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Diss Factsheets

Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Cross-reference
Reason / purpose for cross-reference:
reference to same study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2012
Report date:
2012

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
Version / remarks:
(1981)
Qualifier:
according to guideline
Guideline:
other: Commission Regulation (EC) No 440/2008 of 30 May 2008
Qualifier:
according to guideline
Guideline:
other: OPPTS 870.4300; Combined Chronic Toxicity/Carcinogenicity (August 1998)
GLP compliance:
yes (incl. QA statement)
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Glyoxal
EC Number:
203-474-9
EC Name:
Glyoxal
Cas Number:
107-22-2
Molecular formula:
C2H2O2
IUPAC Name:
oxalaldehyde
Test material form:
liquid
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: B61 (23.03.09); B61 (01.09.09); B62 (06.02.10); B61 (15.07.10); B61 (05.01.11)

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: room temperature, under N2
- Stability under test conditions: stable

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Strain as described in the report: Crl:WI(Han)
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH, Sandhofer Weg 7, 97633 Sulzfeld
- Age at study initiation: 42 +/- 1 days
- Weight at study initiation: no data
- Fasting period before study: no data
- Housing: 5 animals per cage, in H-Temp (PSU) cages, floor area 610x435x215 mm (TECHNIPLAST, Germany)
- Diet: Ground Kliba mouse/rat maintenance diet “GLP”, meal (Provimi Kliba SA, Kaiseraugst, Switzerland), ad libitum
- Water: Drinking water, ad libitum
- Acclimation period: planned, duration not specified

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 30-70
- Air changes (per hr): 10 air changes per hour
- Photoperiod (hrs dark / hrs light): 12 h/ 12 h
- Any deviations will be documented

ANALYSIS OF FOOD, WATER, BEDDING
- The food used in the study will be assayed for chemical and microbial contaminants according to the Fed. Reg. Vol. 44, No. 91 of May. 09, 1979, p 27354 (EPA);
- The drinking water is regularly assayed for chemical contaminants both by the municipal authorities of Frankenthal and by the Environmental Analytics Water/Steam Monitoring of BASF SE as well as for bacteria by a contract laboratory. The Drinking Water Regulation will serve as the guideline for maximum tolerable contaminants;
- The bedding (Type Lingocel FS 14 fibres, dustfree bedding, supplied by SSNIFF, Soest, Germany) is regularly assayed for contaminants (chlorinated hydrocarbons and heavy metals). The values given in Lab Animal, Nov.–Dec. 1979, pp 24–33, will serve as the guideline for maximum tolerable contaminants.

Administration / exposure

Route of administration:
oral: drinking water
Vehicle:
water
Details on oral exposure:
On the day of arrival the animals were subjected to an acclimatization period during which they received ground diet and drinking water ad libitum. Prior to the first ophthalmological examinations, the animals were distributed according to weight among the individual test groups, separated by sex. The weight variation of the animals used did not exceed 20% of the mean weight of each sex. The list of randomization instructions was compiled with a computer. At the start of the administration period (study day 0) the male and female rats were 41-43 days old. The test substance was administered daily in the drinking water for about 12 (satellite groups) and 24 months (main groups). Control animals received drinking water only. At the end of the administration period the animals were sacrificed after a fasting period (withdrawal of food) of at least 16-20 hours.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The analyses of the test-substance preparations were carried out at the Analytical Chemistry Laboratory of the Experimental Toxicology and Ecology of BASF SE, Ludwigshafen, Germany and/or at Competence Center Analytics, BASF SE, Ludwigshafen, Germany. The stability of the test substance in drinking water over a period of 4 days was proven prior to the study with the similar batch B62 (Date of production: 10 Oct 2008). At the start of the study, the concentration was demonstrated using 1 sample of all concentrations.
During the study, analyses of the test-substance preparations with respect to concentration control were conducted after about 3, 6, 9, 12, 15, 16, 18, 21 months as well as towards the end of the study. Concentration control analyses were performed with one sample per test group taken at the time points indicated above. The samples were taken out of randomly selected reserve water bottles being stored in the animal room. Thus, the stability of the test substance in drinking water was also proven under test conditions. Homogeneity was given because the test substance was completely miscible with water, in terms of a pure solution.
Duration of treatment / exposure:
12 months, satellite groups (S)
24 months, main groups
Frequency of treatment:
Daily
Doses / concentrationsopen allclose all
Dose / conc.:
25 mg/kg bw/day (nominal)
Dose / conc.:
75 mg/kg bw/day (nominal)
Dose / conc.:
300 mg/kg bw/day (nominal)
No. of animals per sex per dose:
Main groups: fifty animals/sex and group
Satellite groups: ten animals/sex and group
Control animals:
yes, concurrent no treatment

