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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2001
Report date:
2001

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Version / remarks:
(1999)
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
Version / remarks:
(1998)
Qualifier:
according to guideline
Guideline:
other: EC Commission Directive 87/302/EEC of Nov 18, 1987, Part B: Methods for the determination of toxicity: Teratogenicity study (rodent and non-rodent), Official Journal of the European Communities; No L 133, pp. 24-26 (1988)
GLP compliance:
yes
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: B 61

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Stability under test conditions: Proven by reanalysis after the in life phase of the study

Test animals

Species:
rat
Strain:
Wistar
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Boehringer Ingelheim Pharma KG, Biberach an der Riss, Germany
- Age at study initiation: 9 to 11 weeks old
- Weight at study initiation: 228.9 – 233.4 g
- Housing: The rats were housed singly from day 0- 20 p.c. in type DK 111 stainless steel wire mesh cages supplied by BECKER & CO ., Castrop-Rauxel, FRG
- Diet (e.g. ad libitum): ground Kliba maintenance diet rat/mouse/hamster meal, ad libitum
- Water (e.g. ad libitum): drinking water of tap water quality, ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24°C
- Humidity (%): 30 - 70%
- Air changes (per hr): fully air-conditioned rooms
- Photoperiod (hrs dark / hrs light): 12 h /12 h

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The test substance solutions were analyzed by HPLC
Details on mating procedure:
Two to three untreated females were mated with one untreated fertile male rat of the same breed. Mating took place from ca. 16.00 hours to ca. 7.30 hours on the following day; the mating period was therefore about 15 to 16 hours.
When sperm was detected in the vaginal smear, the females were considered as fertilized and the day was designated as day 0 of gestation.
Duration of treatment / exposure:
d 6-19 post coitum
Frequency of treatment:
7 d/wk
Duration of test:
d 6-20 post coitum
Doses / concentrationsopen allclose all
Dose / conc.:
5 mg/kg bw/day
Remarks:
actual ingested (active ingredient)
Dose / conc.:
25 mg/kg bw/day
Remarks:
actual ingested (active ingredient)
Dose / conc.:
125 mg/kg bw/day
Remarks:
actual ingested (active ingredient)
No. of animals per sex per dose:
25 animals /group were used
Control animals:
yes, concurrent no treatment

Examinations

Maternal examinations:
- The animals were checked daily, at least once for clinical symptoms and twice for mortality on working days. On Saturdays, Sundays or public holidays, the animals were only checked once a day;
- Body weight changes and food consumption were recorded;
Ovaries and uterine content:
Following parameters were examined:
Gravid uterine weight, number of corpora lutea, number and distribution of implantations sites classified as live foetuses and dead implantations. Dead implantations comprised early resorptions, late resorptions and dead foetuses.
Fetal examinations:
The foetuses were dissected from the uterus, sexed weighed and further investigated for any external, soft tissue and/or skeletal findings.
Statistics:
- Pairwise comparison of each dose group with the control group using FISHER´s EXACT test (one-sided) for the hypothesis of equal proportions (for parameters female mortality, females pregnant at terminal sacrifice, number of litters with fetal findings)
- Pairwise comparison of each dose group usingWILCOXON test (one-sided) for the hypothesis of equal medians (for parameters of proportions of fetuses with malformations, variations and/or unclassified observations in each litter)
- Simultaneous comparison of all dose groups with the control group using the DUNNETT-test (two-sided) for the hypothesis of equal means (for all other parameters examined and not mentioned above)
Indices:
The conception rate (CR) as well as the pre- and post- implantation losses (Pre-I¸Post-I) were calculated.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
Signs of toxicity only were seen in the high dose group treated with 125 mg/kg bw/day of Glyoxal; no such signs could be evidenced in the low and mid dose groups. In fact, in the high dose group, sporadically occurring, transient salivation was observed.
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
In the high dose group, statistically significantly lowered corrected body weight gain (about 29% below control) and reduced mean carcass weight was reported.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Statistically significantly reduced food consumption (ca. 7% below control for the period from day 6 to day 19 p.c.) were reported.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
Mean gravid uterus weight was inconspicuous.
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined

Maternal developmental toxicity

Number of abortions:
not specified
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in pregnancy duration:
not specified
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not specified
Changes in number of pregnant:
not specified
Details on maternal toxic effects:
No treatment-related and/or biologically relevant differences between the test groups (treated and control) in conception rate, mean number of corpora lutea, implantation sites, pre- and post-implantation losses, number of resorptions, and in viable foetuses could be evidenced. Differences, when they occurred, were within the normal range of deviations for animals of the strain and age used.

Effect levels (maternal animals)

Key result
Dose descriptor:
NOAEL
Effect level:
25 mg/kg bw/day
Basis for effect level:
other: maternal toxicity

Results (fetuses)

Fetal body weight changes:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed
Changes in sex ratio:
no effects observed
Description (incidence and severity):
The sex distribution of the fetuses in test groups 25 and 125 mg/kg body weight/day was comparable with that of the control fetuses . The differences observed in comparison to the control were without any biological relevance .
Changes in litter size and weights:
not specified
Changes in postnatal survival:
not specified
External malformations:
effects observed, non-treatment-related
Description (incidence and severity):
Anophthalmia of left eye was recorded for one male control fetus. Another eye malformation occurred in one low dose female fetus in the form of microphthalmia . Moreover, another female fetus of this dose group had multiple external (and some corresponding skeletal) malformations
substantiated by cleft palate, gastroschisis, brachydactyly and micromelia of the right forelimb and a mairotated right hindlimb . Finally, one female of high dose dam had a short snout and a cleft palate ; these findings are correlated to different skull malformations of the same fetus.
Skeletal malformations:
effects observed, non-treatment-related
Description (incidence and severity):
Malpositioned and bipartite sternebra (with unchanged cartilage) occurred in one control, one mid dose and one high
dose fetus each. Cleft sternum (with split cartilage) was observed for 2 male fetuses (control and low dose). Absent lumbar vertebra was recorded for one male control fetus and one high dose female fetus; the latter fetus had also a deformed ischium and severely ma!formed skull bones, which are in-line with the external malformations (i .e.short snout, cleft palate) observed in this fetus. Finally, one female fetus of low dose showed various skeletal malformations with
or without involvement of the cartilaginous structures (affecting sternebrae, ribs, different sections of the vertebral column, skull, metacarpal and metatarsal bones) in addition to multiple external malformations (e .g . cleft palate, gastroschisis, brachydacty!y and microme!ia).
Visceral malformations:
effects observed, non-treatment-related
Description (incidence and severity):
In the control group one female fetus showed a situs inversus, while in one male fetus of control rat an bilateral enlargement of the ventricular
chambers occurred. The same heart malformation was also observed for one mid dose female fetus. Soft tissue variations were detected in each group including the control.

Effect levels (fetuses)

open allclose all
Key result
Dose descriptor:
NOAEL
Effect level:
125 mg/kg bw/day
Basis for effect level:
other: teratogenicity
Key result
Dose descriptor:
NOAEL
Effect level:
125 mg/kg bw/day
Basis for effect level:
other: fetotoxicity

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion