Potassium perchlorate

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Published summary of a modern, GLP- and guideline-compliant study

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

2000

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.3100 (90-Day Oral Toxicity in Rodents)

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Ammonium perchlorate

EC Number:

232-235-1

EC Name:

Ammonium perchlorate

Cas Number:

7790-98-9

IUPAC Name:

ammonium perchlorate

Test material form:

not specified

Details on test material:

Ammonium perchlorate (Aldrich); 99.8% purity

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Springborn Ohio
- Age at study initiation: 7 weeks
- Housing: individual
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 2
- Humidity (%): 50 +/- 15
- Air changes (per hr): 12-15
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

oral: drinking water

Vehicle:

water

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Selective ion chromatography (HPLC)

Duration of treatment / exposure:

90-days

Frequency of treatment:

Daily / continuous (in drinking water)

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 0.1, 0.5, 0.2, 1, 10 mg/kg bw/d
Basis:
other: target dose level

No. of animals per sex per dose:

30

Control animals:

yes, concurrent no treatment

Details on study design:

Dose selection was based on a 14-day pilot study and was intended to identify a NOAEL for effects on thyroid hormone levels

Positive control:

Not required

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION:
- Time schedule: weekly

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: Weekly

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: pre-test, Day 90, Day 120 (recovery)
- Dose groups that were examined: all

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Days 14, 90, 120 (recovery)

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Days 14, 90, 120 (recovery)

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

OTHER: oestrus cycling, measurement of throid hormone levels (T3, T4, TSH)

Sacrifice and pathology:

GROSS PATHOLOGY: Yes - all animals
HISTOPATHOLOGY: Yes - comprehensive

Other examinations:

Sperm analysis was performed on all males at termination on Days 90 or 120.

Bone marrow PCEs were assessed for the incidence of micronuclei.

Statistics:

ANOVA, Chi-square test

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

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:

no effects observed

Haematological findings:

no effects observed

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

effeccts on TSH and thyroid hormones in all treated groups

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

increased thyroid weight (absolute and relative) at 10 mg/kg bw/d

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

thyroid histopathology at 10 mg/kg bw/d

Histopathological findings: neoplastic:

no effects observed

Details on results:

The effects of treatment in this study were limited to the thyroid. Increased TSH and reduced T3 and T4 levels were seen in all treated groups; findings were associated with increased thyroid weight and histopathology at the highest dose level of 10 mg/kg bw/d.

Effect levels

1

Dose descriptor:

NOAEL

Effect level:

1 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Statistically significant changes in TSH and thyroid hormone levels were seen in all groups but were not accompanied by changes in thyroid weight or histopathology at 1 or 10 mg/kg bw/d

2

Dose descriptor:

LOEL

Effect level:

0.01 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Statistically significant changes in TSH and thyroid hormone levels were seen in all group

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

A NOEL cannot be determined for this study due to effects on TSH and thyroid hormone levels in all treated groups. However the authors conclude a NOAEL of 1 mg/kg bw/d in the absence of any effects on thyroid weight and histopathology with the exception of the highest dose group (10 mg/kg bw/d).

Applicant's summary and conclusion

Conclusions:

The study identified the thyroid as the target of toxicity for ammonium perchlorate. A NOEL cannot be determined for this study due to effects on TSH and thyroid hormone levels in all treated groups. However the authors conclude a NOAEL of 1 mg/kg bw/d in the absence of any effects on thyroid weight and histopathology with the exception of the highest dose group (10 mg/kg bw/d).

Executive summary:

The purpose of this study was to evaluate the subchronic toxicity of perchlorate when administered to Sprague-Dawley rats as ammonium perchlorate (AP) for 14 or 90 days. The study consisted of an untreated control group and five treatment groups that received continuous exposure to AP via the drinking water at dosage levels of 0.01, 0.05, 0.2, 1.0, and 10.0 mg/kg/day. The study design included a nontreatment recovery period of 30 days to evaluate the reversibility of any AP-induced effects at the 0.05, 1.0, and 10.0 mg/kg/day levels. The study also investigated the potential effects of AP on male sperm parameters, female estrous cyclicity, bone marrow micronucleus formation, and serum hormone levels, i.e., triiodothyronine (T(3)), thyroxine (T(4)), and thyroid stimulating hormone (TSH). No toxicologically meaningful differences were observed between the control and AP-treated groups with respect to survival, clinical observations, body weights, food consumption, water consumption, ophthalmology, hematology, clinical chemistry, estrous cycling, sperm parameters, or bone marrow micronucleus formation. A target organ effect was produced by AP in the thyroids of male and female rats at the 10 mg/kg/day level after 14 and 90 days of exposure. The effect was characterized by significantly increased thyroid weights and thyroid histopathology consisting primarily of follicular cell hypertrophy with microfollicle formation and colloid depletion. These changes were reversible after a nontreatment recovery period of 30 days. Statistically significant changes in TSH and thyroid hormones were observed at all AP dosage levels tested; however, no thyroid organ weight or histopathological effects were observed at AP dosage levels < or = 1.0 mg/kg/day. In the absence of thyroid organ weight and histopathological effects, the toxicological significance of TSH and thyroid hormone changes at AP dosage levels < or = 1.0 mg/kg/day remains to be determined.

A NOEL cannot be determined for this study due to effects on TSH and thyroid hormone levels in all treated groups. However the authors conclude a NOAEL of 1 mg/kg bw/d in the absence of any effects on thyroid weight and histopathology with the exception of the highest dose group (10 mg/kg bw/d).