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Toxicological information

Repeated dose toxicity: dermal

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Administrative data

short-term repeated dose toxicity: dermal
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
October 1987 - November 1987
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference Type:
study report
Report date:

Materials and methods

Test guidelineopen allclose all
according to guideline
OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)
Version / remarks:
according to guideline
EPA OPP 82-2 (Repeated Dose Dermal Toxicity -21/28 Days)
Version / remarks:
GLP compliance:
yes (incl. QA statement)

Test material

Constituent 1
Chemical structure
Reference substance name:
EC Number:
EC Name:
Cas Number:
Molecular formula:
Test material form:
solid: particulate/powder

Test animals

New Zealand White
Details on species / strain selection:
Details on test animals or test system and environmental conditions:
Only healthy, symptom-free animals were used for the study. At the start of the study, the male animals exhibited a mean initial weight of 2.92 (2.64 - 3.23) kg, and the females of 2.75 (2.31 - 3.10) kg. Based on these body weights, the age of the animals was around 13 and 11 weeks, respectively.
Animal housing: During the adaptation and study periods, the animals were individually kept under conventional conditions in Cellidor rabbit cages. Following a study duration of three weeks in standard metal cages. The stool trays located beneath the cages were changed twice weekly. During the six-hour exposure periods, the animals were confined in restraining racks. These prevented the formulation from being rubbed off and orally ingested. All animals used in this study were housed in one animal room during the adaptation, study and post-exposure observation periods. The room was changed in the fourth week of the study for procedural reasons.

Room climate conditions:
The room climate was set as follows.
Room temperature : 22 ± 2° C
Humidity (relative) : about 50%
Light/dark cycles : 12 hours; artificial lighting from 6.00 to 18.00 hours Central European Time
Air exchanges : About 10 times per hour.

Occasional deviations from these standards took place, for example due to cleaning of the animal room. They had no apparent effect on the course of the study.

Feeding: The food consisted of "Ssniff K Sole Diet for Rabbits" produced by Flange Kraftfutterwerk GmbH in Soest, and of tap water from watering bottles. Water was available for unlimited consumption. The food was provided to the animals each day from automatic rabbit food dispensers.

Administration / exposure

Type of coverage:
physiological saline
The test substance was formulated with 2 % v/v Cremophor EL in sterile physiological saline solution prior to each treatment.
Details on exposure:
The fur of the back and flanks of all rabbits was shaved off 48 hours before initiating treatment. The hair which grew back during the study was shaved off the skin areas marked for treatment twice weekly. Once daily on 15 consecutive working days (five times per week), the test substance formulations were applied to four-ply gauze patches with syringes; the patches were fixed to the dorsal and flank skin of the experimental animals using Fixomull-stretch, and allowed to remain there for a period of six hours. The application volume for each concentration was 2 ml/kg body weight. The treatment area measured 11 x 12 cm. The treated skin areas were cleaned with soap and water at the conclusion of each exposure. The rabbits were confined in restraining racks and additionally immobilized by a rubber sleeve during the exposure period to keep the occlusive dressings tight and prevent the animals from gnawing on them. No food or water were provided to the rabbits during this time. This treatment method is used to determine the local and systemic tolerance of the test substance following repeated dermal exposure to estimate the risk to humans in cases of repeated dermal contact with the test substance.
Analytical verification of doses or concentrations:
Details on analytical verification of doses or concentrations:
The homogeneity and stability of the test substance in the treatment medium were examined before initiating the study. The concentration of the test item was verified analytically.
Duration of treatment / exposure:
The test substance was applied once daily on 15 consecutive working days (five times per week).
Doses / concentrationsopen allclose all
Dose / conc.:
100 mg/kg bw/day
Dose / conc.:
300 mg/kg bw/day
Dose / conc.:
1 000 mg/kg bw/day
No. of animals per sex per dose:
Five additional animals per sex were used to monitor the reversibility of the treatment (two-week recovery phase after concluding the application) in the control and the highest dose groups.
Control animals:
yes, concurrent vehicle
Details on study design:
The post-observation period was 2 weeks.


Observations and examinations performed and frequency:
General examinations: The appearance and behavior of the animals were monitored at least once daily during the study and post-exposure observation periods.

Food consumption: The food intakes of the individual animals were determined once weekly from the difference in the weight of food provided and that of the unconsumed food. The mean individual food intakes and their standard deviations were calculated for each group from these primary food intake data.

Body weights: The body weights of the animals were determined by weighing them before initiating the study and at the start of each study week.

Testing for local skin tolerance: The treated skin areas were inspected for inflammation reactions (redness and swelling) before initiating the study and 24 hours after each treatment.

Laboratory tests: Laboratory tests were performed on blood samples taken from all animals before initiating treatment, and samples taken from all survivors following the three-week treatment period (24 hours after the last exposure) and at the end of the two-week post-exposure observation period.

Hematological examinations: The following specific tests were performed. Erythrocyte and leucocyte counts, reticulocyte count, Heinz inclusion bodies, hemoglobin, hematocrit, thrombocyte count, mean corpuscular erythrocyte volume, mean cell hemoglobin content of erythrocytes.

Sacrifice and pathology:
48 to 72 hours after the last treatment, and at the end of the two-week post-exposure observation period, the appropriate groups of rabbits were sacrificed by exsanguination under deep anesthesia.
Other examinations:
Clinical chemistry:

Blood: Aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase, urea, blood sugar, creatinine, bilirupin, DPD method, total protein, inorganic phosphate, sodium, potassium and calcium, chloride.

