## [Two Generation Toxicity Study in Sprague-Dawley Derived Rats]{.underline}

## [with n-Propyl Bromide (nPB)]{.underline}

## 

## Summary and Conclusions 

Two generations of Sprague-Dawley derived rats (F~0~ and F~1~) were
exposed to n-propyl bromide (nPB) for 6 hours/day, 7 days/week via whole
body inhalation for at least 70 days prior to mating, throughout mating,
and through most of gestation and lactation.

Exposure was temporarily stopped during the parturition period, from
gestation day (GD) 20 to postnatal day (PND) 5. F~1~ pups were culled on
PND 4 and were exposed via lactation until PND 21 and then directly via
inhalation until study termination. F~2~ pups were exposed via lactation
until PND 21 and sacrificed. Targeted ambient air nPB concentrations
were 0, 100, 250, 500, and 750 ppm; nominal mean exposure concentrations
were measured and shown to be close to the target concentrations: F~0~
generation -- 0, 99, 252, 505, and 750 ppm, respectively; F~1~
generation -- 0, 100, 252, and 502 ppm, respectively. No live litters
were produced in the F~0~ 750 ppm generation; therefore, there was no
F~1~ treatment group exposed to this dose.

Three deaths unrelated to treatment occurred during the experiment: one
F~0~ 500-ppm female and two F~1~ males (1 control and 1 at 500 ppm). At
750 ppm, F~0~ males displayed a decrease in mean weekly body weights and
cumulative body weight gain throughout the study; F~0~ females exhibited
a reduction in mean body weight during pre-mating weeks 5-10 and
decreased cumulative weight gain throughout the pre-mating period. At
500-ppm, F~0~ females showed a non-significant reduction in mean body
weight, weight gain, food consumption, and food efficiency during
pre-mating, gestation, and lactation. Small, nonsignificant reductions
in mean weekly body weight gains were also observed in the F~1~ males
and females in this dose group. Weight loss in the F~0~ and F~1~ 500-ppm
females during late gestation was associated with a reduction in the
mean litter size.

In the F~0~ generation, there was a statistically significant
dose-response decrease in male and female fertility indices at 500 and
750 ppm and in the mating index at 750 ppm. Infertility was 100% in the
750 ppm group and 52% in the 500 ppm group. At 500 ppm, the mean number
of implantation sites and size of live litters was also statistically
significantly reduced. In the F~1~ generation, no statistically
significant decrease in the fertility or mating index was observed at
any dose, although, there was a significant reduction in the number of
implantation sites and size of live litters at 500 ppm.

Statistically significant changes in female reproductive parameters
included a decrease in absolute and relative ovary weights at 750 ppm in
the F~0~ generation and an increase in the length of the estrus cycle at
≥ 500 ppm in F~0~ females. Estrus cycle length was increased at 500 ppm
in F~1~ females; however, the increase was not reported to be
statistically significant relative to controls. Estrus cycling was not
observed in 2 F~0~ females in the 500 ppm group, 3 F~0~ females in the
750 ppm group, 3 F~1~ females in the 250 ppm group, and 4 F~1~ females
in the 500 ppm group. Analysis of estrus cycle length by the study
authors excluded ammenorheic females. ICF reanalyzed these data and
included data from ammenorheic females in the analysis. Both estrus
cycle length and mean number of estrus cycles within a 3-week period
prior to mating (following 7 weeks exposure) were evaluated. The mean
number of estrus cycles that occurred within the 3-week period of
observation was statistically significantly decreased at ≥ 250 ppm in
F~0~ females and at 500 ppm in F~1~ females. ICF conducted a second
analysis in which data from ammenorheic females were excluded;
statistically significant decreases occurred at the same doses although
the mean number of estrus cycles was slightly increased. ICF considered
these findings to be toxicologically significant.

The number of primordial follicles and corpora lutea were compared
between high-dose groups (750 ppm for F~0~ females and 500 ppm for F~1~
females) and controls; a statistically significant increase in
primordial follicles and a decrease in corporal lutea were observed.
However, these end points were not examined in lower dose groups and
thus, a dose-response could not be determined.

Statistically significant changes in male reproductive and spermatogenic
endpoints included: (1) decreased sperm motility in the F~0~ generation
at exposures ≥ 500 ppm, and in the F~1~ generation at exposures; (2)
decreased number of normal sperm at exposures ≥ 250 ppm in F~0~
generation and at 100 and 500 ppm in the F~1~ generation; (3) reduction
in the absolute weight of the left and right cauda epididymes at
exposures ≥ 500 ppm and in the relative weight of the right cauda
epididymis at 750 ppm in the F~0~ generation, and in the absolute weight
of both epididymes at 500 ppm in the F~1~ generation; (4) decreased
absolute, but not relative, prostate weights in F~0~ (≥ 250 ppm) and
F~1~ (500 ppm) males, and (5) decreased seminal vesicle weights in F~0~
males at 750 ppm and F~1~ males at 250 ppm males. In general, most of
the organ weight changes were in absolute values, and were not
statistically significant when weights were expressed relative to body
weight, and did not show a clearcut dose-response. No associated
macroscopic or microscopic tissue changes were observed except in the
prostate gland which showed acute inflammation in F~1~, but not F~0~,
males exposed to 500 ppm. The study authors concluded that the
biological significance of these findings was unclear. Although the
number of normal sperm in the F~0~ generation was statistically
decreased in the three highest dose group relative to concurrent
controls, these numbers were within the normal background range and thus
this finding was not considered to be toxicologically significant.

Statistically significant changes in organ weights that were observed in
treated groups relative to controls included (1) decreased absolute
brain weight in F~0~ (≥ 250 ppm) and F~1~ (≥ 100 ppm) males and in F~0~
females at 750 ppm and F~1~ females at 500 ppm ; (2) decreased absolute
pituitary weights in F~0~ (750 ppm) and F~1~ (500 ppm) males, and (3)
increased absolute and relative thymus weights in F~1~ males. Most of
these changes did not show a clear dose-response and none were
associated with pathologic or histopathologic changes. Therefore, the
authors concluded that the biological significance of these findings was
unclear. Relative kidney weights were increased in F~0~ males and
females at 750 ppm and absolute kidney weight was increased in F~1~
males at 500 ppm. Microscopic changes in the kidney were also observed
and included significant increases in the incidence of minimal-to-mild
pelvic mineralization, and/or secondary transitional epithelial
hyperplasia following exposure to ≥ 500 ppm in F~0~ females and
increased mononuclear cell infiltrate at 500 ppm in F~1~ males; however,
most of these effects did not show a clear dose-response and were not
considered to be biologically significant by the study authors. Hepatic
effects were also observed in both F~0~ and F~1~ males and females. An
increase in mean relative liver weight occurred in F~0~ animals at
exposures ≥ 500 ppm and in F~1~ animals at 500 ppm. Histopathology was
observed in the F~1~ generation and consisted of an increased incidence
of minimal-to-mild centrilobular hepatocellular degeneration at ≥ 250
ppm in males and at 500 ppm in females. These findings were considered
to be toxicologically significant. An increase in hepatic glycogen was
also observed at 500 ppm in F~1~ males and ≥ 100 ppm in F~2~ females;
however, the biologic significance of this result is unclear.

[]{.mark}

Based on decreased sperm motility in F~1~ males, decreased mean number
of estrus cycles in F~0~ females, and mild liver histopathology, the
study NOAEL is 100 ppm, with a LOAEL of 250 ppm. A summary of
reproductive and developmental NOAELs for toxicologically-relevant end
points for F~0~, F~1~, and F~2~ generations is presented in Table S.1.
One selected reproductive endpoint below is post-natal weight for F~1~
and F~2~ generation pups at certain exposure levels. Pup weight was
measured every seven days and compared with controls. A statistically
significant decrease in weight was observed for both generations of the
500 ppm females' pups, on post-natal day (PND) 28 in the F~1~ generation
and PND 14 and 21 in the F~2~ generation.

# Table S.1 Selected Reproductive and Related Endpoints

# for F~0~, F~1~, and F~2~ Generations

**F~0~ Generation**

+-------------------------------------------+------------+------------+
| **Reproductive Endpoints**                |            |            |
+===========================================+============+============+
| **Female Endpoints (Measure)**            | **NOAEL**  | **LOAEL**  |
|                                           |            |            |
|                                           | **(ppm)**  | **(ppm)**  |
+-------------------------------------------+------------+------------+
| Decrease in fertility Index (%)           | 250        | 500\*\*    |
+-------------------------------------------+------------+------------+
| Increase in mean estrus cycle length      | 250        | 500\*      |
| (days)^b^                                 |            |            |
+-------------------------------------------+------------+------------+
| Decrease in mean no. of estrus cycles     | 100        | 250\*\*    |
| within 3- week period prior to mating --  |            |            |
| all females (N)^c^                        |            |            |
+-------------------------------------------+------------+------------+
| Decrease in mean no. of estrus cycles     | 100        | 250\*\*    |
| within 3- week period prior to mating --  |            |            |
| excluding acyclic females (N)^c^          |            |            |
+-------------------------------------------+------------+------------+
| Decrease in mean no. implantation sites   | 250        | 500\*\*    |
| (N/animal)                                |            |            |
+-------------------------------------------+------------+------------+
| Decrease in litter size (N/litter)        | 250        | 500\*\*    |
+-------------------------------------------+------------+------------+
| **Male Endpoints**                        | **NOAEL**  | **LOAEL**  |
|                                           |            |            |
|                                           | **(ppm)**  | **(ppm)**  |
+-------------------------------------------+------------+------------+
| Decrease in fertility index (%)           | 250        | 500\*\*    |
+-------------------------------------------+------------+------------+
| Decrease in sperm number in left.         | 500        | 750\*\*    |
| epididymis (no. sperm x 10^6^/gram        |            |            |
| tissue)                                   |            |            |
+-------------------------------------------+------------+------------+
| Decrease in motile sperm (%)              | 250        | 500\*\*    |
+-------------------------------------------+------------+------------+

