralysis of the hindlimbs. Two male died, one with a probable cause of death of pneumonia and septicemia and the other of undiagnosed cause. Although among females the cause of death was frequently identified as generalized septicemia, an incidental finding was the presence of unilateral ovarian abscesses or inflammation in 17 of the animals. At the request of the Project Officer, the ovaries from six rats (three animals which had ovarian abscesses, one which was sacrificed because of a large mammary tumor, and two controls killed at the 12-month sacrifice were submitted to our microbiology staff for culture of possible pathogenic microorganisms. The organism E .coli (non-enteropathogenic) was isolated only from the ovaries of the three animals with grossly observable abscesses. Since the female deaths and the incidence of ovarian abscesses occurred in both the control group and in the maleic anhydride treated groups, they do not appear to be treatment related.
During 12 and 18 month: 25 female and 26 male rats died or were sacrificed. Malignant lymphomas and chromophobe adenomas were the most frequent diagnoses for cause of death of male animals, control as well as treated, although other causes were also diagnosed. Suppurative oophoritis was the most frequent cause of female deaths during this period (six animals) and was distributed across all groups of females. Uterine tumors (three adenocarcinomas and one leiomyosarcoma) was the cause of death for four females including two control animals.
At study termination: Survival to study termination: higher in males than in females, but not affected by treatment with maleic anhydride (During the last period of the study, i .e ., after the 18 month sacrifice, 93 males and 123 females died or were sacrificed in extermis. Where histopathologic evaluation was performed (controls and high dose), the most frequently diagnosed causes of death for males were myelomonocytic leukemia (12 males), malignant lymphomas (6 males), and pituitary adenomas (6 males). Similar causes appeared to predominate in the low and middle dosage groups of males as enlarged spleens (14 males) and pituitary masses (10 males) were noted at necropsy. Subcutaneous, fibromas were observed in the control and high dose animals (total of 5 males) and 10 males among the low and middle dosage groups had subcutaneous masses. There was no evidence in the distribution of the various causes of death in males to suggest an effect of maleic anhydride. Uterine adenocarcinomas were seen at approximately equal frequencies in control (18/30) and high dose (20/31) females that died during this period of the study. Uterine masses were present in 16 of the 30 middle dose females that died during the period and in 16 of 32 females in the low dosage group. There were two additional females in each of these latter groups where the necropsy observation suggested the possibility of a uterine mass. The ovarian inflammation observed during the first 18 months of the study was not present during the final study period, or at least ovarian inflammation did not result in the death of any animal during this period.)

BODY WEIGHT AND WEIGHT GAIN: Maleic anhydride fed to male rats at doses of 32 and 100 mg/kg/day resulted in reduced body weights as compared to control males, 10 mg/kg/day did not. Only marginal differences between body weights of control females and those fed the high and mid dose were detected and no effects at the low dose (see table below).

FOOD CONSUMPTION AND COMPOUND INTAKE: Significantly lower food consumption by treated groups occurred sporadically during the first year of the study for both males and females. The most frequent occurrence of these differences was during the first quarter. For males there was also a 3-month period near the end of 18 months. Where significant differences in food consumption occurred, indications of a dose-response relationship were frequently lacking and there were occasional periods where the food consumption for treated groups, particularly female treated groups, was higher than that for the controls of the same sex .

OPHTHALMOSCOPIC EXAMINATION: Progressive development of cataracts during the study in all groups with 100% of the animals examined at 18 months and at study termination bearing cataracts; although there were some differences in the number of inflamed irises between treated and non-treated rats, there were no dose-related differences and no definite evidence of treatment-related effect .

HAEMATOLOGY: At 6 months male animals fed maleic anhydride had erythrocyte counts that were significantly lower than those of control males and hematocrit was lower in the male high and low dose groups. Leukocyte counts were lower than control values at 6 months for females in the high and middle dosage groups. The only significant hematological finding at 12 months was a lower leukocyte count for males in the low dosage group.At 18 and 24 months there were no significant differences between control animals and those fed maleic anhydride in any of the hematologic variables considered.

CLINICAL CHEMISTRY: no effects besides elevated serum urea nitrogen values for the female low dose group at 6 months and for the male middle dose group at 12 months.

URINALYSIS: Elevated urine specific gravity in the female middle dose group at 12 months was determined. This effect was not observed thereafter.

