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Diss Factsheets

Administrative data

short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1988-08-09 to 1988-10-04
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study

Data source

Reference Type:
study report
Report date:

Materials and methods

Test guideline
according to guideline
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
GLP compliance:
Limit test:

Test material

Constituent 1
Chemical structure
Reference substance name:
2,3-epoxypropyltrimethylammonium chloride
EC Number:
EC Name:
2,3-epoxypropyltrimethylammonium chloride
Cas Number:
Molecular formula:
N,N,N-trimethyl(oxiran-2-yl)methanaminium chloride
Details on test material:
IUCLID4 Test substance: other TS: 72.57 % Quab 151

Test animals

other: Bor: WISW (SPFCpb)
Details on test animals or test system and environmental conditions:
- Source: Winkelmann Versuchstierzucht GmbH, Borchen, GERMANY
- Age at study initiation: 7 wk
- Weight at study initiation: 142-191 g (m); 105-142 g (f)
- Housing: 1/Macrolon type II cage
- Diet: standard diet ad libitum
- Water: drinking water ad libitum
- Acclimation period: 2 wk

- Temperature (°C): 20.5-22.5
- Humidity (%): 40-65
- Photoperiod (hrs dark / hrs light): 12 h/12 h

Administration / exposure

Route of administration:
oral: gavage
physiological saline
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: prepared daily. Stabliity and homogeneity not determined.
Analytical verification of doses or concentrations:
Duration of treatment / exposure:
28 days
Frequency of treatment:
1 time daily / 7 days / wk
Doses / concentrations
Doses / Concentrations:
0, 3.16, 10.0, 31.6, 100 mg/kg bw/day
actual ingested
No. of animals per sex per dose:
0, 100 mg/kg bw/day: 10
3.16, 10, 31.6 mg/kg bw/day: 5
Control animals:
yes, concurrent vehicle
Details on study design:
Post-exposure period: 28 days (control and high dose group)
Positive control:


Observations and examinations performed and frequency:
- Time schedule: 2x daily

- Time schedule: daily

- Time schedule for examinations: weekly

- daily


HAEMATOLOGY: Yes (see table 1)
- Time schedule for collection of blood: wk 4 and 8
- Anaesthetic used for blood collection: Yes (CO2)

CLINICAL CHEMISTRY: Yes (see table 1)
- Time schedule for collection of blood: wk 4 and 8

