Registration Dossier

Data platform availability banner - registered substances factsheets

Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Use of this information is subject to copyright laws and may require the permission of the owner of the information, as described in the ECHA Legal Notice.

REACH

2-hydroxy-2-methylpropiophenone

EC number: 231-272-0 | CAS number: 7473-98-5

Life Cycle description
Uses advised against

Toxicological information

Developmental toxicity / teratogenicity

Currently viewing:

Administrative data

Endpoint:: developmental toxicity
Remarks:: extended one-generation reproductive toxicity - with F2 generation and developmental neurotoxicity (Cohorts 1A, 1B with extension, 2A and 2B)
Type of information:: experimental study
Remarks:: Performed on source substance.
Adequacy of study:: key study
Study period:: April 2021 - April 2022
Reliability:: 1 (reliable without restriction)
Rationale for reliability incl. deficiencies:: guideline study

Cross-reference

Reason / purpose for cross-reference:: read-across: supporting information

Reference

Endpoint:

developmental toxicity

Remarks:

extended one-generation reproductive toxicity - with F2 generation and developmental neurotoxicity (Cohorts 1A, 1B with extension, 2A and 2B)

Type of information:

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

Remarks:

Information on target substance.

Adequacy of study:

key study

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
See attachment.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
See attachment.

3. ANALOGUE APPROACH JUSTIFICATION
See attachment.

4. DATA MATRIX
See attachment.

ECHA decisions on testing proposals:

Target substance requirement:
Extended one-generation reproductive toxicity study (Annex X, Section 8.7.3.; test method: OECD TG 443) in rats, oral (gavage) route specified as follows:
- Ten weeks premating exposure duration for the parental (P0) generation;
- Dose level setting shall aim to induce systemic toxicity at the highest dose level;
- Cohort 1A (Reproductive toxicity);
- Cohort 1B (Reproductive toxicity) without extension to mate the Cohort 1B animals to produce the F2 generation.

Source substance requirement:
Additional data generated from the extension to mate the Cohort 1B to produce the F2 generation and also the Cohorts 2A and 2B (developmental neurotoxicity) was a requirement of the decision on a testing proposal for the source Hydroxycyclohexyl phenyl ketone (TPE-D-2114510002-76-01/F) and that this has been included for openness and completeness of reporting of the actual experimental study performed.

Reason / purpose for cross-reference:

read-across source

Qualifier:

according to guideline

Guideline:

other: OECD Guideline 424. Neurotoxicity Study in Rodents

Version / remarks:

21 July 1997

Deviations:

Qualifier:

according to guideline

Guideline:

other: OECD Guideline 443 Extended One-Generation Reproductive Toxicity Study

Version / remarks:

25 June 2018

Deviations:

Limit test:

Species:

rat

Strain:

Wistar

Remarks:

Han Wistar (Crl:WI(Han))

Route of administration:

oral: gavage

Analytical verification of doses or concentrations:

yes

Dose / conc.:

0 mg/kg bw/day

Remarks:

control

Dose / conc.:

100 mg/kg bw/day

Dose / conc.:

300 mg/kg bw/day

Dose / conc.:

900 mg/kg bw/day

No. of animals per sex per dose:

10 animals per sex per dose

Control animals:

yes, concurrent vehicle

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

At 900 mg/kg/day, decreased activity was observed for one male on Day 2 and abnormal, unco
ordinated gait for 3 males and 4 females between Days 2 to 4. Decreased activity, abnormal, uncoord
inated gait or low carriage were occasionally noted for a further 8 females between Days 5 to 70 and
decreased activity on one occasion for each of 2 females during lactation. These findings were cons
idered to be test item-related.
Salivation and/or ploughing (also a chewing action for one female at 900 mg/kg/day) were noted for
all animals given ≥300 mg/kg/day and for several animals given 100 mg/kg/day, on multiple days thro
ughout the dosing period. The incidence of these findings was dose level-related.
Animal 4515F (900 mg/kg/day) had abnormal clincal observations of irregular respiratory rate, hunc
hed posture, erect fur, cold to touch, prominent backbone, abnormal gait, decreased activity and red
discharge from vagina the day after parturition (LD 1) but these mostly resolved before scheduled
termination. The clinical observations were considered to be likely due to the trauma of giving birth
rather than being test item-related.
Animal 4525F (900 mg/kg/day) had abnormal clincal observations of irregular/decreased respiratory
rate, erect fur, eyes partly closed, decreased activity up to 2-4 hours postdose on LD 7 only. No
similar findings were observed for this animal during the dosing period and as a cause could not be determined, these findings were likely related to the dosing procedure.

Mortality:

mortality observed, non-treatment-related

Description (incidence):

None of the unscheduled deaths were considered to be test item-related.
On Study Day 40, approximately 3 hours after dosing, Animal 4510F given 900 mg/kg/day was found
with clinical signs of irregular respiratory rate, hunched posture, partly closed eyes, erect fur, unc
oordinated and abnormal gait and decreased activity and was euthanised. There were no findings
at necropsy or microscopically to suggest the likely cause of death. This animal had not had any
abnormal clinical signs before this (apart from salivation and ploughing) and had consistently gained
body weight.
Animals 2512F and 4502F given 100 or 900 mg/kg/day respectively, were euthanised on LD 1 or LD
0 and due to the very young age of the pups, they were also euthanised. Animal 2512F had clinical
signs of irregular respiratory rate, hunched posture, pale skin and cold to touch, erect fur, uncoor
dinated and abnormal gait in the afternoon of LD 1. Animal 4502F was found subdued, cold to touch,
prostrate/lying on side with decreased respiratory rate approximately 1 hour after dosing on LD 0. Th
ere were no findings at necropsy or microscopically to suggest the likely cause of death and both an
imals had not had any abnormal clinical signs before this (apart from salivation and ploughing for 4
502F) and had consistently gained body weight.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

See Tables 1-4.
For males given 900 mg/kg/day, there was slightly lower body weight gain over the dosing period
resulting in male body weight being 3.6% lower than the concurrent control mean value by Day 134.
For females given ≥ 100 mg/kg/day, a dose level-related higher body weight gain of up to 10.3% at 90
0 mg/kg/day compared to controls was noted during the pre-pairing period and this slightly higher bo
dy weight was generally maintained throughout gestation and lactation.
There was no test item-related effect on male body weight at 100 or 300 mg/kg/day.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

There were occasional slightly higher food consumption values of up to 14.4% of controls noted for
males at 300 or 900 mg/kg/day up to Day 106. At ≥100 mg/kg/day for males from Days 106 to 134,
there was higher food consumption of up to 17.5%. For females given ≥100 mg/kg/day, there was an
overall dose level-related higher food consumption of up to 20.6% of control values during the prep
airing
period, and during gestation and lactation, food consumption was higher for females by up to
13.2% at 300 or 900 mg/kg/day only.

Haematological findings:

effects observed, non-treatment-related

Description (incidence and severity):

Haematology
See tables 18-19.
Coagulation
See tables 15-16.

All differences in haematology or coagulation parameters were considered not to be test item-related
based on their small magnitude, inconsistent direction, absence of a dose response, general overl
ap of individual values with the range of control values and/or were of a magnitude of variation com
monly observed in rats.

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

See tables 12-13.
At ≥300 mg/kg/day for males and ≥100 mg/kg/day for females, triglycerides were lower than controls
by up to 0.75-fold, and for males only at ≥300 mg/kg/day, cholesterol higher by up to 1.30-fold.

Endocrine findings:

effects observed, treatment-related

Description (incidence and severity):

There were slightly higher TSH levels (up to 3.1-fold of controls) for samples taken on the morning of
necropsy in F0 adult males given 300 or 900 mg/kg/day.
There were no test item-related effects for F0 adult males given 100 mg/kg/day or F0 adult females gi
ven up to 900 mg/kg/day or for culled pups on PND 4 or unselected pups on PND 21.
There were no test item-related changes to T4 levels at up to 900 mg/kg/day for samples taken on the
morning of necropsy for the F0 generation animals, for culled pups on PND 4 or unselected pups on
PND 21.
The differences in these parameters were considered not to be test item-related based on their small
magnitude, inconsistent direction, absence of a dose response, general overlap of individual values
with the range of control and/or were of a magnitude of variation commonly observed in rats.

Urinalysis findings:

effects observed, non-treatment-related

Description (incidence and severity):

See tables 27-28.
All differences in urine parameters were considered not to be test item-related based on their small m
agnitude, inconsistent direction, absence of a dose response, general overlap of individual values with
the range of control and/or were of a magnitude of variation commonly observed in rats.

Immunological findings:

no effects observed

Description (incidence and severity):

Splenic Immunophenotyping Evaluation:
The results demonstrated no test item, dose-dependent or sex-dependent effects on any of the
immune cell populations in either the F0 adults rats analysed following administration of Omnirad 184
by oral gavage.

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

Liver weights in animals dosed at ≥ 100 mg/kg/day, were statistically significantly higher than the
controls and showed a dose-related response. In males, liver weights were up to ~35% higher and in f
emales up to ~28% higher (relative to body weight at 900 mg/kg/day). This was considered test item-r
elated.
Kidney weights in animals dosed at ≥ 100 mg/kg/day, were statistically significantly higher than the c
ontrols and showed a dose-related response. In males, kidney weights were up to ~30% higher and
in females up to ~21% higher (relative to body weight at 900 mg/kg/day). Although this could not be
correlated to any microscopic findings, it was considered test item-related in view of the similar weigh
t differences recorded in the F1 cohort 1A and 1B animals.
Additional Organ Weight Difference:
Testis weights (absolute, relative to %body or %brain weights) were statistically significantly higher by ~12% (relative to body weight at 900 mg/kg/day) compared to the controls. Although the fact that males dosed at 900 mg/kg/day had a lower terminal body weight would increase testis weight relative t o body weight, it is important to note that absolute weight was increased also. Although similar weight differences were seen in the F1 cohort 1A and 1B animals. This was however considered incidental
in view of the minor weight difference and no microscopic findings that could be correlated.
Heart weights were statistically higher in females dosed at ≥ 100 mg/kg/day. No microscopic find
ings could be correlated to this, it was not dose-related, and this difference was not seen in the other
gene rations and it was therefore considered not test item-related.
There were individual organ weight values that were different from their respective controls. There
were, however, no patterns or correlating data to suggest these values were test item-related.

Gross pathological findings:

effects observed, non-treatment-related

Description (incidence and severity):

There were no test item-related gross findings.
Gross findings observed were of the nature commonly observed in this strain and age of rat, or occur
red at a similar incidence in control and treated animals, and, therefore, were considered not to be
test item-related.

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Test item-related Microscopic Findings
In the liver, there was diffuse centrilobular hepatocyte hypertrophy of minimal to mild severity. For
males only, this was seen in all dosage groups, whereas for females this was only identified in ani
mals dosed at 900 mg/kg/day. Although this was also found in one control animal (M1021), the
incidence was higher in animals treated with the test material and followed a dose-related distribution.
This finding was therefore considered test item-related in males dosed at ≥ 100 mg/kg/day and in f
emales dosed at 900 mg/kg/day.
The higher liver weights recorded in animals given the test material, were correlated to the histopatholo
gic findings of centrilobular hypertrophy. This correlation was evident in the males dosed at ≥ 100 mg/
kg/day and females dosed at 900 mg/kg/day.
In the glandular portion of the stomach, there was diffuse mucosal hyperplasia with a minimal
severity. This was characterised by an increase in the number of goblet cells. For males only, this was
seen in at ≥ 300 mg/kg/day, whereas for females this was only identified in animals dosed at 900 mg/
kg/day. Although this was also found in one control animal (M1013), the incidence was convincingly
higher in animals treated with Omnirad 184 at ≥ 300 mg/kg/day and showed a dose-related distribut
ion. This finding was therefore considered test item-related in males dosed at ≥ 300 mg/kg/day and in
females dosed at 900 mg/kg/day.
Additional Microscopic Findings:
In the spleen, there was a slightly higher incidence of increased hematopoietic cells with a minimal
severity, primarily in males given the test material at a doses of 100 mg/kg/day and 900 mg/kg/day. A
slightly higher incidence was seen in females dosed at 900 mg/kg/day only. However, due to the
overall low incidences and because this is a common background finding, it was considered not test i
tem-related.
Other microscopic findings were of the nature commonly observed in this strain and age of rat, or
occurred at a similar incidence in control and treated animals, and, therefore, were considered not to
be test item-related.

Other effects:

no effects observed

Number of abortions:

no effects observed

Pre- and post-implantation loss:

no effects observed

Description (incidence and severity):

F0 and F1 Generations:
There were no test item-related effects on number of corpora lutea, implant counts, pre- or post-implantation loss or total number of pups born at up to 900 mg/kg/day.

Total litter losses by resorption:

no effects observed

Early or late resorptions:

effects observed, non-treatment-related

Description (incidence and severity):

F0 Control Animal 1524F and Animal 4511F given 900 mg/kg/day were terminated on GD 24 as they had failed to produce litters. At necropsy, 1524F had 2 implants (one early resorption) and 4511F was not pregnant.

Dead fetuses:

no effects observed

Changes in pregnancy duration:

no effects observed

Description (incidence and severity):

There were no test item-related effects on male or female mating performance or fertility, or duration of gestation in females, at up to 900 mg/kg/day.

Changes in number of pregnant:

no effects observed

Description (incidence and severity):

F0 control 1520F was found not to be pregnant at scheduled necropsy.
F0 Control Animal 1524F and Animal 4511F given 900 mg/kg/day were terminated on GD 24 as they had failed to produce litters. At necropsy, 1524F had 2 implants (one early resorption) and 4511F was not pregnant.
F0 Animals 1501F, 1502F, 1506F, 1518F, 1521F (control), 2517F (100 mg/kg/day), 350F2 (300 mg/kg/day) and 4523F (900 mg/kg/day) did not have a positive mating sign during pairing and therefore gave birth before their expected GD 21.
The following Cohort 1B females were euthanised on GD 24 as they had failed to produce litters and were found not to be pregnant; 1629F (control), 2624F, 2627F, 2628F and 2637F (100 mg/kg/day) and 3629F (300 mg/kg/day).

Other effects:

no effects observed

Key result

Dose descriptor:

NOAEL

Effect level:

900 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

body weight and weight gain

changes in number of pregnant

changes in pregnancy duration

clinical biochemistry

clinical signs

dead fetuses

early or late resorptions

effects on pregnancy duration

food consumption and compound intake

gross pathology

haematology

histopathology: neoplastic

maternal abnormalities

mortality

necropsy findings

number of abortions

pre and post implantation loss

total litter losses by resorption

Key result

Abnormalities:

no effects observed

Fetal body weight changes:

effects observed, treatment-related

Description (incidence and severity):

See tables 5-11.
For animals in Cohorts 1A and 1B, there was a general trend of slightly lower body weight gain (up to
7.0%) for males at 900 mg/kg/day compared to controls, but no test item related-effects for males at
100 or 300 mg/kg/day or females at ≥100 mg/kg/day during pre-pairing, gestation or lactation.
In Cohort 2A and for Surplus animals, body weight gain was variable and did not follow any trend.

Reduction in number of live offspring:

no effects observed

Description (incidence and severity):

F1 and F2 Generations:
Pup numbers and viability on PND 1 to 4 and PND 4 to 21 were comparable to controls at all test item dose levels administered.

Changes in sex ratio:

no effects observed

Description (incidence and severity):

F1 and F2 Generations:
The ratio of male to female pups was similar to controls at all test item dose levels administered.

Changes in litter size and weights:

no effects observed

Description (incidence and severity):

F1 and F2 Generations:
Pup numbers and viability on PND 1 to 4 and PND 4 to 21 were comparable to controls at all test item dose levels administered.

Anogenital distance of all rodent fetuses:

no effects observed

Description (incidence and severity):

F1 and F2 Generations:
There was no effect on anogenital distance or normalised anogenital distance for males or females at up to 900 mg/kg/day.

Changes in postnatal survival:

no effects observed

Description (incidence and severity):

F1 and F2 Generations:
Pup numbers and viability on PND 1 to 4 and PND 4 to 21 were comparable to controls at all test item dose levels administered.

External malformations:

not specified

Skeletal malformations:

not specified

Visceral malformations:

not specified

Other effects:

no effects observed

Description (incidence and severity):

Dam and Litter Observations During Lactation:
There were no test item-related effects noted for the F0 or Cohort 1B dams or their litters during lactation at up to 900 mg/kg/day.

Nipple Retention:
F0 and F1 Generations:
On PND 13, there was no effect on nipple retention in male pups i.e. no nipples were present, at dose levels up to 900 mg/kg/day.

Assessment of Sexual Maturation:
F1 Generation:
There was considered to be no effect on sexual maturation for F1 males or females at up to 900 mg/kg/day.

Acoustic Startle:
F1 Generation:
There were no test item-related effects on maximum response amplitude, average response amplitude or time to maximum response in males or females at up to 900 mg/kg/day.

Motor Activity:
F1 Generation:
For males at 900 mg/kg/day, the number of basic and fine movements were lower than controls by up to 70.1% from 40 to 60 minutes of the 1 hour session; this was 9.6% or 12.7% lower overall for basic or fine movements, respectively. Ambulation values were also lower for the same time period, but this was not confirmed by the overall ambulation values. As there were no clinical findings or detailed functional observations recorded that could have been associated with this reduction in motor activity, the cause of this apparent reduction in motor activity could not be determined.
At 100 or 300 mg/kg/day for males and ≥ 100 mg/kg/day for females, there were no notable effects on overall basic or fine activity or ambulation, compared with control values.

Brain Morphometry Evaluation:
Cohort 2A
No test item-related effects were seen in the brain morphometry parameters.
The length and width of the brain, as measured grossly, were compared between controls and animals at 900 mg/kg/day. The mean values were similar and were considered not to show a test item-relationship.

Cohort 2B
The only statistically significant difference was that the thickness of the cerebral cortex (motor) in males was ~7% less than controls at 900 mg/kg/day. This was considered due to chance and not test item-related, because other parameters were not affected and in females, the thickness of the cerebral cortex (motor) was not statistically significantly less at 900 mg/kg/day compared to the controls (it was only ~5% less).
Other brain morphometry parameters at 900 mg/kg/day were different from the control means, but were within 10% of the controls and not statistically significant, so were considered not test item-related.
The length and width of the brain, as measured grossly, were compared between controls and animals at 900 mg/kg/day. The mean values were similar and were considered not to show a test item-relationship.

Key result

Dose descriptor:

NOAEL

Effect level:

900 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

reduction in number of live offspring

changes in sex ratio

fetal/pup body weight changes

changes in litter size and weights

changes in postnatal survival

external malformations

skeletal malformations

visceral malformations

Key result

Abnormalities:

no effects observed

Developmental effects observed:

Table 1 - Summary of Body Weights (g)

F0 Males

Sex: Male		Day(s) Relative to Start Date
Sex: Male		-7	1	8	15	22	29	36
0 mg/kg/day	Mean	124.9	176.6	225.1	268.9	303.1	333	355.5
Group 1	SD	16.6	18.5	21	23.8	24.7	26.3	27.3
	N	25 -	25 -	25 -	25 -	25 -	25 -	25 -

100 mg/kg/day	Mean	123.8	174.3	225.7	270.7	305.6	333.2	355.7
Group 2	SD	16.3	18.8	23.4	25.2	26.4	28.5	30.7
	N	25	25	25	25	25	25	25
	%Diff	-0.9	-1.3	0.3	0.7	0.8	0.1	0.1
300 mg/kg/day	Mean	121	171.9	222.1	268.3	302.8	332.4	355.9
Group 3	SD	15.1	18.9	21	23.1	22.1	24.6	26.8
	N	25	25	25	25	25	25	25
	%Diff	-3.1	-2.7	-1.3	-0.2	-0.1	-0.2	0.1
900 mg/kg/day	Mean	124.9	178.2	230.5	277.9	310.1	334.8	352.2
Group 4	SD	11.6	14.2	18.9	21.9	24.1	25.7	28.3
	N	25	25	25	25	25	25	25
	%Diff	0	0.9	2.4	3.4	2.3	0.5	-0.9

Sex: Male		Day(s) Relative to Start Date
Sex: Male		43	50	57	64	71	78	85
0 mg/kg/day	Mean	374.2	389	406.9	417.8	427.7	428	435.6
Group 1	SD	30.2	31.6	33.7	35	34.9	33.2	34.4
	N	25 -	25 -	25 -	25 -	25 -	25 -	25 -

100 mg/kg/day	Mean	374.4	392.8	408	417.3	423.9	427.8	437.4
Group 2	SD	32.8	34.9	36.1	35.5	36.7	37.4	37.7
	N	25	25	25	25	25	25	25
	%Diff	0.1	1	0.3	-0.1	-0.9	-0.1	0.4
300 mg/kg/day	Mean	373.7	390.5	404.8	415.6	424	426.6	436.5
Group 3	SD	29.8	32.2	33.2	33.8	36.9	36.4	38.4
	N	25	25	25	25	25	25	25
	%Diff	-0.1	0.4	-0.5	-0.5	-0.9	-0.3	0.2
900 mg/kg/day	Mean	365.9	378.8	393.4	403.8	411.4	415.7	423.1
Group 4	SD	29.7	32	33.1	34.7	35.5	34.6	36.7
	N	25	25	25	25	25	25	25
	%Diff	-2.2	-2.6	-3.3	-3.3	-3.8	-2.9	-2.9

Sex: Male		Day(s) Relative to Start Date
Sex: Male		92	99	106	113	120	127	134
0 mg/kg/day	Mean	441.8	453.6	466.3	472.8	483.5	489.2	496.7
Group 1	SD	35.9	36.1	37.8	37.8	38.9	39	41.7
	N	25 -	25 -	25 -	25 -	25 -	25 -	25 -

100 mg/kg/day	Mean	441.6	450.2	462.2	470.4	478	487.7	492.6
Group 2	SD	37.1	37.6	39.7	40.7	41.1	43.8	45.4
	N	25	25	25	25	25	25	25
	%Diff	-0.1	-0.7	-0.9	-0.5	-1.1	-0.3	-0.8
300 mg/kg/day	Mean	446.7	452.6	463.6	475.6	483.9	492.7	496.6
Group 3	SD	40.7	42.3	44.7	47	49.7	50.9	53.1
	N	25	25	25	25	25	25	25
	%Diff	1.1	-0.2	-0.6	0.6	0.1	0.7	0
900 mg/kg/day	Mean	434.1	442.2	449.5	458.4	464.4	475.5	478.6
Group 4	SD	38	39.8	40.3	40.7	40.7	42.5	44.8
	N	25	25	25	25	25	25	25
	%Diff	-1.7	-2.5	-3.6	-3	-3.9	-2.8	-3.6

Sex: Male		Day(s) Relative to Start Date
Sex: Male		137	138	141	142
0 mg/kg/day	Mean	507.9	501.8	493.1	473.4
Group 1	SD	58.2	33.5	36.1	43.3
	N	8 -	6 -	11 -	5 -

100 mg/kg/day	Mean	488	512.6	490.8	477.7
Group 2	SD	46.5	39.6	50.5	63.9
	N	5	7	13	7
	%Diff	-3.9	2.1	-0.5	0.9
300 mg/kg/day	Mean	458	534.4	491	494.8
Group 3	SD	26.4	57.8	46.4	52.9
	N	4	8	13	8
	%Diff	-9.8	6.5	-0.4	4.5
900 mg/kg/day	Mean	473.8	494.5	480.2	471.2
Group 4	SD	41.8	27.5	54.1	65.1
	N	8	4	13	5
	%Diff	-6.7	-1.5	-2.6	-0.5

Table 2 - Summary of Body Weights (g)

F0 Females - Prior to mating

Sex: Female					Day(s) Relative to Start Date
Sex: Female		-7	1	8	15	22	29	36
0 mg/kg/day	Mean	72.9	110.5	136.4	155.4	173.6	188.9	197.4
Group 1	SD	13.5	13.9	14	13.8	13.3	13.9	14.6
	N	25 -	25 -	25 -	25 -	25 -	25 -	25 -

100 mg/kg/day	Mean	76	114.9	140.8	162	181.1	195.7	206.3
Group 2	SD	10.2	11.1	11.6	13.5	14.4	14.5	16.5
	N	25	25	25	25	25	25	25
	%Diff	4.2	3.9	3.3	4.3	4.3	3.6	4.5
300 mg/kg/day	Mean	74.9	114.2	142.2	162.9	183.5	198.8	209.1*
Group 3	SD	12.4	11.1	10.6	12.3	12.8	14.7	15.6
	N	25	25	25	25	25	25	25
	%Diff	2.8	3.4	4.3	4.9	5.7	5.2	5.9
900 mg/kg/day	Mean	77.2	116.4	147.2*	171.3**	191.6**	208.2**	214.9**
Group 4	SD	14.1	14.3	15.3	17.2	17.4	17.9	18.2
	N	25	25	25	25	25	25	25
	%Diff	5.9	5.3	7.9	10.3	10.3	10.2	8.9

Sex: Female				Day(s) Relative to Start Date
Sex: Female		43	50	57	64	71
0 mg/kg/day	Mean	207.3	214.6	222.2	226.2	230.5
Group 1	SD	14.9	13.1	14.8	14.4	15.6
	N	25 -	25 -	25 -	25 -	25 -

100 mg/kg/day	Mean	216	225.6	229.6	232.8	240.8
Group 2	SD	17.1	18.4	19	20.5	20.5
	N	25	25	25	25	25
	%Diff	4.2	5.2	3.3	2.9	4.5
300 mg/kg/day	Mean	217.2	227.9*	234.7*	238.4	245.9*
Group 3	SD	16.5	18.6	19.4	18.9	19
	N	25	25	25	25	25
	%Diff	4.8	6.2	5.6	5.4	6.7
900 mg/kg/day	Mean	227.0**	233.0**	242.0**	244.5**	250.5**
Group 4	SD	17.2	17.5	18.6	19	19.7
	N	24	24	24	24	24
	%Diff	9.5	8.6	8.9	8.1	8.7

Anova & Dunnett: * = p ≤ 0.05; ** = p ≤ 0.01

Table 3 - Summary of Body Weights (g)

F0 Females - Gestation

Sex: Female			Day(s) Relative to Mating (Litter: A)
Sex: Female		0	7	14	20
0 mg/kg/day	Mean	222.8	246.1	269.9	325.9
Group 1	SD	14.5	13.5	16.3	24
	N	18 -	18 -	18 -	18 -

100 mg/kg/day	Mean	237.2*	259.5	282.3	338.5
Group 2	SD	20.1	20.5	22.9	31.2
	N	24	24	24	24
	%Diff	6.5	5.5	4.6	3.9
300 mg/kg/day	Mean	242.1**	262.4*	284.2	343.6
Group 3	SD	20.5	22.4	24.6	28.1
	N	24	24	24	24
	%Diff	8.6	6.6	5.3	5.4
900 mg/kg/day	Mean	243.7**	264.5*	291.1*	352.5*
Group 4	SD	17.2	21.1	23.4	34.4
	N	22	22	22	22
	%Diff	9.4	7.5	7.9	8.2

Anova & Dunnett: * = p ≤ 0.05; ** = p ≤ 0.01

Table 4 - Summary of Body Weights (g)

F0 Females - Lactation

Group /		1	4	Day	14	21
Sex		1	4	7	14	21
1F	Mean	261.7	274	275.1	282.8	280.1
	SD	19.1	20.8	19.3	21.2	16.6
	N	23	22	23	23	23
	Mean	268.2	280.9	283.3	290.9	288
2F	SD	22.1	22.6	23	23.6	21.7
	N	23	24	24	24	24
	%Diff G1	2.5	2.5	3	2.9	2.8
	Mean	270.8	282.7	285.6	294.8	291
	SD	25.7	25	24.4	23.4	19.9
3F	N	25	25	25	25	25
	%Diff G1	3.5	3.2	3.8	4.2	3.9
	Mean	271.6	286.4	292.2	302.6a	300.1b
4F	SD	23.4	24	24.8	25.7	25.2
	N	22	22	22	22	22
	%Diff G1	3.8	4.5	6.2	7	7.1

Significantly different from control group 1 value :a=p≤0.05,b=p≤0.01 (Dunnett)

Table 5 - Summary of Body Weights (g)

F1 Animals - Cohort 1A

Sex: Male					Day(s) Relative to Start Date
Sex: Male		1 [G]	2 [I]	6 [G]	13 [G]	20 [G]	27 [G]	34 [G]
0 mg/kg/day	Mean	56	-	71.8	119.9	172.1	219.5	269.6
Group 1	SD	5.1	-	8.8	12.2	15.8	19.7	23.4
	N	20 -	-	20 -	20 -	20 -	20 -	20 -
			-
100 mg/kg/day	Mean	56.3	61.0n	70.8	116.4	166.9	213.7	261.2
Group 2	SD	6.6	6.6	9	13.6	16.5	20.5	26.4
	N	19	3 -	18	20	20	20	20
	%Diff	0.7		-1.4	-2.9	-3	-2.6	-3.1
300 mg/kg/day	Mean	57.9	76.0n	76.8	126.3	179.8	227	276.8
Group 3	SD	4.9	-	9.3	14	16.9	19.6	24.9
	N	20	1 -	19	20	20	20	20
	%Diff	3.5		6.9	5.4	4.5	3.4	2.7
900 mg/kg/day	Mean	54.7	59.0n 4.3	70.6	115.8	167.5	212.9	258.5
Group 4	SD	5.5	6 -	8.2	12.5	16.5	21.7	25.5
	N	15		19	20	20	20	20
	%Diff	-2.2		-1.6	-3.4	-2.7	-3	-4.1

[G] - Anova & Dunnett [I] - n - Inappropriate for statistics

Sex: Male					Day(s) Relative to Start Date
Sex: Male		41	48	55	62	68	69	70
0 mg/kg/day	Mean	309.2	343.6	368.2	390.7	408.1	394	405.5
Group 1	SD	26.7	31.5	33	37	40.1	42.2	40.7
	N	20 -	20 -	20 -	20 -	14 -	6 -	20 -

100 mg/kg/day	Mean	300.1	335.3	360.5	382.8	393	408.2	401.6
Group 2	SD	29.4	32.6	35.7	36.5	35.3	42.7	34.3
	N	20	20	20	20	16	6	16
	%Diff	-2.9	-2.4	-2.1	-2	-3.7	3.6	-1
300 mg/kg/day	Mean	317.3	349.4	376.1	396.8	411.1	445.9	411.1
Group 3	SD	28	33	37.6	38.7	46.2	36.6	36.1
	N	20	20	20	20	14	7	19
	%Diff	2.6	1.7	2.1	1.6	0.8	13.2	1.4
900 mg/kg/day	Mean	299.2	325.5	346.4	363.5	386.8	381.7	382.7
Group 4	SD	29	32.1	37.5	40	40.6	48.2	38.9
	N	20	20	20	20	14	11	15
	%Diff	-3.2	-5.3	-5.9	-7	-5.2	-3.1	-5.6

Sex: Male

Day(s) Relative to Start Date

mg/kg/day

Group 1

Mean

100 mg/kg/day

Group 2

Mean

N %Diff

447.0n

69.3

2 -

300 mg/kg/day

Group 3

Mean

N %Diff

900 mg/kg/day

Group 4

Mean

N %Diff

Sex: Female

Day(s) Relative to Start Date

1 [G]

2 [I]

6 [G]

13 [G]

20 [G]

27 [G]

34 [G]

mg/kg/day

Group 1

Mean

52.6

4.9

20 -

66.0

7.8

20 -

103.8

9.7

20 -

136.5

10.7

20 -

157.2

10.2

20 -

176.5

12.3

20 -

100 mg/kg/day

Group 2

Mean

N %Diff

55.3

4.9

5.3

58.0n

3.0

3 -

68.9

5.7

4.5

106.1

9.4

2.2

138.3

11.9

1.3

159.7

14.1

1.6

178.8

16.8

1.3

300 mg/kg/day

Group 3

Mean

N %Diff

55.0

5.0

4.7

71.0n

1 -

69.4

8.9

5.2

105.5

11.3

1.7

138.6

11.6

1.5

160.2

12.3

1.9

179.9

13.8

1.9

900 mg/kg/day

Group 4

Mean

N %Diff

52.1

4.8

-0.8

56.3n 6.0

7 -

66.1

8.2

0.2

103.2

10.6

-0.6

138.6

12.8

1.5

159.9

15.9

1.7

182.0

15.5

3.1

[G] - Anova & Dunnett

Sex: Female

Day(s) Relative to Start Date

41 [G]

48 [G]

55 [G]

62 [G]

68 [G]

69 [G]

70 [I]

mg/kg/day

Group 1

Mean

189.0

12.1

20 -

203.2

14.4

20 -

212.2

15.5

20 -

221.0

18.8

20 -

231.6

18.8

13 -

228.1

18.9

7 -

245.3n

11.0

3 -

100 mg/kg/day

Group 2

Mean

N %Diff

192.4

18.5

1.8

205.7

17.3

1.2

214.1

18.0

0.9

224.2

20.5

1.4

235.2

22.6

1.6

216.7

6.8

-5.0

300 mg/kg/day

Group 3

Mean

N %Diff

194.4

13.6

2.8

206.5

14.6

1.6

216.4

16.9

2.0

226.1

17.7

2.3

231.5

16.3

0.0

242.3

12.6

6.2

220.0n

1 -10.3

900 mg/kg/day

Group 4

Mean

N %Diff

201.6

17.1

6.7

209.2

17.6

3.0

218.0

17.7

2.7

226.5

18.3

2.5

237.5

19.1

2.6

235.6

26.0

3.3

[G] - Anova & Dunnett

Sex: Female

Day(s) Relative to Start Date

71 [G]

72 [I]

73 [G]

74 [G]

mg/kg/day

Group 1

Mean

226.9

16.6

8 -

228.6

21.1

5 -

228.8

17.9

4 -

100 mg/kg/day

Group 2

Mean

N %Diff

228.3

29.4

0.6

223.7n

12.2

3 -

233.8

11.4

2.3

233.8

25.4

2.2

300 mg/kg/day

Group 3

Mean

N %Diff

233.1

15.5

2.7

268.0n

1 -

225.0n

11.3

-1.6

237.7

20.5

3.9

900 mg/kg/day

Group 4

Mean

N %Diff

235.0

23.9

3.6

247.0n

11.3

2 -

232.8

19.2

1.9

235.0n

25.5

2.7

[G] - Anova & Dunnett: n - Inappropriate for statistics

Table 7 - Summary of Body Weights (g)

F1 Animals - Cohort 1B Males

Sex: Male

Day(s) Relative to Start Date

1 [G]

2 [I]

6 [G]

13 [G]

20 [G]

27 [G]

34 [G]

mg/kg/day

Group 1

Mean

54.6

5.4

20 -

70.5

8.5

20 -

116.5

12.0

20 -

167.7

13.3

20 -

212.9

17.3

20 -

261.7

20.9

20 -

100 mg/kg/day

Group 2

Mean

N %Diff

57.4

5.2

5.1

60.0n

8.5

3 -

72.9

8.7

3.5

117.5

14.9

0.8

166.8

20.5

-0.6

211.2

25.9

-0.8

258.5

29.7

-1.2

300 mg/kg/day

Group 3

Mean

N %Diff

56.8

5.7

4.0

70.0n

1 -

74.9

10.8

6.2

124.1

15.9

6.5

175.7

18.3

4.7

222.6

21.4

4.6

271.2

25.8

3.6

900 mg/kg/day

Group 4

Mean

N %Diff

54.5

4.5

-0.1

59.3n 5.9

7 -

69.9

8.7

-0.8

115.4

10.8

-0.9

166.8

12.3

-0.5

212.2

15.2

-0.3

258.6

18.7

-1.2

Sex: Male

Day(s) Relative to Start Date

mg/kg/day

Group 1

Mean

300.5

25.6

20 -

334.6

30.5

20 -

358.4

34.8

20 -

381.5

38.4

20 -

395.5

41.5

20 -

410.3

44.0

20 -

421.2

46.7

20 -

100 mg/kg/day

Group 2

Mean

N %Diff

297.5

32.5

-1.0

330.9

34.9

-1.1

357.3

37.9

-0.3

379.6

39.8

-0.5

399.5

39.4

1.0

414.5

41.7

1.0

429.9

42.0

2.1

300 mg/kg/day

Group 3

Mean

N %Diff

310.2

26.4

3.2

342.6

29.7

2.4

370.5

31.5

3.4

393.0

33.5

3.0

413.3

33.9

4.5

427.1

37.4

4.1

438.9

39.0

4.2

900 mg/kg/day

Group 4

Mean

N %Diff

297.9

23.2

-0.8

324.7

26.1

-2.9

348.3

30.2

-2.8

365.3

33.5

-4.2

383.9

36.0

-2.9

399.6

35.5

-2.6

410.4

40.6

-2.6

Sex: Male

Day(s) Relative to Start Date

104

111

118

125

128

mg/kg/day

Group 1

Mean

431.7

46.1

20 -

434.7

44.9

20 -

441.9

43.5

20 -

453.5

48.3

20 -

464.3

49.9

20 -

473.8

52.6

20 -

484.1

58.9

8 -

100 mg/kg/day

Group 2

Mean

N %Diff

440.9

44.6

2.1

444.3

45.0

2.2

452.5

46.6

2.4

463.5

46.1

2.2

477.7

47.1

2.9

492.3

48.2

3.9

494.2

58.5

2.1

300 mg/kg/day

Group 3

Mean

N %Diff

448.1

41.2

3.8

452.0

38.8

4.0

456.2

39.7

3.2

471.1

40.7

3.9

483.8

43.3

4.2

494.5

45.3

4.4

515.1

42.9

6.4

900 mg/kg/day

Group 4

Mean

N %Diff

415.5

40.8

-3.8

424.9

41.7

-2.3

428.4

41.3

-3.1

442.0

42.1

-2.5

451.7

42.8

-2.7

460.8

41.2

-2.8

463.5

45.3

-4.3

Sex: Male

Day(s) Relative to Start Date

129 [G]

130 [G]

131 [I]

mg/kg/day

Group 1

Mean

465.0

62.2

6 -

475.3

45.0

9 -

100 mg/kg/day

Group 2

Mean

N %Diff

504.9

36.5

8.6

502.0

45.0

5.6

300 mg/kg/day

Group 3

Mean

N %Diff

514.8

41.9

10.7

471.0

41.8

-0.9

485.5n

36.8

4 -

900 mg/kg/day

Group 4

Mean

N %Diff

476.3

43.3

2.4

436.3

10.1

-8.2

529.0n

1 -

Table 8 - Summary of Body Weights (g)

F1 Animals - Cohort 1B Females - Prior to Mating

Sex: Female

Day(s) Relative to Start Date

1 [G]

2 [I]

6 [G]

13 [G]

20 [G]

27 [G]

34 [G]

mg/kg/day

Group 1

Mean

52.6

5.1

20 -

66.2

7.1

20 -

103.6

9.0

20 -

136.1

9.5

20 -

156.9

10.6

20 -

174.8

12.3

20 -

100 mg/kg/day

Group 2

Mean

N %Diff

53.8

7.9

2.4

57.3n

4.0

3 -

66.6

10.4

0.7

103.4

13.9

-0.1

133.7

13.8

-1.7

155.3

14.0

-1.0

173.5

14.1

-0.7

300 mg/kg/day

Group 3

Mean

N %Diff

55.7

4.4

6.0

68.0n

1 -

71.6

7.5

8.3

109.3

8.1

5.5

143.2

9.6

5.3

164.1

10.0

4.6

180.9

11.8

3.5

900 mg/kg/day

Group 4

Mean

N %Diff

51.3

4.3

-2.3

56.3n 6.6

7 -

64.6

7.4

-2.4

102.8

10.3

-0.7

136.6

9.8

0.4

157.6

13.1

0.4

176.8

13.7

1.1

Sex: Female

Day(s) Relative to Start Date

mg/kg/day

Group 1

Mean

189.6

11.3

20 -

204.2

11.0

20 -

210.9

11.8

20 -

218.6

12.6

20 -

227.6

11.8

20 -

232.5

11.5

20 -

236.2

12.5

20 -

100 mg/kg/day

Group 2

Mean

N %Diff

188.1

15.8

-0.8

200.3

15.1

-1.9

209.8

15.4

-0.5

218.7

14.7

0.1

226.3

16.5

-0.6

230.7

18.2

-0.8

232.7

17.3

-1.5

300 mg/kg/day

Group 3

Mean

N %Diff

199.2

12.4

5.1

211.3

13.2

3.5

220.1

14.6

4.4

227.0

15.2

3.9

236.9

15.5

4.1

243.1

16.4

4.5

246.7

17.5

4.5

900 mg/kg/day

Group 4

Mean

N %Diff

195.6

14.1

3.2

203.7

14.7

-0.2

212.2

15.4

0.6

219.5

16.9

0.4

231.0

16.5

1.5

236.4

18.1

1.7

237.4

17.1

0.5

Sex: Female

Day(s) Relative to Start Date

mg/kg/day

Group 1

Mean

240.0

13.4

20 -

100 mg/kg/day

Group 2

Mean

N %Diff

239.6

16.7

-0.2

300 mg/kg/day

Group 3

Mean

N %Diff

251.2

17.1

4.6

900 mg/kg/day

Group 4

Mean

N %Diff

242.7

18.8

1.1

Table 9 - Summary of Body Weights (g)

F1 Animals - Cohort 1B - Gestation

Sex: Female

Day(s) Relative to Mating (Litter: A)

mg/kg/day

Group 1

Mean

241.9

12.7

19 -

261.8

15.3

19 -

284.1

15.0

19 -

337.5

18.9

19 -

100 mg/kg/day

Group 2

Mean

N %Diff

238.8

14.3

-1.3

258.2

14.3

-1.4

277.9

14.9

-2.2

334.6

19.9

-0.9

300 mg/kg/day

Group 3

Mean

N %Diff

253.5

16.6

4.8

271.6

16.9

3.8

291.6

16.6

2.6

348.9

19.3

3.4

900 mg/kg/day

Group 4

Mean

N %Diff

241.1

16.7

-0.3

260.8

20.7

-0.4

278.0

23.3

-2.1

336.5

32.1

-0.3

Table 10 - Summary of Body Weights (g)

F1 Animals - Cohort 1B Females - Lactation

Group /		1	4	Day	14	21
Sex		1	4	7	14	21
1F	Mean	264.2	268.9	276.9	290.6	284.2
	SD	14.4	12.9	14.9	16.8	17.9
	N	18	17	18	18	18
	Mean	262.3	271.3	275.8	288.6	286.3
2F	SD	14.5	15	14.2	16.6	15.4
	N	16	15	16	16	16
	%Diff G1	-0.7	0.9	-0.4	-0.7	0.8
	Mean	278.4a	288.5b	292.6a	306.2a	302.1a
	SD	18.9	16.6	15.7	15.6	16.2
3F	N	19	19	19	19	19
	%Diff G1	5.4	7.3	5.6	5.4	6.3
	Mean	265.9	276.3	283.6	292.4	291.5
4F	SD	21.6	24.5	20.3	21.7	22.9
	N	20	19	20	20	19
	%Diff G1	0.6	2.7	2.4	0.6	2.6

Table 11 - Summary of Body Weights (g)

F1 Animals - Cohort 2A

Sex: Male

Day(s) Relative to Start Date

1 [G]

2 [I]

6 [G]

13 [G]

20 [G]

27 [G]

34 [G]

mg/kg/day

Group 1

Mean

54.6

4.7

10 -

68.4

8.0

10 -

115.1

11.9

10 -

169.5

12.1

10 -

219.4

13.6

10 -

269.5

18.2

10 -

100 mg/kg/day

Group 2

Mean

N %Diff

54.6

5.5

-0.1

59.0n

7.1

2 -

67.0

8.9

-2.0

111.0

12.0

-3.6

160.7

12.0

-5.2

205.3

14.3

-6.4

250.8

18.2

-6.9

300 mg/kg/day

Group 3

Mean

N %Diff

58.5

5.9

7.1

76.0n

1 -

74.7

10.9

9.2

122.9

14.3

6.8

177.1

16.3

4.5

224.4

19.6

2.3

273.9

23.0

1.6

900 mg/kg/day

Group 4

Mean

N %Diff

55.4

3.6

1.5

59.0n 7.1

2 -

67.3

9.2

-1.6

112.4

11.1

-2.3

164.3

12.4

-3.1

211.4

15.1

-3.6

259.5

21.4

-3.7

Sex: Male

Day(s) Relative to Start Date

mg/kg/day

Group 1

Mean

308.0

21.9

10 -

342.0

24.0

10 -

368.4

25.7

10 -

369.8

24.4

4 -

396.8

32.0

5 -

405.0

37.8

3 -

100 mg/kg/day

Group 2

Mean

N %Diff

287.9

19.6

-6.5

320.4

24.2

-6.3

347.9

26.8

-5.6

376.8

42.4

1.9

369.8

20.2

-6.8

360.5

16.2

4 -11.0

300 mg/kg/day

Group 3

Mean

N %Diff

313.5

26.9

1.8

348.1

27.9

1.8

372.8

25.9

1.2

403.3

32.3

9.1

404.0

54.1

1.8

369.5

14.5

-8.8

900 mg/kg/day

Group 4

Mean

N %Diff

298.6

22.8

-3.1

326.5

27.2

-4.5

347.3

31.0

-5.7

362.0

46.0

-2.1

376.9

25.2

-5.0

341.5n 0.7

2 -15.7

Sex: Female

Day(s) Relative to Start Date

1 [G]

2 [I]

6 [G]

13 [G]

20 [G]

27 [G]

34 [G]

mg/kg/day

Group 1

Mean

51.5

4.2

10 -

62.9

6.5

10 -

98.9

9.8

10 -

128.6

9.3

10 -

149.3

8.6

10 -

166.7

9.1

10 -

100 mg/kg/day

Group 2

Mean

N %Diff

54.2

2.9

5.3

54.0n

2.8

2 -

65.4

5.5

4.0

100.5

8.6

1.6

131.3

8.2

2.1

155.1

8.6

3.9

172.1

10.8

3.2

300 mg/kg/day

Group 3

Mean

N %Diff

55.7

7.4

8.2

76.0n

1 -

68.8

10.0

9.3

108.9

13.2

10.1

145.1**

12.9

12.8

167.6**

15.5

12.3

186.0**

18.3

11.6

900 mg/kg/day

Group 4

Mean

N %Diff

53.6

3.7

4.0

57.0n 5.7

2 -

63.2

5.3

0.5

100.5

6.2

1.6

135.7

10.3

5.5

159.2

10.4

6.6

179.3

12.7

7.6

Sex: Female

Day(s) Relative to Start Date

41 [G]

48 [G]

55 [G]

58 [G]

59 [G1]

60 [G]

mg/kg/day

Group 1

Mean

179.8

10.1

10 -

193.9

9.9

10 -

203.7

10.7

10 -

204.8

13.1

4 -

214.0

12.7

5 -

214.3

12.2

3 -

100 mg/kg/day

Group 2

Mean

N %Diff

185.7

12.3

3.3

199.7

13.1

3.0

210.3

14.1

3.2

206.8

12.0

1.0

218.0

20.1

1.9

210.8

12.0

-1.7

300 mg/kg/day

Group 3

Mean

N %Diff

202.3**

20.4

12.5

215.0**

20.3

10.9

223.8*

23.4

9.9

237.2

33.5

15.8

247.0

47.1

15.4

223.5

14.2

4.3

900 mg/kg/day

Group 4

Mean

N %Diff

198.6*

14.7

10.5

210.7*

14.0

8.7

218.6

13.4

7.3

223.0

22.0

8.9

229.9

10.5

7.4

220.7

6.0

3.0

Tables 12. Summary of Clinical Chemistry Values

F0 Animals - Males. Day: 137 Relative to Start Date

Sex: Male

Reporting Biochemistry

AST

(U/L)

[G]

ALT

(U/L)

[G]

ALP

(U/L)

[G]

GGT

(U/L)

[G1]

(U/L)

[G1]

TBIL

(umol/L)

[G1]

UREA

(mmol/L)

[G]

mg/kg/day

Group 1

Mean

71.4

12.3

10 -

51.0

11.7

10 -

128.5

12.4

10 -

1.5

0.0

10 -

217.1 68.4

10 -

1.25

0.00

10 -

7.35

0.66

10 -

100 mg/kg/day

Group 2

Mean

tCtrl

74.6

10.3

1.04

49.1

12.0

0.96

126.0

25.8

0.98

1.5

0.0

1.00

292.7

163.0

1.35

1.25

0.00

1.00

6.90

0.68

0.94

300 mg/kg/day

Group 3

Mean

tCtrl

60.5 *

4.9

0.85

44.5

7.8

0.87

125.1

32.5

0.97

1.5

0.0

1.00

213.2 70.8

0.98

1.25

0.00

1.00

7.16

0.35

0.97

900 mg/kg/day

Group 4

Mean

tCtrl

61.6 *

5.4

0.86

36.8 14.1

0.72

115.4

28.5

0.90

1.5 0.0

1.00

196.8 60.0

0.91

1.25 0.00

1.00

6.94 0.68

0.94

[G] - Anova & Dunnett: * = p ≤ 0.05
[G1] - Kruskal-Wallis & Dunn

Sex: Male

reporting Biochemistry

CREAT

(umol/L)

[G]

GLUC

(mmol/L)

[G]

CHOL

(mmol/L)

[G]

TRIG

(mmol/L)

[G]

TPROT

(g/L)

[G]

ALB

(g/L)

[G]

GLOB

(g/L)

[G]

mg/kg/day

Group 1

Mean

34.2

3.2

10 -

8.251

0.699

10 -

1.789

0.249

10 -

1.949

0.657

10 -

66.29

1.89

10 -

40.36

1.53

10 -

25.93

2.18

10 -

100 mg/kg/day

Group 2

Mean

N tCtrl

32.1

3.5

0.94

8.778

1.195

1.06

1.853

0.393

1.04

1.933

0.681

0.99

66.09 3.31

1.00

41.22 2.83

1.02

24.87 2.61

0.96

300 mg/kg/day

Group 3

Mean

N tCtrl

29.8 *

2.9

0.87

8.113

0.521

0.98

2.170 *

0.404

1.21

1.594

0.199

0.82

66.67

2.46

1.01

41.93

1.91

1.04

24.74

2.11

0.95

900 mg/kg/day

Group 4

Mean

N tCtrl

31.5

3.6

0.92

8.208 0.634

0.99

2.327 **

0.270

1.30

1.457 0.567

0.75

68.21

2.50

1.03

43.17 *

2.11

1.07

25.04

2.86

0.97

Sex: Male

Reporting Biochemistry

A/G

(ratio) [G]

(mmol/L)

[G]

(mmol/L)

[G]

(mmol/L)

[G]

(mmol/L)

[G]

PHOS

(mmol/L)

[G]

mg/kg/day

Group 1

Mean

1.58

0.18

10 -

2.618

0.059

10 -

141.1

1.3

10 -

4.98

0.29

10 -

103.7

1.2

10 -

1.404

0.193

10 -

100 mg/kg/day

Group 2

Mean

N tCtrl

1.69

0.22

1.07

2.637

0.076

1.01

141.4

1.9

1.00

4.90

0.34

0.98

103.7

1.4

1.00

1.531

0.178

1.09

300 mg/kg/day

Group 3

Mean

N tCtrl

1.71

0.17

1.08

2.654

0.055

1.01

140.3

2.2

0.99

4.97

0.15

1.00

102.3

1.8

0.99

1.545

0.152

1.10

900 mg/kg/day

Group 4

Mean

N tCtrl

1.75 0.28

1.11

2.716 **

0.069

1.04

141.3

1.7

1.00

5.02 0.29

1.01

101.4 **

2.0

0.98

1.591 0.187

1.13

Tables 13. Summary of Clinical Chemistry Values

F0 Animals - Females. Day: 115 Relative to Start Date

Sex: Female

Reporting Biochemistry

AST

(U/L)

[G]

ALT

(U/L)

[G]

ALP

(U/L)

[G]

GGT

(U/L)

[G1]

(U/L)

[G]

TBIL

(umol/L)

[G1]

UREA

(mmol/L)

[G]

mg/kg/day

Group 1

Mean

131.2

28.7

9 -

117.1

17.5

9 -

223.4

49.2

9 -

1.5

0.0

9 -

630.0

384.5

9 -

1.25

0.00

9 -

10.50 1.01

9 -

100 mg/kg/day

Group 2

Mean

tCtrl

105.3

10.9

0.80

110.0

18.4

0.94

200.3

73.8

0.90

1.5

0.0

1.00

356.8

132.6

0.57

1.25

0.00

1.00

10.11 0.94

0.96

300 mg/kg/day

Group 3

Mean

tCtrl

116.1

21.8

0.88

105.7

14.1

0.90

157.1

38.5

0.70

1.5

0.0

1.00

614.7

356.8

0.98

1.25

0.00

1.00

9.38

0.84

0.89

900 mg/kg/day

Group 4

Mean

tCtrl

106.4

25.3

0.81

100.4

21.0

0.86

173.2

49.5

0.78

1.5 0.0

1.00

428.3

244.8

0.68

1.25 0.00

1.00

10.57 1.26

1.01

[G] - Anova & Dunnett
[G1] - Kruskal-Wallis & Dunn

Sex: Female

Reporting Biochemistry

CREAT

(umol/L)

[G]

GLUC

(mmol/L)

[G]

CHOL

(mmol/L)

[G1]

TRIG

(mmol/L)

[G]

TPROT

(g/L)

[G]

ALB

(g/L)

[G]

GLOB

(g/L)

[G]

mg/kg/day

Group 1

Mean

29.4

3.2

9 -

4.740

1.150

9 -

2.828

0.449

9 -

0.589

0.061

9 -

56.30 2.58

9 -

40.21 1.79

9 -

16.09 2.22

9 -

100 mg/kg/day

Group 2

Mean

N tCtrl

24.6 *

4.2

0.84

5.008

0.434

1.06

2.641

0.493

0.93

0.461

0.140

0.78

55.21 2.41

0.98

39.51 2.62

0.98

15.70 0.72

0.98

300 mg/kg/day

Group 3

Mean

N tCtrl

24.0 * 2.5

0.82

4.863

0.808

1.03

2.889

0.655

1.02

0.535

0.177

0.91

56.38 2.85

1.00

40.59 2.45

1.01

16.19 1.63

1.01

900 mg/kg/day

Group 4

Mean

N tCtrl

25.6

4.6

0.87

5.003 0.815

1.06

2.827 0.925

1.00

0.479 0.115

0.81

58.48 3.36

1.04

42.81

2.93

1.06

15.68 1.98

0.97

Sex: Female

Reporting Biochemistry

A/G

(ratio) [G]

(mmol/L)

[G]

(mmol/L)

[G]

(mmol/L)

[G]

(mmol/L)

[G]

PHOS

(mmol/L)

[G]

mg/kg/day

Group 1

Mean

2.53

0.34

9 -

2.680

0.100

9 -

140.7

2.1

9 -

5.12

0.42

9 -

99.8

2.2

9 -

1.708

0.538

9 -

100 mg/kg/day

Group 2

Mean

N tCtrl

2.54

0.23

1.00

2.621

0.139

0.98

140.0

3.5

1.00

5.05

0.57

0.99

100.1

1.9

1.00

1.649

0.518

0.97

300 mg/kg/day

Group 3

Mean

N tCtrl

2.50

0.29

0.99

2.694

0.096

1.01

140.1

1.3

1.00

5.24

0.62

1.02

99.3

1.7

1.00

1.538

0.510

0.90

900 mg/kg/day

Group 4

Mean

N tCtrl

2.78 0.47

1.10

2.781 0.183

1.04

140.1

2.3

1.00

5.19 0.42

1.01

97.8

2.9

0.98

1.949 0.766

1.14

Tables 14. Summary of Clinical Chemistry Values

F1 Animals - Cohort 1A. Day 70 Relative to Start Date

Sex: Male

Reporting Biochemistry

AST

(U/L)

[G]

ALT

(U/L)

[G]

ALP

(U/L)

[G]

GGT

(U/L)

[G1]

(U/L)

[G]

TBIL

(umol/L)

[G1]

UREA

(mmol/L)

[G]

mg/kg/day

Group 1

Mean

68.5

6.0

10 -

57.6

11.4

10 -

153.4

23.5

10 -

1.5

0.0

9 -

239.9

42.0

9 -

1.25

0.00

9 -

7.02

0.68

9 -

100 mg/kg/day

Group 2

Mean

tCtrl

63.0

7.2

0.92

52.0

7.9

0.90

153.5

23.8

1.00

1.5

0.0

1.00

239.2

101.7

1.00

1.25

0.00

1.00

6.32

0.62

0.90

300 mg/kg/day

Group 3

Mean

tCtrl

61.3 *

5.3

0.89

49.9

8.6

0.87

143.2

27.9

0.93

1.5

0.0

1.00

210.5 55.4

0.88

1.25

0.00

1.00

6.84

0.59

0.97

900 mg/kg/day

Group 4

Mean

tCtrl

61.2 *

4.0

0.89

42.5 **

13.0

0.74

141.5

23.9

0.92

1.5 0.0

1.00

174.9 37.4

0.73

1.25 0.00

1.00

7.24 0.85

1.03

[G] - Anova & Dunnett: * = p ≤ 0.05; ** = p ≤ 0.01

[G1] - Kruskal-Wallis & Dunn

Sex: Male

Reporting Biochemistry

CREAT

(umol/L)

[G]

GLUC

(mmol/L)

[G]

CHOL

(mmol/L)

[G]

TRIG

(mmol/L)

[G]

TPROT

(g/L)

[G]

ALB

(g/L)

[G]

GLOB

(g/L)

[G]

mg/kg/day

Group 1

Mean

30.8

4.0

9 -

9.268

0.551

9 -

1.723

0.237

9 -

2.458

1.001

9 -

66.48 1.47

9 -

41.30

1.39

10 -

25.16 1.24

9 -

100 mg/kg/day

Group 2

Mean

N tCtrl

28.1

3.8

0.91

8.529 **

0.254

0.92

1.894

0.316

1.10

2.030

0.674

0.83

66.44

1.28

1.00

41.71

2.18

1.01

24.73

2.00

0.98

300 mg/kg/day

Group 3

Mean

N tCtrl

29.8

2.6

0.97

8.735

0.590

0.94

2.007

0.325

1.16

1.784

0.635

0.73

65.87

2.39

0.99

41.11

2.06

1.00

24.76

2.03

0.98

900 mg/kg/day

Group 4

Mean

N tCtrl

32.6

3.7

1.06

8.617 *

0.503

0.93

2.147 *

0.325

1.25

1.522 0.615

0.62

65.97

1.76

0.99

42.49

1.31

1.03

23.48

1.78

0.93

Sex: Male

Reporting Biochemistry

A/G

(ratio) [G]

(mmol/L)

[G]

(mmol/L)

[G]

(mmol/L)

[G]

(mmol/L)

[G1]

PHOS

(mmol/L)

[G]

mg/kg/day

Group 1

Mean

1.64

0.10

9 -

2.592

0.033

9 -

141.0

0.8

10 -

5.09

0.30

10 -

100.5

0.5

10 -

1.747

0.191

9 -

100 mg/kg/day

Group 2

Mean

N tCtrl

1.70

0.19

1.03

2.620

0.064

1.01

142.0

1.2

1.01

5.12

0.30

1.01

101.7 *

0.8

1.01

2.034 **

0.122

1.16

300 mg/kg/day

Group 3

Mean

N tCtrl

1.67

0.19

1.02

2.626

0.074

1.01

141.1

1.5

1.00

4.99

0.20

0.98

101.3

1.2

1.01

1.968 **

0.179

1.13

900 mg/kg/day

Group 4

Mean

N tCtrl

1.83 0.17

1.11

2.657 0.064

1.02

141.6

2.0

1.00

4.95 0.18

0.97

99.9

1.6

0.99

2.065 **

0.116

1.18

Sex: Female

Reporting Biochemistry

AST

(U/L)

[G]

ALT

(U/L)

[G]

ALP

(U/L)

[G]

GGT

(U/L)

[G1]

(U/L)

[G]

TBIL

(umol/L)

[G1]

UREA

(mmol/L)

[G]

mg/kg/day

Group 1

Mean

78.0

10.7

7 -

55.9

14.4

7 -

100.6

26.1

7 -

1.5

0.0

7 -

295.7

114.0

7 -

1.25

0.00

7 -

8.09

1.15

7 -

100 mg/kg/day

Group 2

Mean

tCtrl

71.9

7.5

0.92

54.6

17.9

0.98

93.2

23.3

0.93

1.5

0.0

1.00

242.9

83.5

0.82

1.25

0.00

1.00

7.43

0.78

0.92

300 mg/kg/day

Group 3

Mean

tCtrl

68.3

6.1

0.88

49.9

13.2

0.89

94.3

24.1

0.94

1.5

0.0

1.00

259.2 98.3

0.88

1.25

0.00

1.00

7.70

0.89

0.95

900 mg/kg/day

Group 4

Mean

tCtrl

73.7

9.9

0.94

59.8 26.8

1.07

135.4

38.1

1.35

2.2 1.5

1.47

296.8

105.5

1.00

1.25 0.00

1.00

7.66 1.24

0.95

Sex: Female

Reporting Biochemistry

CREAT

(umol/L)

[G]

GLUC

(mmol/L)

[G]

CHOL

(mmol/L)

[G]

TRIG

(mmol/L)

[G]

TPROT

(g/L)

[G]

ALB

(g/L)

[G]

GLOB

(g/L)

[G]

mg/kg/day

Group 1

Mean

34.0

3.5

7 -

8.577

0.866

7 -

1.589

0.267

7 -

1.421

0.304

7 -

65.96 2.49

7 -

45.56 2.60

7 -

20.40 2.41

7 -

100 mg/kg/day

Group 2

Mean

N tCtrl

34.8

4.5

1.02

7.801

0.566

0.91

1.512

0.297

0.95

1.021

0.261

0.72

67.76 2.46

1.03

46.70 1.56

1.03

21.06 1.80

1.03

300 mg/kg/day

Group 3

Mean

N tCtrl

32.7

4.0

0.96

8.161

0.464

0.95

1.647

0.235

1.04

1.268

0.529

0.89

68.21

2.48

1.03

46.77

2.62

1.03

21.44

2.18

1.05

900 mg/kg/day

Group 4

Mean

N tCtrl

32.4

4.5

0.95

8.082 0.391

0.94

1.913 *

0.234

1.20

0.978 0.268

0.69

67.82

2.61

1.03

46.97

2.19

1.03

20.85

1.87

1.02

Sex: Female

Reporting Biochemistry

A/G

(ratio) [G]

(mmol/L)

[G]

(mmol/L)

[G]

(mmol/L)

[G]

(mmol/L)

[G]

PHOS

(mmol/L)

[G]

mg/kg/day

Group 1

Mean

2.27

0.35

7 -

2.574

0.035

7 -

140.3

1.1

7 -

4.43

0.42

7 -

103.6

1.4

7 -

1.227

0.104

7 -

100 mg/kg/day

Group 2

Mean

N tCtrl

2.24

0.21

0.99

2.581

0.060

1.00

140.2

1.2

1.00

4.78

0.29

1.08

102.9

1.2

0.99

1.436

0.206

1.17

300 mg/kg/day

Group 3

Mean

N tCtrl

2.18

0.30

0.96

2.591

0.053

1.01

140.6

0.8

1.00

4.45

0.20

1.00

104.1

1.3

1.01

1.379

0.205

1.12

900 mg/kg/day

Group 4

Mean

N tCtrl

2.30 0.28

1.01

2.664 **

0.039

1.03

140.4

1.1

1.00

4.86 *

0.27

1.10

102.2

0.9

0.99

1.312 0.263

1.07

Table 15. Summary of Coagulation Values

F0 Animals – Males, Day: 137 Relative to Start Date

Sex: Male

Reporting Coagulation

(sec)

[G]

APTT

(sec)

[G]

FIB

(g/L)

[G]

mg/kg/day

Group 1

Mean

10.55

0.20

10 -

13.51

1.35

10 -

2.278

0.177 10 .

100 mg/kg/day

Group 2

Mean

N tCtrl

10.43

0.15

0.99

12.52

1.72

0.93

2.282

0.122

1.00

300 mg/kg/day

Group 3

Mean

N tCtrl

10.30 **

0.14

0.98

12.35

1.14

0.91

2.286

0.185

1.00

900 mg/kg/day

Group 4

Mean

N tCtrl

10.26 **

0.12

0.97

11.77

1.51

0.87

2.454 *

0.114

1.08

[G] - Anova & Dunnett: * = p ≤ 0.05; ** = p ≤ 0.01

Table 16. Summary of Coagulation Values

F0 Animals – Females, Day: 115 Relative to Start Date

Sex: Female

Reporting Coagulation

(sec)

[G]

APTT

(sec)

[G]

FIB

(g/L)

[G]

mg/kg/day

Group 1

Mean

10.19

0.21

9 -

11.17

1.22

9 -

1.713

0.292 9 .

100 mg/kg/day

Group 2

Mean

N tCtrl

10.48

0.34

1.03

12.17

1.55

1.09

1.612

0.157

0.94

300 mg/kg/day

Group 3

Mean

N tCtrl

10.27

0.32

1.01

11.82

1.49

1.06

1.743

0.316

1.02

900 mg/kg/day

Group 4

Mean

N tCtrl

10.39

0.73

1.02

11.16

2.64

1.00

1.682 0.425

0.98

[G] - Anova & Dunnett

Table 17. Summary of Coagulation Values

F1 Animals - Cohort 1A, Day: 70 Relative to Start Date

Sex: Male

Reporting Coagulation

(sec)

[G]

APTT

(sec)

[G]

FIB

(g/L)

[G]

mg/kg/day

Group 1

Mean

10.50

0.14

9 -

12.27

1.80

9 -

2.580

0.172 9 .

100 mg/kg/day

Group 2

Mean

N tCtrl

10.40

0.11

0.99

12.79

2.10

1.04

2.516

0.141

0.98

300 mg/kg/day

Group 3

Mean

N tCtrl

10.34 *

0.14

0.98

12.09

2.30

0.99

2.655

0.219

1.03

900 mg/kg/day

Group 4

Mean

N tCtrl

10.33 *

0.05

0.98

11.51

2.25

0.94

2.707 0.250

1.05

[G] - Anova & Dunnett: * = p ≤ 0.05

Sex: Female

Reporting Coagulation

(sec)

[G]

APTT

(sec)

[G]

FIB

(g/L)

[G]

mg/kg/day

Group 1

Mean

10.31

0.26

9 -

12.21

1.52

8 -

2.116

0.251 9 .

100 mg/kg/day

Group 2

Mean

N tCtrl

10.17

0.17

0.99

12.33

1.57

1.01

2.128

0.172

1.01

300 mg/kg/day

Group 3

Mean

N tCtrl

10.15

0.14

0.98

11.65

0.99

0.95

2.186

0.194

1.03

900 mg/kg/day

Group 4

Mean

N tCtrl

10.02 **

0.17

0.97

11.71

1.65

0.96

2.182 0.099

1.03

[G] - Anova & Dunnett: ** = p ≤ 0.01

Table 18. Summary of Hematology Values

F0 Animals – Males Day: 137 Relative to Start Date

Sex: Male

Reporting Hematology

WBC

(10^9/L)

[G]

NEUT

(10^9/L)

[G]

LYMPH

(10^9/L)

[G1]

MONO

(10^9/L)

[G]

EOS

(10^9/L)

[G]

BASO

(10^9/L)

[G1]

LUC

(10^9/L)

[G1]

mg/kg/day

Group 1

Mean

4.651

0.478

10 -

0.961

0.257

10 -

3.480

0.289

10 -

0.065

0.014

10 -

0.116

0.046

10 -

0.008

0.004

10 -

0.019

0.006

10 -

100 mg/kg/day

Group 2

Mean

N tCtrl

4.340

0.805

0.93

0.769

0.202

0.80

3.390

0.784

0.97

0.062

0.018

0.95

0.096

0.024

0.83

0.006

0.005

0.75

0.016

0.008

0.84

300 mg/kg/day

Group 3

Mean

N tCtrl

4.469

0.783

0.96

0.687 *

0.169

0.71

3.605

0.697

1.04

0.057

0.021

0.88

0.089

0.023

0.77

0.010

0.000

1.25

0.019

0.007

1.00

900 mg/kg/day

Group 4

Mean

N tCtrl

5.192 0.960

1.12

0.854 0.199

0.89

4.126 0.908

1.19

0.079 0.028

1.22

0.092 0.040

0.79

0.009 0.006

1.13

0.027 0.013

1.42

[G] - Anova & Dunnett: * = p ≤ 0.05

[G1] - Kruskal-Wallis & Dunn

Sex: Male

Reporting Hematology

RBC

(10^12/L)

[G]

HGB

(g/L)

[G]

HCT

(L/L)

[G]

MCV

(fL)

[G]

MCH

(pg)

[G]

MCHC

(g/L)

[G]

RDWG

(%)

[G]

mg/kg/day

Group 1

Mean

8.813

0.449

10 -

153.6

4.7

10 .

0.4464

0.0164

10 -

50.68

1.37

10 -

17.43

0.57

10 -

343.9

7.0

10 -

11.88

0.31

10 -

100 mg/kg/day

Group 2

Mean

N tCtrl

8.630

0.303

0.98

150.7

6.5

0.98

0.4441

0.0155

0.99

51.52

2.26

1.02

17.46

1.03

1.00

338.9

7.5

0.99

12.00

0.48

1.01

300 mg/kg/day

Group 3

Mean

N tCtrl

8.572

0.317

0.97

149.6

5.2

0.97

0.4388

0.0129

0.98

51.25

1.89

1.01

17.47

0.71

1.00

341.1

6.6

0.99

12.01

0.52

1.01

900 mg/kg/day

Group 4

Mean

N tCtrl

8.573 0.220

0.97

147.4

5.4

0.96

0.4364 0.0139

0.98

50.92

1.39

1.00

17.17

0.55

0.99

337.5

4.5

0.98

12.16

0.48

1.02

Sex: Male

Reporting Hematology

PLT

(10^9/L)

[G]

RETIC

(10^9/L)

[G]

mg/kg/day

Group 1

Mean

781.6

146.2

10 -

155.83

19.62

10 -

100 mg/kg/day

Group 2

Mean

N tCtrl

765.3

76.5

0.98

142.51

41.33

0.91

300 mg/kg/day

Group 3

Mean

N tCtrl

760.4

92.6

0.97

160.37

18.17

1.03

900 mg/kg/day

Group 4

Mean

N tCtrl

883.4

160.3

1.13

171.47

21.32

1.10

Table 19. Summary of Hematology Values

F0 Animals – Females Day: 115 Relative to Start Date

Sex: Female

Reporting Hematology

WBC

(10^9/L)

[G]

NEUT

(10^9/L)

[G]

LYMPH

(10^9/L)

[G]

MONO

(10^9/L)

[G]

EOS

(10^9/L)

[G]

BASO

(10^9/L)

[G]

LUC

(10^9/L)

[G]

mg/kg/day

Group 1

Mean

5.168

1.072

8 -

1.669

0.559

8 -

3.265

0.790

8 -

0.109

0.031

8 -

0.095

0.038

8 -

0.011

0.006

8 -

0.023

0.009

8 -

100 mg/kg/day

Group 2

Mean

N tCtrl

5.529

0.603

1.07

1.737

0.408

1.04

3.564

0.620

1.09

0.113

0.025

1.04

0.077

0.039

0.81

0.012

0.008

1.07

0.025

0.010

1.11

300 mg/kg/day

Group 3

Mean

N tCtrl

5.866

1.252

1.14

1.903

0.424

1.14

3.694

0.894

1.13

0.143

0.060

1.31

0.091

0.038

0.96

0.013

0.007

1.16

0.026

0.013

1.16

900 mg/kg/day

Group 4

Mean

N tCtrl

5.570 0.802

1.08

1.762 0.315

1.06

3.555 0.672

1.09

0.144 0.051

1.32

0.073 0.013

0.77

0.008 0.004

0.71

0.028 0.011

1.24

Sex: Female

Reporting Hematology

RBC

(10^12/L)

[G]

HGB

(g/L)

[G]

HCT

(L/L)

[G]

MCV

(fL)

[G]

MCH

(pg)

[G]

MCHC

(g/L)

[G]

RDWG

(%)

[G]

mg/kg/day

Group 1

Mean

7.958

0.449

8 -

157.3

3.4

8 .

0.4679

0.0124

8 -

58.88 2.37

8 -

19.80 0.92

8 -

336.4 5.2

8 -

12.00 1.06

8 -

100 mg/kg/day

Group 2

Mean

tCtrl

7.678

0.380

0.96

153.3

5.2

0.97

0.4515

0.0208

0.97

58.86

1.56

1.00

19.99

0.77

1.01

339.8

8.3

1.01

11.84

0.79

0.99

300 mg/kg/day

Group 3

Mean

tCtrl

7.466

0.606

0.94

152.7

5.1

0.97

0.4468

0.0194

0.95

59.99 2.69

1.02

20.48 1.21

1.03

341.6 7.1 9

1.02

11.82

0.97

0.99

900 mg/kg/day

Group 4

Mean

tCtrl

7.528 0.566

0.95

151.3

8.8

0.96

0.4428 0.0316

0.95

58.85

1.83

1.00

20.10

1.07

1.02

341.5 10.8

1.02

12.17

1.05

1.01

Sex: Female

Reporting Hematology

PLT

(10^9/L)

[G]

RETIC

(10^9/L)

[G]

mg/kg/day

Group 1

Mean

894.6

119.2

8 -

177.99

20.44

8 -

100 mg/kg/day

Group 2

Mean

N tCtrl

794.3

132.8

0.89

178.18

31.61

1.00

300 mg/kg/day

Group 3

Mean

N tCtrl

872.4

121.5

0.98

161.09

22.77

0.91

900 mg/kg/day

Group 4

Mean

N tCtrl

833.4

177.2

0.93

173.25

30.61

0.97

Table 20. Summary of Hematology Values

F1 Animals – Cohort 1A. Day 70 Relative to Start Date

Sex: Male

Reporting Hematology

WBC

(10^9/L)

[G]

NEUT

(10^9/L)

[G]

LYMPH

(10^9/L)

[G]

MONO

(10^9/L)

[G]

EOS

(10^9/L)

[G]

BASO

(10^9/L)

[G1]

LUC

(10^9/L)

[G1]

mg/kg/day

Group 1

Mean

6.989

1.038

10 -

0.930

0.183

10 -

5.762

0.940

10 -

0.121

0.043

10 -

0.108

0.036

10 -

0.008

0.009

10 -

0.059

0.018

10 -

100 mg/kg/day

Group 2

Mean

N tCtrl

7.203

0.765

1.03

0.970

0.322

1.04

5.976

0.743

1.04

0.099

0.031

0.82

0.091

0.031

0.84

0.011

0.006

1.38

0.054

0.023

0.92

300 mg/kg/day

Group 3

Mean

N tCtrl

7.256

0.780

1.04

0.993

0.193

1.07

6.050

0.666

1.05

0.086

0.030

0.71

0.074

0.023

0.69

0.007

0.005

0.88

0.047

0.009

0.80

900 mg/kg/day

Group 4

Mean

N tCtrl

8.090 *

0.978

1.16

1.081 0.253

1.16

6.736 1.071

1.17

0.115 0.030

0.95

0.080 0.032

0.74

0.011 0.006

1.38

0.064 0.023

1.08

[G] - Anova & Dunnett: * = p ≤ 0.05

[G1] - Kruskal-Wallis & Dunn

Sex: Male

Reporting Hematology

RBC

(10^12/L)

[G]

HGB

(g/L)

[G]

HCT

(L/L)

[G]

MCV

(fL)

[G]

MCH

(pg)

[G]

MCHC

(g/L)

[G]

RDWG

(%)

[G]

mg/kg/day

Group 1

Mean

9.078

0.461

10 -

163.2

4.9

10 .

0.4747

0.0207

10 -

52.33

1.52

10 -

17.99

0.90

10 -

343.7 10.9

10 -

11.47

0.49

10 -

100 mg/kg/day

Group 2

Mean

N tCtrl

8.551 *

0.488

0.94

156.9 *

5.4

0.96

0.4471 **

0.0181

0.94

52.33

2.09

1.00

18.37

0.87

1.02

350.8

6.2

1.02

11.59

0.52

1.01

300 mg/kg/day

Group 3

Mean

N tCtrl

8.522 **

0.298

0.94

157.1 *

4.1

0.96

0.4519 *

0.0171

0.95

53.06

1.54

1.01

18.44

0.54

1.03

347.7

7.0

1.01

11.63

0.51

1.01

900 mg/kg/day

Group 4

Mean

N tCtrl

8.340 **

0.285

0.92

154.7 **

4.4

0.95

0.4456 **

0.0166

0.94

53.45

1.51

1.02

18.56

0.67

1.03

347.4

7.6

1.01

11.84

0.32

1.03

[G] - Anova & Dunnett: * = p ≤ 0.05; ** = p ≤ 0.01

Sex: Male

Reporting Hematology

PLT

(10^9/L)

[G]

RETIC

(10^9/L)

[G]

mg/kg/day

Group 1

Mean

763.2

131.0

10 -

193.85

15.23

10 -

100 mg/kg/day

Group 2

Mean

N tCtrl

876.8

89.5

1.15

171.56

23.85

0.89

300 mg/kg/day

Group 3

Mean

N tCtrl

899.7

76.1

1.18

198.49

23.89

1.02

900 mg/kg/day

Group 4

Mean

N tCtrl

823.3

144.5

1.08

208.78

30.71

1.08

Sex: Female

Reporting Hematology

WBC

(10^9/L)

[G]

NEUT

(10^9/L)

[G1]

LYMPH

(10^9/L)

[G]

MONO

(10^9/L)

[G1]

EOS

(10^9/L)

[G]

BASO

(10^9/L)

[G]

LUC

(10^9/L)

[G]

mg/kg/day

Group 1

Mean

5.104

1.013

9 -

0.587

0.094

9 -

4.321

0.997

9 -

0.070

0.018

9 -

0.081

0.019

9 -

0.003

0.005

9 -

0.038

0.010

9 -

100 mg/kg/day

Group 2

Mean

N tCtrl

5.207

1.111

1.02

0.671

0.142

1.14

4.371

1.058

1.01

0.053

0.017

0.76

0.074

0.028

0.92

0.004

0.005

1.33

0.029

0.014

0.76

300 mg/kg/day

Group 3

Mean

N tCtrl

4.656

0.870

0.91

0.708

0.238

1.21

3.780

0.791

0.87

0.060

0.021

0.86

0.067

0.020

0.83

0.003

0.005

0.90

0.034

0.008

0.90

900 mg/kg/day

Group 4

Mean

N tCtrl

5.515 1.387

1.08

0.681 0.323

1.16

4.640 1.417

1.07

0.076 0.039

1.09

0.079 0.031

0.97

0.004 0.005

1.20

0.037 0.014

0.98

[G] - Anova & Dunnett

[G1] - Kruskal-Wallis & Dunn

Sex: Female

Reporting Hematology

RBC

(10^12/L)

[G]

HGB

(g/L)

[G]

HCT

(L/L)

[G]

MCV

(fL)

[G]

MCH

(pg)

[G]

MCHC

(g/L)

[G]

RDWG

(%)

[G]

mg/kg/day

Group 1

Mean

7.842

0.436

9 -

151.6

5.3

9 .

0.4248

0.0164

9 -

54.23 1.82

9 -

19.38 0.95

9 -

356.8 8.1

9 -

10.70 0.38

9 -

100 mg/kg/day

Group 2

Mean

N tCtrl

7.868

0.225

1.00

148.8

6.5

0.98

0.4244

0.0173

1.00

53.91 1.31

0.99

18.89 0.64

0.97

350.7 8.5 9

0.98

10.91 0.36

1.02

300 mg/kg/day

Group 3

Mean

N tCtrl

7.867

0.362

1.00

149.7

5.4

0.99

0.4244

0.0143

1.00

54.01

2.25

1.00

19.06

0.93

0.98

352.6

4.3

0.99

10.68

0.35

1.00

900 mg/kg/day

Group 4

Mean

N tCtrl

7.744 0.368

0.99

144.3

5.5

0.95

0.4116 0.0156

0.97

53.20

1.94

0.98

18.64

0.75

0.96

350.5

6.8

0.98

10.82

0.33

1.01

Sex: Female

Reporting Hematology

PLT

(10^9/L)

[G]

RETIC

(10^9/L)

[G1]

mg/kg/day

Group 1

Mean

833.0

141.8

9 -

183.07

34.30

9 -

100 mg/kg/day

Group 2

Mean

N tCtrl

801.3

145.2

0.96

178.02

22.41

0.97

300 mg/kg/day

Group 3

Mean

N tCtrl

796.3

97.2

0.96

185.18

28.61

1.01

900 mg/kg/day

Group 4

Mean

N tCtrl

910.6

58.3

1.09

177.80

38.40

0.97

Table 21. Summary of Reproductive Performance

F0 Females

Sex: Female

Day(s) Relative to Pairing (Litter: A

)

0 mg/kg/day

Group 1

100 mg/kg/day

Group 2

300 mg/kg/day

Group 3

900 mg/kg/day

Group 4

Group Size - Females

N+ve

Mean

%Diff

N+ve

N+ve %

% ProA

5.3

5.1

76.0

24.0

100.0

25/25

3.2

2.5

-39.4

96.0

4.0

100.0

25/25

2.7

2.6

-49.2

96.0

4.0

100.0

25/25

3.0

2.7

-43.2

95.8

4.2

100.0

24/24

Paired - Females

Mated Females

Pre-coital Interval (Days)

Confirmed Mating Days 1-7

Confirmed Mating Days 8-14

Female Mating Index

Mated Females - Pregnant or Not Pregnant with confirmed mating date (by sperm or plug).

Table 22. Summary of Reproductive Performance

F1 Animals - Cohort 1B Females

Sex: Female

Day(s) Relative to Pairing (Litter: A

)

0 mg/kg/day

Group 1

100 mg/kg/day

Group 2

300 mg/kg/day

Group 3

900 mg/kg/day

Group 4

Group Size - Females

N+ve

Mean

%Diff

N+ve

N+ve %

% ProA

2.7

1.0

100.0

0.0

100.0

20/20

3.9

3.7

45.3

90.0

10.0

100.0

20/20

3.5

2.7 20

32.1

95.0

5.0

100.0

20/20

2.5

1.2 20

-7.5

100.0

0.0

100.0

20/20

Paired - Females

Mated Females

Pre-coital Interval (Days)

Confirmed Mating Days 1-7

Confirmed Mating Days 8-14

Female Mating Index

Mated Females - Pregnant or Not Pregnant with confirmed mating date (by sperm or plug).

Table 23. Mating Performance and Fertility

F0 Animals

Number of Nights to Positive Mating Sign	Group/Dose Level (mg/kg/day)
	1 (0)	2 (100)	3 (300)	4 (900)
	Number of Animals (Number of these not becoming pregnant)
1	6(1)*	4	8	7(1)
2	2	5	6	5
3	6	8	7	3
4	5	7	3	8
No clear indication of mating	6(1)	1	1	1
Mean number of nights to positive mating sign	2.5	2.8	2.2	2.5
Number passing one estrus	0	0	0	0
Number of males paired	25	25	25	24
Number of siring males	24	25	25	23
Male Mating Index	0.96	1.00	1.00	1.00
Male Fertility Index	1.00	1.00	1.00	0.96
Male Pregnancy Index	0.96	1.00	1.00	0.96
Female Mating Index	0.96	1.00	1.00	1.00
Female Fertility Index	1.00	1.00	1.00	0.96
Female Pregnancy Index	0.96	1.00	1.00	0.96

*Includes Animal 1524 that had 2 implant sites (no live or dead pups)

Table 24. Mating Performance and Fertility

F1 Animals

Number of Nights to Positive Mating Sign	Group/Dose Level (mg/kg/day)
	1 (0)	2 (100)	3 (300)	4 (900)
	Number of Animals (Number of these not becoming pregnant)
1	3	5	2	7
2	5	2	4	2
3	9	5(2)	8	6
4	2	5	4	5
5	1(1)	1	0	0
6	0	0	1	0
No clear indication of mating	0	2(2)	1(1)	0
Mean number of nights to positive mating sign	2.7	2.7	2.9	2.5
Number passing one estrus	0	1	1	0
Number of males paired	20	20	20	20
Number of siring males	19	16	19	20
Male Mating Index	1.00	0.90	0.95	1.00
Male Fertility Index	0.95	0.89	0.95	1.00
Male Pregnancy Index	0.95	0.80	0.95	1.00
Female Mating Index	1.00	0.90	0.95	1.00
Female Fertility Index	0.95	0.89	0.95	1.00
Female Pregnancy Index	0.95	0.80	0.95	1.00

Table 25. Summary of Duration of Gestation and Overall Litter Performance

F0 Animals

F0 Generation	Group/Dose Level (mg/kg/day)
F0 Generation	1	2	3	4
	(0)	(100)	(300)	(900)
Number Pregnant	24	25	25	23
Duration of Gestation (Days) 21	1	1	0	0
22	17	17	23	20
23	0	6	1	2
No clear indication of mating	6	1	1	1
Mean Duration	21.9	22.2	22.0	22.1
Number of females producing a live litter	23	25	25	23
Gestation index as %	96	100	100	100
Mean number of implant sites per pregnancy ± standard deviation	12.0 ± 3.4	12.5 ± 2.4	12.6 ± 1.9	12.9 ± 1.6
Mean total number of pups born per litter ± standard deviation	11.0 ± 3.0	11.2 ± 2.3	11.0 ± 2.5	11.0 ± 3.3
Mean number of live pups per litter ± standard deviation: Lactation Day 1	11.0 ± 3.0	11.1 ± 2.2	10.9 ± 2.6	11.1 ± 2.6
Lactation Day 4	10.9 ± 3.1	11.2 ± 2.2	10.9 ± 2.6	11.0 ± 2.7
Lactation Day 4^a	7.7 ± 1.1	7.9 ± 0.4	7.8 ± 0.7	7.7 ± 0.9
Lactation Day 7	7.7 ± 1.1	7.9 ± 0.4	7.8± 0.7	7.7 ± 0.9
Lactation Day 14	7.7 ± 1.1	7.9 ± 0.4	7.8 ± 0.7	7.7 ± 0.9
Lactation Day 21	7.7 ± 1.1	7.9 ± 0.4	7.8 ± 0.7	7.7 ± 0.9
Number of males on Lactation Day 1 (%)	120 (47)	135 (49)	145 (53)	116 (47)
Number of females on Lactation Day 1 (%)	134 (53)	143 (51)	127 (47)	129 (53)

^aAfter cull of pups on PND 4 to standardise the size of the litter

Table 26. Summary of Duration of Gestation and Overall Litter Performance

F1 Animals

F1 Generation	Group/Dose Level (mg/kg/day)
F1 Generation	1	2	3	4
	(0)	(100)	(300)	(900)
Number Pregnant	19	16	19	20
Duration of Gestation (Days) 21	1	3	1	1
22	15	9	17	18
23	3	4	1	1
Mean Duration	22.1	22.1	22.0	22.0
Number of females producing a live litter	19	16	19	20
Gestation index as %	100	100	100	100
Mean number of implant sites per pregnancy ± standard deviation	12.6 ± 1.7	12.3 ± 2.3	13.0 ± 1.6	12.5 ± 2.3
Mean total number of pups born per litter ± standard deviation*	11.6 ± 1.9	11.1 ± 2.8	10.5 ± 2.8	11.3 ± 2.2
Mean number of live pups per litter ± standard deviation*: Lactation Day 1	11.3 ± 2.2	11.1 ± 3.0	10.4 ± 2.7	11.1 ± 2.1
Lactation Day 4	11.3 ± 2.2	11.0 ± 2.9	10.3 ± 2.8	11.0 ± 2.1
Lactation Day 4^a	7.9 ± 0.5	7.7 ± 0.9	7.6 ± 1.2	7.9 ± 0.5
Lactation Day 7	7.9 ± 0.5	7.7 ± 0.9	7.6 ± 1.2	7.9 ± 0.5
Lactation Day 14	7.9 ± 0.5	7.7 ± 0.9	7.6 ± 1.2	7.9 ± 0.5
Lactation Day 21	7.9 ± 0.5	7.7 ± 0.9	7.6 ± 1.2	7.8 ± 0.5
Number of males on Lactation Day 1 (%)	96 (47)	96 (54)	93 (49)	100 (45)
Number of females on Lactation Day 1 (%)	108 (53)	81 (46)	96 (51)	121 (55)

^aAfter cull of pups on PND 4 to standardise the size of the litter

* Excludes Animal 1628 that had a total litter loss

Table 27. Summary of Urinalysis Values

F0 Animals - Males
Day: 131 Relative to Start Date

Sex: Male			Reporting Urinalysis
		VOLUME	SPECIFIC	URINE pH
		(mL)	GRAVITY	[G]
		[G]	[G1]
0 mg/kg/day	Mean	4.32	1.0152	7.5
Group 1	SD	2.94	0.0089	0.94
	N	10	10 -	10 -
		-
100 mg/kg/day	Mean	5.64	1.0135	8
Group 2	SD	2.99	0.0052	0.62
	N	10	10	10
	tCtrl	1.31	1	1.07
300 mg/kg/day	Mean	4.22	1.0215	8.15
Group 3	SD	2.11	0.0086	0.63
	N	10	10	10
	tCtrl	0.98	1.01	1.09
900 mg/kg/day	Mean	5.25	1.0300 **	7.35 0.71
Group 4	SD	2.39	0.0133	10
	N	10	10	0.98
	tCtrl	1.22	1.01

Table 28. Summary of Urinalysis Values

F0 Animals - Females
Day: 108 Relative to Start Date

Sex: Female			Reporting Urinalysis
		VOLUME	SPECIFIC	URINE pH
		(mL)	GRAVITY	[G1]
		[G]	[G]
0 mg/kg/day	Mean	4.85	1.0188	8.6
Group 1	SD	2.33	0.0052	0.32
	N	10 -	10 -	10 -

100 mg/kg/day	Mean	5.23	1.0192	8.45
Group 2	SD	2.96	0.0069	0.16
	N	10	10	10
	tCtrl	1.08	1	0.98
300 mg/kg/day	Mean	6.01	1.0199	8.2
Group 3	SD	1.68	0.0039	0.42
	N	10	10	10
	tCtrl	1.24	1	0.95
900 mg/kg/day	Mean	7.05 2.58	1.0218 0.0051	8.05 *
Group 4	SD	10	10	0.72
	N	1.45	1	10
	tCtrl			0.94

[G] - Anova & Dunnett
[G1] - Kruskal-Wallis & Dunn: * = p ≤ 0.05

Table 29. Summary of Urinalysis Values

F1 Animals - Cohort 1A
Day: 60 Relative to Start Date

Sex: Male			Reporting urinalysis
		VOLUME	SPECIFIC	URINE pH
		(mL)	GRAVITY	[G]
		[G]	[G]
0 mg/kg/day	Mean	2.67	1.0182	8.11
Group 1	SD	1.87	0.0078	0.6
	N	10 -	10 -	9 -

100 mg/kg/day	Mean	3.07	1.0168	7.9
Group 2	SD	0.95	0.0123	0.61
	N	10	10	10
	tCtrl	1.15	1	0.97
300 mg/kg/day	Mean	1.96	1.0302 *	7.11 ** 0.70
Group 3	SD	1.25	0.0118	9
	N	10	10	0.88
	tCtrl	0.73	1.01
900 mg/kg/day	Mean	2.94 1.43	1.0346 **	6.25 **
Group 4	SD	10	0.0091	0.42
	N	1.1	10	10
	tCtrl		1.02	0.77

Day: 60 Relative to Start Date

Sex: Female

Reporting Urinalysi

VOLUME

(mL)

[G]

SPECIFIC

GRAVITY

[G]

URINE pH

[G]

mg/kg/day

Group 1

Mean

1.88

1.25

10 -

1.0226

0.0117

10 -

7.00

0.94

9 -

100 mg/kg/day

Group 2

Mean

N tCtrl

3.20

2.88

1.70

1.0161

0.0086

0.99

7.15

0.91

1.02

300 mg/kg/day

Group 3

Mean

N tCtrl

1.33

1.08

0.71

1.0333

0.0118

1.01

6.61

0.55

0.94

900 mg/kg/day

Group 4

Mean

N tCtrl

2.61 1.55

1.39

1.0267 0.0087

1.00

6.44 0.68

0.92

[G] - Anova & Dunnett

Conclusions:

The administration of the target substance once daily (or twice daily 3 hours apart on some occasions) via
oral gavage was well tolerated in Han Wistar rats at dose levels of up to 900 mg/kg/day with no
test item-related deaths. There were occasional observations of decreased activity, abnormal, un
coordinated gait and low carriage for F0 animals at 900 mg/kg/day and for F0 and F1 animals, dose le
vel-related salivation and/or ploughing. F0 and F1 males at 900 mg/kg/day had slightly lower body we
ight gain, and F0 and F1 females a slightly higher dose level-related body weight gain at ≥ 100 mg/kg/
day. Food consumption was generally slightly higher for males and females at ≥ 100 mg/kg/day. Ther
e were no test item-related effects on F0 and F1 generation fertility, mating or reproduction, or F1 and
F2 generation pup numbers, survival or development. For males at 900 mg/kg/day, motor activity
was 9.6% or 12.7% lower overall for basic or fine movements, respectively, but this was not confirme
d by overall ambulation values, or any associated clinical findings, detailed functional observations or
brain morphometry values for Cohort 2A. Triglyceride values were lower for F0 males given ≥300 mg/
kg/day, F0 females and F1 animals given ≥100 mg/kg/day, and cholesterol values higher for F0 male
s only at ≥300 mg/kg/day and F1 animals at 900 mg/kg/day. There were slightly higher TSH levels
(up to 3.1-fold of controls) on the morning of necropsy in F0 and F1 adult males given 300 or 900 mg/kg/day. There were no test item-related effects on haematology, coagulation, urinalysis, T4 values
or the immune cell populations analysed for immunophenotyping, at up to 900 mg/kg/day. Target
organ effects were observed at dose levels of ≥100 mg/kg/day and consisted of centrilobular hypertro
phy in the liver and stomach mucosal hyperplasia of the glandular region. Higher liver and/or kidney
weights were seen in both sexes. In neurological investigations, there were no test item-related brain
weight differences, gross or histological findings or effects on the brain dimensions. There were no
histological findings in the reproductive tissues of the females that had not been observed to litter tha
t would have caused reduced fertility. The NOAEL (No Observed Adverse Effect Level) for F0 and F1
adult toxicity, male and female fertility and reproduction was considered to be 900 mg/kg/day as the i
n-life and pathological findings were considered not to be adverse. For F1 and F2 developmental para
meters, the NOAEL was considered to be 900 mg/kg/day as there were no test item-related effects on
the pup numbers, survival or development.

Executive summary:

Read-across approach:

The methodology used for choosing potential read-across source substances for this current assessment was two-fold:

Identify substances that have a similar molecular structure to the target substance, for example, having common functional groups as well as likely having structurally-similar degradation products, and

Identify which of these source substances have the necessary toxicology data to fulfil the data gap.

The substance finally selected for the read-across source met the scientific hypothesis and comparison criteria below:

The target and source substance are small molecules with common functional groups which will influence their toxicokinetic behaviour. The predicted metabolic route and hence breakdown products within the body are common for both substances.

A comparison of existing mammalian (rat) toxicity data shows that both substances were of low toxicity, with both having high values for No Observed Adverse Effect Levels (NOAEL) for repeated dose toxicity studies in rats. In particular, no developmental toxicity was observed in either substance at the dose levels tested.

The intended use of both substances is as Photoinitiators which means high commonality in the manufacture, formulation and use. Thus the potential for (accidental) human and environmental exposure is the same for both substances.

It is therefore concluded that the target substance will have the same reproductive toxicity outcomes as that of the source substance for an Extended One Generation Reproductive Toxicity (EOGRT) Study.

Executive summary of the study:

The objective of this study was to determine the potential toxicity of the test item, when given by oral gavage to adult rats and their offspring. This study was designed to provide an evaluation of reproduction and development as well as a thorough evaluation of systemic toxicity in pregnant and lactating females and their offspring. Detailed examination of key developmental endpoints, such as offspring viability, neonatal health, developmental status at birth, physical and functional development until adulthood, nervous and immune system development was expected to identify any specific target organs in the offspring. In addition, the study provided information about the effects of the test item on the integrity and performance of the adult male and female reproductive systems and a neurobehavioural assessment of the F1 generation.

The study design was as follows:

Text Table 1 Experimental Design – F0 Animals

Group No.	Treatment	Dose Level (mg/kg/day)	Dose Volume^a (mL/kg)	Dose Conc. (mg/mL)	Corrected Dose Conc. (mg/mL)	Corrected Dose Levels (mg/kg/day)	Number of Animals
Group No.	Treatment	Dose Level (mg/kg/day)	Dose Volume^a (mL/kg)	Dose Conc. (mg/mL)	Corrected Dose Conc. (mg/mL)	Corrected Dose Levels (mg/kg/day)	Males	Females
1	Control	0	10	0	0	0	25	25
2	Test item	100	10	10	10.03	100	25	25
3	Test item	300	10	30	30.09	301	25	25
4	Test item	900	10	90	90.27	903	25	25

^aDose volume was based on the most recent body weight measurement.
Control/vehicle = 0.5% (w/v) Carboxymethylcellulose (CMC) medium viscosity and 0.1% (w/v) Tween 80 in Milli-Q water
Conc. = concentration

Text Table 2 Experimental Design – F1 Unselected PND (Post Natal Day) 21 Pups

Group No.^a	Number of Animals^b
Group No.^a	Males	Females
1	10	10
2	10	10
3	10	10
4	10	10

^aUnselected pups were not dosed, group number refers to dam group number.

^bThese pups had TSH and T4 blood sampling and necropsy procedures.

Text Table 3 Experimental Design – Cohort 1A (Reproductive)

Group No.	Treatment	Dose Level (mg/kg/day)	Dose Volume^a (mL/kg)	Dose Conc. (mg/mL)	Corrected Dose Conc. (mg/mL)	Corrected Dose Levels (mg/kg/day)	Number of Animals
Group No.	Treatment	Dose Level (mg/kg/day)	Dose Volume^a (mL/kg)	Dose Conc. (mg/mL)	Corrected Dose Conc. (mg/mL)	Corrected Dose Levels (mg/kg/day)	Males	Females
1	Control	0	10	0	0	0	20	20
2	Test item	100	10	10	10.03	100	20	20
3	Test item	300	10	30	30.09	301	20	21^d
4	Test item	900^bc	10^bc	90^bc	90.27	903	20	20

^aDose was based on the most recent body weight measurement.
^b From 19 Aug 2021, F1 Group 4 animals were dosed twice daily (approximately 3 hours apart) at 10 mL/kg and
450 mg/kg (45 mg/mL), equivalent to 900 mg/kg/day.

^c From 30 Aug 2021, F1 Group 4 animals were dosed once daily at 10 mL/kg and 900 mg/kg/day.
^d One female given 300 mg/kg/day died within minutes of receiving its first dose on Day 1, and another female
was added to the group.

Control/vehicle = 0.5% (w/v) CMC medium viscosity and 0.1% (w/v) Tween 80 in Milli-Q water
Conc. = concentration

Text Table 4 Experimental Design – Surplus F1 Animals

Group No.	Treatment	Dose Level (mg/kg/day)	Dose Volume^a (mL/kg)	Dose Conc. (mg/mL)	Corrected Dose Conc. (mg/mL)	Corrected Dose Levels (mg/kg/day)	Number of Animals
Group No.	Treatment	Dose Level (mg/kg/day)	Dose Volume^a (mL/kg)	Dose Conc. (mg/mL)	Corrected Dose Conc. (mg/mL)	Corrected Dose Levels (mg/kg/day)	Males	Females
1	Control	0	10	0	0	0	10	10
2	Test item	100	10	10	10.03	100	10	10
3	Test item	300	10	30	30.09	301	10	10
4	Test item	900^bc	10^bc	90^bc	90.27	903	10	10

^aDose was based on the most recent body weight measurement.

^b From 19 Aug 2021, F1 Group 4 animals were dosed twice daily (approximately 3 hours apart) at 10 mL/kg and 450 mg/kg (45 mg/mL), equivalent to 900 mg/kg/day.

^c From 30 Aug 2021, F1 Group 4 animals were dosed once daily at 10 mL/kg and 900 mg/kg/day.
Control/vehicle = 0.5% (w/v) CMC medium viscosity and 0.1% (w/v) Tween 80 in Milli-Q water
Conc. = concentration

Text Table 5 Experimental Design – Cohort 1B (Reproductive)

Group No.	Treatment	Dose Level (mg/kg/day)	Dose Volume^a (mL/kg)	Dose Conc. (mg/mL)	Corrected Dose Conc. (mg/mL)	Corrected Dose Levels (mg/kg/day)	Number of Animals
Group No.	Treatment	Dose Level (mg/kg/day)	Dose Volume^a (mL/kg)	Dose Conc. (mg/mL)	Corrected Dose Conc. (mg/mL)	Corrected Dose Levels (mg/kg/day)	Males	Females
1	Control	0	10	0	0	0	20	20
2	Test item	100	10	10	10.03	100	20	20
3	Test item	300	10	30	30.09	301	20	20
4	Test item	900^bc	10^bc	90^bc	90.27	903	20	20

^aDose was based on the most recent body weight measurement.

^b From 19 Aug 2021, F1 Group 4 animals were dosed twice daily (approximately 3 hours apart) at 10 mL/kg and 450 mg/kg (45 mg/mL), equivalent to 900 mg/kg/day.

Text Table 6 Experimental Design – F2 Unselected PND 21 Pups

Group No.^a	Number of Animals^b
Group No.^a	Males	Females
1	10	10
2	10	10
3	10	10
4	10	10

^aUnselected pups were not dosed, group number refers to dam group number.

^bThese pups had TSH and T4 blood sampling and necropsy procedures.

Text Table 7 Experimental Design – Cohort 2A (Neurobehavioural)

Group No.	Treatment	Dose Level (mg/kg/day)	Dose Volume^a (mL/kg)	Dose Conc. (mg/mL)	Corrected Dose Conc. (mg/mL)	Corrected Dose Levels (mg/kg/day)	Number of Animals
Group No.	Treatment	Dose Level (mg/kg/day)	Dose Volume^a (mL/kg)	Dose Conc. (mg/mL)	Corrected Dose Conc. (mg/mL)	Corrected Dose Levels (mg/kg/day)	Males	Females
1	Control	0	10	0	0	0	10	10
2	Test item	100	10	10	10.03	100	10	10
3	Test item	300	10	30	30.09	301	10	10
4	Test item	900^bc	10^bc	90^bc	90.27	903	10	10

^aDose was based on the most recent body weight measurement.

^b From 19 Aug 2021, F1 Group 4 animals were dosed twice daily (approximately 3 hours apart) at 10 mL/kg and 450 mg/kg (45 mg/mL), equivalent to 900 mg/kg/day.

Text Table 8 Experimental Design – Cohort 2B (Neuropathology)^a

Group No.	Number of Animals
Group No.	Males	Females
1	10	10
2	10	10
3	10	10
4	10	10

^aCohort 2B were not dosed as they were terminated on PND 21/22.

In Week 17 of the study (F0 dosing and the start of F1 dosing), the 900 mg/kg/day dosing formulation could not be pulled up into the gavage tube being used for newly weaned pups, due to an unknown viscosity property, resulting in some subsets of F0 and/or F1 animals either not being dosed or being given the 300 mg/kg/day formulation either once or twice daily instead (refer to section 4.6.1 for details). From 19 Aug 2021, Group 4 F1 animals were dosed twice daily 3 hours apart at 450 mg/kg (equivalent to 900 mg/kg/day) until they were old enough for the next size gavage tube on 30 Aug 2021. Although there were occasions when animals were not dosed or received a dose level lower than that required by the study protocol, there was considered to be no overall impact on the results or study outcome due to the length of time that each generation was administered the test item dose levels correctly.

The following parameters and end points were evaluated in this study: clinical observations, body weights, food consumption, estrous cycles, mating performance, fertility indices, duration of gestation and overall litter performance, litter survival indices, litter and pup weights, pre-weaning physical development of F1 pups, assessments of sexual maturation of F1 animals, clinical pathology parameters (haematology, coagulation, clinical chemistry, and urinalysis), thyroid stimulating hormone (TSH) and thyroxine (T4) analysis, gross necropsy findings, splenic immunophenotyping analysis, organ weights, sperm evaluation, ovarian follicle counts and histopathological examinations.

None of the unscheduled deaths in any generation were considered to be test item-related.

For the F0 generation at 900 mg/kg/day, test item-related clinical observations of decreased activity, abnormal/uncoordinated gait and low carriage were occasionally seen for males and/or females before pairing, and decreased activity only during lactation. For F0 and F1 generations, salivation and/or ploughing were noted for all animals given ≥300 mg/kg/day and for several animals given 100 mg/kg/day, throughout the dosing periods. F0 and F1 males given 900 mg/kg/day had slightly lower body weight gain, and F0 females a slightly higher dose level-related body weight gain at ≥ 100 mg/kg/day. Food consumption was generally slightly higher for males and females at ≥ 100 mg/kg/day.

There were no test item-related effects on F0 and F1 generation fertility, mating or reproduction, or F1 and F2 generation pup numbers, survival or development.

For males at 900 mg/kg/day, during the last 20 minutes of the 1 hour session, motor activity was 9.6% or 12.7% lower overall for basic or fine movements, respectively. Ambulation values were also lower for the same time period, but this was not confirmed by the overall ambulation values. As there were no clinical findings or detailed functional observations recorded that could have been associated with this, the cause of this apparent reduction in motor activity could not be determined.

For F0 males given ≥300 mg/kg/day and F0 females given ≥100 mg/kg/day, triglycerides were lower by up to 0.75-fold, and for males only, cholesterol higher by up to 1.3-fold. For F1 animals at ≥100 mg/kg/day, triglycerides were lower than controls by up to 0.62-fold, and at 900 mg/kg/day only, cholesterol higher by up to 1.25-fold. There were slightly higher TSH levels (up to 3.1-fold of controls) for samples taken on the morning of necropsy in F0 and F1 adult males given 300 or 900 mg/kg/day. There were no test item-related effects on haematology, coagulation, urinalysis, T4 values or the immune cell populations analysed for immunophenotyping, at up to 900 mg/kg/day.

In the F0 animals dosed from 10 weeks prior to mating and continuing throughout mating and gestation until the females were at least LD 21, microscopically, centrilobular hypertrophy in the liver was considered test item-related in all dose groups in males but only at 900 mg/kg/day in females and mucosal hyperplasia of the glandular region, appearing as an increased number of goblet cells, was considered test item-related at ≥ 300 mg/kg/day in males and only at 900 mg/kg/day in females. Higher liver and kidney weights were seen in both sexes at all dose levels.

In the F1 cohort 1A animals, dosed from PND 21 until at least PND 90, microscopically there was diffuse centrilobular hypertrophy in the liver. This finding was considered test item-related at all dose levels in males and only at ≥ 300 mg/kg/day in females. In the stomach, there was mucosal hyperplasia of the glandular regions, appearing as an increased number of goblet cells. This finding was considered test item-related in males and females at ≥ 300 mg/kg/day. Liver weights were higher at ≥ 300 mg/kg/day in males and females. In addition, higher kidney weights were seen in females at all dose levels and at ≥ 300 mg/kg/day in males.

In the F1 cohort 1B animals, that were used to produce an F2 generation, and that were dosed from PND 21 until at least LD 21, microscopically there was diffuse centrilobular hypertrophy in the liver. This finding was considered test item-related at all dose levels in males and only at ≥ 300 mg/kg/day in females. Liver weights were higher at all dose levels in males and only at 900 mg/kg/day in females. In addition, higher kidney weights were seen in animals dosed at 900 mg/kg/day. Stomachs were not assessed microscopically in these animals. There were no test item-related organ weight differences in the female reproductive tissues.

There were no test item-related organ weight differences in a limited list of tissues in F1 and F2 pups that were euthanised at PND 21 without active dosing.

In the F1 cohort 2A and 2B animals used for neurological investigations (euthanised on PND 21 or dosed from PND 21 until at least PND 78-80), there were no test item-related brain weight differences, gross or histological findings or effects on the brain dimensions.

There were no test item-related gross findings in the entire study, and there were only 6 premature deaths, all of which were considered not test item-related.

There were no histological findings in the reproductive tissues of the females that had not been observed to litter that would have caused reduced fertility.

In conclusion, administration of the test item by once daily (or twice daily 3 hours apart on some occasions) oral gavage was well tolerated in Han Wistar rats at dose levels of up to 900 mg/kg/day with no test item-related deaths. There were occasional observations of decreased activity, abnormal, uncoordinated gait and low carriage for F0 animals at 900 mg/kg/day and for F0 and F1 animals, dose level-related salivation and/or ploughing. F0 and F1 males at 900 mg/kg/day had slightly lower body weight gain, and F0 and F1 females a slightly higher dose level-related body weight gain at ≥ 100 mg/kg/day. Food consumption was generally slightly higher for males and females at ≥ 100 mg/kg/day. There were no test item-related effects on F0 and F1 generation fertility, mating or reproduction, or F1 and F2 generation pup numbers, survival or development. For males at 900 mg/kg/day, motor activity was 9.6% or 12.7% lower overall for basic or fine movements, respectively, but this was not confirmed by overall ambulation values, or any associated clinical findings, detailed functional observations or brain morphometry values for Cohort 2A. Triglyceride values were lower for F0 males given ≥300 mg/kg/day, F0 females and F1 animals given ≥100 mg/kg/day, and cholesterol values higher for F0 males only at ≥300 mg/kg/day and F1 animals at 900 mg/kg/day. There were slightly higher TSH levels (up to 3.1-fold of controls) on the morning of necropsy in F0 and F1 adult males given 300 or 900 mg/kg/day. There were no test item-related effects on haematology, coagulation, urinalysis, T4 values or the immune cell populations analysed for immunophenotyping, at up to 900 mg/kg/day. Target organ effects were observed at dose levels of ≥100 mg/kg/day and consisted of centrilobular hypertrophy in the liver and stomach mucosal hyperplasia of the glandular region. Higher liver and/or kidney weights were seen in both sexes. In neurological investigations, there were no test item-related brain weight differences, gross or histological findings or effects on the brain dimensions. There were no histological findings in the reproductive tissues of the females that had not been observed to litter that would have caused reduced fertility. The NOAEL (No Observed Adverse Effect Level) for F0 and F1 adult toxicity, male and female fertility and reproduction was considered to be 900 mg/kg/day as the in-life and pathological findings were considered not to be adverse. For F1 and F2 developmental parameters, the NOAEL was considered to be 900 mg/kg/day as there were no test item-related effects on the pup numbers, survival or development.

Data source

Reference

Reference Type:: study report
Title:: Unnamed
Year:: 2022

Materials and methods

Test guidelineopen all close all

Test guideline 1

Qualifier:: according to guideline
Guideline:: other: OECD Guideline 424. Neurotoxicity Study in Rodents
Version / remarks:: 21 July 1997
Deviations:: no

Test guideline 2

Qualifier:: according to guideline
Guideline:: other: OECD Guideline 443 Extended One-Generation Reproductive Toxicity Study
Version / remarks:: 25 June 2018
Deviations:: no

GLP compliance:: yes (incl. QA statement)
Limit test:: no

Test material

Test material information

Test material form:: solid: particulate/powder
Details on test material:: Purity 99.7-99.9%

Specific details on test material used for the study:: - Identification: Omnirad 184
- Alternate identification: Hydroxycyclohexyl phenyl ketone
- EC number: 213-426-9
- CAS number: 947-19-3
- Physical description: Light white solid
- Storage condition of test material: Ambient, protected from light
- Stability and homogeneity of the test material in the vehicle/solvent under test conditions (e.g. in the exposure medium) and during storage: Test Item is stable in the vehicle when prepared and stored under the same conditions at concentrations bracketing those used in the present study

Test animals

Species:: rat
Strain:: Wistar
Remarks:: Han Wistar (Crl:WI(Han))
Details on test animals or test system and environmental conditions:: TEST ANIMALS
- Source: Charles River UK, Margate, Kent, UK
- Age at study initiation: ca 6-7 weeks for males and 5-6 weeks for females
- Weight at study initiation: 150 to 250 g (males)/100 to 150 g (females)
- Housing: Group housed (up to 3 or 4 animals of the same sex and same dosing group together). A
few days prior to mating, F0 and Cohort 1B males were be transferred to individual cages with solid
bottoms. F0 and Cohort 1B females were transferred to these cages for mating. Mated F0 and Co
hort 1B females were transferred to individual solid bottomed cages. White paper tissue was supplied
as nesting material from Gestation Day 20. F0 and Cohort 1B females with litters were retained in t
his type of cage until termination. On a suitable day after completion of mating, the F0 and Cohort 1B
males were re-housed with their original cage mates.
- Diet (e.g. ad libitum): Special Diet Services VRF1. Ad libitum, except during designated procedures
- Water (e.g. ad libitum): Public supply tap water. Freely available to each animal from water bottles
(except during
designated procedures).
- Acclimation period: The F0 animals were allowed to acclimate to the Test Facility rodent toxicology
accommodation for 10 days before the commencement of dosing (replacement animals at least 5
days).
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 to 23°C
- Humidity (%): 40 - 70%
- Air changes (per hr): Ten or more air changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours light and 12 hours dark (except during designated pro
cedures)
IN-LIFE DATES: From: 12 Apr 2021 To: 21 Dec 2021

Administration / exposure

Route of administration:: oral: gavage
Vehicle:: CMC (carboxymethyl cellulose)
Remarks:: CMC (carboxymethyl cellulose) CMC (carboxymethyl cellulose) 0.5% (w/v) Carboxymethylcellulose (CMC) medium viscosity and 0.1% (w/v) Tween 80 in Milli-Q Water
Details on exposure:: PREPARATION OF DOSING SOLUTIONS: Dose formulations divided into aliquots where required to
allow them to be dispensed on each dosing occasion
VEHICLE
- Justification for use and choice of vehicle: Carboxymethylcellulose, analysis performed in a s
eparate study showed good stability in this vehicle
- Concentration in vehicle: 10, 30, 90mg/mL
- Amount of vehicle: 10ml/kg
Analytical verification of doses or concentrations:: yes
Details on analytical verification of doses or concentrations:: Analyses was performed by Gas Chromatography (GC) using a validated analytical procedure.
Concentration and Homogeneity Analysis
Sample Allocation: 2 for analysis, 3 for backup for control; 2 for analysis and 3 for backup per stratum for Groups 2-4.
Sampling Containers: Appropriate sized volumetric flasks
Storage Conditions: Temperature set to maintain 4°C, protected from light
Acceptance Criteria: For concentration: mean sample concentration results within or equal to
± 15% of theoretical concentration. Each individual sample concentration result within or equal to ±
20%. For homogeneity, relative standard deviation (RSD) of concentrations of ≤ 10% for each group.
Stability analyses performed previously in conjunction with 426730 demonstrated that the Test Item
is stable in the vehicle when prepared and stored under the same conditions at concentrations
bracketing those used in the present study.
Details on mating procedure:: Frequency: F0 - Day 71
Cohort 1B – PND 107-111
Procedure: Pairing was on a 1 male to 1 female basis. During the evening (after 5 pm), females
were housed with their allocated co-group male partner. The animals were paired in ascending numer
ical order. Vaginal lavages were taken early each morning from the day of pairing until mating
had occurred and the stage of estrous observed in each vaginal lavage was recorded. The day of
detection of a copulatory plug in situ and/or of sperm in the lavage was designated Gestation Day 0.
The pairing period for each pair of animals was a maximum of 14 nights (unless a longer period was
deemed appropriate).
If evidence of mating was not observed by the end of the pairing period, the female was separated f
rom the male during the morning following the last night of pairing and treated as if mating had occ
urred during that night. Procedures for that female were continued as if it had mated on the last
night of pairing.
For each female the time taken to show a positive mating sign and the number of failed opportunities t
o mate (estruses passed without a sign of mating) was evaluated.
Duration of treatment / exposure:: F0 Males: 10 weeks prior to mating and continuing throughout and after mating until the day before t
ermination.
F0 Females: 10 weeks prior to mating and continuing throughout mating and gestation until at least
LD 21.
Cohort 1A: From PND 21 until the day before necropsy
Surplus Animals: From PND 21 until the day before necropsy
Cohort 1B: From PND 21 until the day before necropsy
Cohort 2A: From PND 21 until the day before necropsy
Frequency of treatment:: Once daily.
From 19 Aug 2021, F1 Group 4 animals were dosed twice daily (approximately 3 hours apart) at
10mL/kg and 450 mg/kg (45 mg/mL), equivalent to 900 mg/kg/day.
From 30 Aug 2021, F1 Group 4 animals were dosed once daily at 10 mL/kg and 900 mg/kg/day.
Duration of test:: F0 Males: 10 weeks prior to mating and continuing throughout and after mating until the day before t
ermination.
F0 Females: 10 weeks prior to mating and continuing throughout mating and gestation until at least
LD 21.
Cohort 1A: From PND 21 until the day before necropsy
Surplus Animals: From PND 21 until the day before necropsy
Cohort 1B: From PND 21 until the day before necropsy
Cohort 2A: From PND 21 until the day before necropsy

Doses / concentrationsopen all close all

Doses / concentrations 1

Dose / conc.:: 0 mg/kg bw/day
Remarks:: control

Doses / concentrations 2

Dose / conc.:: 100 mg/kg bw/day

Doses / concentrations 3

Dose / conc.:: 300 mg/kg bw/day

Doses / concentrations 4

Dose / conc.:: 900 mg/kg bw/day

No. of animals per sex per dose:: 10 animals per sex per dose
Control animals:: yes, concurrent vehicle
Details on study design:: Dose selection rationale:
- F0 animals were randomly assigned to groups. Males and females were randomised separately.
- Fasting period before blood sampling for clinical biochemistry: animals not fasted

