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Description of key information

In a combined repeat dose and reproductive/developmental toxicity screening test (OECD 422) 13 male and 13 female Crj: CD(SD) rats per dose received trimethyl phosphate via gavage at dose levels of 0, 40, 100 and 250 mg/kg bw/day. In male rats, the administration period was two weeks prior to mating, 2 weeks within the mating period and 2 weeks after the completion of mating period (42 days). In females, in addition to maximum four weeks pre-mating and mating period, they were administered through pregnant period until day 3 of post delivery (approximately 63). Significant decrease of body weight, significant change in haematology and clinical chemistry examines (e.g. decreased erythrocytes) were observed in parental animals. Renal toxic findings and neurotoxic effects were also seen in gross and histopathological examines (e.g. nephropathy, degeneration of nerve fibre). Increases of kidney weight were observed at the lowest dose level (40 mg/kg/day).

Bomhard et al. (1997) conducted a newer 30-Month Chronic Toxicity/Carcinogenicity Study in Wistar Rats with Administration in Drinking Water. Trimethylphosphate (TMP) was administered to 50 male and 50 female Wistar rats through their drinking water at doses of 0, 1, 10, or 100 mg/kg body weight up to 30 months. The animals of the highest dose group revealed a weakness of hind limbs beginning with week 46. Mortality rates were increased at 100/50 mg/kg starting within the period between weeks 39 and 52. Despite the dose reduction in week 54, increased further up to 70% on average in week 100 when this group was terminated.

In males administered with 10 mg/kg there was significant retardation with up to about 10% lower than the control body weights. There was a marked effect (up to 20% lower body weights in males and 15% in females) when TMP was administered at 100/50 mg/kg.

At doses of100/50 mg/kg hemoglobin, hematocrit, and occasionally also erythrocyte count were significantly reduced, and the proportion of reticulocytes increased essentially in males up to month 18. There was also a trend to higher thrombocyte counts up to month 18 in this group which attains statistical significance on a few occasions. In addition, a relative increase of segmented neutrophils and a corresponding decrease of lymphocytes was observed in this dose group at various time points.

At the 12-month interim termination some male and female rats of the highest dose group showed signs of hind limb skeletal muscle wasting, and the incidences of changes of the testes (small, contents fluid) appeared to be slightly increased. In addition, three high dose males showed signs of emaciation. Final necropsy of high dose animals in month 24 indicates a slight increase in the frequency of small hind limbs, scarring of the kidneys, and small, soft testes.

The peripheral nervous damage already clinically apparent in males and females of the high dose group manifested itself essentially as muscle wasting of the hind limbs as seen during gross pathological investigations. Histopathologically, males and females showed a peripheral nerve degeneration. In addition, a remarkable spinal cord degeneration and a myopathy of skeletal muscles were observed in several animals.

In consideration of the reduced survival times and the findings made at interim necropsy, the incidence and degree of myopathies of the skeletal muscle in male rats of the high dose group is also to be seen as increased in a dose-related manner. The early myopathic changes consisted of atrophy and breakdown of groups of muscle fibers, indicating the possible neurogenic origin of the lesion.

At doses of 100/50 mg/kg an increased incidence of degeneration (males) and loss of nerve fibers (males and females) in the spinal cord occurred. In the peripheral nerve fiber damage was associated with reactive cell proliferation, mainly of Schwann cells, resulting in hypercellularity.

The most important toxic effect was neurotoxicity, consisting of degeneration and loss of nerve fibers in the peripheral nerves and the spinal cord, associated with myopathic changes, and occurring at doses of 100/50 mg/kg. The no-observed-adverse-effect-level, based on the suppression of body weight gain, is 1 mg/kg in males and 10 mg/kg in females.