NEUROBEHAVIOUR: No treatment related effects on posture, gait, tone of facial muscles, pupillary reflex, extensor thrust reflex, or crossed extensor reflex (at 24 months: inability to detect the pupillary reflex due to opacities: of the 317 male and 227 female animals, evaluated at 24 months, the pupillary reflex could be obtained in only 21 males and 40 females; these were scattered across the various treatment groups; furthermore, there were one male control animal with restricted use of the left hindlimb and a male in the low dose group for which tilting of the head and a lateral locomotion were observed.

ORGAN WEIGHTS: The only treatment related effects observed were higher brain weight for female animals in the low dosage group at 12 months, lower liver weight for male animals in the middle dosage group at 24 months

GROSS PATHOLOGY: no treatment related effects; At the terminal period(> 18 months), uterine tumors were observed at high frequencies but without any relation to treatment. For this period of the study, the percentage of females in each group that had uterine tumors ranged from 22-32%, an incidence that is higher than would be expected for this strain of rat

HISTOPATHOLOGY NON-NEOPLASTIC: No treatment related effects.
At 6 months, the most frequent lesion was related to chronic murine pneumonia and consisted of a trace level of peribronchial lymphoid filtration in the lungs of all animals. Various levels of mammary hyperplasia and galactocele occurred in most males and a few females, treated and control, with no apparent relationship to treatment. Calcified microconcretions occurred in renal tubules at the corticomedullary junction. They were observed in tissues of control and treated females, although more frequently in treated animals. However, numbers were too small to relate differences in incidence to treatment.Thus, the level of spontaneous lesions and the type of lesions observed at the 6-month sacrifice were not unusual for rats of this age.
At 12 months, a variety of spontaneous lesions were observed in all groups and they did not appear to be related to the experimental regimen.
At 18 months, similar to earlier periods, there were no histologic lesions that could be associated with feeding of maleic anhydride diets. A wide variety of spontaneous lesions were obserrved in these animals and there was no dose or treatment-related response present.

HISTOPATHOLOGY: NEOPLASTIC: No increases in tumor incidence that were considered related to maleic anhydride exposure. There was an unusally high incidence of uterine adenocarcinomas in this study. The tumors were present in similar numbers in both the control and treated animals (23/86 and 20/82, respectively). The report stated that Uterine adenocarcinomas is not a common spontaneous lesion in this strain of rat, although no historical control data was provided. The authors speculated that this may have been related to altered hormonal status caused by the continuous light exposure.


Relevance of carcinogenic effects / potential:
Maleic anhydride did not show any carcinogenic effects.
Dose descriptor:
NOAEL
Effect level:
>= 100 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
histopathology: neoplastic
Dose descriptor:
NOEL
Effect level:
10 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
food consumption and compound intake

There was a high incidence of cataracts in the animals of this study with 100% of the animals examined at 18 months and at study termination bearing cataracts, however, the severity of these was independent of maleic anydride consumption.

Conclusions:
In a carcinogenicity oral study, test item did not show any carcinogenic effects. Based on the results, the NOAEL for carcinogenicty is considered to be higher or equal to 100 mg/kg bw/day and the NOEL for systemic toxicity is considered to be 10 mg/kg bw/day based on the reduced body weights and food consumption.
Executive summary:

 In a carcinogenicity toxicity study maleic anhydride was administered to 126 rats, Fischer 344/sex/dose in diet at dose levels of 0, 10, 32 or 100 mg/kg bw/day) for 2 years.

 

Under the conditions tested maleic anhydride produced only marginal toxicity which was evidenced by small (< 6%)but dose related decreases, compared to controls, in the body weights of male rats fed 100 and 32 mg/kg/day. The female rats in these two groups also had reduced body weights but the reductions were even smaller and of shorter duration than those observed in males.

Furthermore, marginal decreases in food consumption were observed and in general were also limited to these two groups suggesting that reduced food consumption may have contributed to the reduction in body weights. The 10 mg/kg/day dose had no sustained significant effects on body weights.

Neither neurologic nor ophthalmologic evaluations revealed differences between control and maleic anhydride treated rats. There was a high incidence of cataracts in the animals of this study with 100% of the animals examined at 18 months and at study termination bearing cataracts, however, the severity of these was independent of maleic anydride consumption. For male animals sacrificed at 6 months, a decrease in hematocrit and red blood cell counts for males treated with maleic anhydride may have indicated a mild anemia but this was not detected at any other period in the study. Although statistical differences between control and treated rats were occasionally observed in the clinical laboratory data, dose-response relationships were not present. The organ weight data similarly revealed no distinct treatment-related differences.

Other findings (e.g. gross pathology, histopathologic evaluations) in the study were, in general, consistent with expectations for rats of this strain and their ages at the time of the observations. However, there were several exceptions like the high incidence of uterine adenocarcinomas in female rats or lesions of the eye like atrophy, fibrosis, cataracts or inflammation of the iris, none of which had any relation to treatment. According to the authors the cause of these atypical findings cannot be established with certainty. One explanation that has been considered is the possibility that the rats were exposed to sustained periods of constant illumination. This was suggested in part by the eye lesions as even short periods (10 days) of constant illumination produced retinal lesions in rats (Heywood, 1973). Further, a problem with control of the light cycles in the animal rooms was identified and corrected at 18 months which could have influenced the endocrine balance in the rats.

 

The NOAEL for carcinogenicty is considered to be higher or  equal to 100 mg/kg bw/day and the NOEL for systemic toxicity is considered to be 10 mg/kg bw/day based on the reduced body weights and food consumption..

 

At the doses tested, there was not a treatment related increase in tumor incidence when compared to controls.  Dosing was considered adequate based on carcinogenicity.

 

This carcinogenicity study in the rats is acceptable and satisfies the guideline requirement for a carcinogenicity study (OPPTS 870.4200); OECD 451 in rats.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
100 mg/kg bw/day
Study duration:
chronic
Species:
rat

Carcinogenicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

From the available data, there is no indication given for a carcinogenic potential of maleic anhydride. Therefore criteria for classification according to CLP Regulation are not met.

Additional information

In a carcinogenicity toxicity study maleic anhydride was administered to 126 rats, Fischer 344/sex/dose in diet at dose levels of 0, 10, 32 or 100 mg/kg bw/day) for 2 years.

 

Under the conditions tested maleic anhydride produced only marginal toxicity which was evidenced by small (< 6%)but dose related decreases, compared to controls, in the body weights ofmale rats fed 100 and 32 mg/kg/day. The female rats in these two groups also had reduced body weights but the reductions were even smaller and of shorter duration than those observed in males.

Furthermore, marginal decreases in food consumption were observed and in general were also limited to these two groups suggesting that reduced food consumption may have contributed to the reduction in body weights. The10 mg/kg/day dose had no sustained significant effects on bodyweights.

Neither neurologic nor ophthalmologic evaluations revealed differences between control and maleic anhydride treated rats. There was a high incidence of cataractsinthe animals of this study with 100% of the animals examined at 18 months and at study termination bearing cataracts, however, the severity of these was independent of maleic anydride consumption. For male animals sacrificed at 6 months, a decrease in hematocrit and red blood cell counts for males treated with maleic anhydride may have indicated a mild anemia but this was not detected at any other period in the study. Although statistical differences between control and treated rats were occasionally observed in the clinical laboratory data,dose-response relationships were not present. The organ weight data similarly revealed no distinct treatment-related differences.

Other findings (e.g. gross pathology, histopathologic evaluations) in the study were, in general, consistent with expectations for rats of this strain and their ages at the time of the observations. However, there were several exceptions like the high incidence of uterine adenocarcinomas in female rats or lesions of the eye like atrophy, fibrosis, cataracts or inflammation of the iris, none of which had any relation to treatment. According to the authors the cause of these atypical findings cannot be established with certainty. One explanation that has been considered is the possibility that the rats were exposed to sustained periods of constant illumination. This was suggested in part by the eye lesions as even short periods (10 days) of constant illumination produced retinal lesions in rats (Heywood, 1973). Further, a problem with control of the light cycles in the animal rooms was identified and corrected at 18 months which could have influenced the endocrine balance in the rats.

 

The NOAEL for carcinogenicty is considered to be higher or  equal to 100 mg/kg bw/day and the NOEL for systemic toxicity is considered to be 10 mg/kg bw/day based on the reduced body weights and food consumption.

 

At the doses tested, there was not a treatment related increase in tumor incidence when compared to controls . Therefore criteria for classification according to CLP Regulation are not met.