Registration Dossier

Toxicological information

Toxicity to reproduction

Currently viewing:

Administrative data

Endpoint:
two-generation reproductive toxicity
Remarks:
based on test type (migrated information)
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Study period:
No data
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: Publication available for review, poorly described methods, deviations from Guideline, insufficient for full assessment.

Data source

Reference
Reference Type:
publication
Title:
The effects of disodiumetidronate on the reproductive functions and embryology of albino rats and New Zealand rabbits
Author:
Nolen, GA and Buehler, EV
Year:
1971
Bibliographic source:
Toxicol Appl Pharmacol, 18, 548 - 561

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
To investigate the potential for reproductive and developmental toxicity.
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Disodium salt of ethane-1-hydroxy-1-diphosphonic acid
No further details.

Test animals

Species:
rat
Strain:
not specified
Sex:
male/female

Administration / exposure

Route of administration:
oral: feed
Vehicle:
other: feed
Details on mating procedure:
One male, one female placed in mating cages. Start of pregnancy determined from positive vaginal smear.
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
Exposure period: continuous or GD 5-15
Frequency of treatment:
Daily
Details on study schedule:
F0 females were allowed to deliver two litters (F1a, F1b) while a third (F1c) was used for a teratology evaluation (see later record). F1a litters discarded after weaning, F1b litters used for breeding F2 generation. F2a litters discarded after weaning, F2b litters used for teratology (see later record). Disodium HEDP was either administered continuously to both sexes, or to pregnant females on GD 5 - 15.
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 0.1% or 0.5%
Basis:
nominal in diet
No. of animals per sex per dose:
22
Control animals:
yes, concurrent vehicle

Examinations

Parental animals: Observations and examinations:
Sex: males and females

Age: not stated

Weight: not stated

Supplier: Charles River (strain not specified)

Group sizes: 22/sex/treatment for F0/F1; 20/sex/treatment for F1b/F2

Housing: individually housed, stainless steel cages, for 8 wk pre-mating; housed in pairs during mating; pregnant females individually housed in nesting cages.

Acclimation: 8 weeks

Note: doses stated to represent 1/12 or 1/3 of the LD50 dose (1.34 g/kg) hence target doses presumed to be 112 mg/kg bw/d and 447 mg/kg bw/d.

- vehicle: ground Purina Laboratory Chow, ad libitum

- dosing schedule: either fed continuously to both sexes or to pregnant females only on GD 5-15; start of continuous treatment period not stated.

- water: ad libitum



Standardisation of litters

Culled to 8 pups during lactation (no further details)

PARENTAL ASSESSMENTS

- body weights: weekly, from 8 wk pre-mating

- food intake : weekly, from 8 wk pre-mating

- no other parameters recorded

NECROPSY

- 5 weanling F1b pups/sex/treatment (not used for breeding) were subject to necropsy and histological examination (no further details)

- 5 dams/treatment group evaluated histologically during each teratology phase (no further details)
Statistics:
ANOVA performed "on the appropriate data", partitioning used the Tukey minimum significant difference test (no further details).

Results and discussion

Results: P0 (first parental animals)

Effect levels (P0)

Key result
Dose descriptor:
NOAEL
Effect level:
> 447 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No effects on P0 observed at high dose level

Results: F1 generation

Effect levels (F1)

Key result
Dose descriptor:
NOAEC
Generation:
F1
Effect level:
447 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
developmental neurotoxicity

Overall reproductive toxicity

Key result
Reproductive effects observed:
no
Lowest effective dose / conc.:
447 mg/kg bw/day
Treatment related:
no
Dose response relationship:
no
Relevant for humans:
not specified

Any other information on results incl. tables

GENERAL

Growth, feed consumption and feed efficiency from weaning to maturity not significantly affected by treatment (data not reported)

Effects with dose level: 0, 0.1%, 0.5%

MATERNAL TOXICITY

There were a total of 5 unscheduled maternal deaths among females given 0.5% HEDP on GD 5-15:

·        Four F0 females (2 continuous treatments, 2 treated on GD 5 - 15) died prior to study termination (i.e. before birth of F1b). Cause: 1 case of pneumonia, 1 thyroid tumor, 2 unspecified.