Examinations

Observations and examinations performed and frequency:
MORTALITY AND CLINICAL OBSERVATIONS
A check for moribund or dead animals will be made twice daily from Mondays to Fridays and once daily on Saturdays, Sundays and public holidays; all animals will be checked daily for any abnormal clinical signs. Abnormalities and changes will be documented for each animal.

DETAILLED CLINICAL OBSERVATION
All animals will be subjected to detailed clinical observations outside their cages once before the beginning of the administration period (day 0) and subsequently once a week (in the morning). For observation, the animals will therefore be removed from their cages and placed in a standard arena (50 x 37.5 x 25 cm). The scope of examinations and the scoring of the findings that are observed will be based on the current index of findings in Datatox F1 software and includes but is not limited to the following parameters listed:
abnormal behavior in handling, fur, skin, posture, salivation, respiration, activity/arousal level, tremors, convulsions, abnormal movements, gait abnormalities, lacrimation, palpebral closure, exophthalmos, feces (appearance/consistency), urine, pupil size.
BODY WEIGHT
Body weight will be determined before the start of the administration period in order to randomize the animals. During the administration period the body weight will be determined on day 0 (start of administration period) and thereafter at weekly intervals until week 13. Thereafter, body weight measurement will be carried out at 4-week intervals and additionally at the end of the administration period. The difference between the body weight on the respective day of weighing and the body weight on day 0 will be calculated as body weight change.

FOOD CONSUMPTION
Food consumption will be determined weekly during the first 13 weeks and at 4-week intervals thereafter until test ending (as representative value over 3 or 4 days). Food consumption will be calculated as mean food consumption in grams per animal and day.

FOOD EFFICIENCY
Food efficiency (group means) will be calculated based upon individual values for body weight and average food consumption for animal in each cage.

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study)
Drinking water consumption will be determined weekly during the first 13 weeks and at 4-week intervals thereafter until test ending (as representative value over 3 or 4 days). Water consumption will be calculated as mean water consumption in grams per animal and day. The test substance intake will be calculated for each animal on the basis of water consumption and body weight and will be given in mg/kg body weight/day.

OPHTHALMOSCOPIC EXAMINATION
At test initiation the eyes of all satellite animals will be examined using an ophthalmoscope after administration of a mydriatic. At the end of the administration period, the eyes of the satellite animals of the control and high dose will be examined. The eyes of the animals of the other satellite groups will be examined only if there is a striking discrepancy between the examined groups.

HAEMATOLOGY AND CLINICAL CHEMISTRY
For the purpose of haematology and clinical chemistry, blood samples will be taken from fasted animals by puncturing the retroorbital venous plexus under Isoflurane anesthesia. Blood sampling and examination will be carried out in a randomized sequence.
The haematological parameters considered will include leukocytes, erythrocytes, hemoglobin, hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), platelets, differential blood count, reticulocytes, preparation of blood smears, and prothrombin time.
The clinical chemical parameters considered will include alanine aminotransferase, aspartate aminotransferase,alkaline phosphatase, serum γ-glutamyl transferase, sodium, potassium, chloride, inorg. phosphate, calcium, urea, creatinine, glucose, total bilirubin, total protein, albumin, globulins, triglycerides, cholesterol and magnesium.

URINALYSIS
On the afternoon preceding the day fixed for urinalysis, the animals will be transferred individually into metabolism cages (no food or drinking water provided). On the following day, the samples will be examined in a randomized sequence. Following parameters will be considered: volume, color, turbidity, pH value, protein, glucose, ketones, urobilinogen, bilirubin, blood, specific gravity and microscopy of sediment.
Sacrifice and pathology:
The animals will be sacrificed by decapitation under Isoflurane anesthesia. The exsanguinated animals will be necropsied and assessed by gross pathology. Animals which die intercurrently will be necropsied as soon as possible after their death and assessed by gross pathology.

