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Diss Factsheets

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:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study without detailed documentation

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
2003

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
Deviations:
no
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Ammonium perchlorate
EC Number:
232-235-1
EC Name:
Ammonium perchlorate
Cas Number:
7790-98-9
Molecular formula:
ClHO4.H3N
IUPAC Name:
ammonium perchlorate
Test material form:
solid

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
The test animals were obtained from Charles River Laboratories (Raleigh, NC)and aged 59 days (female) and 73 days (male), respectively.

Administration / exposure

Route of administration:
oral: drinking water
Vehicle:
water
Details on exposure:
Exposure was started 14 days before cohabitation and continued through sacrifice.
Duration of treatment / exposure:
90 days for exposure period starting 14 days prior to cohabitation.
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (nominal)
Remarks:
control group
Dose / conc.:
0.01 mg/kg bw/day (nominal)
Dose / conc.:
0.1 mg/kg bw/day (nominal)
Dose / conc.:
1 mg/kg bw/day (nominal)
Dose / conc.:
30 mg/kg bw/day (nominal)
Dose / conc.:
0 mg/kg bw/day (actual dose received)
Remarks:
control group; consumed average doses during the 3-week gestation period
Dose / conc.:
0.01 mg/kg bw/day (actual dose received)
Remarks:
consumed average doses during the 3-week gestation period
Dose / conc.:
0.08 mg/kg bw/day (actual dose received)
Remarks:
consumed average doses during the 3-week gestation period
Dose / conc.:
0.7 mg/kg bw/day (actual dose received)
Remarks:
consumed average doses during the 3-week gestation period
Dose / conc.:
21.69 mg/kg bw/day (actual dose received)
Remarks:
consumed average doses during the 3-week gestation period
Control animals:
yes, concurrent no treatment
Details on study design:
All rats in the main study and in the satellite study were observed for viability at least twice daily and for general appearance at least once during the pre-exposure period.
daily examination during the exposure period for clinical observations: effects abortions, premature deliveries, and deaths caused by the test item
daily recording of: body weights, feed and water consumption
A main study (fetal examination at day 21 after mating) and a satellite study (maternal and fetal blood samples for determination of T3, T4 and TSH levels) were performed.

Examinations

Fetal examinations:
Cesarean-sectioning observations on day 21 after mating were based on 19, 19, 17, 20, and 20 pregnant dams in the five respective exposure groups.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
Effects were considered non-treatment related as they were not dose-dependent.
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Only transient and of a singular occurence increases and decreases measured, not statistically significant.
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
Changes in concentrations of thyroid hormons (TSH, T4, T3) and increase in thyroid weights, see detailed table.
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
not examined
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
not examined

Maternal developmental toxicity

Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
effects observed, treatment-related
Description (incidence and severity):
The averages for litter size and for the number of live fetuses were significantly reduced (p <= 0.05) in the 30.0 mg/kg-day exposure group.
These reductions were not considered treatment-related because:
(1) the values were within the ranges observed historically at the testing fadlity
(2) the values were not loxicologically important because there were no significant increases in fetal deaths or resorptions nor significant reductions in number of implantations.
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in pregnancy duration:
not examined
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 examined
Changes in number of pregnant:
no effects observed

Effect levels (maternal animals)

open allclose all
Key result
Dose descriptor:
LOAEL
Effect level:
30 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
clinical biochemistry
Key result
Dose descriptor:
NOAEL
Effect level:
1 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: no effect was observed at this concentration

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
Reduction in number of live offspring:
not examined
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
not examined
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed
Other effects:
effects observed, non-treatment-related
Description (incidence and severity):
general fetale alterations, not further specified:
All alterations observed were determined to be unrelated to the test substance because the incidences were not exposure dependent; the observalion occurred in anly one or two high-exposure group fetuses; or the incidences are within the averages observed historically at the laboratory.
Changes in concentrations of thyroid hormons (TSH, T4, T3) and increase in thyroid weights, see detailed table.

Effect levels (fetuses)

Key result
Dose descriptor:
LOAEL
Effect level:
30 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Changes in concentrations of thyroid hormons (TSH, T4, T3), increase in thyroid weights and developmental delays in ossification.

Overall developmental toxicity

open allclose all
Key result
Developmental effects observed:
yes
Lowest effective dose / conc.:
30 mg/kg bw/day (nominal)
Treatment related:
yes
Relation to maternal toxicity:
developmental effects in the absence of maternal toxicity effects
Dose response relationship:
yes
Relevant for humans:
yes
Key result
Developmental effects observed:
no
Lowest effective dose / conc.:
1 mg/kg bw/day (nominal)
Treatment related:
yes