The overall conclusion of this study is, that TMPO proved not to be carcinogenic in Wistar rats. Particularly, the incidence of fibromas/fibrosarcomas in the subcutaneous tissue of male rats was not increased in either a statistically or a biologically significant manner. The few tumors of this type that occurred were within the range of historical controls known from 2-year and 30-month studies (Bomhard, 1992; Bomhard and Rinke, 1994). Therefore, the observations of the previous study with F344 rats (DHEW, 1978) could not be reproduced.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Referenceopen allclose all

Endpoint:
repeated dose toxicity: oral, other
Remarks:
Males: 42 days including 14 days before mating. Females: from 14 days before mating to day 3 of lactation
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
GLP compliance:
yes
Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female
Route of administration:
oral: gavage
Vehicle:
water
Duration of treatment / exposure:
Males: 42 days
Females: from 14 days prior to mating to Day 3 of lactation
Frequency of treatment:
7 days/week
Dose / conc.:
0 mg/kg bw/day (nominal)
Dose / conc.:
40 mg/kg bw/day (nominal)
Dose / conc.:
100 mg/kg bw/day (nominal)
Dose / conc.:
250 mg/kg bw/day (nominal)
No. of animals per sex per dose:
13 animals/group
Control animals:
yes, concurrent vehicle
Mortality:
mortality observed, treatment-related
Description (incidence):
Twelve males and one female given 250 mg/kg died during the 4th to 6th week of the dosing period.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Body weight gain of the males and females of the 250 mg/kg dose groups were significantly reduced.
Twelve and 2 pregnant females given 40 and 100 mg/kg, respectively, demonstrated significant decrease in body weight gain during mid and late pregnancy.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Food consumption of the males of the 250 mg/kg dose group was significantly reduced.
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
In the males of the 100 mg/kg dose group, significantly decreased erythrocyte counts, hemoglobin concentration, hematocrit and A/G ratio, and increased platelet count, percentage of segmented neutrophils, cholinesterase activity, total cholesterol and calcium levels were noted. Similar alteration in hematological and clinical chemistry parameters was observed in one surviving male of the 250 mg/kg dose group.
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
At terminal necropsy, compound-related alterations in organ weights included significant increases in the kidney weight of males of the 40 and 100 mg/kg dose groups and in the thymus weight of males of the 100 mg/kg dose group and of females of the 40 mg/kg dose group, and a significant decreases in the epididymal weight of males of 100 mg/kg dose group.
Neuropathological findings:
effects observed, treatment-related
Description (incidence and severity):
Progressive development of a paralytic gait and decreased motor activity in twelve males and one female.
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
On histopathological examination, major lesions noted in males and females given 100 mg/kg or more included nephropathy characterized by tubular and papillary alteration such as increased eosinophilic droplets in tubular epithelium, increased regeneration of tubules and papillary necrosis, atrophy of the thymus, liver and testis, increased atretic follicles in the ovary (250 mg/kg female only), and degeneration of nerve fiber in the spinal cord or the peripheral nerves (e.g., sciatic nerve). The incidence and severity of these lesions increased with dose and were greater in males than females.
Key result
Dose descriptor:
NOEL
Effect level:
< 40 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
Key result
Dose descriptor:
LOEL
Effect level:
40 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
Critical effects observed:
no
Conclusions:
The NOELs for repeat dose toxicity are considered to be less than 40 mg/kg/day for both sexes.
Endpoint:
chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
Wistar
Details on species / strain selection:
Weanling Wistar rats of the strain BOR:WISW (SPF Cpb) from a specific pathogen-free colony.
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Winkelmann (Borchen, Germany)
- Age at study initiation: 4–5 weeks
- Weight at study initiation: mean body weight (body weight range) of male rats at the start of the
study was 89 g (73–104 g), while that of the females was 91 g (67–106 g).
- Housing: individually, under conventional conditions in Type II Makrolon cages on low-dust wood
granules
- Diet (e.g. ad libitum): Altromin 1324 pellets was provided ad libitum.
- Water (e.g. ad libitum): fresh tap water was available ad libitum.
- Acclimation period: for 9 days in the same room in which they were housed for the study
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 2°C
- Humidity (%): 55 +/- 10%
- Air changes (per hr): 10 times
- Photoperiod (hrs dark / hrs light): 12-h light/dark
Route of administration:
oral: drinking water
Vehicle:
unchanged (no vehicle)
Duration of treatment / exposure:
30 months
Frequency of treatment:
daily
Dose / conc.:
0 mg/kg bw/day (nominal)
Dose / conc.:
1 mg/kg bw/day (nominal)
Dose / conc.:
10 mg/kg bw/day (nominal)
Dose / conc.:
100 mg/kg bw/day (nominal)
No. of animals per sex per dose:
25
Control animals:
yes, concurrent no treatment
Details on study design:
Dose selection rationale: The dose levels chosen were based on the results of the NCI bioassay in conjunction with subchronic NCI studies which indicated a rather flat dose–response curve (DHEW, 1978). Thus, the dosage regimen of 0, 1, 10, and 100 mg/kg per day was selected. The high dose was expected to represent the maximum tolerated dose (MTD), while the low dose was intended to affirm a chronic no-observed-adverse-effect-level. During the course of the first year of treatment, it turned out that the 100 mg/kg dose was too high. It was therefore reduced to 50 mg/kg in week 54. Sixty rats per sex per goup were utilized of which 10 rats per sex per group were sacrificed at 12 months. The remaining 50 animals per sex per group were intended for a treatment period of up to 30
months.
Observations and examinations performed and frequency:
Observations and examinations performed and frequency
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice a day (once daily on weekends and on bank holidays)