Liver tissue: N-demethylase, O-demethylase, cytochrome P-450, Triglycerides.

Organ weights: Organs of sacrificed animals were weighed.
The arithmetic group means, standard deviations, and upper and lower confidence limits at confidence levels were calculated from the body weights, dermal findings, medical laboratory tests and organ weights, and the test cohort results compared with those for the control cohort using the significance test (two-tailed U test) of Mann and Whitney and Wilcoxon at significance levels of a = 5 % and a = 1 %. Significant differences relative to the control group are marked with a "+" for p < 0.05 and with "++" for p < 0.01 in the mean figure tables located in the results section.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Description (incidence and severity):
The appearance, behaviour and mortality were unaffected in all dose groups. No delayed effects were observed.
Dermal irritation:
no effects observed
no mortality observed
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Body weight development was unaffected in all dose groups.
Food consumption and compound intake (if feeding study):
no effects observed
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
Several hematological parameters - such as the erythrocyte count, the hematocrit and hemoglobin values, and the reticulocyte count in male animals; and the MCHC value in the females - differed from the control figures to a statistically significant extent at the start of the study. Since these differences were distributed throughout various groups, were not large, and also lay within the reference range, they represent normal biological scattering, and no significance is attached to them.

In the 1000 mg/kg b.w. group, the erythrocyte and reticulocyte counts as well as the hematocrit and hemoglobin values (both sexes), and the MCHC value (males only) differed from those of the controls to a statistically significant extent at the end of the treatment period. The reticulocyte counts were higher and the values of the other parameters lower than in the controls. The elevated Heinz body count in the males of this group is due to the high figure obtained for a male. In the 100 mg/kg b.w. group, the erythrocyte counts as well as the hematocrit and hemoglobin values were depressed in male animals and elevated in females, and the thrombocyte counts were depressed (females only); the deviations were independent of the dose but statistically significant.

All other values are within the reference range for this strain of animals except for the reticulocyte count and hemoglobin concentration parameters, where several results lay outside the range. The differential blood count in the dose groups underwent no treatment-related effect relative to the controls. One normoblast was found in each of two 1000 mg/kg b.w. group males, one at the start of the study, and one after 21 days. The hematology test results are compiled as mean figures in the Tables 4 and 5, "Overall remarks, attachments section".
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
The results determined for the dose groups at the onset of the study exhibited no significant differences relative to the controls in any of the parameters examined. At the end of the treatment period, the test results for male animals showed no significant differences relative to the controls.

The ALAT activities were higher in the 1000 mg/kg b.w. females. Except in two animals, the individual values lay within the reference range. ALAT activities of both animals lay at the upper limit of the 2a range even before the study was initiated. However, no toxicological significance is thus attached to these elevated figures, especially since no further correlatives for hepatic damage were present.

The N- and O-demethylase activities, the cytochrome P-450 level and the content of triglycerides in the liver tissue were examined. The results show that no significant induction of the microsomal enzyme systems examined resulted from the treatment, and no biologically relevant differences between the treated and control animals were present.

In addition, no toxicological significance is attached to the elevated concentrations of the P-450 system.
Urinalysis findings:
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Distinctly swollen spleen was observed at 300 and 1000 mg/kg bw.
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
300 mg/kg bw: engorgement and pronounced hemosiderosis in the spleen
1000 mg/kg bw: engorgement and pronounced hemosiderosis in the spleen
The effect was reversible after the 14 days post-treatment observation period.
Other effects:
no effects observed
Description (incidence and severity):
Macroscopic assessment of the skin in the vicinity of the treatment area showed no redness in the animals of any group. The skinfold measurement results similarly showed no significant alterations in any of the groups. The treatment area was partially squamous in one animal.

Effect levels

Key result
Dose descriptor:
Effect level:
100 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
histopathology: neoplastic

Target system / organ toxicity

Key result
Critical effects observed:
Lowest effective dose / conc.:
300 mg/kg bw/day
Treatment related:
Dose response relationship:
Relevant for humans:

Applicant's summary and conclusion

Based on the results of a 3-week dermal rabbit study at dose levels of 100, 300 and 1000 mg/kg bw/d, the NOAEL was concluded to be 100 mg/kg bw/d, based findings consistent with haemolysis at higher dose levels.
Executive summary:

The local and systemic toleration of the test substance triflumuron by rabbits with intact skin was tested in a three-week subacute dermal toxicity study with a two-week recovery period. The test substance was formulated with 2 % v/v Cremophor EL in sterile physiological saline solution, and doses as specified below in an application volume of 2 ml/kg body weight applied to the shorn dorsal and flank skin on each of 15 consecutive working days (five days per week); the dose was then allowed to remain in contact with the skin for a period of six hours. The dose groups were 0, 100, 300 and 1000 mg/kg bw/d. The treatment was tolerated without symptoms by all groups. In none of the dose groups did the body weight development of the animals differ significantly from that of the controls. Neither the clinical chemistry, haematology and organ weight tests which were performed, nor the macroscopic and microscopic assessments of the internal organs afforded any results which could speak for treatment-related effects or damage in the groups exposed to doses up to and including 100 mg/kg bw/d. An effect on the red blood count was observed in the haematology results at 1000 mg/kg bw/d, and was confirmed by splenic alterations. Splenic alterations were also observed at 300 mg/kg bw/d. A slight effect on the red blood count was still apparent in the haematology at the end of the recovery phase, whereas histopathological correlates were no longer observed. No test substance-related local skin reactions were observed. The NOAEL for this study was therefore 100 mg/kg bw/d.