Mecoprop

Carcinogenicity

Description of key information

Under the conditions of the study the 24-month administration of the test material led to a dose-dependent increase in the kidney weights of the male rats of the 100 and 400 ppm groups, while the kidney weights of the female animals remained uninfluenced. This shows that the male rats responded clearly more sensitively to the test material administered than did the female animals.

The findings obtained confirm the results of the 90-day study on the test material in rats, where increased kidney weights could be seen in the animals of the 450 and 150 ppm groups. In this former study the effects were also more distinct in the male than in the female rats. 

The administration of the test material over a period of 24 months at a dose level of 20 ppm did not lead to any test material-induced changes. Due to the present test results a carcinogenic potential of the test material is to be ruled out.

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:

16 May 1984 to 12 June 1986

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Original study report only partly available, but sufficient data are contained in this part, and moreover secondary source (Danish EPA) assesses study as reliable, therefore at least rel. 2 is warranted.

Qualifier:

according to guideline

Guideline:

OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)

Version / remarks:

(1981)

Deviations:

yes

Remarks:

, use of two satellite groups of 10 and 15 rats/sex at each dose level for 12 and 24 months, respectively, whereas testing guideline of 1981 stipulates only one high dose satellite group of 20 animals/sex - but no conflict to testing guideline of 2009.

GLP compliance:

yes

Species:

rat

Strain:

Wistar

Remarks:

Chbb = THOM (SPF)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: 42 days
- Weight at study initiation:
Main groups: Males 167 g (141 g - 192 g); females 136 g (120 g - 156 g)
Satellite group I: Males 164 (14-183); females 135 g (111 g - 149 g)
- Housing: During the test, the rats were housed individually in type DK III stainless steel wire cages, floor area about 900 cm^2 (Becker & CO, Castrop-Rauxel, Germany).
- Diet: Ad libitum
- Water: Ad libitum
- Acclimation period: 14 days acclimatisation period during which they received ground diet and water ad libitum and were accustomed to the environmental conditions.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24 °C
- Humidity (%): 30 - 70 % relative humidity
- Air changes (per hr): No data (completely air conditioned rooms).
- Photoperiod (hrs dark / hrs light): The day/night rhythm was 12 hours (12 hours light from 06:00 - 18:00 h, 12 hours dark from 18:00 - 6:00 h).

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Remarks:

Diet pre-mix used

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: To prepare the test material preparations, the test material was weighed out depending on the dose group, and thoroughly mixed with a small amount of the feed in a beaker, using a spatula. The premix was subsequently prepared, initially in a BRAUN mixer (Mx 32) and further in the study also in a BOSCH household mixer. This premix was then adjusted to the required concentration by adding the appropriate amount of feed and was mixed in a laboratory mixer supplied by GEBR. LÖDIGE, for about 10 minutes.

DIET PREPARATION
- Rate of preparation of diet: The feed/substance mix was freshly prepared at intervals of not more than 24 days. The stability of the test material in the feed was verified for a period of 33 days.
- Mixing appropriate amounts with (Type of food): Kliba rats/mice/hamsters maintenance diet.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The stability of the test material in the maintenance diet was analytically investigated before the study began. To verify homogeneity of the test material preparations, samples were sent to the Analytical Laboratory before the start of the study and than again in the initial phase of the administration period after the mixing procedure had been optimised (additional premix).
Furthermore, samples of each one of the doses were sent to the analytical laboratory at the beginning of the study and thereafter at 3-monthly intervals.
The content of the test material in the feed/test material mixes was determined by means of HPLC.

Duration of treatment / exposure:

24 months

Frequency of treatment:

Continuously in diet

Post exposure period:

None

Dose / conc.:

20 ppm (nominal)

Dose / conc.:

100 ppm (nominal)

Dose / conc.:

400 ppm (nominal)

No. of animals per sex per dose:

Main group: 50 per sex per dose.
Satellite group I: 10 per sex per dose level was dosed for 12 months.
Satellite group II: 15 per sex per dose level was dosed for 24 months.