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once a week

DERMAL IRRITATION (if dermal study): No

BODY WEIGHT: Yes
- Time schedule for examinations: once per week during the first 3 months and once every other
week for the remainder of the study.

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, was determined weekly throughout the study. The individual food and water intake was, in addition, measured at approximately 13-week intervals. These data were used to calculate mean individual daily food and water consumption.

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: weekly throughout the study. The individual water intake was, in addition measured at approximately 13-week intervals. These data were used to calculate mean individual daily water consumption.

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: performed in weeks 98/99 and 128 on 10 rats per group. The pupillary reflex of both eyes was first tested in a darkened room and the anterior regions of the eye were inspected. After dilating the pupils with Mydriaticum Roche drops the refractive elements of the eyes and the fundus were examined using an indirect ophthalmoscope.

HAEMATOLOGY: Yes
- Time schedule for collection of blood: were conducted after 6, 12, 14 months on 10 randomly select ed animals per group. Blood sampling from the remaining groups was 27 days later.
- Anaesthetic used for blood collection: Yes, diethylether
- Animals fasted: No
- Parameters checked: glucose concentrations in deproteinized whole blood were taken from one of the caudal veins of nonanesthetized animals; erythrocytes, reticulocytes, leukocytes, differential blood, and platelet counts, hemoglobin, hematocrit, mean corpuscular hemoglobin, mean corpuscular volume, mean corpuscular hemoglobin concentration, and thromboplastin time (Hepato-Quick method; not measured at 14 months).
Blood plasma or serum was evaluated for alkaline phosphatase, lactate dehydrognase, aspart ate aminotransferase, and alanine aminotransferase activity, and concentrations of total bilirubin, cholesterol, creatinine, albumin, total protein, urea nitrogen, triglycerides, inorganic phosphate, calcium, potassium, sodium, and chloride.

URINALYSIS: Yes
- Time schedule for collection of urine: were conducted after 6, 12, 14 months on 10 randomly selected animals per group. Was collected at room temperature over periods of about 16 h (overnight). During the urine collection periods the animals received water ad libitum, but no feed.
- Metabolism cages used for collection of urine: Yes / No / No data
- Animals fasted: Yes / No / No data
- Parameters checked: volume, total protein, specific gravity, and pH (month 14 only) and semiquantitatively for blood glucose, bilirubin, protein, ketone bodies, and pH (except month 14).
Sediment from each urine sample was microscopically examined.

