Perchloric acid

Toxicity to reproduction

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:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Well conducted study performed according to OECD and EPA guidelines. The top-dose was not based on dose-limiting toxicity but on antithyroid effects, limiting the sensitivity of the study for classification for effects on Fertility. Justification for read-across : Perchloric acid, once absorbed in the general circulation is expected to be transformed into perchlorate moiety because of the blood buffering effect. Mammalian toxicity data of a perchlorate salt : ammonium perchlorate (CAS no. 7790-98-9), has been used for read across where data gaps for perchloric acid exist.

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

2001

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.3800 (Reproduction and Fertility Effects)

Deviations:

not specified

Test guideline 2

Qualifier:

according to guideline

Guideline:

OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)

Deviations:

yes

Remarks:

Highest dose chosen with the aim to induce antithyroid effects, but not based on dose-limiting toxicity.

GLP compliance:

not specified

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

Molecular formula:

ClHO4.H3N

IUPAC Name:

ammonium perchlorate

Test material form:

solid: particulate/powder

Remarks:

migrated information: powder

Details on test material:

Name: Ammonium perchlorate
Purity: 99.8%
Supplier: Aldrich Chemical Company, Inc. (Milwaukee, WJ
Batch: 03907LF

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories Inc. (Portage, MI)
- Age at study initiation: (P) 38 and 39 days old on arrival
- Weight at study initiation: no data
- Fasting period before study: no data
- Housing: individual except during mating and lactation (females)
- Diet (e.g. ad libitum): no data
- Water (e.g. ad libitum): continuons access to test material in their drinking water.
- Acclimation period: no data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2° C
- Humidity (%): 50 ± 15%
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

oral: drinking water

Vehicle:

water

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
Test formulations of ammonium perchlorate in deionized water were prepared weekly at concentrations that yielded target doses of 0, 0.3, 3, and 30 mg/kgday.
Perchlorate stock solution at a concentration of 50 mg/ml was prepared, then each week appropriate dilutions of the stock solution were made to deliver the target dose, based on actual measured body weight and water consumption from the previous week.

Details on mating procedure:

- M/F ratio per cage: 1
- Length of cohabitation: 2 weeks
- Proof of pregnancy: vaginal plug or sperm in vaginal smear, referred to as day 0 of pregnancy
- No replacement of males or further mating.
- Verification of same strain and source of both sexes: yes
- After successful mating each pregnant female was caged (how): in a nesting box

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The concentrations of the ammonium perchlorate dosing solutions were verified by ion chromatographie analysis to be within an acceptable range of± 10%.

Duration of treatment / exposure:

P1: 113 to 137 days
F1 adults: 125 to 142 days
(incl. at least 70 days before mating, up to 2-week mating, 3-week gestation, 3-week lactation)

Frequency of treatment:

Continuous (treated water ad libitum)

Details on study schedule:

- F1 parental animals not mated until 70 days of exposure after selected from the F1 litters.
- Selection of parents from F1 generation when pups were weaned/21 days of age.
- Age at mating of the mated animals in the study: at least 15 weeks

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 0.3, 3, and 30 mg/kg/day.
Basis:
nominal conc.

No. of animals per sex per dose:

30

Control animals:

yes, concurrent vehicle

Details on study design:

- Rationale for animal assignment: random

Positive control:

no

Examinations

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily for viability

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: daily

FOOD CONSUMPTION: Yes
- Time schedule: daily

WATER CONSUMPTION AND COMPOUND INTAKE: Yes
- Time schedule for examinations: daily
- Calculated as mg/kg/day from body weight data

THYROID HORMONE LEVELS:
TSH, T3 and T4 in serum at sacrifice after weaning of pups.

Oestrous cyclicity (parental animals):

Estrous cycling for the P generation female rats was evaluated daily beginning 21 days before the scheduled cohabitation period and continuing until evidence of mating. This was considered to be DG 0.

Sperm parameters (parental animals):

A sample from the left cauda epididymis was used for evaluation of sperm motility using the Hamilton Thome Computer Assisted Sperm Analyzer (CASA). A suspension prepared from the remaining portion of the left cauda epididymis was used to morphologically examine approximately 200 sperm per rat at 400x to IOOOx magnification. Morphological end points analyzed consisted predominantly of head and tail abnormalities.
The suspension remaining after the preparation of slides for morphology for each rat was homogenized to determine cauda epididymal sperm concentration (sperm per gram oftissue weight).