Control animals:

yes, plain diet

Details on study design:

- Dose selection rationale: The selection of the doses was based on the results of a 3-month feeding study with the test material in rats. In this study, dosages of 450, 150 and 50 ppm were used. The following test material-related findings were obtained:
450 ppm: Increase in the creatinine values in the plasma of the female animals; increase in the absolute and relative kidney weights in the male animals.
150 ppm: Increase in the absolute and relative kidney weights in the males; increase in the relative kidney weights in the females.
50 ppm: No changes to be attributable to the test material administration.
On the basis of the above findings, the following dose levels were fixed for the current study on a potential carcinogenic and chronic-toxic effect:
20 ppm as a definite no effect level; 100 ppm was chosen as the intermediate dose and 400 ppm as the highest dose.
Marginal toxic effects on administration of 400 ppm could probably be expected, however, without any adverse effect on the normal lifespan.
- Rationale for animal assignment: 12 days prior to the start of administration (day 0), the male and female rats were allocated to the test groups on the basis of their weights. The list of randomisation instructions was generated by a computer.
- Rationale for selecting satellite groups:
Main group: Determination of the body weight and feed consumption up to 24 months, urinalysis at the end of the study, subsequently necropsy.
Satelite group I: Determination of the body weight and feed consumption up to 12 months, urinalyses. hormone analyses (T3/T4), interim sacrifice after 12 months.
Satelite group II: Clinico-chemical and haematological examinations, necropsy after 24 months.
- Post-exposure recovery period in satellite groups: No.

Positive control:

None

Observations and examinations performed and frequency:

CLINICAL OBSERVATIONS: Yes
- Time schedule: The state of health was checked daily; furthermore, the animals were subjected to additional inspection and palpation once a week. A check for mortality was made twice daily (Mondays to Fridays) and once daily (Saturdays, Sundays and public holidays).

BODY WEIGHT: Yes
- Time schedule for examinations: The animals of the main groups and satellite group I were weighed once a week, including week 14 of the administration; subsequently, body weight was determined at 4-weekly intervals. The body weights were determined on the same day of the week each time. There was an additional determination of the amount of feed consumed and of the body weight, which took place at the end of the study outside the 4-weekly cycle (satellite group I and main groups).

FOOD CONSUMPTION AND COMPOUND INTAKE: Yes
- Time schedule for examinations: For animals of main group and satellite group I once a week up to 14 weeks and thereafter once a month until the end of the study. The mean amount of daily ingested test material (in mg) per kg body weight was determined at the same intervals as was feed consumption.
To determine the amount of feed consumed, the feed box with contents was weighed and the value obtained was subtracted from the initial value.
The feed consumption of the main groups and satellite group I was weighed once a week, including week 14 of administration, for the course of the preceding week; subsequently it was determined at 4-weekly intervals.
The mean amount of daily ingested test material (in mg) per kg body weight was determined at the same intervals as was feed consumption.
The values given represent a group mean calculated from the amounts of test material ingested by each individual animal, and were determined using the formula:

(FC x D) / BWx

Where:
FC = Mean daily feed consumption (in g) within one week of the study (from day x-7 to day x)
D = Dose in ppm
BWx = Mean bodyweight (in g) on day x of the study

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: The eyes of the animals in the main groups (control, and highest dose group) were examined for changes to the refracting media using a focusable hand-held slit lamp before the start of the study and after about 6 and 12 months. Further eye examinations were carried out after about 18 months and at the end of the study in each of the first 10 of the surviving animals of both sexes in the control and highest dose group, using a hand-held slit lamp. If changes to the refracting media had either been expected or existed, photographs would have been taken where necessary, using a KOWA camera.
During examinations of the eyes before the start of the study and after about 12 months of the study, the fundus of 10 male and 10 female rats of the control and highest dose

