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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
Study period:
27 Jan 1994 - 21 Feb 1994
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1995
Report date:
1995

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
1,1',1''-nitrilotripropan-2-ol
EC Number:
204-528-4
EC Name:
1,1',1''-nitrilotripropan-2-ol
Cas Number:
122-20-3
Molecular formula:
C9H21NO3
IUPAC Name:
1,1',1''-nitrilotripropan-2-ol
Test material form:
solid
Specific details on test material used for the study:
- Analytical purity: 92 %
- Lot/batch No.: 10-4852
- Storage condition of test material: Room temperature, under nitrogen atmosphere

Test animals

Species:
rat
Strain:
Wistar
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: THOMAE, Biberach an der Riss, FRG
- Age at study initiation: 77-89 days
- Weight at study initiation: 242 g (mean)
- Housing: singly in type DK III stainless steel wire mesh cage.
- Diet: ground Kliba 343 feed, Klingenthalmuehle AG, Kaiseraugst, Switzerland, ad libitum
- Water: tap water, ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24°C
- Humidity (%): 30-70%
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Remarks:
double distilled
Details on exposure:
Doses of 0, 100, 400 and 1000 mg/kg bw/day were administered in a volume of 10 mL/kg, at a concentration of 0, 1000, 4000 and 10000 mg/100 mL, respectively.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Test substance: purity and stability were analyzed by gas chromatography (GC); and homogeneity was proven visually.
Test solutions: analysis of stability (for 3 hrs) in double distilled water was carried out in a range-finding study. Concentrations were analyzed twice during the study by GC. Test solutions were freshly prepared on the day of dosing.
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1/1
- Length of cohabitation: overnight
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
Duration of treatment / exposure:
on day 6 through day 15 post coitum (p.c.)
(Sacrifice on day 20 p.c.)
Frequency of treatment:
once a day during the period of major organogenesis (day 6 to day 15 p.c.)
Duration of test:
20 days
Doses / concentrationsopen allclose all
Dose / conc.:
100 mg/kg bw/day (nominal)
Dose / conc.:
400 mg/kg bw/day (nominal)
Dose / conc.:
1 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
25
Control animals:
yes, concurrent vehicle

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS
- Time schedule: once a day and more often when clinical signs of toxicity were elicited. Mortality was check twice a day on workdays and once a day during weekends and public holidays.

BODY WEIGHT and FOOD CONSUMPTION
- Time schedule for examinations: days 0 (only bw), 1, 3, 6, 8, 10, 13, 15, 17, 20 p.c.

POST-MORTEM EXAMINATIONS
- Sacrifice on gestation day # 20
- Organs examined: uterus and ovaries after gross pathology