+--------------------------------------------+-----------+-------------+
| **Selected Organ Weights** (n=25)^a^       |           |             |
+============================================+===========+=============+
| **Male**                                   | **NOAEL** | **LOAEL**   |
|                                            |           |             |
|                                            | **(ppm)** | **(ppm)**   |
+--------------------------------------------+-----------+-------------+
| Final mean body wt (g) (mean % decrease)   | 500       | 750\*\*     |
+--------------------------------------------+-----------+-------------+
| Decrease in relative left testis (g/100 g) | 500       | 750\*       |
+--------------------------------------------+-----------+-------------+
| Decrease in absolute right cauda           | 250       | 500\*\*     |
| epididymis (g)                             |           |             |
+--------------------------------------------+-----------+-------------+
| Decrease in relative right cauda           | 500       | 750\*\*     |
| epididymis                                 |           |             |
|                                            |           |             |
| (g/ 100 g)                                 |           |             |
+--------------------------------------------+-----------+-------------+
| Decrease in absolute left cauda epididymis | 250       | 500\*\*     |
| (g)                                        |           |             |
+--------------------------------------------+-----------+-------------+
| Decrease in absolute prostate gland (g)    | 100       | 250\*\*     |
+--------------------------------------------+-----------+-------------+
| **Female**^a^                              | **NOAEL** | **LOAEL**   |
|                                            |           |             |
|                                            | **(ppm)** | **(ppm)**   |
+--------------------------------------------+-----------+-------------+
| Decrease in relative liver (g/100 g)       | 500       | 750\*\*     |
+--------------------------------------------+-----------+-------------+
| Decrease in relative kidney (g/100 g)      | 500       | 750\*\*     |
+--------------------------------------------+-----------+-------------+
| Decrease in absolute ovary (g)             | 500       | 750\*\*     |
+--------------------------------------------+-----------+-------------+
| Decrease in relative ovary (g/100 g)       | 500       | 750\*\*     |
+--------------------------------------------+-----------+-------------+

+------------------------------------------+------------+-------------+
| **Other Important Endpoints**            | **NOAEL**  | **LOAEL**   |
|                                          |            |             |
|                                          | **(ppm)**  | **(ppm)**   |
+------------------------------------------+------------+-------------+
| Liver histopathology                     | 100        | 250\*       |
+------------------------------------------+------------+-------------+

**F~1~ Generation**

+-------------------------------------+-----------+-------------------+
| **Reproductive Endpoints**          |           |                   |
+=====================================+===========+===================+
| **Female Endpoint (Measure)**       | **NOAEL** | **LOAEL**         |
|                                     |           |                   |
|                                     | **(ppm)** | **(ppm)**         |
+-------------------------------------+-----------+-------------------+
| Mean length of estrus cycles (days) | 500       | N/A               |
+-------------------------------------+-----------+-------------------+
| Decrease in mean no. of estrus      | 250       | 500\*             |
| cycles within 3 weeks -all          |           |                   |
| females^c^                          |           |                   |
+-------------------------------------+-----------+-------------------+
| Decrease in mean no. of estrus      | 250       | 500\*             |
| cycles within 3 weeks -excluding    |           |                   |
| acyclic females^d^                  |           |                   |
+-------------------------------------+-----------+-------------------+
| Decrease in Implantation sites      | 250       | 500 \*\*          |
+-------------------------------------+-----------+-------------------+
| Decrease in number of pups born     | 250       | 500 \*\*          |
+-------------------------------------+-----------+-------------------+
| **Male Endpoint**                   | **NOAEL** | **LOAEL**         |
|                                     |           |                   |
|                                     | **(ppm)** | **(ppm)**         |
+-------------------------------------+-----------+-------------------+
| Decrease in motile sperm (%)        | 100       | 250\*             |
+-------------------------------------+-----------+-------------------+

+------------------------------------------+------------+-------------+
| **Other Important Endpoints**            | **NOAEL**  | **LOAEL**   |
|                                          |            |             |
|                                          | **(ppm)**  | **(ppm)**   |
+------------------------------------------+------------+-------------+
| Liver histopathology                     | 250        | 500\*       |
+------------------------------------------+------------+-------------+

+---------------------------------------------+-----------+---+-----------+
| **Selected Organ Weights** (n=25)^a^        |           |   |           |
+=============================================+===========+===+===========+
| **Male (Measure)**                          | **NOAEL** | * |           |
|                                             |           | * |           |
|                                             | **(ppm)** | L |           |
|                                             |           | O |           |
|                                             |           | A |           |
|                                             |           | E |           |
|                                             |           | L |           |
|                                             |           | * |           |
|                                             |           | * |           |
|                                             |           |   |           |
|                                             |           | * |           |
|                                             |           | * |           |
|                                             |           | ( |           |
|                                             |           | p |           |
|                                             |           | p |           |
|                                             |           | m |           |
|                                             |           | ) |           |
|                                             |           | * |           |
|                                             |           | * |           |
+---------------------------------------------+-----------+---+-----------+
| Decrease in relative liver (g/100 g)        | 250       |   | 500 \*\*  |
+---------------------------------------------+-----------+---+-----------+
| Decrease in absolute right cauda epididymis | 250       |   | 500\*\*   |
| (g)                                         |           |   |           |
+---------------------------------------------+-----------+---+-----------+
| Decrease in absolute left cauda epididymis  | 250       |   | 500\*\*   |
| (g)                                         |           |   |           |
+---------------------------------------------+-----------+---+-----------+

+---------------------------------------------+-----------+-----------+
| **Pup Weight for F1**                       | **NOAEL** | **LOAEL** |
|                                             |           |           |
|                                             | **(ppm)** | **(ppm)** |
+=============================================+===========+===========+
| Decreased pup weight at postnatal day 28    | 250       | 500\*\*   |
+---------------------------------------------+-----------+-----------+

**F~2~ Generation**

+---------------------------------------------+-----------+-----------+
| **Pup Weight for F2**                       | **NOAEL** | **LOAEL** |
|                                             |           |           |
|                                             | **(ppm)** | **(ppm)** |
+=============================================+===========+===========+
| Decreased pup weight at postnatal day 14    | 250       | 500\*\*   |
| and 21                                      |           |           |
+---------------------------------------------+-----------+-----------+

N/A = not available

> a There were no statistically significant changes in mean final body
> weights of in any of the dose groups in either generation, with the
> exception of 750-ppm F~0~ males.
>
> ^b^ Statistical analysis calculated by ICF
>
> ^c^ Calculated by ICF Poisson regression model
>
> ^d^ Calculated by ICF excluding females that did not have a full
> estrus cycle and analyzed using a quasi-likelihood Poisson-like
> regression model
>
> \*Significantly different from control, p\<0.05.
>
> \*\*Significantly different from control, p\<0.01.
>
> \*\*\* Significantly different from control, p\<0.001.

## Materials and Methods

In a two-generation reproductive toxicity study (Stump, 2001), groups of
25 male and female rats (Crl:CD^^(SD) IGS BR) were exposed to 99.8%
pure n-propyl bromide (nPB) via whole-body inhalation for 6 hours/day, 7
days/week at target concentrations of 0, 100, 250, 500 or 750 ppm.
Compound impurities were as follows: 0.015% 2-bromopropane; unknown
propyl ether 0.002%; 0.017% propyl ether; 0.004% 1,2-dibromopropane;
0.062% unknown 1,2-dibromopropanes; 0.046% unknown
1,2,3-tribromopropanes. These values are within the Office of
Prevention, Pesticides and Toxic Substances (OPPTS) health effects
guideline standards of purity and stability (OPPTS, 1998).

The animals were acclimatized for 15 days after receipt; all animals
were housed singly except at mating and weaning. Animal husbandry and
care were in accordance with appropriate OPPTS health effects harmonized
guidelines (OPPTS, 1998). Exposure chambers were constructed of wire
mesh and the animals were not given either water or food during
exposure~~s~~ periods. The concentrations were monitored during exposure
and the measured mean exposure concentrations were as follows: F~0~
generation -- 0, 99, 252, 505, and 750 ppm; F~1~ generation -- 0, 100,
252, and 502 ppm. There was no 750 ppm group for the F~1~ generation
because no live litters were produced at this exposure level in the F~0~
generation. Homogeneity of the test article's distribution within 4
different areas in the exposure chamber was measured during method
development prior to exposures. The test article was distributed evenly
in the exposure chamber, with a mean percent deviation from the
reference concentration ranging from -- 4.6% to + 4.3%.

The F~0~ generation was \~ 6 weeks old at the start of exposure and
exposed for 70 days prior to mating (1:1). Exposure to male animals of
both generations continued throughout mating to the day prior to study
termination. Exposure to female animals in both generations continued
throughout mating, from gestation day (GD) 1- 21, and from postnatal
(PND) 4 through the day prior to study termination. Thus, exposure was
temporarily stopped around the time of parturition (GD 21-PND4). In the
F~1~ generation, pups were directly exposed via whole body inhalation to
nPB on PND 22, following weaning on PND 21. Selected F~1~ generation
animals (4 pups/sex/litter, culled on PND 4) were exposed for 70 days
prior to mating; females were not exposed during the period GD 21-PND 4.
F~2~ pups were exposed via lactation until PND 21 and sacrificed at that
time.

