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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Early, but well documented, profound study meeting today standards. A higher dose level may have been selected for detection of a reproductive potential, but seems sufficient for risk assessment.

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1971

Materials and methods

Principles of method if other than guideline:
Method: Procter & Gamble (USA)
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
other: Charles River CD

Administration / exposure

Route of administration:
oral: feed
Details on exposure:
Two levels of Na3NTA, 0-1 and 0-5 % of the diet, were chosen for the rat studies on the basis of information from the subacute and long-term studies of Nixon (1971) and Nixon, Buehler & Niewenhuis (1971) . The lower level was without effect in these studies, while the 0-5 % level produced some mild toxicity.
Na3NTA was mixed into ground Purina Chow at the appropriate levels and the two diets were fed to groups of 20 male and 20 female Charles River CD rats continuously through two generations, or to groups of 20 female rats only during each period of organogenesis (days 6-15 of pregnancy). A similar group of 20 males and 20 females fed ground Purina Chow served as the control.
Details on mating procedure:
The weanling rats from both F, and F1b generations were distributed into groups on the basis of body weight and litter mates, except that animals selected for the second-generation breeders were chosen only from their own respective groups. The rats were randomly caged individually in a carefully controlled environment and were fed and watered ad lib. For each generation, records of individual weekly feed consumption and body-weight gain were kept during the first 8 wk from weaning. Afterwards, the parent rats were weighed at the beginning of each mating phase and no records of feed consumption were kept.
The original parent rats (F0) were bred three times while the second-generation parents (F1b) were bred twice. The first litters of both generations (F1a and F2a were discarded at weaning while the second litters of the first generation (F1b) were kept and used as second generation breeders. The third litters of the first generation (F1c) and the second ones of the second generation (F2b) were used for teratological studies. The day of conception (day 0) was determined by vaginal smears and one-half of each group of dams was sacrificed on day 13 and the other half on day 21 of pregnancy.
All live-born litters were counted at birth and again 4 days later, when the pups were weighed and their sex determined. Each litter was reduced to 8 pups, divided as evenly as possible between the sexes. This was done to equalize, as much as possible, the stress of lactation on the groups of dams. The pups were weaned and weighed 21 days after birth.
Duration of treatment / exposure:
10 d
Frequency of treatment:
continuous from day 6 through 15 of pregnancy
Duration of test:
day 6 - 15 of pregnancy
Doses / concentrations
Remarks:
Doses / Concentrations:
0.1 and 0.5 % [= 50-75 and 250-375 mg/(kg bw *d)]
Basis:
nominal conc.
No. of animals per sex per dose:
20
Control animals:
yes, concurrent no treatment
Details on study design:
Sex: female
Duration of test: for two generations

Examinations

Maternal examinations:
The numbers of corpora lutea, implantations and resorptions were recorded in dams sacrificed on day 13 of gestation to assess early embryo mortality and, to some extent, dominant lethal effects in the groups where the males were also given Na3NTA.
Fetal examinations:
The foetuses removed from dams sacrificed at day 21 of gestation were dried of amniotic fluids and weighed, and their sex was determined. They were inspected for gross abnormalities and sacrificed by means of excessive ether. One-third of each litter was cleared in KOH and stained with Alizarin Red S (Staples & Schnell, 1964) for the determination of skeletal defects, while the remaining foetuses were fixed in Bouin's solution and razor-blade sectioned (Wilson, 1965) to be examined for soft-tissue defects. Representative sections of the vital organs and tissues were taken from five rats of each sex from each group at the end of each teratological phase and at 8 wk after weaning, in second-generation rats. These were fixed in Bouin's solution, embedded in paraffin, and stained with haematoxylin and eosin for histopathological examination.

Results and discussion

Results: maternal animals

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
>= 250 mg/kg bw/day
Basis for effect level:
other: maternal toxicity

Results (fetuses)

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
>= 250 mg/kg bw/day
Basis for effect level:
other: teratogenicity

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

Na3.NTA.H20 was neither embryo- or maternally toxic nor
teratogenic at either dietary levels. All of the defects
were in the soft tissues and predominantly in the urinary
tract: hydroureter and/or hydronephrosis comprised most of
the anomalies observed. As there was no substance-related
context, authors assumed that it could have been caused by
some virus.

Applicant's summary and conclusion