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes, The adrenals, brain, heart, kidneys, liver, lungs, ovaries, spleen, and testes were weighed at scheduled necropsies. Organ weight/final body weight ratios were calculated. The following tissues were collected from all rats: aorta, adrenal glands, bone marrow (in sternum), brain (in toto), cecum, colon, duodenum, epididymides, esophagus, eyes with optic nerve, femur with joint, Harderian glands, heart, ileum, jejunum, kidneys, liver, lungs, lymph nodes (mesteric / cervical), mammary glands/area, muzzle, ovaries, pancreas, pituitary, prostate, rectum, salivary gland (submandibular), sciatic nerve, seminal vesicle, skeletal muscle, skin, spinal cord, spleen, sternum, stomach testes, thymus (if present), thyroid (/ parathyroids), tongue, trachea, urinary bladder, ureter, urethra, uterus, vagina, and all gross lesions.

HISTOPATHOLOGY: Yes, all tissues were examined microscopically.
Statistics:
The statistical evaluation of data was performed using SAS routines.
Provided that the variates in question can be considered approximately normally distributed with equal variances across treatments, the Dunnett test is used; if heteroscedasticity appeared more likely a p value adjusted Welch test is applied. If the evidence based on historical experience indicates that the assumptions for a parametric analysis of variance cannot be maintained, distributionfree tests in lieu of ANOVA are carried out, i.e., the Kruskal-Wallis test followed by adjusted Mann–Whitney–Wilcoxon U tests where appropriate. Significant differencies from the control group are indicated with ‘‘*’’ for p ¡ 0.05 and ‘‘**’’ for p ¡ 0.01.
Incidences of microscopically detected tumors were evaluated by the Peto test (Peto et al., 1980).
Where appropriate, lesions were pooled and subjected again to statistical analyses to determine a possible effect of the treatment.
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
The animals of the highest dose group revealed a weakness of hind limbs beginning with week 46. This was observed in a total of 55 males and 26 females of this group. In addition, these animals showed an increased incidence of sunken flanks (especially in males), distended abdomen (especially in females), and poor general condition. Dose reduction at week 54 had no remarkably improving effect on these clinical signs. Hind limb weakness was also noticed in a few animals of the other groups including control starting mostly around week 120, which has to be attributed to old age.
Mortality:
mortality observed, non-treatment-related
Description (incidence):
Mortality rates were increased at 100/50 mg/kg starting within the period between weeks 39 and 52. Despite the dose reduction in week 54, increased further up to 70% on average in week 100 when this group was terminated.
At 1 mg/kg there was no effect while at 10 mg/kg the numbers of dead animals were slightly higher but only toward the end of the study.
Mortality in the dose group 10 mg/kg corresponded to that in the control group during the first 2 years of study. In the last 6 months mortality, especially of males, was slightly higher than in the control group. A substance-related effect, however, seems to be questionable as the rate was still within the range of historical studies and no indications of substance-specificcauses of death were given. The survival rates of the 1 mg/kg group corresponded to those of the controls.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
There was no toxicologically relevant effect on body weights at 1 mg/kg (Fig. 3). In 10 mg/kg males there was significant retardation with up to about 10% lower than control body weights. At 100/50 mg/kg there was a marked effect (up to 20% lower body weights in males and 15% in females).
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Male and female rats up to 10 mg/kg consumed approximately the same amount of feed per animal per day and kg body weight as the control animals.
At 100 mg/kg (during the first 54 weeks) a slightly decreased mean feed intake was noticed in male s. Adjusting the feed intake to body weights revealed a slightly higher intake in both sexes receiving 100/50 mg/kg.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
no effects observed
Description (incidence and severity):
Rats of all dose groups consumed approximately the same amount of water as the control animals.
Ophthalmological findings:
no effects observed
Description (incidence and severity):
Did not reveal any test substance-related changes. The findings resembled those common in old-age rats.
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
TMPO treatment did not affect hematology parameters in males and females at 1 and 10 mg/kg.
At 100/50 mg/kg hemoglobin, hematocrit, and occasionally also erythrocyte count were significantly reduced, and the proportion of reticulocytes increased essentially in males up to month 18.
There was also a trend to higher thrombocyte counts up to month 18 in this group which attains statistical significance on a few occasions.