Litter observations:

STANDARDISATION OF LITTERS: not indicated, but there were at most 30 rats/sex/dose/offspring generation

PARAMETERS EXAMINED
The following parameters were examined in F1 / F2 offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical abnormalities
Each litter was evaluated for viability at !east twice each day of the 21-day postpartum period. Dead pups observed at these times were removed from the nesting box.
The pups present in each litter were counted once each day. Physical signs (including gross external physical anomalies) were recorded for the pups once each day during the preweaning and postweaning periods. Pup body weights and observations of nursing behavior were recorded along with the sex of the pups on DLs 1 (birth), 4, 7, 14, and 21. In addition, body weights and feed and water consumption were recorded for F 1 generation adult rats.

GROSS EXAMINATION OF DEAD PUPS:
- evaluation of vital status at birth (to identify stillborn pups)
- gross exam. for external and internal abnormalities; possible cause of death was determined for pups born or found dead.
Gross necropsy, blood collection for thyroid hormone anal ysis, histopathology, and anal y sis of sperm parameters were conducted on F1 generation adult rats as was described for the P generation.
F2 generation pups were sacrificed on DL 21. At !east three pups/sex/litter were necropsied and examined for gross lesions, including a single cross-section of the head for apparent hydrocephaly.
Histopathological evaluation was performed on adrenal glands, brain, thyroid/parathyroid, liver, spleen, kidneys, and thymus. The brain, thymus, and spleen were also weighed. Following fixation, thyroids were carefully trimmed and weighed, and sent to Research Pathology Services, Inc., for histopathological evaluation. Whole blood samples, pooled by sex per litter, collected into serum separator tubes, and centrifuged, were sent for analysis of TSH, T3, and T4 levels as previously cited.
THYROID HORMONE LEVELS:
TSH, T3 and T4 in serum at sacrifice of pups after weaning

Postmortem examinations (parental animals):

SACRIFICE
- Male and female animals: all surviving animals after the last litter of each generation was weaned

GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera

HISTOPATHOLOGY / ORGAN WEIGHTS
Organs/tissues were prepared for microscopic examination and weighed as required by OECD 416.

Postmortem examinations (offspring):

SACRIFICE
- The F1 offspring not selected as parental animals and all F2 offspring were sacrificed at 21 days of age (weaning).
- 3 pups/sex/litter/generation were subjected to postmortem macroscopic and microscopic examination as follows:

GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.

HISTOPATHOLOGY / ORGAN WEIGTHS
Organs/tissues were prepared for microscopic examination and weighed as required by OECD 416. Thyroids/parathyroids were also weighed.

Statistics:

Clinical observations and other proportion data were analyzed using the variance test for homogeneity of the binomial distribution. Continuous data (e.g., body weights, body weight changes, feed consumption data, organ weights, duration of gestation, litter averages for pup body weights, percent male pups, pup viability, and cumulative survival) were analyzed using Bartlett's test of homogeneity of variances and the analysis of variance, when appropriate (i.e., when Bartlett's test was not significant [p > .05]). If the analysis of variance was significant (p =< .05), Dunnett's test was used to identify the statistical significance of the individual groups. If the analysis of variance was not appropriate (i.e., when Bartlett's test was significant (p =< .05), the Kruskal-Wallis test was used, when 75% or fewer ties were present; when more than 75% ties were present, Fisher's Exact Test was used. In cases where the Kruskal-Wallis test was statistically significant (p =< .05), Dunn's method of multiple comparisons was used to identify the statistical significance of the individual groups. Ail other natural delivery data involving discrete data were evaluated using the Kruskal-Wallis test procedures previously described.

Reproductive indices:

Mating index:
Number of mated animals
-----------------------x 100
Number of paired animals

Fertility index:
Number of pregnant female partners
---------------------------------x 100
Number of mated pairs

Gestation index:
Number of females with live born pups
----------------------------------x 100
Number of pregnant females

Offspring viability indices:

Live birth index:
Number of live born pups
----------------------- x 100
Number of delivered pups

Viability index on day 4 post-partum:
Number of surviving pups on day 4 post-partum
------------------------------------------- x 100
Number of live born pups

Lactation index on day 21 post-partum:
Number of surviving pups on day 21 post-partum
-------------------------------------------- x 100
Number of surviving pups on day 4 post-partum

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

no effects observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Other effects:

no effects observed

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:

no effects observed

Reproductive function: sperm measures:

no effects observed

Reproductive performance:

no effects observed

Details on results (P0)

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
P: There were no deaths, abortions, or premature deliveries attributed to exposure to ammonium perchlorate. No clinical observations were considered related to the ammonium perchlorate exposure because the incidences were not dose-dependent and the observations that were noted commonly occur in this laboratory with this strain of rat.