All animals were observed twice daily for clinical signs, appearance,
behavior, and mortality. Body weights, food consumption values were
recorded daily. Developmental landmarks (balanopreputial separation and
vaginal patency) were also evaluated. Culled F~1~ pups were necropsied
on PND 21 or 28 and culled F~2~ pups were necropsied on PND 21. Parental
animals were necropsied after weaning and selected organs were weighed
and/or examined macroscopically and microscopically. Measured
reproductive endpoints included sperm motility, morphology and numbers
for males in all dose groups and ovarian primordial follicle counts and
corpora lutea counts in the control and high-dose F~0~ and F~1~ females.
Estrus cycle stage and length were monitored during the 3-week period
prior to mating (following 7 weeks exposure) in both F~0~ and F~1~
groups

**Statistical Analyses**

Most analyses by Stump were conducted using two-tailed tests for a
minimum significance level of 5% comparing each treated group to the
control group. Each mean was presented with the standard deviation and
the number of animals used to calculate the mean. Data obtained from
nongravid animals were excluded from statistical analyses following the
mating period. Statistical analyses were not performed when weekly food
or body weight data for one or more animals were not available because
the animals remained in the lactation phase. Statistical tests were
performed using appropriate computing devises or programs and are
referenced in the report tables. The following analyses used different
statistical tests:

### 

### 

### Table 1. Statistical Tests Used in Analyses

  ----------------------------- -----------------------------------------
  **Statistical Test**          **Parameter**

  Chi-square test with Yates    Parental Mating and Fertility Indices
  correction factor             

  One-way ANOVA with Dunnet's   Parental Weekly Body Weights and Weight
  Test                          Changes, Gestation and Lactation Body
                                Weights, Parental Food Consumption, Food
                                Efficiency, Gestation length, Pre-coital
                                Interval, Implantation Sites, Unaccounted
                                Sites, Offspring Weights and Weight
                                Changes, Absolute and Relative Organ
                                Weights, Live Litter Size, Sperm
                                Production Rate, Epididymal and
                                Testicular Sperm Numbers, Ovarian
                                Primordial Follicle Counts, Number of
                                Pups Born, Balanopreputial Separation,
                                Vaginal Patency

  Kruskal-Wallis Test with      Sperm Motility, Percent Morphologically
  Mann-Whitney U-Test           Normal Sperm, Pup Sexes at birth (% Males
                                per litter), Proportional Postnatal
                                Survival

  Fisher's Exact Test           Histopathological Findings
  ----------------------------- -----------------------------------------

## Study Results

*F~0~ Generation*

One 500-ppm F~0~ female was euthanized *in extremis* due to an
abnormality of the eye that was not considered to be treatment-related.
No clinical signs of toxicity were noted that were considered to be
treatment-related. In the F~0~ animals, mean body weights in the 750-ppm
males were reduced by 5.4-12.7% from week 3 through study termination
(at week 19), which correlated with sporadic decreases in weekly weight
gains and food efficiency. The 750-ppm males displayed reduced
cumulative weight gains throughout the study. Generally, the 750-ppm
F~0~ males and females displayed comparable food consumption as compared
to controls, showing only sporadic reductions in food efficiency. The
mean body weight of 750-ppm females was reduced by 5.0-5.8% during weeks
5-10, as compared to controls, with associated reductions in cumulative
weight gains during the pre-mating period. The 750-ppm females were
never pregnant; therefore no data on weight and weight gain during
parturition and/or lactation were available. The 500-ppm males displayed
a general decrease in weight (4.7-6.3% during study weeks 12-19) and
weight gain, but the data were only sporadically statistically different
from controls. The 500-, 250-, and 100-ppm females and 250- and 100-ppm
males did not display a treatment-related reduction in weight, weight
gain, food consumption, or food efficiency. During gestation, a
reduction in weight gain was observed on GD 11-14, 14-20, and 0-20 for
the 500- and 250-ppm females. However, the only statistically
significant finding was a decrease at 500 ppm on GD 14-20 and GD 0-20;
these results correlated with a statistically significant reduction in
overall food consumption during these periods. Reduced gestation weights
were statistically significant in the 500-ppm females on GD 14 and 20,
and were attributed to a reduction in litter size. During lactation,
slight nonsignificant reductions in body weight were observed in the
500-ppm females (Lactation Day (LD) 1-4 and LD 7-14).

**Table 2. F~0~ Females Reproductive Endpoints^a^**

+--------------------+-------+--------+---------+---------+---------+
| **Endpoint**       | **0   | **100  | **250   | **500   | **750   |
|                    | ppm** | ppm**  | ppm**   | ppm**   | ppm**   |
+====================+=======+========+=========+=========+=========+
| Fertility index    | 92.0  | 100    | 88.0    | 5       | 0.0\*\* |
| (%)                |       |        |         | 2.0\*\* |         |
|                    | 25    | 25     | 25      |         | 25      |
| N                  |       |        |         | 25      |         |
+--------------------+-------+--------+---------+---------+---------+
| Mating index (%)   | 96.0  | 100    | 100     | 84.0    | 68.0\*  |
|                    |       |        |         |         |         |
| N                  | 25    | 25     | 25      | 25      | 25      |
+--------------------+-------+--------+---------+---------+---------+
| Evidence of mating | 1     | 0      | 3       | 10      | 17      |
| w/out delivery     |       |        |         |         |         |
| (no.)              |       |        |         |         |         |
+--------------------+-------+--------+---------+---------+---------+
| Estrus cycle       | 4.2   | 4.     | 4       | 5.5     | 5.6     |
| length (days)^b^   | ±0.49 | 5±1.05 | .7±0.90 | ±2.17\* | ±1.79\* |
|                    |       |        |         |         |         |
| N                  | 25    | 25     | 25      | 23      | 22      |
+--------------------+-------+--------+---------+---------+---------+
| Mean no. of estrus | 3.96  | 3.8    | 3.52±0  | 2       | 2       |
| cycles within 3    | ±0.54 | 4±0.62 | .65\*\* | .88±1.1 | .56±1.2 |
| weeks^c^           |       |        |         | 7\*\*\* | 6\*\*\* |
|                    | 25    | 25     | 25      |         |         |
| N                  |       |        |         | 25      | 25      |
+--------------------+-------+--------+---------+---------+---------+
| Mean no. of estrus | 3.96  | 3.8    | 3.52±0  | 3       | 2       |
| cycles within 3    | ±0.54 | 4±0.62 | .65\*\* | .00±1.0 | .78±1.0 |
| weeks excluding    |       |        |         | 2\*\*\* | 4\*\*\* |
| ammenorheic        | 25    | 25     | 25      |         |         |
| females^d^         |       |        |         | 24      | 23      |
|                    |       |        |         |         |         |
| N                  |       |        |         |         |         |
+--------------------+-------+--------+---------+---------+---------+
| Implantation sites | 15.3  | 14.    | 13      | 9.0±4   | NA      |
|                    | ±2.53 | 3±3.09 | .8±4.23 | .54\*\* |         |
| N                  |       |        |         |         |         |
|                    | 23    | 25     | 22      | 11      |         |
+--------------------+-------+--------+---------+---------+---------+
| Number of born     | 15.0  | 13.    | 12      | 8.5±4   | NA      |
|                    | ±2.42 | 6±3.09 | .5±4.27 | .41\*\* |         |
| N                  |       |        |         |         |         |
|                    | 23    | 25     | 22      | 11      |         |
+--------------------+-------+--------+---------+---------+---------+
| Unaccounted Sites  | 0.3   | 0.     | 1.3±1   | 0       | NA      |
|                    | ±0.57 | 7±0.95 | .36\*\* | .5±0.69 |         |
| N                  |       |        |         |         |         |
|                    | 23    | 25     | 22      | 11      |         |
+--------------------+-------+--------+---------+---------+---------+

^a^ Data were provided on pp. 123-124, 207

^b^ Statistical analysis calculated by ICF

^c^ Calculated by ICF and analyzed using a quasi-likelihood Poisson-like
regression model

^d^ Calculated by ICF excluding females that did not have a full estrus
cycle and analyzed using a quasi-likelihood Poisson-like regression
model

\*Significantly different from control, p\<0.05.

\*\*Significantly different from control, p\<0.01.

\*\*\* Significantly different from control, p\<0.001.

### Table 3. Primordial Follicles and Corpora Lutea^a^ for the F~0~ Animals

+-----------------+-----------------+-----------------+-----------------+
| N=25            | **0 ppm**       | **500 ppm**     | **750 ppm**     |
+=================+=================+=================+=================+
| ### Primo       | 107.8±55.80     | NA              | 134.2±58.29     |
| rdial follicles |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| **Corpora       | 178.9±51.61     | 156.8±56.03     | 126.9±67.49\*\* |
| lutea**         |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+

^a^ Data were derived from pp. 245 of the study report

\*\*Significantly different from control, p\<0.01.

A decrease in reproductive performance was statistically significant in
the 500- and 750-ppm animals with fertility indices (both male and
female) of 52.0 and 0.0%, respectively. No live litters were produced at
750 ppm. Historical control fertility indices for males and females were
89.3% and 90.4%, respectively. Mating indices (both male and female) for
the 500- and 750-ppm animals were 84.0% and 68.0%, respectively;
however, only the 750-ppm value reached statistical significance as
compared to controls (96.0%) and was lower than historical control data
(96.0 and 97.0% for males and females, respectively). An increase in the
number of females that displayed evidence of mating without delivery was
observed and 2 females from the 500-ppm group were nongravid (i.e.,
showed no evidence of implantation). The mean number of days between
pairing and coitus were extended in the 500- and 750-ppm groups, to 4.3
and 4.8 days, respectively, as compared to concurrent control (mean of
3.4 days) and historical control mean of 2.0-3.5 days) data. The mating
interval could not be determined for 1 female in the control group, 4
females in the 500 ppm group, and 8 females in the 750-ppm group,
because there was no evidence of mating. Implantation sites were reduced
in the 500-ppm females and the mean number of unaccounted-for sites was
comparable to controls. An increase in the number of unaccounted- for
sites in the 250-ppm females was statistically significant with a slight
decrease in the number of implantation sites; however, a clear
dose-response was not apparent.

An increase in estrus cycle length was statistically significant in the
500- and 750-ppm females; the data are summarized in Table 2. However,
the estrus cycle data reported by the study authors excluded females who
showed no evidence of cycling (2 and 3 for the 500- and 750-ppm groups,
respectively). Therefore, ICF evaluated the individual data by (1)
counting the number of estrus cycles within the three-week period prior
to mating; (2) including females who did not complete an estrus cycle;
and (3) conducting statistical analysis of dose-response using a Poisson
regression model. ICF also analyzed the F~1~ generation estrus cycle
data in a similar manner (See F~1~ generation section for these
results). A dose-dependent decrease in the number of estrus cycles was
observed in females exposed to ≥ 250-ppm. For comparison purposes, ICF
conducted a second analysis of the estrus cycle data, excluding acyclic
females. Although exclusion of these individuals skewed the data, the
statistical significance of the findings stayed at the same
concentration levels*.* A similar dose response was observed that was
significantly higher than controls at ≥ 250 ppm.

**Table 4. F~0~ Males Reproductive Endpoints^a^**

+-----------------+--------+---------+---------+---------+----------+
| **Endpoint**    | **0    | **100   | **250   | **500   | **750    |
|                 | ppm**  | ppm**   | ppm**   | ppm**   | ppm**    |
+=================+========+=========+=========+=========+==========+
| Fertility index | 92.0   | 100     | 88.0    | 5       | 0.0\*\*  |
| (%)             |        |         |         | 2.0\*\* |          |
|                 | 25     | 25      | 25      |         | 25       |
| N               |        |         |         | 25      |          |
+-----------------+--------+---------+---------+---------+----------+
| Mating index    | 96.0   | 100     | 100     | 84.0    | 68.0\*   |
| (%)             |        |         |         |         |          |
|                 | 25     | 25      | 25      | 25      | 25       |
| N               |        |         |         |         |          |
+-----------------+--------+---------+---------+---------+----------+
| Evidence of     | 1      | 0       | 3       | 8       | 17       |
| mating w/out    |        |         |         |         |          |
| delivery (no.)  |        |         |         |         |          |
+-----------------+--------+---------+---------+---------+----------+
| L. Epididymis   | 471.9  | 459.4   | 480.    | 429.3   | 369.6±9  |
| (no. sperm in   | ±81.11 | ±101.94 | 1±80.21 | ±101.46 | 0.66\*\* |
| million/gram    |        |         |         |         |          |
| tissue)         | 25     | 25      | 25      | 25      | 25       |
|                 |        |         |         |         |          |
| N               |        |         |         |         |          |
+-----------------+--------+---------+---------+---------+----------+
| Motile sperm    | 86.8   | 88      | 83.     | 71.9±9  | 53.2±1   |
| (%)             | ±11.90 | .8±7.22 | 4±10.41 | .27\*\* | 9.59\*\* |
|                 |        |         |         |         |          |
| N               | 25     | 25      | 25      | 23      | 15       |
+-----------------+--------+---------+---------+---------+----------+
| Normal sperm    | 99     | 99      | 99.3    | 98.2±2  | 90.6±    |
|                 | .7±0.6 | .7±0.52 | ±0.83\* | .59\*\* | 8.74\*\* |
| N               |        |         |         |         |          |
|                 | 25     | 25      | 25      | 24      | 24       |
+-----------------+--------+---------+---------+---------+----------+
| Normal shaped   | 0.     | 0       | 0       | 1       | 4.8±4.28 |
| head separated  | 2±0.46 | .2±0.36 | .4±0.54 | .4±2.15 |          |
| from flagellum  |        |         |         |         | 24       |
|                 | 25     | 25      | 25      | 24      |          |
| N               |        |         |         |         |          |
+-----------------+--------+---------+---------+---------+----------+
| Head absent     | 0.     | 0       | 0       | 0       | 4.6±5.91 |
| from flagellum  | 1±0.22 | .1±0.24 | .3±0.46 | .5±0.77 |          |
|                 |        |         |         |         | 24       |
| N               | 25     | 25      | 25      | 24      |          |
+-----------------+--------+---------+---------+---------+----------+

^a^ Data were provided on pp. 123, 195, 197-198

\*Significantly different from control, p\<0.05.

\*\*Significantly different from control, p\<0.01.

Spermatogenic analysis showed a reduction in sperm motility and in the
mean number of morphologically normal sperm from the 750-ppm males.
There were two types of sperm abnormalities; one in which abnormal heads
were separated from the flagellum and another in which normal flagella
were without the head. The 500-ppm males displayed a reduction in sperm
motility and number of morphologically normal sperm cells, similarly
abnormal sperm cell types. The number of normal sperm was statistically
decreased in the 250-ppm males; however, they were very close to control
values and not considered to be toxicologically significant. Relative to
controls, the right epididymes were small on two 750- and one 500-ppm
males. A 750-ppm male had a small left epididymis. The testes were small
in one 500- and 750-ppm males and one 500-ppm male had soft testes.

### Table 5a. Selected F~0~ Male Organ Weights (n=25)^a^

+---------+----------+----------+----------+------------+------------+
| **      | **0      | **100    | **250    | **500      | **750      |
| Organ** | ppm**    | ppm**    | ppm**    | ppm**      | ppm**      |
+=========+==========+==========+==========+============+============+
| Final   | 548±56.0 | 526±52.3 | 530±63.3 | 515±61.3   | 48         |
| Body Wt |          |          |          |            | 3±44.6\*\* |
| (g)     |          |          |          |            |            |
+---------+----------+----------+----------+------------+------------+
| Brain   | 2.       | 2.       | 2.08±0   | 2.         | 2.05       |
| (g)     | 19±0.091 | 15±0.114 | .087\*\* | 10±0.177\* | ±0.091\*\* |
+---------+----------+----------+----------+------------+------------+
| R       | 0.40     | 0.41     | 0.39     | 0.         | 0.         |
| elative | 3±0.0401 | 1±0.0384 | 8±0.0554 | 410±0.0446 | 428±0.0453 |
| brain   |          |          |          |            |            |
| (g/100  |          |          |          |            |            |
| g)      |          |          |          |            |            |
+---------+----------+----------+----------+------------+------------+
| Liver   | 20.      | 18.      | 19.      | 2          | 2          |
| (g)     | 09±3.206 | 63±3.008 | 42±2.934 | 0.85±4.147 | 1.25±2.953 |
+---------+----------+----------+----------+------------+------------+
| R       | 3.66     | 3.53     | 3.67     | 4.03       | 4.401±     |
| elative | 2±0.4292 | 8±0.4238 | 5±0.4573 | 4±0.4949\* | 0.4206\*\* |
| liver   |          |          |          |            |            |
| (g/100  |          |          |          |            |            |
| g)      |          |          |          |            |            |
+---------+----------+----------+----------+------------+------------+
| Kidney  | 3.       | 3.       | 3.       | 3.62±0.334 | 3.62±0.329 |
| (g)     | 77±0.418 | 58±0.358 | 59±0.274 |            |            |
+---------+----------+----------+----------+------------+------------+
| R       | 0.69     | 0.68     | 0.68     | 0.         | 0.7454±    |
| elative | 0±0.0649 | 4±0.0654 | 4±0.0629 | 708±0.0862 | 0.0706\*\* |
| kidney  |          |          |          |            |            |
|         |          |          |          |            |            |
| (g/100  |          |          |          |            |            |
| g)      |          |          |          |            |            |
+---------+----------+----------+----------+------------+------------+
| Spleen  | 0.       | 0.       | 0.       | 0.87±0.110 | 0.92±0.157 |
| (g)     | 91±0.167 | 86±0.144 | 85±0.120 |            |            |
+---------+----------+----------+----------+------------+------------+
| R       | 0.16     | 0.16     | 0.16     | 0.         | 0.192±     |
| elative | 7±0.0291 | 4±0.0231 | 2±0.0212 | 170±0.0231 | 0.0353\*\* |
| spleen  |          |          |          |            |            |
|         |          |          |          |            |            |
| (g/100  |          |          |          |            |            |
| g)      |          |          |          |            |            |
+---------+----------+----------+----------+------------+------------+
| L.      | 1.       | 1.       | 1.       | 1.77±0.227 | 1.75±0.188 |
| testis  | 79±0.186 | 79±0.217 | 69±0.146 |            |            |
| (g)     |          |          |          |            |            |
+---------+----------+----------+----------+------------+------------+
| R       | 0.32     | 0.34     | 0.32     | 0.         | 0.36       |
| elative | 9±0.0413 | 3±0.0474 | 3±0.0422 | 348±0.0666 | 4±0.0426\* |
| L.      |          |          |          |            |            |
| testis  |          |          |          |            |            |
| (g/100  |          |          |          |            |            |
| g)      |          |          |          |            |            |
+---------+----------+----------+----------+------------+------------+
| R.      | 0.3327   | 0.331    | 0.3053   | 0.2912±0   | 0.2405±0   |
| Cauda   | ±0.03631 | 1±0.4453 | ±0.04188 | .05206\*\* | .04804\*\* |
| Epi     |          |          |          |            |            |
| didymis |          |          |          |            |            |
| (g)     |          |          |          |            |            |
+---------+----------+----------+----------+------------+------------+
| R.      | 0.6      | 0.06     | 0.05     | 0.         | 0.050±     |
| Cauda   | 1±0.0096 | 4±0.0121 | 9±0.0098 | 057±0.0120 | 0.0097\*\* |
| Epi     |          |          |          |            |            |
| didymis |          |          |          |            |            |
|         |          |          |          |            |            |
| (g/ 100 |          |          |          |            |            |
| g)      |          |          |          |            |            |
+---------+----------+----------+----------+------------+------------+
| L Cauda | 0.3252   | 0.3242   | 0.3050   | 0.2877±0   | 0.2401±0   |
| Epi     | ±0.03673 | ±0.03149 | ±0.03556 | .03170\*\* | .03529\*\* |
| didymis |          |          |          |            |            |
| (g)     |          |          |          |            |            |
+---------+----------+----------+----------+------------+------------+
| L.      | 0.06     | 0.06     | 0.05     | 0.         | 0.         |
| Cauda   | 0±0.0100 | 2±0.0087 | 8±0.0096 | 056±0.0084 | 050±0.0068 |
| Epi     |          |          |          |            |            |
| didymis |          |          |          |            |            |
|         |          |          |          |            |            |
| (g/ 100 |          |          |          |            |            |
| g)      |          |          |          |            |            |
+---------+----------+----------+----------+------------+------------+
| P       | 1.       | 1.       | 1.14±0   | 1.         | 1.14       |
| rostate | 33±0.247 | 27±0.241 | .169\*\* | 14±0.232\* | ±0.178\*\* |
| (g)     |          |          |          |            |            |
+---------+----------+----------+----------+------------+------------+
| P       | 0.24     | 0.24     | 0.21     | 0.         | 0.         |
| rostate | 4±0.0525 | 5±0.0597 | 8±0.0442 | 224±0.0503 | 237±0.0405 |
|         |          |          |          |            |            |
| (g/ 100 |          |          |          |            |            |
| g)      |          |          |          |            |            |
+---------+----------+----------+----------+------------+------------+

^a^ Data were provided on pp.208-211 and 214-216 of the study report

\*Significantly different from control, p\<0.05.

\*\*Significantly different from control, p\<0.01.

A decrease in the absolute brain weight was statistically significant in
males at ≥250 ppm as compared to controls; the study authors attributed
this finding to a decrease in body weight and did not consider it to be
toxicologically significant. However, the extent of the decrease in
brain weight prompted further histopathological examinations of the
brain to determine if any lesions could explain the weight loss. No
corresponding lesions were found. A decrease in the absolute adrenal and
relative spleen weights of the 750-ppm males was statistically
significant; these decreases were also attributed to general weight loss
relative to controls as no macroscopic or microscopic lesions were noted
at necropsy.

Decreases in the absolute prostate (≥250 ppm), right epididymis (≥500
ppm), pituitary (750 ppm), and seminal vesicles/coagulating gland (750
ppm) weights were statistically significant although relative weights of
these organs/tissues were not. Further, none of these decreases were
dose related. A decrease in the left and right cauda epididymes absolute
weights was statistically significant as compared to the controls. These
decreases were considered to be treatment-related based on that
spermatogenic effects observed in the 500- and 750-ppm males. Other
organ weight changes included an increase in the relative left testis
weight (750 ppm) and in relative liver (≥500 ppm), kidney (750 ppm), and
spleen (750 ppm) weights as compared to concurrent controls. The liver
and kidneys displayed microscopic lesions; these findings are summarized
in Table 5a and 5b and discussed further below.

**^Table\ 5b.\ Selected\ F0\ Female\ Organ\ Weights\ (n=25)^**a

+---------+----------+----------+----------+-----------+-------------+
| **      | **0      | **100    | **250    | **500     | **750 ppm** |
| Organ** | ppm**    | ppm**    | ppm**    | ppm^b^**  |             |
+=========+==========+==========+==========+===========+=============+
| Final   | 331±20.7 | 330±22.3 | 327±24.8 | 332±38.3  | 319±25.5    |
| Body Wt |          |          |          |           |             |
| (g)     |          |          |          |           |             |
+---------+----------+----------+----------+-----------+-------------+
| Brain   | 1.       | 1.       | 1.       | 1.8       | 1.8         |
| (g)     | 96±0.078 | 92±0.094 | 94±0.084 | 9±0.105\* | 6±0.072\*\* |
+---------+----------+----------+----------+-----------+-------------+
| R       | 0.59     | 0.58     | 0.59     | 0.5       | 0           |
| elative | 5±0.0446 | 5±0.0458 | 5±0.0454 | 77±0.0674 | .586±0.0431 |
| brain   |          |          |          |           |             |
| (g/100  |          |          |          |           |             |
| g)      |          |          |          |           |             |
+---------+----------+----------+----------+-----------+-------------+
| Liver   | 12.      | 13.      | 12.      | 12        | 13.70±1.735 |
| (g)     | 55±1.292 | 08±1.443 | 91±1.199 | .86±1.595 |             |
+---------+----------+----------+----------+-----------+-------------+
| R       | 3.80     | 3.95     | 3.94     | 3.8       | 4.302       |
| elative | 0±0.3414 | 8±0.3716 | 8±0.2402 | 88±0.3862 | ±0.4402\*\* |
| liver   |          |          |          |           |             |
|         |          |          |          |           |             |
| (g/100  |          |          |          |           |             |
| g)      |          |          |          |           |             |
+---------+----------+----------+----------+-----------+-------------+
| Kidney  | 2.       | 2.       | 2.       | 2         | 2.37±0.253  |
| (g)     | 22±0.211 | 27±0.244 | 25±0.177 | .27±0.217 |             |
+---------+----------+----------+----------+-----------+-------------+
| R       | 0.67     | 0.68     | 0.69     | 0.6       | 0.746       |
| elative | 2±0.0548 | 6±0.0660 | 2±0.0734 | 88±0.0646 | ±0.0861\*\* |
| kidney  |          |          |          |           |             |
|         |          |          |          |           |             |
| (g/100  |          |          |          |           |             |
| g)      |          |          |          |           |             |
+---------+----------+----------+----------+-----------+-------------+
| Ovaries | 0.1227   | 0.1265   | 0.1152   | 0.111     | 0.09575±0.  |
| (g)     | ±0.02592 | ±0.02404 | ±0.02360 | 9±0.01514 | 0.02798\*\* |
+---------+----------+----------+----------+-----------+-------------+
| R       | 0.03     | 0.03     | 0.03     | 0.0       | 0.031       |
| elative | 7±0.0078 | 8±0.0068 | 5±0.0072 | 34±0.0056 | ±0.0079\*\* |
| ovaries |          |          |          |           |             |
|         |          |          |          |           |             |
| (g/100  |          |          |          |           |             |
| g)      |          |          |          |           |             |
+---------+----------+----------+----------+-----------+-------------+

^a^ Data were provided on pp.212-213 and 218-219 of the study report

^b^ N=24

\*Significantly different from control, p\<0.05.

\*\*Significantly different from control, p\<0.01.

An increase in the relative liver and kidney weights was statistically
significant in the 750-ppm females. The 750-ppm females also displayed a
significant decrease in relative ovary weights that correlated with the
infertility of these animals. The 750-ppm females displayed a decrease
in absolute brain weight that was attributed to the decreased weight of
these animals and was not considered by the study authors to be
toxicologically significant. A dose-dependent decrease in absolute (22%)
and relative ovary weights (16%) was observed in the 750-ppm females,
relative to controls.

### 

### 

### Table 6. Selected Histopathology Data for the F~0~ Animals (n=25)^a^

<table>
<colgroup>
<col style="width: 25%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 6%" />
<col style="width: 7%" />
<col style="width: 6%" />
</colgroup>
<thead>
<tr class="header">
<th></th>
<th colspan="5"><strong>Male</strong></th>
<th colspan="5"><strong>Female</strong></th>
</tr>
<tr class="odd">
<th></th>
<th><strong>0 ppm</strong></th>
<th><strong>100 ppm</strong></th>
<th><strong>250 ppm</strong></th>
<th><strong>500 ppm</strong></th>
<th><strong>750 ppm</strong></th>
<th><strong>0 ppm</strong></th>
<th><strong>100 ppm</strong></th>
<th><strong>250 ppm</strong></th>
<th><strong>500 ppm<sup>b</sup></strong></th>
<th><strong>750 ppm</strong></th>
</tr>
</thead>
<tbody>
<tr class="odd">
<td colspan="11"><h4 id="kidneys">Kidneys</h4></td>
</tr>
<tr class="even">
<td><strong>Pelvic Mineralization</strong></td>
<td>1</td>
<td>0</td>
<td>1</td>
<td>2</td>
<td>6</td>
<td>2</td>
<td>3</td>
<td>5</td>
<td>12*</td>
<td>14*</td>
</tr>
<tr class="odd">
<td><strong>Transitional Cell Hyperplasia</strong></td>
<td>0</td>
<td>0</td>
<td>1</td>
<td>3</td>
<td>4</td>
<td>1</td>
<td>0</td>
<td>2</td>
<td>6*</td>
<td>5</td>
</tr>
<tr class="even">
<td colspan="11"><h4 id="testes">Testes</h4></td>
</tr>
<tr class="odd">
<td><strong>Seminiferous Tubules Degeneration</strong></td>
<td>1</td>
<td>2</td>
<td>0</td>
<td>3</td>
<td>6</td>
<td colspan="5">N/A</td>
</tr>
<tr class="even">
<td colspan="11"><h4 id="ovaries">Ovaries</h4></td>
</tr>
<tr class="odd">
<td><strong>Decreased Corpora Lutea</strong></td>
<td colspan="5">N/A</td>
<td>3</td>
<td>0</td>
<td>3</td>
<td>6</td>
<td>11*</td>
</tr>
<tr class="even">
<td><strong>Luteinized Follicular Cyst</strong></td>
<td colspan="5">N/A</td>
<td>2</td>
<td>4</td>
<td>3</td>
<td>5</td>
<td>9*</td>
</tr>
<tr class="odd">
<td><strong>Follicular Cyst</strong></td>
<td colspan="5">N/A</td>
<td>7</td>
<td>1*</td>
<td>3</td>
<td>3</td>
<td>6</td>
</tr>
<tr class="even">
<td><strong>Interstitial Hyperplasia</strong></td>
<td colspan="5">N/A</td>
<td>3</td>
<td>0</td>
<td>0</td>
<td>3</td>
<td>7</td>
</tr>
<tr class="odd">
<td colspan="11"><h4 id="liver">Liver</h4></td>
</tr>
<tr class="even">
<td><strong>Centrilobular Hepatocellular Vacuolation</strong></td>
<td>0</td>
<td>0</td>
<td>7*</td>
<td>22*</td>
<td>24*</td>
<td>0</td>
<td>0</td>
<td>0</td>
<td>6*</td>
<td>16*</td>
</tr>
<tr class="odd">
<td><strong>Increased Glycogen</strong></td>
<td>14</td>
<td>14</td>
<td>20</td>
<td>21</td>
<td>24*</td>
<td>15</td>
<td>18</td>
<td>22</td>
<td>23*</td>
<td>23*</td>
</tr>
</tbody>
</table>

^a^ Data were derived from pp. 227-244 of the study report

\*Significantly different from control, p\<0.05.

The males manifested a slight nonsignificant increase in minimal
mineralization of the pelvic kidney and the females displayed a
minimal-to-mild increase that was statistically significant at ≥500 ppm.
The kidneys of treated males had a slight nonsignificant increase in the
incidence of minimal transitional cell hyperplasia. The females
displayed a more pronounced effect and the incidence for the 500-ppm
females was statistically significant from controls. However,
statistical significance for this end point was not achieved at 750 ppm,
indicating a lack of dose-response. Statistically significant increases
in the incidence of mild-to-minimal centrilobular hepatocellular
vacuolation was noted in males (≥250 ppm) and females (≥500 ppm). An
increase in liver glycogen was statistically significant for males at
750 ppm and for females at ≥500 ppm.

Increases in incidence and severity of seminiferous tubules degeneration
were noted in the treated males at ≥500 ppm; although these incidences
were not statistically significantly different from controls, the study
authors considered these changes to be treatment-related because of
spermatogenic effects observed at these doses. A statistically
significant decrease in corpora lutea and an increase in luteinized
follicular cysts were observed in the ovaries of 750 ppm females.
Microscopic determination of the number of primordial follicles and
corpora lutea in the ovaries are presented in Table 6; a significant
increase in primordial follicles and decrease in corpora lutea was
observed at 750 ppm, relative to controls. However, lower doses were not
analyzed for these end points; therefore, no dose-response conclusions
can be made.

*F~1~ Generation*

One control male (at week 22) and one 50-ppm male (at week 18) were
euthanized *in extremis* and the deaths were not attributed to
treatment. In the F~1~ animals, the 500-ppm group displayed a
significant reduction in live litter size, attributed to reductions in
body weight. Postnatal survival was unaffected by treatment. Body
weights were increased in the 500-ppm pups during PND 1 (both sexes) and
4 (females), and decreased in the 250- and 500-ppm males on PND 28. Body
weight gains were decreased in 500-ppm males on PND 4-7, 7-14, and
21-28; decreases in body weight gains were also observed at PND 21-28 in
≥100-ppm males and 750-ppm females, although mean body weights did not
differ from controls. The absolute brain weights of the ≥ 100-ppm F~1~
males and 100-ppm females sacrificed at PND 21 displayed a statistically
significant reduction; however, relative weights were unaffected. An
increase in the average day at balanopreputial separation of the 500-ppm
males was statistically significant as compared with concurrent controls
(9% increase); however, there was no dose-response. Vaginal patency was
increased in the 500-ppm females by 5% compared with concurrent
controls; however, this delay was not statistically significant.

Mean body weight gains were reduced in the 500-ppm F~1~ males (weeks
19-20 and 20-21) as compared to controls; percent decrease in body
weights gains ranged from 9.3-18.5% during weeks 19-37; 500-ppm females
displayed reduced body weight gains (weeks 19-28) with a 6.7-11.8%
decrease in body weight being observed, as compared to controls, during
weeks 19-28. The 100-ppm males displayed a reduction in body weight
during weeks 26-37; however, the decrease was not dose-related and not
attributed to treatment. F~1~ 500-ppm females displayed reduced weight
gain (during GD 7-11, 11-14, 14-20, and 0-20) and body weight (at GD 14
and 20) that coincided with a decrease in litter size (42%), number of
implantations (37%), and food efficiency. Further, mean body weights and
food consumption were reduced in the F~1~ 500-ppm females through LD 4,
7, and 14. The 250-ppm females displayed a reduction in mean body weight
gains during GD 14-20 with a slight reduction in food efficiency (GD
7-11, 11-14, and 14-20) and a significant overall reduction in food
efficiency (GD 0-20). The 100-ppm females displayed a reduction in mean
body weight gains during GD 4-7 with a slight reduction in food
efficiency (GD 4-7 and 11-14). However, weight gain and food efficiency
data of the 250- and 100-ppm females were comparable to controls.

**Table 7. F~1~ Females Reproductive Endpoints^a^**

+---------------------------+--------+----------+----------+----------+
| **Endpoint**              | **0    | **100    | **250    | **500    |
|                           | ppm**  | ppm**    | ppm**    | ppm**    |
+===========================+========+==========+==========+==========+
| Fertility index (%)       | 100.0  | 84.0     | 80.0     | 100.0    |
|                           |        |          |          |          |
| N                         | 25     | 25       | 25       | 25       |
+---------------------------+--------+----------+----------+----------+
| Mating index (%)          | 88.0   | 68.0     | 64.0     | 72.0     |
|                           |        |          |          |          |
| N                         | 25     | 25       | 25       | 25       |
+---------------------------+--------+----------+----------+----------+
| Evidence of mating w/out  | 3      | 4        | 4        | 8        |
| delivery (no.)            |        |          |          |          |
+---------------------------+--------+----------+----------+----------+
| Estrus cycle length       | 4.     | 4.5±0.91 | 4.9±1.43 | 5.1±1.68 |
| (days)^b^                 | 5±1.25 |          |          |          |
|                           |        | 24       | 22       | 21       |
| N                         | 24     |          |          |          |
+---------------------------+--------+----------+----------+----------+
| Mean no. of estrus cycles | 3.6    | 3        | 2        | 2.6      |
| within 3 weeks^c^         | 4±1.15 | .68±1.11 | .88±1.36 | 8±1.35\* |
|                           |        |          |          |          |
| N                         | 25     | 25       | 25       | 25       |
+---------------------------+--------+----------+----------+----------+
| Mean no. of estrus cycles | 3.6    | 3        | 3        | 2.9      |
| within 3 weeks excluding  | 4±1.15 | .68±1.11 | .13±1.10 | 1±1.12\* |
| ammenorheic females^d^    |        |          |          |          |
|                           | 25     | 25       | 23       | 23       |
| N                         |        |          |          |          |
+---------------------------+--------+----------+----------+----------+
| Implantation sites        | 15.    | 1        | 1        | 9.8±     |
|                           | 5±2.11 | 5.8±3.29 | 3.5±4.12 | 4.93\*\* |
| N                         |        |          |          |          |
|                           | 22     | 17       | 16       | 17       |
+---------------------------+--------+----------+----------+----------+
| Number of born            | 14.    | 1        | 1        | 8.6±     |
|                           | 9±1.97 | 5.1±3.35 | 3.1±4.12 | 4.51\*\* |
| N                         |        |          |          |          |
|                           | 22     | 17       | 16       | 17       |
+---------------------------+--------+----------+----------+----------+
| Unaccounted Sites         | 0.     | 0.6±1.22 | 0.4±0.63 | 1.2±1.09 |
|                           | 5±0.86 |          |          |          |
| N                         |        | 17       | 16       | 17       |
|                           | 22     |          |          |          |
+---------------------------+--------+----------+----------+----------+

^a^ Data were provided on pp. 272-275 and 356 of the study report

^b^ Statistical analysis calculated by ICF

^c^ Calculated by ICF Poisson regression model

^d^ Calculated by ICF excluding females that did not have a full estrus
cycle and analyzed using a quasi-likelihood Poisson-like regression
model

\*Significantly different from control, p\<0.05.

\*\*Significantly different from control, p\<0.01.

Mating, fertility, and number of unaccounted-for implantation sites were
unaffected by treatment. Estrus cycle length was extended by 13% in the
500-ppm females (historical controls range is 4.1-5.1 days); however,
the data were not significantly different from concurrent controls.
Three 250-ppm females and four 500-ppm females did not complete an
estrus cycle; the study authors excluded the data from these individuals
from their statistical analysis. ICF re-evaluated the estrus cycle data
by determining the number of estrus cycles within the 3 weeks prior to
mating, including data from all females, and performing a statistical
analysis of dose-response using a Poisson regression model. A
significant reduction in estrus cycle number was observed at 500 ppm.
ICF performed further analysis of the estrus cycle data; results from
acyclic females were excluded from this analysis. Although exclusion of
the results from these individuals skewed the distribution of the data,
the statistical significance remained at the same concentration levels.
Gestation length was not affected by treatment; only one 250-ppm female
experienced dystocia, which was not considered by the study authors to
be treatment-related.

## Table 8. F~1~ Males Reproductive Endpoints^a^

+-----------------------+-----------+-----------+---------+-----------+
| **Endpoint**          | **0 ppm** | **100     | **250   | **500     |
|                       |           | ppm**     | ppm**   | ppm**     |
+=======================+===========+===========+=========+===========+
| Fertility index (%)   | 87.5      | 68.0      | 64.0    | 70.8      |
|                       |           |           |         |           |
| N                     | 24        | 25        | 25      | 24        |
+-----------------------+-----------+-----------+---------+-----------+
| Mating index (%)      | 100.0     | 84.0      | 80.0    | 100.0     |
|                       |           |           |         |           |
| N                     | 24        | 25        | 25      | 24        |
+-----------------------+-----------+-----------+---------+-----------+
| Evidence of mating    | 3         | 8         | 9       | 7         |
| w/out delivery (no.)  |           |           |         |           |
+-----------------------+-----------+-----------+---------+-----------+
| L. Epididymis (no.    | 640       | 609       | 573.    | 635       |
| sperm in million/gram | .1±141.82 | .1±115.22 | 7±97.17 | .3±160.50 |
| tissue)               |           |           |         |           |
|                       | 23        | 23        | 24      | 24        |
| N                     |           |           |         |           |
+-----------------------+-----------+-----------+---------+-----------+
| Motile sperm (%)      | 88.9±4.52 | 86.4±4.96 | 84.8    | 74.4±     |
|                       |           |           | ±6.02\* | 14.06\*\* |
| N                     | 24        | 25        |         |           |
|                       |           |           | 25      | 24        |
+-----------------------+-----------+-----------+---------+-----------+
| Normal sperm (%)      | 99.5±0.79 | 98.9      | 99      | 95.3      |
|                       |           | ±0.95\*\* | .1±1.13 | ±6.51\*\* |
| N                     | 24        |           |         |           |
|                       |           | 25        | 25      | 24        |
+-----------------------+-----------+-----------+---------+-----------+
| Normal shaped head    | 0.2±0.47  | 0.5±0.68  | 0       | 1.6±4.12  |
| separated from        |           |           | .4±0.73 |           |
| flagellum (%)         | 24        | 25        |         | 24        |
|                       |           |           | 25      |           |
| N                     |           |           |         |           |
+-----------------------+-----------+-----------+---------+-----------+
| Head absent from      | 0.2±0.57  | 0.6±0.75  | 0       | 2.0±2.99  |
| flagellum (%)         |           |           | .4±0.61 |           |
|                       | 24        | 25        |         | 24        |
| N                     |           |           | 25      |           |
+-----------------------+-----------+-----------+---------+-----------+

^a^ Data were provided on pp. 274, 345-348 of the study report

\*Significantly different from control, p\<0.05.

\*\*Significantly different from control, p\<0.01.

Spermatogenic analysis indicated a reduction in sperm motility and the
number of morphologically normal sperm in 500-ppm males. There were two
types of sperm abnormalities; one in which sperm had a normal head
separated from the flagellum and another in which normal flagella were
without the head. The mean testicular and epididymal sperm counts were
comparable among all treatment and control groups. The 250-ppm males
displayed a significant reduction in sperm motility. At 100-ppm, males
also showed a significant decrease in number of morphologically normal
sperm cells; however, this value was within the range of historical
control values, and there was no clear dose-response. Therefore, this
finding was not considered to be toxicologically significant.

**Table 9a. Selected F~1~ Male Organ Weights^a^**

+--------------------+-----------+-----------+-----------+------------+
| **Organ**          | **0 ppm** | **100     | **250     | **500      |
|                    |           | ppm**     | ppm**     | ppm**      |
+====================+===========+===========+===========+============+
| Final Body Wt (g)  | 583±65.7  | 543±63.9  | 562±55.3  | 526±43.3   |
|                    |           |           |           |            |
| N                  | 24        | 25        | 25        | 24         |
+--------------------+-----------+-----------+-----------+------------+
| Brain (g)          | 2         | 2.11±     | 2.12±     | 2.01       |
|                    | .21±0.092 | 0.111\*\* | 0.109\*\* | ±0.079\*\* |
| N                  |           |           |           |            |
|                    | 24        | 25        | 25        | 24         |
+--------------------+-----------+-----------+-----------+------------+
| Relative brain     | 0.3       | 0.3       | 0.3       | 0.         |
| (g/100 g)          | 82±0.0379 | 92±0.0401 | 79±0.0365 | 384±0.0313 |
|                    |           |           |           |            |
| N                  | 24        | 25        |           | 24         |
+--------------------+-----------+-----------+-----------+------------+
| Liver (g)          | 20        | 18        | 19        | 2          |
|                    | .18±3.353 | .54±2.304 | .94±2.994 | 1.25±4.126 |
| N                  |           |           |           |            |
|                    | 24        | 25        | 25        | 24         |
+--------------------+-----------+-----------+-----------+------------+
| Relative liver     | 3.4       | 3.4       | 3.5       | 4.017±     |
| (g/100 g)          | 55±0.3775 | 24±0.3348 | 38±0.3198 | 0.5570\*\* |
|                    |           |           |           |            |
| N                  | 24        | 25        |           | 24         |
+--------------------+-----------+-----------+-----------+------------+
| Kidney (g)         | 3         | 3.37±     | 3         | 3.         |
|                    | .73±0.455 | 0.354\*\* | .52±0.349 | 40±0.450\* |
| N                  |           |           |           |            |
|                    | 24        | 25        | 25        | 24         |
+--------------------+-----------+-----------+-----------+------------+
| Relative kidney    | 0.6       | 0.6       | 0.6       | 0.         |
| (g/100 g)          | 40±0.0548 | 24±0.0672 | 27±0.0523 | 645±0.0587 |
|                    |           |           |           |            |
| N                  | 24        | 25        | 25        | 24         |
+--------------------+-----------+-----------+-----------+------------+
| R. Cauda           | 0.317     | 0.3129    | 0.302     | 0.2720±0   |
| Epididymis (g)     | 8±0.03778 | ±0.0.3862 | 9±0.03885 | .03787\*\* |
|                    |           |           |           |            |
| N                  | 24        | 25        | 25        | 24         |
+--------------------+-----------+-----------+-----------+------------+
| Relative r. Cauda  | 0.0       | 0.0       | 0.0       | 0.         |
| Epididymis (g/ 100 | 55±0.0075 | 58±0.0104 | 54±0.0083 | 052±0.0073 |
| g)                 |           |           |           |            |
|                    | 24        | 25        | 25        | 24         |
+--------------------+-----------+-----------+-----------+------------+
| L Cauda Epididymis | 0.330     | 0.332     | 0.322     | 0.2967±0   |
| (g)                | 4±0.03279 | 5±0.03912 | 1±0.03981 | .04462\*\* |
|                    |           |           |           |            |
| N                  | 24        | 25        | 25        | 24         |
+--------------------+-----------+-----------+-----------+------------+
| Relative l. Cauda  | 0.0       | 0.0       | 0.0       | 0.         |
| Epididymis (g/ 100 | 57±0.0061 | 62±0.0111 | 58±0.0089 | 056±0.0075 |
| g)                 |           |           |           |            |
|                    | 24        | 25        | 25        | 24         |
| N                  |           |           |           |            |
+--------------------+-----------+-----------+-----------+------------+
| Thymus (g)         | 0.231     | 0.246     | 0.270     | 0.2762     |
|                    | 9±0.05952 | 3±0.06420 | 2±0.05165 | ±0.05771\* |
| N                  |           |           |           |            |
|                    | 24        | 25        | 25        | 24         |
+--------------------+-----------+-----------+-----------+------------+
| Relative thymus    | 0.0       | 0.0       | 0.048     | 0.052±     |
| (g/100 g)          | 40±0.0114 | 45±0.0110 | ±0.0091\* | 0.0102\*\* |
|                    |           |           |           |            |
| N                  | 24        | 25        | 25        | 24         |
+--------------------+-----------+-----------+-----------+------------+
| Prostate (g)       | 1         | 1         | 1         | 1.05±0.205 |
|                    | .16±0.258 | .00±0.285 | .06±0.243 |            |
| N                  |           |           |           | 24         |
|                    | 24        | 25        | 25        |            |
+--------------------+-----------+-----------+-----------+------------+
| Relative prostate  | 0.2       | 0.1       | 0.1       | 0.         |
| (g/100 g)          | 00±0.0405 | 87±0.0595 | 90±0.0502 | 201±0.0371 |
|                    |           |           |           |            |
| N                  | 24        | 25        | 25        | 24         |
+--------------------+-----------+-----------+-----------+------------+

^a^ Data were provided on pp. 357-360, 363-366 of the study report

\*Significantly different from control, p\<0.05.

\*\*Significantly different from control, p\<0.01.

The kidneys (100- and 500-ppm males) displayed a decrease in absolute
weight that was not considered to be treatment-related or
toxicologically significant, due lack of a dose-response and absence of
macroscopic or microscopic kidney lesions. Mean absolute brain weights
were reduced in a non-dose related fashion for the ≥100-ppm males and
500-ppm females; therefore, these change were not considered to be
toxicologically significant. A decrease in absolute pituitary weight was
statistically significant in the 500-ppm males; however, no lesions were
found that suggested an association with treatment. No microscopic or
macroscopic lesions were observed in the epididymides but the effect was
similar to those observed in the F~0~ males. Absolute and relative
thymus weights were increased in the 500-ppm F~1~ males; however, no
macroscopic or microscopic lesions were noted in this gland.

**Table 9b. Selected F~1~ Female Organ Weights (N=25)^a^**

  -----------------------------------------------------------------------------------------
  **Organ**             **0 ppm**        **100 ppm**      **250 ppm**      **500 ppm**
  --------------------- ---------------- ---------------- ---------------- ----------------
  Final Body Wt (g)     321±27.3         325±28.1         318±26.7         309±29.5

  Brain (g)             1.97±0.076       1.96±0.073       1.92±0.067       1.89±0.102\*\*

  Relative brain (g/100 0.615±0.0.520    0.606±0.0549     0.608±0.0470     0.617±0.0588
  g)                                                                       

  Liver (g)             12.27±1.571      12.57±1.559      12.44±1.641      12.53±1.894

  Relative liver (g/    3.811±0.2847     3.873±0.3744     3.914±0.4246     4.059±0.4546
  100 g)                                                                   

  Ovaries (g)           0.1131±0.01554   0.1077±0.03170   0.1056±0.02791   0.1062±0.02302

  Relative ovaries      0.035±0.0027     0.022±0.0032     0.022±0.0042     0.021±0.0045
  (g/100 g)                                                                
  -----------------------------------------------------------------------------------------

^a^ Data were provided on pp. 361-362, 367-369 of the study report

\*\*Significantly different from control, p\<0.01.

The F~1~ males and females exposed to 500 ppm displayed an increase in
relative liver weight as compared to controls; however, the values for
females were not statistically significant. These increases were
considered treatment-related, because associated histopathology was
observed, consisting of an increase in hepatic centrilobular
vacuolation. An statistically significant increase in the number of
primordial follicles (19%) relative to controls was observed in the 500
ppm group. However, this end point was not measured in lower dose
groups, and thus a dose-response could not be determined.

### Table 10. Primordial Follicles and Corpora Lutea^a^ for F~1~ Animals

+------------------------+-------------------+------------------------+
| N=25                   | **0 ppm**         | **500 ppm**            |
+========================+===================+========================+
| ##                     | 105.6±44.96       | 141.8±50.26\*          |
| # Primordial follicles |                   |                        |
+------------------------+-------------------+------------------------+
| **Corpora lutea**      | 171.7±40.89       | 171.7±49.18            |
+------------------------+-------------------+------------------------+

^a^ Data were derived from p. 390 of the study report

\*\*Significantly different from control, p\<0.01.

The liver (≥250-ppm males and ≥100-ppm females) and kidneys (500-ppm
males and ≥250-ppm females) displayed treatment-related lesions that
correlated with lesions found in the F~0~ generations.

### Table 11. Selected Histopathology Data for the F~1~ Animals^a^

+----------------------+----+----+-----+-----+----+----+----+-----+
| **Incidence**        | ** |    |     |     | ** |    |    |     |
|                      | Ma |    |     |     | Fe |    |    |     |
|                      | le |    |     |     | ma |    |    |     |
|                      | ** |    |     |     | le |    |    |     |
|                      |    |    |     |     | ** |    |    |     |
+======================+====+====+=====+=====+====+====+====+=====+
|                      | *  | *  | **  | **  | *  | *  | *  | **  |
|                      | *0 | *1 | 250 | 500 | *0 | *1 | *2 | 500 |
|                      | p  | 00 | pp  | pp  | p  | 00 | 50 | pp  |
|                      | pm | p  | m** | m** | pm | p  | p  | m** |
|                      | ** | pm |     |     | ** | pm | pm |     |
|                      |    | ** |     |     |    | ** | ** |     |
+----------------------+----+----+-----+-----+----+----+----+-----+
| ####                 |    |    |     |     |    |    |    |     |
| Kidneys {#kidneys-1} |    |    |     |     |    |    |    |     |
+----------------------+----+----+-----+-----+----+----+----+-----+
| **Pelvic             | 0  | 1  | 0   | 3   | 4  | 5  | 7  | 8   |
| Mineralization**     |    |    |     |     |    |    |    |     |
+----------------------+----+----+-----+-----+----+----+----+-----+
| **Mononuclear        | 11 | 9  | 1\* | 2   | 5  | 5  | 5  | 7   |
| Infiltrate**         |    |    |     | 0\* |    |    |    |     |
+----------------------+----+----+-----+-----+----+----+----+-----+
| **Transitional Cell  | 1  | 1  | 2   | 1   | 2  | 3  | 2  | 2   |
| Hyperplasia**        |    |    |     |     |    |    |    |     |
+----------------------+----+----+-----+-----+----+----+----+-----+
| #### Prostate        |    |    |     |     |    |    |    |     |
+----------------------+----+----+-----+-----+----+----+----+-----+
| **Acute              | 3  | \- | \-  | 1   |    |    |    |     |
| Inflammation**       |    |    |     | 3\* |    |    |    |     |
+----------------------+----+----+-----+-----+----+----+----+-----+
| ####                 |    |    |     |     |    |    |    |     |
| Ovaries {#ovaries-1} |    |    |     |     |    |    |    |     |
+----------------------+----+----+-----+-----+----+----+----+-----+
| **Decreased Corpora  |    |    |     |     | 3  | 3  | 7  | 4   |
| Lutea**              |    |    |     |     |    |    |    |     |
+----------------------+----+----+-----+-----+----+----+----+-----+
| **Luteinized         |    |    |     |     | 2  | 3  | 2  | 3   |
| Follicular Cyst**    |    |    |     |     |    |    |    |     |
+----------------------+----+----+-----+-----+----+----+----+-----+
| **Follicular Cyst**  |    |    |     |     | 5  | 5  | 7  | 10  |
+----------------------+----+----+-----+-----+----+----+----+-----+
| **Interstitial       |    |    |     |     | 12 | 10 | 13 | 18  |
| Hyperplasia**        |    |    |     |     |    |    |    |     |
+----------------------+----+----+-----+-----+----+----+----+-----+
| #                    |    |    |     |     |    |    |    |     |
| ### Liver {#liver-1} |    |    |     |     |    |    |    |     |
+----------------------+----+----+-----+-----+----+----+----+-----+
| **Total              | 0  | 0  | 1   | 2   | 0  | 0  | 2  | 6\* |
| Centrilobular        |    |    | 5\* | 3\* |    |    |    |     |
| Hepatocellular       |    |    |     |     |    |    |    |     |
| Vacuolation**        |    |    |     |     |    |    |    |     |
+----------------------+----+----+-----+-----+----+----+----+-----+
| **Increased          | 19 | 18 | 17  | 2   | 16 | 24 | 23 | 2   |
| glycogen**           |    |    |     | 4\* |    | \* | \* | 3\* |
+----------------------+----+----+-----+-----+----+----+----+-----+

^a^ Data were provided on pp. 375- of the study report. N=24, 25, 25, 24
males treated with 0, 100, 250, 500 ppm of nPB and 25 all treated
females

\*Significantly different from control, p\<0.05.

\*\*Significantly different from control, p\<0.01.

In the F~2~ animals, a 41% decrease in live animals born per dam (PND 0)
was observed in the 500-ppm pups. The 500-ppm pup weights were reduced
at PND 14 (16% males and 14% females) and PND 21 (18% males and 15%
females); weight gain was reduced in the 500-ppm pups at PND 4-7 (33%
males and 31%), 7-14 (26% males and 24% females), and 14-21 (20% males
and 16% females). The absolute brain, thymus, and spleen weights were
reduced in the 500-ppm F~2~ males and the absolute thymus and splean
weights were decreased in 500-ppm females. A decrease in the relative
brain and spleen weights in 500 ppm males and in relative spleen weights
in 500-ppm females was also statistically significant.

# References

National Research Council (1996) *Guide to the Care and USE of
Laboratory Animals, Institute of Laboratory Animal Resources*,
Commission of Life Sciences. National Academy Press, Washington, D.C.

The Office of Prevention, Pesticides and Toxic Substances (OPPTS)
*Harmonized Test Guidelines, Series 870 Health Effects Test Guidelines
\-- Final Guidelines* EPA 712--C--98--189 August 1998

Stump D.G. 2001. *An Inhalation Two-Generation Reproductive Toxicity
Study of 1-Bromopropane in Rats.* Conducted by WIL Research
Laboratories, Inc., Sponsored by Brominated Solvents Consortium. May 24,
2001.

**[Appendix 1: List of Acronyms]{.underline}**

  ------------------- ---------------------------------------------------
  ANOVA               Analysis of Variance

  Crl:CD^^(SD) IGS   Type of Sprague Dawley Rat Species
  BR                  

  FSH                 Follicle Stimulating Hormones

  GD                  Gestation Day

  LD                  Lactation Day

  LOAEL               Low Observable Adverse Effect Level

  nPB                 normal-Propyl Bromide

  PND                 Postnatal Day

  PPM                 Parts per Million

  NOAEL               No Observable Adverse Effect Level

  OPPTS               The Office of Prevention, Pesticides and Toxic
                      Substances
  ------------------- ---------------------------------------------------