Any other information on results incl. tables

Cesarean-sectioning observations, all doses reported in nominal concentrations mg/kg bw/day

 parameter  0.0 0.01  0.1  1.0  30.0 
 litters  19 19 17 20  20 
% pregnant 95  95  85  100  100 
corpora lutea 19.3  17.9  18.1  19.8  19.8 
implants  17.0  14.7  14.4  16.6  14.8
preimplantation losses 2.3 (12%) 3.2 (18%) 3.7 (20%) 3.2 (16%) 5.0 (25%)
 litter size 16.6  14.3  13.9  16.2  14.8 
 no. of fetuses 316  271  236  325  282 
early resorptions  0.4 0.4  0.5  0.4  0.8 
late resorptions 0.0  0.0  0.0  0.0  0.0 
male fetuses per litter 47.2 53.0 47.3  50.9  47.8 
 fetal weight per litter 4.30  4.45  4.62  4.54  4.49 
 male fetal body weight 4.40  4.59  4.74  4.68  4.48 
female fetal body weight 4.20  4.28  4.49  4.40  4.38 

fetal alteration observations in rat litters, all doses reported in nominal concentrations mg/kg bw/day

 parameter 0.0  0.01  0.1  1.0  30.0 
 fetuses 316  271  236  325  282 
 litters 19  19  17  20  20 
litters with any alteration 7 (36.8%)  4 (21.0%)  8 (47.0%)  4 (20.0%)  4 (20.0%) 
 fetuses with any alteration 8 (2.5%)  4 (1.5%)  12 (5.1%)  5 (1.5%)  5 (1.8%) 
 % fetuses with any alteration per litter 2.6  1.3  5.2  1.5  1.9 

Developmental delays in ossification occurred in the 30.0 mg/kg-day group.

Thyroid effects in satellite group rats, all doses reported in nominal concentrations mg/kg bw/day

 parameter 0.0  0.01  0.1  1.0  30.0 
 terminal body weight (g) 412.5  423.2  423.8  424.0  427.0 
 absolute thyroid weight (mg) 18.36 18.81  20.48  21.49  26.28 
 relative thyroid weight 0.04  0.04  0.05  0.05  0.06 
decreased colloid 0/16 0/16  0/16  0/15 

16/16 

 hypertrophy

0/16 

0/16 

0/16 

0/15 

14/16 

 hyperplasia

0/16 

0/16 

0/16 

0/15 

2/16 

 TSH (ng/mL)

6.05 

8.18 

9.09 

9.94 

14.87 

 T4 (µg/dL)

2.31 

2.06 

1.28 

1.19 

1.06 

 T3 (ng/dL)

99.7 

97.3 

95.8 

93.1 

87.4 

Thyroid effects in satellite group rat fetuses, all doses reported in nominal concentrations mg/kg bw/day

 parameter 0.0  0.01  0.1  1.0  30.0 
 male fetuses - decreased colloid 0/16  2/16  0/16  12/16  16/16 
 male fetuses - hypertrophy 0/16  0/16  0/16  0/16  0/16 
 male fetuses - hyperplasia 0/16  0/16  0/16  1/16  0/16 
 female fetuses - decreased colloid 0/16  1/16  1/16  13/16  16/16 
 female fetuses - hypertrophy 0/16  0/16  0/16  0/16  0/16 
 female fetuses - hyperplasia 0/16  0/16  0/16  1/16  0/16 
 TSH (ng/mL) 7.22  7.29  7.80  8.26  10.78 
 T4 (µg/dL) 1.59  1.50  1.47  1.46  1.38 
 T3 (ng/dL) 23.4  19.3  16.9  16.7  15.6 

Applicant's summary and conclusion

Conclusions:
A developmental toxicity study was conducted with ammonium perchlorate (AP) in the drinking water at doses of 0.0, 0.01, 0.1, 1.0, and 30.0 mg/kg-day beginning 14 days before cohabitation and continuing through sacrifice. Twenty-four rats/group were cesarean-sectioned on day of gestation (DG) 21 and fetuses examined for visceral and skeletal alterations. An additional 16 litters/group were sacrificed on DG 21 for maternal and fetal serum TSH, T(3), and T(4) (thyroid-stimulating hormone, triiodothyronine, and thyroxine) levels and thyroid histopathology. Clinical and necropsy observations, body weights, feed and water consumption, and cesarean-sectioning parameters were comparable among the groups with only delays in ossification observed in the 30 mg/kg-day group. Maternal thyroid weights were increased in the 30.0 mg/kg-day group. Decreased colloid was present in male and female fetal thyroids in the 1.0 and 30.0 mg/kg-day groups. Maternal TSH was increased and T(4) was decreased at all levels, and T(3) was reduced at 30.0 mg/kg-day. Fetal TSH was increased at 1.0 and 30.0 mg/kg-day, T(4) was reduced at 30.0 mg/kg-day, and T(3) was decreased at all levels. The maternal no-observable-adverse-effect level (NOAEL) was 1.0 mg/kg-day; exposures of 30.0 mg/kg-day increased absolute and relative maternal thyroid weights and histopathology findings. The developmental NOAEL was 1.0 mg/kg-day; developmental delays in ossification occurred in the 30.0 mg/kg-day group. The colloid depletion in the thyroids and increased TSH and decreased T(3) and T(4) levels at lower exposures were considered adaptive and not adverse. No adverse effects on development at occurred levels that did not cause maternal toxicity.