F1: There were no deaths, abortions, or premature deliveries. All clinical observations that occurred in the F1 generation male and female rats were considered unrelated to the test substance.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
P: Average body weights for male or female rats (during the precohabitation, gestation, and lactation periods) were comparable among the four exposure groups through DS 134.
F1: Terminal body weights for the male F1 generation rats were significantly increased in the 0.3 mg/kg-day dose group, a non-dose-dependent event, unrelated to ammonium perchlorate exposure. Terminal body weights for the female rats were unaffected by the test substance.

TEST SUBSTANCE INTAKE (PARENTAL ANIMALS)
P: Absolute (g/day) and relative (g/kg/day) water consumption values for male rats in both 0.3 and 30 mg/kg-day dose groups were significantly reduced (p =< .05), compared to the control group. These reductions in water consumption were considered treatment-related because they were dose-dependent and occurred over the entire exposure period. In contrast, average maternai absolute and relative water consumption values during the precohabitation, gestation, and lactation periods were comparable among the four groups.
Absolute (g/day) and relative (g/kg/day) feed consumption values for the male and female rats were generally unaffected by doses of ammonium perchlorate as high as 30 mg/kg-day.
F1: Absolu te and relative water and feed consumption values for F1 generation male and female (during precohabitation, gestation, and lactation periods) rats were unaffected by exposures up to 30 mg/kg-day of ammonium perchlorate.

REPRODUCTIVE FUNCTION: ESTROUS CYCLE (PARENTAL ANIMALS)
P: Estrous cycling, mating, and fertility parameters in P generation females were unaffected by doses as high as 30 mg/kg-day. There were no differences between controls and treated groups in the number of estrous stages per 14 days or the number of rats with normal length of estrous cycles.
F1: Estrous cycling observations were comparable among the treated female rats prior to cohabitation. There were no differences between controls and treated groups in the number of estrous stages per 14 days or the number of rats with normal Iength of estrous cycles.

REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS)
P: No statistically significant or dose-dependent differences occurred in sperm motility, sperm count, sperm density, or morphology by doses of ammonium perchlorate as high as 30 mg/kg-day.
F1: No statistically significant or dose-dependent differences occurred; sperm motility, count, morphology, and density were unaffected by doses of ammonium perchlorate as high as 30 mg/kg-day.

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
P: Mating and fertility parameters in male P generation rats were unaffected by exposure to ammonium perchlorate at doses up to 30 mg/kg-day.
F1: There was no effect on the number of days in cohabitation or the number of rats mating during the first or second week of cohabitation. The average day of vaginal patency for the treated F 1 female rats was comparable to control rats.
Mating and fertility in F 1 male rats were comparable between control and dose groups. Doses of ammonium perchlorate as high as 30 mg/kg-day did not affect the average day of preputial separation for the FI male rats. The fertility index and the numbers of rats pregnant per rats in cohabitation were significantly increased in the 0.3, 3, and 30 mg/kg-day dose groups, compared to the control group. This increase in fertility of the male rats exposed to ammonium perchlorate was considered unrelated to treatment because the values were not dose-dependent and were probably due to the lower fertility in the control group used for the statistical comparison.

ORGAN WEIGHTS (PARENTAL ANIMALS)
P: Absolute thyroid weights for the female rats were significantly increased in the 30 mg/kg-day dose group, compared to the control group. The ratios of thyroid weight to terminal body weight and to the absolute brain weight were significantly increased in the 30 mg/kg-day dose group for both the male and female rats. Absolute and relative weights for the other organs collected at necropsy were comparable to control values.
F1: Thyroid weights and the ratios of the thyroid weight to the terminal body weight and to the brain weight were significantly increased for the male rats in the 3 and 30 mg/kg-day dose groups, and for the female rats in the 0.3, 3, and 30 mg/kg-day dose groups. These increases in absolute and relative thyroid weights are considered treatment-related because they were dose-dependent.