HAEMATOLOGY: Yes
- Time schedule for collection of blood: The blood required was taken from the retroorbital venous plexus of the non-fasted animals in the mornings. The blood samplings and the subsequent analysis of the blood and plasma samples - except for the differential blood counts and the reticulocytes - were carried out in randomised sequence 6 days before the test material was administered (acclimatisation period; blood sampling 0) and about 26, 52, 78, and 104 weeks after the start of the administration (administration period; blood samplings 1, 2, 3, and 4). The lists of randomisation instructions were generated with a random number generator on a computer.
The haematological examinations were carried out before and during the administration period in 15 animals per test group and sex (satellite group II). For blood sampling 4, the animals that died in satellite group II were supplemented to 15 animals per test group and sex by adding main group animals. For the hormone analyses, blood was taken after 52 weeks from 10 animals per group and sex of satellite group I.
- Parameters checked: Haemoglobin, erythrocytes, haematocrit, mean haemoglobin content per erythrocyte, mean cell volume, mean corpuscular haemoglobin concentration, platelets, leukocytes, differential blood count, reticulocytes, prothrombin time.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: The blood required was taken from the retroorbital venous plexus of the non-fasted animals in the mornings. The blood samplings and the subsequent analysis of the blood and plasma samples - except for the differential blood counts and the reticulocytes - were carried out in randomised sequence 6 days before the test material was administered (acclimatisation period; blood sampling 0) and about 26, 52, 78, and 104 weeks after the start of the administration (administration period; blood samplings 1, 2, 3, and 4). The lists of randomisation instructions were generated with a random number generator on a computer.
The clinico-chemical examinations were carried out before and during the administration period in 15 animals per test group and sex (satellite group II). For blood sampling 4, the animals that died in satellite group II were supplemented to 15 animals per test group and sex by adding main group animals. For the hormone analyses, blood was taken after 52 weeks from 10 animals per group and sex of satellite group I.
- Parameters checked: Total bilirubin, creatinine, urea, sodium, potassium, glucose, inorganic phosphate, calcium, chloride, triglycerides, total cholesterol, total protein, albumin, globulins, glutamic-pyruvic transaminase, glutamic-oxalacetic transaminase, alkaline phosphatase, triiodothyronine (T 3), thyroxine (T 4).

URINALYSIS: Yes
- Time schedule for collection of urine: The urine of each individual animal was collected overnight from the satellite group I animals about 26 and 52 weeks after the administration began (administration period: Urine collections 1 and 2) and from 10 animals per group of the main group animals about 104 weeks after the administration began (administration period; urine colleection 3).
- Parameters checked: pH, protein, glucose, ketones, bilirubin, blood, nitrite, urobilinogen, sediment.
Except sediment microscopy, all the urine constituents were determined semi-quantitatively with test strips and a reflection photometer. The sediment was evaluated under a microscope.

Sacrifice and pathology:

The rats that survived in satellite groups I were killed at the end of the 12-month administration period and the surviving main and satellite groups II rats at the end of the 24-month administration period after a fasting period (Satellite group I; withdrawal of feed and water, Satellite group II and main group withdrawal of feed).
The animals that survived in satellite group I were subject to an interim kill after about 52 weeks; the rats surviving in the main group and satellite group II were sacrificed after about 104 weeks.

GROSS PATHOLOGY: Yes, all animals
HISTOPATHOLOGY: Yes

Statistics:

Clinical examinations: For the statistical evaluation of the test, means and standard deviation were calculated for the variables feed consumption, body weight and test material intake for the animals in each test group. Statistical significance of the clinical data (body weight) was determined by analysis of variance (ANOVA) followed by a Dunnett's test.

Blood and plasma examinations: Following statistical adjustment (NALIMOV criterion), the means and standard errors were calculated and have been printed out in the tables together with the individual figures.
For judging the significance, the t test (with the exception of the differential blood count) was used to compare the individual dose groups both with the control group and with their corresponding intitial values (blood sampling 0).

Urinalyses
The assessment as to whether specific features are pronounced to various extents in the control and test groups was carried out by the chi^2 test in corresponding two-by-two contingency tables.

Clinical signs:

effects observed, non-treatment-related

Description (incidence and severity):

The three doses (20, 100 and 400 ppm) administered as addition to the diet did not lead to any disturbances the general state of health of any one of the animals participating in the test. As the duration of the test increased, findings such as decubitus in the tarsal region or alopecia, etc., became more frequent in the animals used. The changes are spontaneous ones, also regularly to be found in untreated older rats.

Dermal irritation (if dermal study):

not examined

Mortality:

no mortality observed

Description (incidence):

The mortality of the male and female animals was not influenced by the administration of the test material.