·        Another high dose female (treated on GD 5 - 15) "died on day 25 of the third phase" (i.e. phase of study unclear), two days subsequent to delivery of 7 dead pups, with 5 pups remaining in the uterus.

PREGNANCY DATA

·        Number of pregnancies (%): no significant effect or qualitative trend after continuous feeding to both sexes or on GD 5 - 15 to pregnant females of F0 or F1b generations.

·        Pregnancy rates (%): no significant effect or qualitative trend after continuous feeding to both sexes or on GD 5 – 15 to pregnant females of F0 or F1b generations.

NECROPSY / HISTOPATHOLOGY FINDINGS

·        No treatment related pathology present (no further details)

LITTER DATA

Treatment during organogenesis (GD 5 - 15) resulted in a significant reduction (P<0.05) in the number of live F1a pups born to F0 dams fed 0.05% disodium HEDP and a non-significant increase in the number of stillborn F1b fetuses at this treatment level. F0 dams given 0.1% disodium.

HEDP on GD 5 - 15 had significantly more pups than controls or test animals fed the same dietary level continuously.

Mean live litter size:

·        F0 for F1a:

+ Continuous feeding: 13.0/12.2/12.6

+ Fed GD 5 - 15: 13.0/12.7/9.8 (P<0.05)

·        F0 for F1b:

+ Continuous feeding: 10.4/10.2/12.8

+ Fed GD 5 - 15: 10.4/13.5 (P<0.05)/12.7

Mean number stillborn per litter:

·        F0 for F1a:

+ Continuous feeding: 2/4/2

+ Fed GD 5 - 15: 2/2/5

·        F0 for F1b:

+ Continuous feeding: 6/10/9

+ Fed GD 5 - 15: 6/15/22

The number of live births for the F2a litters was indistinguishable from control.

Preweaning mortality, mean number weaned per litter, mean weaning weight: no significant effect or qualitative trend

In F1a, F1b and F2a litters after continuous feeding to both sexes or on GD 5 - 15 to pregnant females.

Applicant's summary and conclusion

Conclusions:
Pregnancy rate was unaffected by treatment with 0.1% or 0.5% disodium HEDP (equivalent to approx. 112 mg/kg bw/d or 447 mg/kg bw/d), given either continuously to both sexes or to females only on GD 5-15. Live litter size was decreased in dams given 0.5% on GD 5-15, suggesting fetotoxicity.
Executive summary:

The disodium salt of HEDP was fed in a 2-generation study via the diet to Charles River rats at dose levels of 0, 112 or 447 mg active salt/kg bw/d (Nolen and Buehler, 1971).

The test material was dosed continuously to both sexes, or to pregnant females between gestation days 5-15. No treatment-related effects on pregnancy rate were observed. The F0 females were allowed to deliver two litters (i.e., F1a, F1b) while a third (F1c) was used for a teratology evaluation.

For the mating procedure, one male and female rat was placed in a mating cage. The start of pregnancy was determined on the basis of a positive vaginal smear. Five weanlings of F1a were subject to necropsy and histological examinations. The remaining pups of F1a were discarded after weaning. Litters of F1b were used for breeding the F2 generation. The group sizes were 22/sex/treatment for F0 and F1 and 20/sex/treatment for F1b and F2.

In-life observations such as body weights and food intake were recorded from 8 weeks pre-mating on. The litter observations were not described. Generally, growth, feed consumption and feed efficiency from weaning to maturity were not significantly affected by the treatment. There were also no treatment-related effects on pregnancy rate, number of live litter size and mean number of stillborn per litter.

The NOAEL for reproductive toxicity was determined to be greater than 447 mg/kg bw/d, the highest dose tested. There was only limited information available with regard to the study design. However, a few deviations from the OECD guideline protocol were apparent.