HISTOPATHOLOGY (PARENTAL ANIMALS)
P: Exposure-related histomorphologic changes were observed only in the thyroid gland. These changes occurred in both males and females and were primarily hypertrophy and hyperplasia of the thyroid follicular epithelium. In many of the affected thyroids there were increased numbers of small follicles (hyperplasia) and these follicles had enlarged (hypertrophied) follicular epithelial cells. In the thyroids with a moderate or marked hyperplasiahypertrophy, there was a decrease or complete absence of visible colloid in the affected follicles.
The degree of the thyroid change ranged from minimal to marked and generally occurred in an exposure-related fashion. The incidence of hyperplasia/ hypertrophy was significantly increased (p =< .05) in the 3 and 30 mg/kg-day dose groups. An increased incidence of the hyperplasia/hypertrophy, albeit not significant, also occurred in the 0.3 mg/kg-day dose group and was judged to be exposure-related.
All other microscopic changes observed in the other organs and tissues specified for examination from the male and female rats exposed to 30 mg/kg-day of ammonium perchlorate were considered to have occurred spontaneously and be typical of those that occur in rodent reproductive studies. Therefore, all other pathologic changes were unrelated to exposure.
F1: Exposure-related histomorphologic changes were observed in the thyroid gland of the adult male and female F1 generation rats. These changes were primarily hypertrophy and hyperplasia of the thyroid follicular epithelium and were similar to that seen in the thyroid of the P generation. The incidence of hyperplasia/hypertrophy was significantly increased (p =<.05) in male rats from the 3 and 30 mg/kg-day dose groups and in female rats
from the 30 mg/kg-day dose group.
All the microscopic changes observed in the other organs and tissues specified for examination from the F1 generation male and female parental rats were considered to have occurred spontaneously.

Effect levels (P0)

1

Key result

Dose descriptor:

NOAEL

Remarks:

Parental toxicity

Effect level:

0.3 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Relevant antithyroid effects in P1 and F1 adults from 3 mg/kg/day.

Remarks on result:

other: Generation: P1 and F1 adults (migrated information)

2

Key result

Dose descriptor:

NOAEL

Remarks:

Offspring toxicity

Effect level:

0.3 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Based on antithyroid effects at higher doses. Relevant antithyroid effects in F1 and F2 pups from 3 mg/kg/day.

Remarks on result:

other: Generation: F1 and F2 pups (migrated information)

3

Key result

Dose descriptor:

NOAEL

Remarks:

Reproduction toxicity

Effect level:

>= 30 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Absence of effects towards reproduction at up to the maximal tested dose.

Remarks on result:

other: Generation: all generations (migrated information)

Results: F1 generation

General toxicity (F1)

Clinical signs:

no effects observed

Mortality / viability:

no mortality observed

Body weight and weight changes:

no effects observed

Sexual maturation:

no effects observed

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

no effects observed

Histopathological findings:

effects observed, treatment-related

Details on results (F1)

NECROPSY, ORGAN WEIGHTS
F2: All clinical and necropsy observations in the F2 generation pups were considered unrelated to ammonium perchlorate treatment. Thyroid weight was significantly increased for the female F2 generation pups in the 30 mg/kgday dose group. The weights of all other organs were unaffected by exposures to ammonium perchlorate as high as 30 mg/kg-day.

NATURAL DELIVERY AND LITTER OBSERVATIONS
P: Natural delivery observations were unaffected by exposure to ammonium perchlorate doses as high as 30 mg/kg-day. The gestation index was 100% in each group. The number of dams delivering litters, the duration of gestation, averages for implantations, live litter sizes and stillbirths, dams with stillborn pups, viability and lactation indices, sex ratios, and pup body weights were comparable among the four groups and did not significantly
differ. No dams had all pups die before DL 21. The lactation index was significantly increased in the 3 (p =< 0.05) and 30 (p =< 0.01) mg/kg/day dose groups compared to the control group. These increases were not considered treatment-related because the expected effect of a toxicant would be a decrease, rather than an increase. in pup survival.
F1: Observations in natural delivery and lactation were unaffected by treatment. The percentages of liveborn pups and stillborn pups were significantly decreased and increased, respectively, in the 30 mg/kg-day dose group. These changes are considered unrelated to ammonium perchlorate treatment because the average number of Iiveborn and stillborn pups per litter were comparable in the four exposure groups.

HISTOPATHOLOGY
F1: Exposure-related histomorphologic changes were observed in the thyroid gland of F1 generation male and female pups. These changes were primarily hypertrophy and hyperplasia of the thyroid follicular epithelium. Similar to the observations in P adults, in many of the affected thyroids there were increased numbers of small follicles (hyperplasia) and these follicles had enlarged (hypertrophied) follicular epithelial cells. In the thyroids with a moderate or marked hyperplasia/hypertrophy, there was a decrease or complete absence of visible colloid in the affected follicles.
The degree of the thyroid change ranged from minimal to marked and generally occurred in an exposure-related fashion. The incidence of hyperplasia/hypertrophy was significantly increased (p =< 0.05) in the 30 mg/kg/day dose group for both the male and female pups and in the 3 mg/kg/day dose group for the female pups. An increased incidence and severity of hyperplasia/hypertrophy, albeit not significant, also occurred in the 3 mg/kg/day dose group in the male pups and was considered to be exposure-related. The incidence in the 0.3 mg/kg/day dose group F1 generation male and female pups was comparable to the control group. All other microscopic changes observed in the other organs and tissues specified for examination were considered to have occurred spontaneously.
F2: Exposure-related histomorphologic changes were observed in the thyroid gland of male and female F2 generation pups. The incidence of hyperplasia/ hypertrophy was significantly increased in the 3 and 30 mg/kg/day dose groups. The incidence in the 0.3 mg/kg/day dose group is considered comparable to the control group.