Body weight and weight changes:

effects observed, non-treatment-related

Description (incidence and severity):

The body weight of the male and female animals of all doses in the main groups as well as that of the females in satellite group I was comparable to that of the control animals.
There was a significant reduction in body weight between days 154 and 364 in the satellite group I male rats dosed 20 and 100 ppm; a dose-response relationship was not seen, and hence the reduction was assessed as being incidental in nature.

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

The amount of feed consumed daily by the male and female animals of all dose groups (20, 100, and 400 ppm) in the main groups and satellite group I during the specific duration of the study did not differ substantially when compared to the untreated control rats.
The amounts of test material taken up (mg/kg body weight) each day by the animals in the specific dose groups corresponded to the dose factor chosen. The mean amounts (in mg/kg body weight) of test material taken up in the course of the study are:
20 ppm main group males: 1.1 mg/kg bodyweight.
20 ppm satellite group 1 males: 1.3 mg/kg bodyweight.
20 ppm main group females: 1.4 mg/kg bodyweight.
20 ppm satellite group 1 females: 1.6 mg/kg bodyweight.
100 ppm main group males: 5.5 mg/kg bodyweight.
100 ppm satellite group 1 males: 6.5 mg/kg bodyweight.
100 ppm main group females: 6.9 mg/kg bodyweight.
100 ppm satellite group 1 females: 7.9 mg/kg bodyweight.
400 ppm main group males: 22.2 mg/kg bodyweight.
400 ppm satellite group 1 males: 26.1 mg/kg bodyweight.
400 ppm main group females: 27.9 mg/kg bodyweight.
400 ppm satellite group 1 females: 31.8 mg/kg bodyweight.

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

effects observed, non-treatment-related

Description (incidence and severity):

The ophthalmological examinations carried out with of a hand-held slit lamp before the start of the test and subsequently every 6 months showed no test material-induced impairment of the refracting media.
At no time was there any difference between the treated and untreated rats in terms of frequency distribution of the corneal findings in the form of remainders of the pupillary membrane or isolated corneal stipplings. Incidentally, these changes are frequently to be found in untreated Wistar rats. The examination with a KOWA camera carried out before the start of the test and after about 12 months showed no changes in the eye fundus.

Haematological findings:

effects observed, non-treatment-related

Description (incidence and severity):

From the haematology point of view, the 24-month administration of the test material to male and female rats in doses of 20, 100, and 400 ppm did not cause any changes that could be ascribed to the test material administered.
The significant differences from the control group are not regarded as being related to the test material. Plausibility criteria have been introduced in order to avoid a detailed assessment and discussion of each individual statistically significant difference for each parameter.
The purpose of these criteria is to give all the reasons why there is no relation to administration of the test material, or why such a relation is improbable.

Clinical biochemistry findings:

effects observed, non-treatment-related

Description (incidence and severity):

From the clinical chemistry point of view, the 24-month administration of the test material to male and female rats in doses of 20, 100, and 400 ppm did not cause any changes that could be ascribed to the test material administered.
The significant differences from the control group are not regarded as being related to the test material. Plausibility criteria have been introduced in order to avoid a detailed assessment and discussion of each individual statistically significant difference for each parameter.
The purpose of these criteria is to give all the reasons why there is no relation to administration of the test material, or why such a relation is improbable.

Urinalysis findings:

not specified

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

400 ppm: Significant increase in the relative kidney weights of the male rats of satellite group I and significant increase in the absolute and relative kidney weights of the males of the main group and satellite group II.
100 ppm: Significant increase in the relative kidney weights of the male rats of satellite group I and significant increase in the absolute kidney weights of the males of the main group and satellite group II.
20 ppm: No changes whatsoever that could be associated with the test material administered.

The 24-month administration of the test material therefore showed a dose-dependent increase in the kidney weights of the male rats of the 100 and 400 ppm groups, while the kidney weights of the female animals remained uninfluenced.

Gross pathological findings:

not specified

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Dose descriptor:

NOAEL

Effect level:

400 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No indications for carcinogenicity found up to the highest dose group (400 ppm).

Dose descriptor:

NOAEL

Effect level:

20 ppm

Based on:

test mat.