- Time schedule for collection of urine: wk 4 and 8

- Time schedule for examinations: wk 0, 4
pain, pinna nd corneal reflexes

Sacrifice and pathology:
See table 2
Body weights, food consumption, and organ weights of each group and sex were compared with the corresponding control values using the DUNNETT-Test. The haematology parameters were evaluated using the DUNNETT- or STEEL-Test. For values of clinical chemistry examinations the DUNNETT -Test was used in case of normal distribution, otherwise the STEEL-Test was employed.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Food efficiency:
not examined
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Details on results:
Most high dose animals exhibited in their clinical picture piloerection and sunken sides. Two females and one male showed disturbed general condition before death or decreased muscle tone. In the high dose group, four females and one male died during the last week of administration. One female was sacrificed moribund at day 16 of treatment. The food consumption decreased in the mid- and high-dose groups. The food consumption dropped to less than 50 % of the controls within two weeks in high dose females and within four weeks in high dose males. Unlike the female rats, who had an almost complete recovery in their food consumption one week after the end of administration, the male recovery returned to normal after seven weeks. In the 31.6 and 100 mg/kg groups, the bodyweight development slowed in parallel with the changes in food consumption. The body weight gain in the 31.6 and 100 mg/kg dose groups was significantly reduced during weeks 2-4 of the treatment period. The body weight in the 100 mg/kg group males at day 28 was about 45% lower than the control group and in the 31.6 mg/kg group at that time the mean weight was about 18% lower and in the 10 mg/kg group a 12 % reduction was noted. The 100 mg/kg dose females had about 38 % lower mean body weight than the control. No significant difference was noted in other groups or in the recovery group. After the recovery period, the male 100 mg/kg recovery group had still about 29% lower mean body weight, when compared to control.
In haematology, both sexes of the 100 mg/kg group had statistically significantly increased red blood cell count (RBCM100: 8%; RBCF100: 11%), haemoglobin content (HbM100: 8%; HbF100: 11%) and relative and absolute monocyte count (MonMctrl: 3, MonM%100: 5; MonFctrl: 2, MonF100: 6). In the males of the 100 mg/kg group, white blood cell count (-32%) and relative (%LymRELCtrlM: 90, %LymREL100M: 80) and absolute (LymABSCtrlM: 11.16, LymREL100M: 6.84) lymphocyte numbers decreased. Males of the 100 mg/kg group had statistically significantly increased number of segmented neutrophils (%NeuSEGCtrlM: 6, %NeuSEG100M: 15). Females additionally exhibited statistically significantly increased haematocrit (15%) and relative lymphocyte counts (%LymRELCtrlF: 92, %LymREL100F: 80) and a decreased platelet count (-14%). The changes in the neutrophil values persisted in males until the end of the recovery period. After the recovery period males exhibited slightly reduced values for erythrocytes, haematocrit, haemoglobin, leucocytes and lymphocytes. In the females of the recovery group, only RBC and Hb figures were significantly reduced.
In clinical chemistry, the males and females of the high dose group had an increase (M: 28%, F: 63%)) in the activity of aspartate aminotransferase (ASAT) and gamma-glutamyltransferase. The males and females of the high dose group also had statistically significantly increased (M: 117 %, F: 667 %) gamma-glutamyltransferase (GGT), and, only in the 10 (31%) and 31.6 (41%) mg/kg group males, an increased alanine aminotransferase (ALT). Male rats of the high dose group had higher chlorine level (99 vs. 96 mmol/l). Alkaline phosphatase (M:-42 %, F:51 %), total protein (M:-9 %, F: 13) were reduced in both sexes of the high dose group. Glucose (-14 %) and cholesterol (-35 %) values were reduced additionally in high dose males. Blood urea was decreased in the high dose males (-28 %) and dose-dependently in all but the lowest dose females (-22 %, -30 % and -42 %). Only females had a reduction in cholinesterase, which was significant in all but the 10 mg/kg dose group. Triglycerides in males of 31.6 mg/kg dose group (-46 %) and in males and females at 100 mg/kg (M:-38 %, F: -34 %) were decreased. Additionally, K+ and Ca2+ -levels of the high dose males (Ca2+ and K+: -7 %) and females (Ca2+: 15 %, K+: 8 %) were statistically significantly reduced. In males, the deviations in clinical chemistry the decrease in blood urea and triglycerides did not return to normal after 8 weeks. In the female recovery group, total protein, blood urea, cholinesterase and albumin levels were significantly reduced at week 8. The authors considered the changes in clinical chemistry parameters as adaptive to exposure and decreased food intake.
In organ weight measurements, male testis (-35-40%) and brain weight (-10 %) were reduced in the high dose group and remained so in the recovery group at week 9. Also the brain to body weight ratio and brain to testis weight ratio were bigger in that group. As stated above, the body weight in the high dose group was about 50% less than that of the control animals. The male absolute liver weight was slightly reduced in the 10 (19 %) mg/kg and 100 mg/kg (50 %) group with no change in the ratio to body weight. The only significant organ weight change that correlated with the administrated dose was found in the heart (Males from low to high dose: -21 %, -26 %, 43 %). In females, the absolute weighs of liver (41 %) and heart (-38 %) were decreased in the high dose group without a change in the ratio to body. Ovary weights were reduced in the 31.6 (~40 %) and 100 mg/kg (max 60 %) groups.