Effect levels (F1)

Key result

Dose descriptor:

NOAEL

Generation:

other: F1 and F2

Effect level:

0.3 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Based on antithyroid effects at higher doses. Relevant antithyroid effects in F1 and F2 pups from 3 mg/kg/day.

Overall reproductive toxicity

Reproductive effects observed:

not specified

Any other information on results incl. tables

Thyroid and pituitary hormone analyses

P: For the P generation adult male rats, a significant increase (p ≤ .05) in TSH levels and a concomitant significant decrease (p ≤ 0.05) in T4 values occurred in the 30 mg/kg-day dose group, as compared to the control group value. Significant increases (p ≤ 0.05) in serum T3 levels occurred in the 0.3 and 3 mg/kg-day dose groups, as compared to the control group value but it is not considered an effect of ammonium perchlorate exposure as a decrease would be expected. Thyroid and pituitary hormone levels in the female P generation rats were unaffected by exposure to ammonium perchlorate as high as 30 mg/kg-day.

F1 Generation pups: Serum T3 level was significantly reduced (p ≤ 0.05) for the female pups in the 30 mg/kg-day dose group, compared to the control group value. This reduction in serum T3 level is considered an effect of ammonium perchlorate exposure because the reduction was exposure dependent and ammonium perchlorate is known to cause a decrease in serum T3 production (Siglin et al. 2000). TSH levels were significantly reduced (p ≤ 0.05) for male pups in the 0.3 and 3 mg/kg-day dose groups, compared to the control group value. Serum T4 values were significantly increased (p ≤ 0.05) for female pups in the 0.3 mg/kg/day dose group but it is not considered an effect of ammonium perchlorate exposure as a decrease would be expected.

F1 adult rats: For the F1 generation adult male and female rats, a significant increase in serum TSH levels occurred in the 30 mg/kg-day dose group, as compared to the control group value. A concomitant significant decrease in serum T4 values occurred in male rats in the same dose group. Significant increases in serum T4 levels occurred in male rats in the 0.3 and 3 mg/kg-day dose groups, as compared to the control group value. These increases in serum T4 levels are not considered to be treatment related.

F2: Thyroid and pituitary hormone levels in the F2 generation pups were unaffected by parental exposure to doses of ammonium perchlorate as high as 30 mg/kg-day.

Applicant's summary and conclusion

Conclusions:

Parental NOAEL was 0.3 mg/kg/day due to antithyroid effects. However, the parental MTD was above 30 mg/kg/day in the absence of relevant general toxicity (excluding antithyroid effects).

Offspring NOAEL was 0.3 mg/kg/day based on anti-thyroid effects at higher doses.

Reproduction NOAEL set at 30 mg/kg/day in the absence of effects on reproductive function at the doses investigated.

The top-dose was not based on dose-limiting toxicity but on antithyroid effects, limiting the sensitivity of the study for classification for effects on Fertility.

Executive summary:

A two-generation study was conducted in rats exposed to ammonium perchlorate at 0, 0.3, 3 and 30 mg/kg/day.

At 30 mg/kg/day, there was a clear antithyroid effect in P1 and F1 adults and F1 and F2 pups: lower serum T3 (female pups) or T4 levels (male adults), higher serum TSH level (adult P1 males, adult F1 males and females), higher absolute and (when determined) relative thyroid weights (in all conditions), minimal to marked thyroid follicle hypertrophy and hyperplasia (in all conditions). There was no general parental toxicity: the maximal tolerated dose was not reached, limiting sensitivity of the study according to summary author. No effects on reproduction and in particular fertility and pup growth were noted. At 3 mg/kg/day, no relevant hormonal effects were noted; thyroid weight was affected in adults only; however, incidence and severity of thyroid follicle lesions was increased in all conditions (except possibly in F1 adult females were it was not obvious). At 0.3 mg/kg/day, no relevant hormonal effects were noted; thyroid weight was minimally increased in F1 adult females but this was considered not biologically relevant; no relevant effect on thyroid lesions.