OTHER: The correct body weight gain was calculated after terminal sacrifice.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other: furthermore, calculations of conception rate and pre- and postimplantation losses were carried out:
- conception rate (%) = number of pregnant animals / number of fertilized animals x 100.
- preimplantation loss (%) = (number of corpora lutea - number of implantations) / number of corpora lutea x 100.
- postimplantation loss (%) = (number of implantations - number of live fetuses) / number of implantations x 100.
Fetal examinations:
- External examinations: Yes: all per litter: fetus was weighed, sexed, examined macroscopically for external findings, and viability, condition of the placentae, umbilical cords, fetal membranes and fluids were examined.
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: No
Statistics:
The data were evaluated statistically using the computer systems of the Department of Toxicology of BASF AG. The Dunnett-test was used for a simultaneous comparison of several dose groups with the control. The hypothesis of equal means was tested. This test was performed two-sided and was used for the statistical evaluation of the following parameters: food consumption, body weight, body weight change, corrected body weight gain (net maternal body weight change), weight of the uterus before it was opened, number of corpora lutea, number of implantations, number of resorptions and number of live fetuses, proportion of preimplantation loss, postimplantation loss, resorptions and live fetuses in each litter, litter mean fetal body weight and litter mean placental weight. Fisher's Exact Test was used for a pairwise comparison of each dose group with the control for the hypothesis of equal proportions. This test was performed one-sided and was used for female mortality, females pregnant at terminal sacrifice and the number of litters with fetal findings. The Wilcoxon-Test was used for a comparison of each dose group with the control for the hypothesis of equal medians. This test was performed one-sided and was used for the proportion of fetuses with malformations, variations, retardations and/or unclassified observations in each litter. If the results of these tests were significant, labels (* for p< 0.05, ** for p< 0.01) were printed in the summary tables.
Historical control data:
Yes.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
no effects observed
Description (incidence and severity):
There were no abnormal clincial findings in any dam of anyone group.
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Description (incidence):
There were no mortalities in any of the groups.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
There were no statistically significant differences between the controls and the substance-treated dams concerning mean body weights. At the beginning of the treatment period (days 6-8 p.c.), however, the dams of the highest dose group (1,000 mg/kg bw/day) showed a statistically significantly reduced body weight gain (only about 36% of the weight gain of the concurrent control group. The corrected body weight gain (terminal body weight on day 20 p.c. minus weight of the uterus before it was opened minus body weight on day 6 p.c.) was statistically significantly lower in the high dose group (about 87% of the value of the concurrent control group), which is related to the test substance administration. For further details see attached document (result tables).
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
In the 1000 mg/kg group statistically significantly decreased food consumption at the beginning of the treatment period (days 6-10 p.c.; about 13% (days 6 to 8 p.c.) or about 16% (days 8 to 10 p.c.) lower than the values of the concurrent control group, which is related to the test substance administration.
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):
The uterus weights of the animals were not influenced by the administration of the test substance. The differences between the groups are without biological relevance. For further details see attached document (result tables).
Gross pathological findings:
no effects observed
Description (incidence and severity):
At necropsy, single animals of the control and all substance treated groups showed lungs with edema and/or marginal emphysema; these findings, which showed no relation to dosing, have to be related to the sacrifice of the animals.
- number (%) of dams with lung edema in 0, 100, 400, 1000 mg/kg bw/d group: 9, 4, 5, 6 (36, 16, 20, 24 %)
- number (%) of dams with marginal lung emphysema in 0, 100, 400, 1000 mg/kg bw/d group: 3, 2, 2, 2 (12, 8, 8, 8 %).
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined
Other effects:
not examined

Maternal developmental toxicity

Number of abortions:
no effects observed
Description (incidence and severity):
For further details see attached document (result tables).
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
For further details see attached document (result tables).
Total litter losses by resorption:
no effects observed
Description (incidence and severity):
For further details see attached document (result tables).
Early or late resorptions:
no effects observed
Description (incidence and severity):
For further details see attached document (result tables).
Dead fetuses:
no effects observed
Description (incidence and severity):
For further details see attached document (result tables).
Changes in pregnancy duration:
no effects observed
Changes in number of pregnant:
no effects observed
Description (incidence and severity):
The conception rate varied between 92% (test group 3 - 1,000 mg/kg body weight/day) and 100% (control group and test group 2 - 400 mg/kg body weight/day). For further details see attached document (result tables).
Other effects:
not examined
Details on maternal toxic effects:
There were no substance-related and/or biologically relevant differences between the groups in conception rate, in the mean number of corpora lutea and implantation sites or in the values calculated for the pre- and the postimplantation losses, the number of resorptions (total, early, late) and viable fetuses. The differences evident are considered to be incidental and within the normal range of deviations for animals of this strain and age. For further details see attached document (result tables).

Effect levels (maternal animals)

Key result
Dose descriptor:
NOAEL
Effect level:
400 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
body weight and weight gain
food consumption and compound intake

Maternal abnormalities

Key result
Abnormalities:
no effects observed

Results (fetuses)

Fetal body weight changes:
no effects observed
Description (incidence and severity):
The mean fetal weights in test groups 1, 2 and 3 (100, 400 and 1,000 mg/kg body weight/day) were not influenced by the test substance administration and there were no biologically relevant differences concerning the means of the control group and of the substance-treated groups. For further details see attached document with result tables.
Reduction in number of live offspring:
no effects observed
Description (incidence and severity):
There were no substance-related and/or biologically relevant differences between the groups in the number of viable fetuses. For further details see attached document with result tables.
Changes in sex ratio:
no effects observed
Description (incidence and severity):
The sex distribution of the fetuses in test groups 1 - 3 (100, 400 and 1,000 mg/kg body weight/day) was comparable with the control fetuses. The differences observed in comparison to the control are without any biological relevance. For further details see attached document with result tables.
Changes in litter size and weights:
not examined
Changes in postnatal survival:
not examined
External malformations:
no effects observed
Description (incidence and severity):
There are no statistically significant differences between the control and the substance-treated groups with respect to external malformation, variation and/or retardation which could be related to the test substance administration.