In addition, a relative increase of segmented neutrophils and a corresponding decrease of lymphocytes was observed in this dose group at various time points.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
Slightly increased cholesterol concentrations were noted in 100/50 mg/kg males and females.
At 12 months the relative amount of the alpha1-globulin fraction in 100/50 mg/kg males exceeded the historical range, in consequence the albumin and the gamma-globulin fractions were significantly lower than those of the controls. A similar but not statistically significant trend is apparent at months 18 and 24.
All other values did not indicate a test substance related effect.
Urinalysis findings:
effects observed, treatment-related
Description (incidence and severity):
Urinary protein excretion seems to be increased especially in 100/50 mg/kg males at months 18 and 23.
The urinary pH value (semiquantitatively determined) was distinctly lower in high dose females at 6 months and in all treated female groups at 12 months.
Additional investigations at 14 months using a quantitative method roughly confirmed the 12 months results: the pH values of all female groups were significantly but not strictly dose-dependently lower than in controls.
At month 23 (shortly before termination of the highest dose group) the pH seems to be rather low in high dose males and females but comparison is difficult due to the absence of values of the remaining groups in this week.
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):
It is striking that some organs (which usually show a correlation with body weights) of high dose males and females were unaffected in terms of absolute weights or even slightly increased compared with the controls.
These organs were the adrenals, heart, lungs, and kidneys in males as well as the adrenals, heart, liver, and kidneys in females.
Related to body weight, the values were in some cases markedly increased, and the differences were mostly statistically significant when compared to control values.
The increased relative organ weights in high dose group were obviously produced by decreased weight of body, to a large extent attributable to neurotoxicity and muscle wasting.
No remarkable differences were observed in the remaining dose groups at the 30 month termination.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
At the 12-month interim termination some male and female rats of the highest dose group showed signs of hind limb skeletal muscle wasting, and the incidences of changes of the testes (small, contents fluid) appeared to be slightly increased. In addition, three high dose males showed signs of emaciation.
Necropsy of intercurrently died animals revealed higher incidences of the following findings in high dose group (taking into account the markedly shorter survival time in this group): muscle wasting, changes in the lungs (e.g., mottled, reddish, pale), changes in the heart (e.g., thick, hard, abnormal color), changes in the liver (e.g., thick, scarring,), scarring of the kidney in males and females, small seminal vesicles, changes in the testes (small, soft), and fluid contents of the thoracic cavity in males
, and skin edema in females.
Final necropsy of high dose animals in month 24 indicates a slight increase in the frequency of small hind limbs, scarring of the kidneys, and small, soft testes.
At study termination after 30 months no changes attributable to the treatment with TMPO were found.
Neuropathological findings:
effects observed, treatment-related
Description (incidence and severity):
Clinical observations and gross pathological and histopathological investigations gave no indications of damage to the central or peripheral nervous system in dose groups up to and including 10 mg/kg. The peripheral nervous damage already clinically apparent in males and females of the high dose group manifested itself essentially as muscle wasting of the hind limbs as seen during gross pathological investigations.
Histopathologically, males and females showed a peripheral nerve degeneration. In addition, a r emarkable spinal cord degeneration and a myopathy of skeletal muscles were observed in several animals.
The neurotoxic effect of TMPO has already been described in previous studies for other species (dog, rabbit).
In consideration of the reduced survival times and the findings made at interim necropsy, the incidence and degree of myopathies of the skeletal muscle in male rats of the high dose group is also to be seen as increased in a dose-related manner. The early myopathic changes consisted of atrophy and breakdown of groups of muscle fibers, indicating the possible neurogenic origin of the lesion.
More advanced myopathy, however, was very similar to more diffuse muscle damage occurring in aging rats. Degenerating fibers in the peripheral nerve showed fragmentation of axons and myelin sheaths and in the spinal cord the lesion was most prominent in the dorsal columns at the cervical level. These features are compatible with distally accentuated axonopathy.