ORGAN WEIGHTS
In addition to the weight of the anesthetized animals, the weights of following organs will be determined: liver, kidneys, adrenal glands, testes, epididymides, ovaries, uterus, spleen, brain, heart.

ORGAN/TISSUE FIXATION IN FORMALDEHYDE 4% SOL.:
In addition to all gross lesions, following organs and tissues will be fixed: salivary glands (mandibular and sublingual glands), esophagus, stomach (forestomach and glandular stomach), duodenum, jejunum and ileum, cecum, colon and rectum, liver, pancreas, brain, pituitary gland, sciatic nerve, spinal cord (cervical, thoracic and lumbar cords), eyes, adrenal glands, thyroid glands, parathyroid glands, trachea, lungs, pharynx, larynx, nose (nasal cavity), aorta, heart, bone marrow (femur), lymph nodes (mesenteric and axillary lymph nodes), spleen, thymus, kidneys, urinary bladder, testes, ovaries, oviducts, uterus and vagina, epididymides, prostate and seminal vesicle, female mammary gland, skin, skeletal muscle, sternum with marrow, femur with knee joint, and extraorbital lacrimal glands.

HISTOPATHOLOGY:
Fixation will be followed by histotechnical processing and examination by light microscopy and assessment of findings. As a basic rule and in addition to all gross lesions, organs/tissues obtained from the control and high dose groups (main and satellite) will be examined in a comparative manner (salivary glands,esophagus, stomach, duodenum, jejunum and ileum, cecum, colon and rectum, liver, pancreas, brain, pituitary gland, sciatic nerve, spinal cord, eyes, adrenal glands, thyroid glands, parathyroid glands, trachea, lungs, pharynx, larynx, nose, aorta, heart, bone marrow lymph nodes, spleen, thymus, kidneys, urinary bladder, testes, ovaries, oviducts, uterus and vagina, epididymides, prostate and seminal vesicle, female mammary gland, skin).
Animals that die or are sacrificed in a moribund state will be processed histotechnically and assessed like control animals.
Statistics:
- Means and standard deviations were calculated;
- The Dunnett test was used for statistical analyses of body weight, body weight change, food consumption, water consumption and food efficiency;
- The KRUSKAL-WALLIS and WILCOXON test was used for statistical analyses of blood parameters (except for differential blood count and reticulocytes) and of the weight of the anesthetized animals as well as the absolute and relative organ weights;
- The FISHER's exact test was used for statistical analyses of urinalysis parameters (except for volume, color, turbidity and specific gravity)