The external examination of the fetuses revealed two malformations in one fetus of test group 2 (400 rng/kg body weight/day). This fetus (No . 4 of animal No. 71) showed anophthalmia on the right side and a microphthalmia of the left eye. Due to the missing dose-response relationship and the isolated nature of this finding, it is considered tobe spontaneous in nature. Moreover, this finding can also be found at a low incidence in the historical control data from the breeder. No external variations were found in any group. Only one so-called unclassifiad observation (placentae fused) was recorded for one fetus of test group 0 (0 mg/kg body weight/day) and one fetus of test group 1 (100 mg/kg body weight/day); a finding without dose-response relationship and thus considered not relevant.

For further details see attached documents (result tables and historical control data).
Skeletal malformations:
effects observed, non-treatment-related
Description (incidence and severity):
There are no statistically significant differences between the control and the substance-treated groups with respect to skeletal malformation, variation and/or retardation which could be related to the test substance administration.

The few statistically significant differences which occurred were exclusively related to fetal skeletal variations and retardations and consisted of:
- an increased rate of affected fetuses/litter and an increased litter incidence with shortened 13th rib(s) at 100, 400 and 1,000 mg/kg body weight/day, respectively
- a consequently increased rate of low and intermediate dose fetuses/litter with total skeletal variations
- an increased litter incidence of incompletely ossified or smaller sternebra(e) in the 400 mg/kg body weight group.
These findings are considered to be spontaneous in nature because no dose-response relationship is given and/or the respective values are fully in the historical control range (see respective tables below).

Various malformations of the sternum and the vertebral column were seen in the control and the three dose groups, occurring without any statistically significant differences between the substance-treated groups and the concurrent control group: 0, 100, 400, 1000 mg/kg bw/d: 8/177, 8/176, 6/193, 15/178 fetuses; 8/25, 5/25, 5/25, 10/23 litters. Furthermore, all of the aforementioned skeletal malformations or very similar ones can be found at comparable or even higher fetal/litter incidences in the historical control data.
The variations elicited, which were related to the ribs, the sternum, the skull and the vertebral column, appeared without a clear dose-response relationship, can be found in a similar frequency in the historical control data and/or the differences between the groups are without biological relevance.

For further details see attached documents (result tables and historical control data).
Visceral malformations:
no effects observed
Description (incidence and severity):
There are no statistically significant differences between the control and the substance-treated groups with respect to soft tissue malformation, variation and/or retardation which could be related to the test substance administration.

The examination of the organs of the fetuses revealed three different malformations. Hydrocephaly was recorded for one fetus of test group 2 (400 mg/kg body weight/day) (No. 4 of animal No. 71), truncus arteriosus communis was seen in one fetus of test group 1 (100 mg/kg body weight/day) (No. 2 of animal No. 49) and dilatation of both heart ventricles (globular shaped heart) occurred in three fetuses; in one fetus of test group 0 (No. 10 of animal No. 16), in one fetus of test group 2 (No. 4 of animal No. 71) and in one fetus of test group 3 (No. 12 of animal No. 80). Two of these malformations (hydrocephaly and dilatation of both ventricles) are also present at a low incidence in the historical control data. The isolated and disparate nature of the three soft tissue malformations and the missing dose-response relationship does not suggest any treatment-related aetiology; therefore, these malformations are considered tobe spontaneous in nature. Variations (dilated renal pelvis and/or hydroureter) were detected in all groups without any statistically significant and/or biologically relevant differences between the groups. Both findings are very common ones in the rat strain used and all respective values are fully in the range of biological variation. No so-called unclassified observations (like bloody imbibition of kidney(s)) were recorded during the soft tissue examination.

For further details see attached documents (result tables and historical control data).
Other effects:
no effects observed
Description (incidence and severity):
The mean placental weights in test groups 1, 2 and 3 (100, 400 and 1,000 mg/kg body weight/day) were not influenced by the test substance administration and were similar to the control values. For further details see attached document (result tables).

Effect levels (fetuses)

Key result
Dose descriptor:
NOEL
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Remarks on result:
other: There were no (adverse toxic) effects observed up to the highest dose tested.

Fetal abnormalities

Key result
Abnormalities:
no effects observed

Overall developmental toxicity

Key result
Developmental effects observed:
no

Any other information on results incl. tables

For further details see attached documents (result tables and historical control data).

Applicant's summary and conclusion

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