Sex:

male

Basis for effect level:

organ weights and organ / body weight ratios

Dose descriptor:

NOAEL

Effect level:

400 ppm

Based on:

test mat.

Sex:

female

Basis for effect level:

other: No adverse effects observed at highest dose level tested.

Critical effects observed:

not specified

Treatment related changes in organ weights:

	0 ppm (m/f)	20 ppm (m/f)	100 ppm (m/f)	400 ppm (m/f)
Dose, mg/ kg bw/day*	-/-	1.1/1.4	5.5/6.9	22.2/27.9
kidney weight, g	3.80/2.69	3.83/2.77	4.07^#/1.97	4.31^##/2.82
relative kidney weight, g	0.60/0.76	0.61/0.74	0.62/0.76	0.66^##/0.77

*: calculated for the main group       ^#and^##: 5% and 1% significance level (Dunnett's test)

Analyses

- Analysis of the test material: The active ingredient content of the test material was determined before the start of the study, after about 19 months, and at the end of the study.

The active ingredient content was 92.7 % before the beginning of the study. The stability of the test material was verified after 19 months by the analytical results and at the end of the study HPLC yielded 91.9 % and the gas chromatographic method yielded a content of 94.9 %. In accordance with the study protocol, after one year the test material samples were sent for reanalysis; however, no results were passed on. This is of subordinate significance, since, as it had been expected, the stability of the test material was confirmed by analysis at the end of the test.

The homogeneity of the test material was confirmed analytically before the start of the test.

The technical active ingredient was subjected. to a storage test, which after 2 years of storage at room temperature, at 30, 40, and 50 °C showed that its degree of purity had not declined.

Analysis of the test material preparations: In the analysis of the samples drawn before the start of the study, the homogeneity of the test material preparations could not be unambiguously verified; therefore, new samples were analysed. The results of these investigations confirm the homogeneous distribution of the test material in the vehicle.

The stability of the test material in the maintenance diet over 33 days was demonstrated at the start of study.

- Analysis of feed: The feed was regarded as suitable on the basis of the duration of use and the results of the tests for contaminants. The guideline for maximum tolerable contaminants was the Proposed Guidelines of EPA of May 9, 1979, Fed. Reg. Vol. 44, No. 91, p. 27354.

Only the copper values were found to have dropped; they were however acceptable since they were within the range of error expected with this method of determination.

- Analysis of drinking water: The drinking water used was regarded as suitable on the basis of the results obtained.

Conclusions:

Under the conditions of the study the administration of the test material over a period of 24 months at a dose level of 20 ppm did not lead to any test material-induced changes. Due to the present test results a carcinogenic potential of the test material is to be ruled out.
A dose-dependent increase in the kidney weights of the male rats of the 100 and 400 ppm groups was observed, while the kidney weights of the female animals remained uninfluenced.
 

Executive summary:

The carcinogenicity of the test material was assessed according to OECD Test Guideline 453 and in compliance with GLP.

Three different doses (20, 100 and 400 ppm) of the test material were administered with the diet to 450 Wistar rats (225 males and 225 females) for 24 months.

Each dose group was split up into a main group (50 animals per sex) and into the satellite groups I and II comprising 10 and 15 animals per sex respectively.

A group of untreated animals (75 males and 75 females) was maintained in parallel for comparison. It was likewise split into a main group and satellite groups I and II. The feed consumption and body weight of the animals in the main group and of satellite group I was determined once a week up to 14 weeks and thereafter once a month until the end of the study. The state of health of all animals was checked daily; furthermore, the animals were subjected to additional inspection and palpation once a week.

At the beginning of the study and then about every 6 months, animals of the main groups (control and highest dose) were examined ophthalmologically.

Blood samples for haematological and clinico-chemical examinations were taken five times altogether from the animals of the satellite group II (at the last blood sampling, dead animals in this satellite group were supplemented by animals of the main groups).

Urinalyses were carried out on the animals of satellite group I two times in the first year, and on 10 animals of each main group about 104 weeks after the beginning of the administration period.

The animals that survived in satellite group I were subject to an interim kill after about 52 weeks; the rats surviving in the main group and satellite group II were sacrificed after about 104 weeks.

All animals used ware assessed by gross pathology. This was followed by a comprehensive histopathological examination.

The following findings were obtained and assessed or discussed to be test material-related:

400 ppm: Significant increase in the relative kidney weights of the male rats of satellite group I and significant increase in the absolute and relative kidney weights of the males of the main group and satellite group II.

100 ppm: Significant increase in the relative kidney weights of the male rats of satellite group I and significant increase in the absolute kidney weights of the males of the main group and satellite group II.

20 ppm: No changes whatsoever that could be associated with the test material administered.

 

Under the conditions of the study the 24-month administration of the test material led to a dose-dependent increase in the kidney weights of the male rats of the 100 and 400 ppm groups, while the kidney weights of the female animals remained uninfluenced. This shows that the male rats responded clearly more sensitively to the test material administered than did the female animals.

The findings obtained confirm the results of the 90-day study on the test material in rats, where increased kidney weights could be seen in the animals of the 450 and 150 ppm groups. In this former study the effects were also more distinct in the male than in the female rats. 

The administration of the test material over a period of 24 months at a dose level of 20 ppm did not lead to any test material-induced changes. Due to the present test results a carcinogenic potential of the test material is to be ruled out.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Study duration:

chronic

Species:

rat

Quality of whole database:

Single study conducted according to standardised guidelines and in compliance with GLP.

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

In accordance with the criteria for classification as defined in Annex I, Regulation (EC) No 1272/2008, the material does not require classification with respect to carcinogenicity.

Additional information

The carcinogenicity of the test material was assessed according to OECD Test Guideline 453 and in compliance with GLP. The study was awarded a reliability score of 2 in accordance with the criteria set forth by Klimisch et al. (1997).

Three different doses (20, 100 and 400 ppm) of the test material were administered with the diet to 450 Wistar rats (225 males and 225 females) for 24 months.

Each dose group was split up into a main group (50 animals per sex) and into the satellite groups I and II comprising 10 and 15 animals per sex respectively.

A group of untreated animals (75 males and 75 females) was maintained in parallel for comparison. It was likewise split into a main group and satellite groups I and II. The feed consumption and body weight of the animals in the main group and of satellite group I was determined once a week up to 14 weeks and thereafter once a month until the end of the study. The state of health of all animals was checked daily; furthermore, the animals were subjected to additional inspection and palpation once a week.

At the beginning of the study and then about every 6 months, animals of the main groups (control and highest dose) were examined ophthalmologically.

Blood samples for haematological and clinico-chemical examinations were taken five times altogether from the animals of the satellite group II (at the last blood sampling, dead animals in this satellite group were supplemented by animals of the main groups).

Urinalyses were carried out on the animals of satellite group I two times in the first year, and on 10 animals of each main group about 104 weeks after the beginning of the administration period.

The animals that survived in satellite group I were subject to an interim kill after about 52 weeks; the rats surviving in the main group and satellite group II were sacrificed after about 104 weeks.

All animals used ware assessed by gross pathology. This was followed by a comprehensive histopathological examination.

The following findings were obtained and assessed or discussed to be test material-related:

400 ppm: Significant increase in the relative kidney weights of the male rats of satellite group I and significant increase in the absolute and relative kidney weights of the males of the main group and satellite group II.

100 ppm: Significant increase in the relative kidney weights of the male rats of satellite group I and significant increase in the absolute kidney weights of the males of the main group and satellite group II.

20 ppm: No changes whatsoever that could be associated with the test material administered.

 

Under the conditions of the study the 24-month administration of the test material led to a dose-dependent increase in the kidney weights of the male rats of the 100 and 400 ppm groups, while the kidney weights of the female animals remained uninfluenced. This shows that the male rats responded clearly more sensitively to the test material administered than did the female animals.

The findings obtained confirm the results of the 90-day study on the test material in rats, where increased kidney weights could be seen in the animals of the 450 and 150 ppm groups. In this former study the effects were also more distinct in the male than in the female rats. 

The administration of the test material over a period of 24 months at a dose level of 20 ppm did not lead to any test material-induced changes. Due to the present test results a carcinogenic potential of the test material is to be ruled out.