Gross macroscopical examination revealed small spleen and thymus in both sexes of the high dose group than in other groups, which in microscopy was seen as a reduction of lymphatic tissue. The effect on thymus could not be adequately assessed in the intermediate dose groups, as this organ was not taken at necropsy. The uterus of the two highest doses was reduced in size. However, the spleen, thymus or uterus weights were not reported.
In the microscopic observations, the proximal convoluted tubule (PCT) of the kidneys had dose related necrosis and vacuolisation (lipid or fat deposits). In the 3.16 mg/kg dose group 3/5 males had minimal and 2/5 slight vacuolisation. All female rats of the 3.16 mg/kg group had minimal vacuolisation. In the 10 mg/kg dose group, slight vacuolisation was present also in females (3/5). There was one case of minimal necrosis and hyperplasia, both in male rats of the 3.16 mg/kg group. One control male also showed tubular hyperplasia. In the 10 mg/kg group, proximal tubular vacuolisation was minimal in 5/10 and slight in 5/10 animals, minimal necrosis and hyperplasia were present in 7/10 animals. Nuclear polyploidy was present in 7/10 rats and 6/10 of those also had hyperplasia.
The 31.6 mg/kg 7/10 animals of both sexes showed slight to 3/10 moderate vacuolisation of the kidney proximal tubular cells, proximal tubular hyperplasia (minimal in 8/10, slight in 2/10), and polyploid nuclei in the proximal tubules and one case of an abnormal mitotic figure and reduced cellularity of the bone marrow. Minimal PCT-necrosis was present 9/10 animals of this group. Minimal testicular atrophy was observed in 1/5 males and follicular atrophy of the ovaries was observed in 5/5 females (1/5 slight, 2/5 moderate, 4/5 marked). Persistent corpora lutea were reported in 4/5 females (2/5 moderate, 2/5 marked)
In the high dose group, vacuolisation was seen the proximal tubular cells of the kidney of in all animals and graded slight (1/10), moderate (5/10), marked (3/10) or massive (1/10). In the recovery group, the changes were slight in 5/10, moderate in 5/10 animals. Minimal PCT hyperplasia was present in 6/10 animals of the dose group, two of the remaining animals had moderate to marked hyperplasia of the collective tubules and transepithelial cells. In the recovery group PCT hyperplasia (minimal to moderate) was observed in 8/10 animals. Also minimal to moderate nuclear polyploidy was seen in 9/10 dose group and 9/10 recovery group animals. Minimal to moderate necrosis was present in the PCT epithelium of all animals which was noted in the papilla of one male rat as marked.
Testicular atrophy was minimal in 1/5 males, moderate in 1/5 males and marked in 1/5 males of the dose group and minimal, slight or moderate in 1 each of 5 recovery group males. Follicular atrophy of the ovaries was moderate in 2/5, marked in 1/5 and massive in 1/5 females of the dose group and slight in 1/5, marked in 3/5, and massive in 1/5 animals of the recovery group. Persistent corpora lutea were reported in 4/5 females of the dose group (3/5 marked, 1/5 moderate) and 5/5 animals of the recovery group. Two of the recovery group females died after 14 and 16 days of treatment.
In the spleen lymphoid atrophy (minimal 1/5, slight 1/5, moderate 1/5, marked 1/5) was observed in 5/5 males and 4/5 females (1/5 minimal, 1/5 slight, 2/5 marked) of the dose group and the 2/5 females that died premature in the recovery group. None of the animals that survived the recovery period had lymphoid atrophy in the spleen.
The changes in the kidneys and the gonads persisted after the 4-week recovery period (100 mg/kg).
Again, only in the two highest doses, there was a reduction of all cell lines in the bone marrow, which correlated with the white blood cell reduction seen in the haematology. The high dose animals showed occasional maturation disorders, vacuolisation and abnormal mitoses in the bone marrow cells. The changes in the bone marrow, thymus or spleen were reversible after the recovery period.
Some animals of the high dose animals had mild focal hyper- and parakeratosis of the forestomach or mild erosions and haemorrhages in the glandular stomach attributed to the local irritant property of EPTAC. The small intestine of these animals had villous atrophy and crypt necrosis. The changes in the stomach and small intestine were reversible.

Effect levels

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Dose descriptor:
Effect level:
< 3.16 mg/kg bw/day (actual dose received)
Dose descriptor:
Effect level:
3.16 mg/kg bw/day (actual dose received)
Basis for effect level:
other: kidney effects

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

A well reported 4 wk oral study in rats, conducted largely in accordance with the current guideline and GLP, identified kidney effects at the lowest tested dose of 3.16 mg/kg bw/day. The gonads and bone marrow were also identified as the main target organs.