Results and discussion

Results of examinations

Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
In the satellite groups no test substance-related clinical signs were observed for male and female Wistar rats. In the main groups abnormal clinical signs were equally distributed between control and test substance-treated animals or occurred incidentally in single animals.
Mortality:
mortality observed, non-treatment-related
Description (incidence):
The oral administration of Glyoxal 40% via the drinking water at dose levels of 0 mg/kg bw/d (test group 0), 25 (test group 1), 75 (test group 2) and 300 mg/kg bw/d (test group 3) to male and female Wistar rats over a period of either 12 (satellite groups) or 24 months (main groups) did not cause a higher incidence of treatment-related mortality.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
With regard to clinical observations, the effects on mean body weights and body weight change values observed in male and female animals of test groups 3S and 3 (300 mg/kg bw/d) were assessed as being related to the test compound administration. Differences observed at lower dose levels were not assessed as being of toxicological relevance.
Regarding pathology, the treatment with Glyoxal 40% caused decrease of terminal body weight in males of test group 3S (300 mg/kg bw/d) of the satellite group of -8%. Furthermore, males and females of the test group 3 (300 mg/kg bw/d) of the final sacrifice group showed also a decrease in terminal body weight of -11% and -12% respectively. These decreases in the terminal body weight were regarded to be a manifestation of a systemic toxic effect. It could not be addressed to a special organ but is regarded to be adverse.
Food consumption and compound intake (if feeding study):
effects observed, non-treatment-related
Description (incidence and severity):
In the satellite group (12 month period of treatment) no changes in food consumption were observed. In the main groups food consumption was increased on several time points but no clear dose-response relationship was observed and the findings were assessed as incidental.
Food efficiency:
no effects observed
Description (incidence and severity):
No test substance-related effects on food efficiency were obtained.
Water consumption and compound intake (if drinking water study):
effects observed, non-treatment-related
Description (incidence and severity):
Relevant changes in water consumption were observed most likely related to the taste of the test item.
Ophthalmological findings:
effects observed, treatment-related
Description (incidence and severity):
Vasodilatation in fundus oculi was observed only in 8 female animals of test group 3S (300 mg/kg bw/d) and in 6 female animals of test group 2S (75 mg/kg bw/d) at the end of the administration period of 12 months. This finding showed a clear dose-response relationship. Because a histopathological correlate was not observed, the vasodilation in fundus oculi was considered to be treatment-related, but assessed as non-adverse.
Haematological findings:
effects observed, non-treatment-related
Description (incidence and severity):
After 3 months of compound administration, in male animals of test groups 2S and 3S (75 and 300 mg/kg bw/d) hemoglobin values were higher compared to controls. These alterations were not accompanied by any other changes of red blood cell parameters in these rats and the means were within the historical control range.
After study months 6 and 12, in females of test group 2S (75 mg/kg bw/d) and at the later date also in females of test group 3S (300 mg/kg bw/d) relative reticulocyte counts were lower compared to controls. After the 6th study month, reticulocyte counts were not changed dose-dependently. The values were not accompanied by any other alteration among red blood cell parameters. Therefore, these alterations were regarded as not adverse.
Clinical biochemistry findings:
effects observed, non-treatment-related
Description (incidence and severity):
Regarding clinical pathology, a decreased ALT activity in male and female rats of test group 3 (300 mg/kg bw/d) was observed. Neither any other clinical pathology alteration indicating a microsomal enzyme induction nor any relevant liver weight increases were found in these dosed rats. Therefore, other reasons for an ALT activity decrease, including an effect on the pyridoxal 5’-phosphate levels, cannot be excluded. Lower cholesterol and globulin values in rats of both sexes of test group 3 (300 mg/kg bw/d) and, additionally, in males of test group 2 (75 mg/kg bw/d) were most probably due to a dysregulation of the liver cell metabolism or a decreased intestinal absorption of cholesterol combined with a lower synthesis of transport globulins.
Urinalysis findings:
effects observed, non-treatment-related
Description (incidence and severity):
The reason for the urinary excretion of higher keton body and urobilinogen levels in males could not be elucidated. The higher urine volume in males of test group 2 (75 mg/kg bw/d) after the 6th study month were regarded as incidental and not treatment-related.
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
The terminal body weight was reduced in male and female animals of test group 3 (300 mg/kg bw/d). This was regarded to be related to treatment. The weight reduction of the male thyroid gland, female heart and liver in the same test group was regarded to be a consequence to the reduced terminal body weight. The increase of kidney and spleen weight in females of test group 1 (25 mg/kg bw/d) was regarded to be incidental due a missing dose-response relationship and no significant deviations in the relative organ weights. All other mean absolute weight parameters did not show significant differences when compared to the control group.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Female animals of the final sacrifice group showed macroscopically an increase of erosions/ulcer in the glandular stomach (0/0/2/5) which was confirmed and even outnumbered by histopathology (0/1/6/9). The single erosion/ulcer in one animal of test group 1 (25 mg/kg bw/d) was regarded to be an incidental finding as erosion/ulcer are normally detected in a low incidence in the glandular stomach in long term studies. In former studies with Glyoxal 40% erosions/ulcer were already observed in the glandular stomach. Therefore, the erosions/ulcer in females of test group 2 (75 mg/kg bw/d) and test group 3 (300 mg/kg bw/d) were regarded to be substance related and adverse in nature.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
The total numbers of primary, benign, malignant, systemic, and metastasized neoplasms were comparable between control and high-dose animals. They were biologically equally distributed over the control and treatment groups.

Effect levels

Key result
Dose descriptor:
NOAEL
Effect level:
ca. 25 mg/kg bw/day (nominal)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: systemic toxicity

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion