Registration Dossier

Diss Factsheets

Toxicological information

Developmental toxicity / teratogenicity

Currently viewing:

Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
21.05.1980 to 09.06.1980
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1982
Report date:
1982

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
No record of gravid uterine weight, number of corpora lutea not recorded, no analytical confirmation of dosing solutions.
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Reference substance name:
Heptasodium trihydrogen [[bis[2-[bis(phosphonatomethyl)amino]ethyl]amino]methyl]phosphonate
EC Number:
268-990-9
EC Name:
Heptasodium trihydrogen [[bis[2-[bis(phosphonatomethyl)amino]ethyl]amino]methyl]phosphonate
Cas Number:
68155-78-2
Molecular formula:
C9H28N3O15P5.7Na
Test material form:
liquid

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River
- Age at study initiation: No data
- Weight at study initiation: 180-200 g
- Fasting period before study: No data
- Housing: Individually in suspended stainless steel mesh cages.
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: None, animals were received mated and allocated to cages.


ENVIRONMENTAL CONDITIONS
- Temperature (°F): 72 ±2
- Humidity (%): 40-60
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: From: 26.05.1980 To: 09.06.1980

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: Aqueous solution
Details on exposure:
No data
Analytical verification of doses or concentrations:
no
Details on mating procedure:
No data. Animals were received on gestational day 1, having already been mated.
Duration of treatment / exposure:
GD 6 - 19
Frequency of treatment:
daily
Duration of test:
20 days
Doses / concentrationsopen allclose all
Dose / conc.:
500 mg/kg bw/day
Dose / conc.:
1 000 mg/kg bw/day
Dose / conc.:
2 000 mg/kg bw/day
No. of animals per sex per dose:
25
Control animals:
other: 0.9% (w/v) aqueous NaCl
Details on study design:
- Dose selection rationale: No data

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily for visible toxic effects.


DETAILED CLINICAL OBSERVATIONS: No


BODY WEIGHT: Yes
- Time schedule for examinations: Gestational days 3, 6, 8, 10, 13, 15, 17 and 20.


FOOD CONSUMPTION: No


WATER CONSUMPTION: No


POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: Gross examination of all animals that included examination of external surfaces and thoracic and abdominal cavities.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: yes
Examinations included:
- Gravid uterus weight: No
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: No data
Statistics:
Comparison of body weights between treatment and control groups was performed using Dunnett's test. Counted data (corpora lutea, implants, resorptions, live and dead fetuses) and data expressed as percentage were analysed, when appropriate with the Mann-Whitney U test. Response data (pregnancy rates, number of litters with post-implantation loss, and fetuses or litters with abnormalities and variants) were analysed, when appropriate, with Fisher's exact test and the chi-square test.
Indices:
None
Historical control data:
No data

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
9/25 dams had soft stools in the 2000 mg/kg bw/day group beginning on gestation day 14 (9th day of the treatment) and persisted through to gestation day 17. This finding was not observed in the other treated groups or the controls.
Mortality:
no mortality observed
Description (incidence):
No deaths occurred prior to the scheduled sacrifice.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
The only statistically significant (P<0.01) effect observed was lower body weight gain (mean value approximately 68% of the control mean) between gestation day 6 and 20 for dams in the 2000 mg/kg bw/day group (33.6/27.6/27.5/22.9). However, terminal body weights were not statistically significantly affected (mean terminal body weights with uterine contents by dose: 360.1/368.1/357.0/346.1 and mean terminal body weights without uterine contents: 265.8/264.5/260.1/257.2).
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
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
Gross pathological findings:
no effects observed
Description (incidence and severity):
There were no treatment-related findings in the gross necropsy.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed

Maternal developmental toxicity

Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
There were no significant differences between any of the treatment groups and the control group in the number of pre- or postimplantation losses.
Total litter losses by resorption:
no effects observed
Description (incidence and severity):
There were no significant differences between any of the treatment groups and the control group in the resorptions.
Early or late resorptions:
no effects observed
Description (incidence and severity):
There were no significant differences between any of the treatment groups and the control group in the resorptions.
Dead fetuses:
no effects observed
Description (incidence and severity):
There were no significant differences between any of the treatment groups and the control group in the mean number of live fetuses.
Changes in pregnancy duration:
no effects observed
Changes in number of pregnant:
no effects observed
Description (incidence and severity):
There was no effect on pregnancy rate.
Other effects:
no effects observed
Description (incidence and severity):
There was no effect on the mean number of corpora lutea.

Effect levels (maternal animals)

Key result
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Based on:
act. ingr.
Remarks:
active acid
Basis for effect level:
body weight and weight gain

Maternal abnormalities

Abnormalities:
effects observed, treatment-related
Localisation:
other: body weight gain

Results (fetuses)

Fetal body weight changes:
no effects observed
Description (incidence and severity):
There were no effects on fetal body weight.
Reduction in number of live offspring:
no effects observed
Description (incidence and severity):
There were no significant differences between any of the treatment groups and the control group in the mean number of live fetuses.
Changes in sex ratio:
no effects observed
Description (incidence and severity):
There were no effects on sex ratios (males/litter: 5.6/5.8/5.9/4.8. Females/litter: 5.9/6.5/5.4/6.4).
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
not examined
External malformations:
effects observed, non-treatment-related
Description (incidence and severity):
There were no treatment-related gross external malformations present.
Subcutaneous haematomas were present in controls and all treated groups, however the incidence increased at 500 mg/kg bw/day (P<0.05) and was considered unrelated to treatment by the study authors (no dose relationship was present). The occurrence of one female fetus that was hydrocephalic and one female with gastroschisis in the 1000 mg/kg bw/day group was considered by the study authors to be spontaneous. The hydrocephalic female also exhibited a developmental variation (underdeveloped renal papilla) that was not considered to be related to treatment.
Skeletal malformations:
effects observed, non-treatment-related
Description (incidence and severity):
Skeletal examination revealed single incidences of dwarfism (one female fetus of 500 mg/kg bw/day group) and fused sternebrae (one female fetus of the 2000 mg/kg bw/day group), which were considered spontaneous. Two fetuses from different litters in the 2000 mg/kg bw/day group and one fetus of the 1000 mg/kg bw/day group had vertebral anomalies (missing, reduced or fused vertebral arches). Although the incidence of these anomalies was not statistically significant compared with the control group, the rare spontaneous occurrence of such anomalies and the pattern of incidence indicated that they might have been treatment-related. Various skeletal variations occurred, but none showed a clear dose-response and so were considered spontaneous. Review of these results for the REACH assessment concluded that the effects should not be considered adverse as they were not statistically significant and were only observed in the presence of maternal toxicity. The limit dose for a prenatal developmental toxicity study conducted to OECD 414 is 1000 mg/kg bw/day, therefore the high dose used in this old study was double the limit dose. When findings up to the limit dose are considered, vertebral anomalies were observed in only one fetus. Therefore, this finding is not considered adverse.
Visceral malformations:
no effects observed

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Effect level:
>= 2 000 mg/kg bw/day
Based on:
act. ingr.
Remarks:
active acid
Sex:
male/female
Basis for effect level:
other: No adverse developmental effects observed.

Fetal abnormalities

Abnormalities:
no effects observed

Overall developmental toxicity

Developmental effects observed:
no

Applicant's summary and conclusion

Conclusions:
In the prenatal developmental toxicity study with DTPMP-7Na, conducted according to a protocol similar to OECD Test Guideline 414 and in compliance with GLP, clear maternal toxicity (approx. 30% decrease in body weight gain, soft stools) was noted in pregnant Sprague-Dawley rats given 2000 mg/kg bw/day DTPMP-7Na (expressed as active acid) on gestation days 6-19, therefore the NOAEL for maternal toxicity was concluded to be 1000 mg/kg bw/day. The NOAEL for developmental toxicity was concluded to be 2000 mg/kg bw/day (active acid) based on no adverse developmental effects.