Histopathological findings: non-neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
Nonneoplastic changes: At interim sacrifice after 12 months the majority of 100/50 mg/kg males and females showed a peripheral nerve and spinal cord degeneration. In addition, a myopathy of skeletal muscles was observed in some animals. Moderate or marked interstitial edema in the testes was diagnosed in two high dosed animals while it was only minimal in three controls. Spermatozoa in both epididymides were absent in another animal.
In addition, three high dose animals of the main group, dying around the time of interim necropsy, showed a moderate (one animal) or marked (two animals) tubular atrophy of the testes.
At 100/50 mg/kg an increased incidence of degeneration (males) and loss of nerve fibers (males and females) in the spinal cord occurred. In the peripheral nerve fiber damage was associated with reactive cell proliferation, mainly of Schwann cells, resulting in hypercellularity.
Changes of the nervous system, including sporadic hypercellularity, in animals dosed up to 10 mg/kg were those normally observed in aging laboratory rats. Therefore, they are considered spontaneous and unrelated to treatment.
In the testes the incidence of tubular atrophy is increased in high dose males. The changes are more severe in degree and mostly bilateral, whereas in the remaining groups unilateral changes are predominant.
The spectrum of findings in several high dose animals observed in the heart, lungs, liver, and kidneys indicates a dysfunction of the cardiovascular and respiratory system, which may be at least partly related to disturbed innervation, especially if the nerve fibers regulating the breathing or those in the autonomic nervous system were affected. This, how ever, could not be demonstrated using the routine histopathologic evaluation. Such findings were, e.g., chronic conges tion of the lungs and kidneys, formation of thrombi in the heart atria in males and females, necrosis, and lymphocytic infiltration of the liver in males. A few female animals of this group also showed further changes which possibly were associated with circulatory and respiratory dysfunction, such as edema of subcutaneous tissue and increased hematopoietic activity in the adrenal glands and bone marrow (observed as hypercellularity).
Some normally occurring, age-related changes appeared to be enhanced in the high-dose group.
They included atrophy of the retina and chronic progressive nephropathy in both sexes and hemosiderosis of spleen and adrenals in males.
Histopathological findings: neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
Neoplastic changes: The 12-month interim examination revealed no neoplastic changes. Once more, the shorter survival time of the animals of the high dose group must be taken into account in the analysis of neoplasms. This is especially relevant for a number of tumors increasing sharply with older age.
The number of animals with tumors according to whether the animals died spontaneously or were sacrificed in moribund states, at scheduled necropsy, and for all animals indicate neither a dose-dependent difference in the total number of animals with tumors nor in tumor-bearing animals euthanized or dying during treatment or euthanized on schedule.
The number of animals with more than one tumor was likewise not affected by treatment.
Details on results:
The tumor incidence, time of occurrence, spectrum of types, and localizations provided no indication of any relationship to treatment in the dose range investigated. Owing to the earlier termination of the high-dose group, a definitive statement about a potential carcinogenic effect of TMPO at in the highdose level appears somewhat limited. However, the survival-adjusted statistical analyses revealed no evidence of carcinogenicity in the 100/50 mg/kg group. Moreover, when the data from this group are compared to historical data from 2-year studies (Bomhard and Rinke, 1994), no evidence of a carcinogenic effect is provided.
Key result
Dose descriptor:
NOAEL
Effect level:
1 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
body weight and weight gain
Key result
Dose descriptor:
NOAEL
Effect level:
10 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
body weight and weight gain
Critical effects observed:
no
Conclusions:
The NOAEL, based on the suppression of body weight gain, is 1 mg/kg in males and 10 mg/kg in females.
The incidence time of occurrence, spectrum of types, and localizations of tumors provided no indication of a tumorigenic/carcinogenic effect of the test substance. TMP is therefore considered not to be carcinogenic in Wistar rats under the conditions of that study.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
1 mg/kg bw/day
Study duration:
chronic
Species:
rat
Quality of whole database:
comparable to guideline study with acceptable restrictions
reliability 2

Additional information

Justification for classification or non-classification