Examinations

Maternal examinations:: F0 Animals
CAGE SIDE OBSERVATIONS:
Pre and Postdose Observations, All F0 animals.
Frequency: Once predose and up to 4 hours postdose after the end of each group for each sex.
DETAILED CLINICAL OBSERVATIONS:
All F0 animals Weekly; from at least Week 1 and throughout the study.
BODY WEIGHT:
All F0 animals.
Males: weekly beginning Week -1.
Females: weekly beginning Week -1 until pairing for mating and then on GD 0, 7, 14 and 20 and LD 1,
4, 7, 14 and 21.
FOOD CONSUMPTION:
All F0 animals.
Males: weekly from Week -1 until pairing for mating. Then weekly after mating and re-housing.
Females: weekly beginning week -1 until pairing for mating and then on GD 0-7, 7-14 and 14-20, and
LD 1-7, 7-14 and 14-21
WATER CONSUMPTION:
All F0 animals. Regular basis throughout the study.
Mortality:
All F0 animals. At least twice daily (once at the start and once towards the end of the working day)
beginning upon arrival through termination/release.
Ovaries and uterine content:: The ovaries and uterine content was examined after termination
Examinations included:
- Gravid uterus weight
- Number of corpora lutea
- Number of implantations
- Number of early resorptions
- Number of late resorptions
Blood sampling:: Blood sampling for TSH and T4 analysis
Fetal examinations:: The numbers of live and dead pups born in each litter were recorded as soon as possible after
completion of parturition on LD 0. The live pups were counted and examined daily for the presence o
f milk in the stomach and for any externally visible abnormalities up to and including PND 4 and then
on PND 7, 14 and 21. Individual pup weights were taken for each litter on PND 1, 4, 7, 14 and 21. A
head count of the pups was performed each day.
Ano-genital distance was measured for the pups of both sexes on PND 1. Nipple retention was
assessed in males on PND 13.
Assessment of Sexual Maturation Cohorts 1A+ Surplus Animals, 1B and 2A:
Commencing on PND 28, females were examined daily for vaginal opening. The day on which the va
gina became open was recorded, as was the body weight on that day.
Commencing on PND 35, males were examined daily for balanopreputial separation. The day on wh
ich separation occurred was recorded, as was the body weight on that day.
GROSS EXAMINATION OF DEAD PUPS:
Pups Found Dead or Euthanised Prematurely Before PND 14: Where practicable, these animals were
sexed and then checked for the presence of milk in the stomach and for the presence of any extern
ally visible abnormalities. Any externally abnormal pups were fixed in 10% neutral buffered formalin
for optional further examination. Externally normal pups were discarded.
Pups Found Dead or Euthanised Prematurely On or After PND 14: These animals were subject to a
gross necropsy. An external examination was followed by an inspection of the cranial, thoracic and
abdominal contents. Internal sex was also confirmed. Representative samples of any abnormal t
issues were taken and fixed in neutral buffered 10% neutral buffered formalin. These carcasses were
then discarded.
ASSESSMENT OF DEVELOPMENTAL NEUROTOXICITY:
Perfusion fixation, neuropathology and brain morphometry was performed for all animals. The fixed b
rains were removed and weighed, and the length and maximum width of the brain was measured for
all animals selected for neuropathology.
Brain, dorsal root ganglion, and spinal cords tissues were prepared for neuropathology examination.
Neuropathology and brain morphometry were performed.
ASSESSMENT OF DEVELOPMENTAL IMMUNOTOXICITY:
Lymph nodes were weighed to evaluate immunotoxic effects from 10 rats/sex/group from Groups 1-4.
One-half of the spleen was used for immunophenotyping assessment from 10 rats/sex/group from
Groups 1-4.
Necropsy (F1 and F2 Culled PND 4 and Unselected PND 21 pups):
Culled pups on PND 4 were necropsied. Necropsy consisted of external examination followed by
macroscopic examination of the tissues and organs of the cranial, thoracic and abdominal cavities
in situ. Samples of any grossly abnormal tissues were preserved in 10% neutral buffered formalin or
other appropriate fixative. The carcasses were discarded.
All unselected pups on PND 21 were necropsied. Necropsy consisted of external examination
followed by macroscopic examination of the tissues and organs of the cranial, thoracic and abdomina
l cavities in situ. Representative samples of abnormal tissues were preserved in 10% neutral buffere
d formalin or other appropriate fixative. For F1 and F2 pups, tissue samples and weights of the foll
owing tissues were taken from 10 male and 10 female pups per group and were preserved in 10%
neutral buffered formalin or other appropriate fixative: Brain, mammary gland, parathyroid gland,
thyroid gland, liver, ovary, spleen, testes, thymus.
Where 10 pups of each sex were not available for organ weight and tissue collection, additional pups
of the opposite sex were selected such that 20 animals per group had organ weights and tissues
collected.
Necropsy (Cohort 1B Animals):
Animals were subjected to a complete necropsy examination, which included evaluation of the carcas
s and musculoskeletal system; all external surfaces and orifices; cranial cavity and external surfaces
of the brain; and thoracic, abdominal, and pelvic cavities with their associated organs and tissues.
The reproductive tracts of all F1 females were examined for signs of implantation, the number of any
implantation sites being recorded. The total number of corpora lutea graviditatis were recorded for
each female. For F1 females necropsied on GD 24 as they had failed to produce a litter, the uteri
of all non-pregnant females were fixed in 10% neutral buffered formalin after being examined for
implantation sites. On GD 24, if a female was found to be pregnant, the number and type of any impl
antation sites were recorded and the total number of corpora lutea graviditatis were recorded also.
Transcardial Perfusion Fixation of Cohorts 2A and 2B:
All animals were subjected to a limited examination, with special attention being paid to the reproducti
ve organs.
The head (with brain exposed), spinal cord and hindlimbs (Cohort 2A) and head (with brain exposed)
(Cohort 2B) was placed in 10% neutral buffered formalin and allowed to fix for at least 7 days. The
fixed brains were removed and weighed, and the length and maximum width of the brain was
measured for all animals selected for neuropathology. Subsequently, the brain was fixed in 10% neut
ral buffered formalin together with selected PNS tissues.
Statistics:: Body Weight Changes: Calculated between each scheduled interval
Food Consumption: Calculated between appropriate intervals
Organ Weight Relative to Body Weight: Calculated against the terminal body weight for scheduled
intervals
Organ Weight Relative to Brain Weight: Calculated against the brain weight for scheduled intervals
Descriptive Statistical Analyses:
Means, standard deviations, percentages, numbers, and/or incidences have been reported as approp
riate by dataset.
Inferential Statistical Methods:
All statistical tests were conducted at the 5% significance level. All pairwise comparisons were c
onducted using two sided tests and have been reported at the 1% and 5% levels.
The pairwise comparisons of interest are listed below:
Group 2 vs. Group 1
Group 3 vs. Group 1
Group 4 vs. Group 1
Analyses were performed according to the matrix below when possible but excluded any group with
less than 3 observations.
See Table 43 below.
Parametric/Non-parametric:
Levene’s test was used to assess the homogeneity of group variances.
The groups were compared using an overall one-way ANOVA F-test if Levene’s test was not signif
icant or the Kruskal-Wallis test if it was significant. If the overall F-test or Kruskal Wallis test was found
to be significant, then pairwise comparisons were conducted using Dunnett’s or Dunn’s test, respect
ively.
Non-Parametric:
The groups were compared using an overall Kruskal-Wallis test. If the overall Kruskal-Wallis test
was found to be significant, then the above pairwise comparisons were conducted using Dunn’s test
(equivalent to Wilcoxon Rank-Sum test in Nevis 2012 tables).
Indices:: Reproductive indices
Female Mating Index = Number of Females with Evidence of Mating (or no confirmed mating date and
pregnant) / Number of Females Paired
Female Fertility Index = Number of Pregnant Females / Number of Females with Evidence of Mating
(or no confirmed mating date and pregnant)
Female Pregnancy Index = Number of Pregnant Females / Number of Females Paired
Male Mating Index = Number of Males with Evidence of Mating (or female partner confirmed pregna
nt) / Number of Males Paired
Male Fertility Index = Number of Males Impregnating a Female / Number of Males with Evidence of
Mating (or female partner confirmed pregnant)
Male Pregnancy Index = Number of Males Impregnating a Female / Number of Males Paired
The following natural delivery/reproductive parameters were included, as appropriate:
Gestation Length: The gestation length was calculated from GD 0 to the day the first pup was
observed.
Gestation Index:
Percentage of pregnancies that result in birth of live litters = (Number of Animals with Live Offspring /
Number of Animals Pregnant) x 100

Offspring viability indices
Live Birth Index:
Percentage of pups born alive = (Number of Live Newborn Pups / Number of Newborn
Pups) x100
Sex Ratio (% males):
Percentage of male pups per litter = (Number of Live Male Pups / Total Number of Live Pups) x100
Viability Index:
Percentage of pups born that survive 4 days postpartum = (Number of Live Pups on Day 4 Postpa
rtum / Number of Live Newborn Pups) x100
Lactation Index:
Percentage of pups that survive 21 days postpartum = (Number of Live Pups on Day 21 Postpartum /
Number of Live Pups on Day 4 (postculling) Postpartum) x100
Post-Implantation Loss/Litter = (Number of Implants – Total Newborn Pups / Number of Implants)
x100

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:: effects observed, treatment-related
Description (incidence and severity):: At 900 mg/kg/day, decreased activity was observed for one male on Day 2 and abnormal, unco
ordinated gait for 3 males and 4 females between Days 2 to 4. Decreased activity, abnormal, uncoord
inated gait or low carriage were occasionally noted for a further 8 females between Days 5 to 70 and
decreased activity on one occasion for each of 2 females during lactation. These findings were cons
idered to be test item-related.
Salivation and/or ploughing (also a chewing action for one female at 900 mg/kg/day) were noted for
all animals given ≥300 mg/kg/day and for several animals given 100 mg/kg/day, on multiple days thro
ughout the dosing period. The incidence of these findings was dose level-related.
Animal 4515F (900 mg/kg/day) had abnormal clincal observations of irregular respiratory rate, hunc
hed posture, erect fur, cold to touch, prominent backbone, abnormal gait, decreased activity and red
discharge from vagina the day after parturition (LD 1) but these mostly resolved before scheduled
termination. The clinical observations were considered to be likely due to the trauma of giving birth
rather than being test item-related.
Animal 4525F (900 mg/kg/day) had abnormal clincal observations of irregular/decreased respiratory
rate, erect fur, eyes partly closed, decreased activity up to 2-4 hours postdose on LD 7 only. No
similar findings were observed for this animal during the dosing period and as a cause could not be determined, these findings were likely related to the dosing procedure.
Mortality:: mortality observed, non-treatment-related
Description (incidence):: None of the unscheduled deaths were considered to be test item-related.
On Study Day 40, approximately 3 hours after dosing, Animal 4510F given 900 mg/kg/day was found
with clinical signs of irregular respiratory rate, hunched posture, partly closed eyes, erect fur, unc
oordinated and abnormal gait and decreased activity and was euthanised. There were no findings
at necropsy or microscopically to suggest the likely cause of death. This animal had not had any
abnormal clinical signs before this (apart from salivation and ploughing) and had consistently gained
body weight.
Animals 2512F and 4502F given 100 or 900 mg/kg/day respectively, were euthanised on LD 1 or LD
0 and due to the very young age of the pups, they were also euthanised. Animal 2512F had clinical
signs of irregular respiratory rate, hunched posture, pale skin and cold to touch, erect fur, uncoor
dinated and abnormal gait in the afternoon of LD 1. Animal 4502F was found subdued, cold to touch,
prostrate/lying on side with decreased respiratory rate approximately 1 hour after dosing on LD 0. Th
ere were no findings at necropsy or microscopically to suggest the likely cause of death and both an
imals had not had any abnormal clinical signs before this (apart from salivation and ploughing for 4
502F) and had consistently gained body weight.
Body weight and weight changes:: effects observed, treatment-related
Description (incidence and severity):: See Tables 1-4.
For males given 900 mg/kg/day, there was slightly lower body weight gain over the dosing period
resulting in male body weight being 3.6% lower than the concurrent control mean value by Day 134.
For females given ≥ 100 mg/kg/day, a dose level-related higher body weight gain of up to 10.3% at 90
0 mg/kg/day compared to controls was noted during the pre-pairing period and this slightly higher bo
dy weight was generally maintained throughout gestation and lactation.
There was no test item-related effect on male body weight at 100 or 300 mg/kg/day.
Food consumption and compound intake (if feeding study):: effects observed, treatment-related
Description (incidence and severity):: There were occasional slightly higher food consumption values of up to 14.4% of controls noted for
males at 300 or 900 mg/kg/day up to Day 106. At ≥100 mg/kg/day for males from Days 106 to 134,
there was higher food consumption of up to 17.5%. For females given ≥100 mg/kg/day, there was an
overall dose level-related higher food consumption of up to 20.6% of control values during the prep
airing
period, and during gestation and lactation, food consumption was higher for females by up to
13.2% at 300 or 900 mg/kg/day only.
Haematological findings:: effects observed, non-treatment-related
Description (incidence and severity):: Haematology
See tables 18-19.
Coagulation
See tables 15-16.

All differences in haematology or coagulation parameters were considered not to be test item-related
based on their small magnitude, inconsistent direction, absence of a dose response, general overl
ap of individual values with the range of control values and/or were of a magnitude of variation com
monly observed in rats.
Clinical biochemistry findings:: effects observed, treatment-related
Description (incidence and severity):: See tables 12-13.
At ≥300 mg/kg/day for males and ≥100 mg/kg/day for females, triglycerides were lower than controls
by up to 0.75-fold, and for males only at ≥300 mg/kg/day, cholesterol higher by up to 1.30-fold.
Endocrine findings:: effects observed, treatment-related
Description (incidence and severity):: There were slightly higher TSH levels (up to 3.1-fold of controls) for samples taken on the morning of
necropsy in F0 adult males given 300 or 900 mg/kg/day.
There were no test item-related effects for F0 adult males given 100 mg/kg/day or F0 adult females gi
ven up to 900 mg/kg/day or for culled pups on PND 4 or unselected pups on PND 21.
There were no test item-related changes to T4 levels at up to 900 mg/kg/day for samples taken on the
morning of necropsy for the F0 generation animals, for culled pups on PND 4 or unselected pups on
PND 21.
The differences in these parameters were considered not to be test item-related based on their small
magnitude, inconsistent direction, absence of a dose response, general overlap of individual values
with the range of control and/or were of a magnitude of variation commonly observed in rats.
Urinalysis findings:: effects observed, non-treatment-related
Description (incidence and severity):: See tables 27-28.
All differences in urine parameters were considered not to be test item-related based on their small m
agnitude, inconsistent direction, absence of a dose response, general overlap of individual values with
the range of control and/or were of a magnitude of variation commonly observed in rats.
Immunological findings:: no effects observed
Description (incidence and severity):: Splenic Immunophenotyping Evaluation:
The results demonstrated no test item, dose-dependent or sex-dependent effects on any of the
immune cell populations in either the F0 adults rats analysed following administration of Omnirad 184
by oral gavage.
Organ weight findings including organ / body weight ratios:: effects observed, treatment-related
Description (incidence and severity):: Liver weights in animals dosed at ≥ 100 mg/kg/day, were statistically significantly higher than the
controls and showed a dose-related response. In males, liver weights were up to ~35% higher and in f
emales up to ~28% higher (relative to body weight at 900 mg/kg/day). This was considered test item-r
elated.
Kidney weights in animals dosed at ≥ 100 mg/kg/day, were statistically significantly higher than the c
ontrols and showed a dose-related response. In males, kidney weights were up to ~30% higher and
in females up to ~21% higher (relative to body weight at 900 mg/kg/day). Although this could not be
correlated to any microscopic findings, it was considered test item-related in view of the similar weigh
t differences recorded in the F1 cohort 1A and 1B animals.
Additional Organ Weight Difference:
Testis weights (absolute, relative to %body or %brain weights) were statistically significantly higher by ~12% (relative to body weight at 900 mg/kg/day) compared to the controls. Although the fact that males dosed at 900 mg/kg/day had a lower terminal body weight would increase testis weight relative t o body weight, it is important to note that absolute weight was increased also. Although similar weight differences were seen in the F1 cohort 1A and 1B animals. This was however considered incidental
in view of the minor weight difference and no microscopic findings that could be correlated.
Heart weights were statistically higher in females dosed at ≥ 100 mg/kg/day. No microscopic find
ings could be correlated to this, it was not dose-related, and this difference was not seen in the other
gene rations and it was therefore considered not test item-related.
There were individual organ weight values that were different from their respective controls. There
were, however, no patterns or correlating data to suggest these values were test item-related.
Gross pathological findings:: effects observed, non-treatment-related
Description (incidence and severity):: There were no test item-related gross findings.
Gross findings observed were of the nature commonly observed in this strain and age of rat, or occur
red at a similar incidence in control and treated animals, and, therefore, were considered not to be
test item-related.
Histopathological findings: non-neoplastic:: effects observed, treatment-related
Description (incidence and severity):: Test item-related Microscopic Findings
In the liver, there was diffuse centrilobular hepatocyte hypertrophy of minimal to mild severity. For
males only, this was seen in all dosage groups, whereas for females this was only identified in ani
mals dosed at 900 mg/kg/day. Although this was also found in one control animal (M1021), the
incidence was higher in animals treated with Omnirad 184 and followed a dose-related distribution.
This finding was therefore considered test item-related in males dosed at ≥ 100 mg/kg/day and in f
emales dosed at 900 mg/kg/day.
The higher liver weights recorded in animals given Omnirad 184, were correlated to the histopatholo
gic findings of centrilobular hypertrophy. This correlation was evident in the males dosed at ≥ 100 mg/
kg/day and females dosed at 900 mg/kg/day.
In the glandular portion of the stomach, there was diffuse mucosal hyperplasia with a minimal
severity. This was characterised by an increase in the number of goblet cells. For males only, this was
seen in at ≥ 300 mg/kg/day, whereas for females this was only identified in animals dosed at 900 mg/
kg/day. Although this was also found in one control animal (M1013), the incidence was convincingly
higher in animals treated with Omnirad 184 at ≥ 300 mg/kg/day and showed a dose-related distribut
ion. This finding was therefore considered test item-related in males dosed at ≥ 300 mg/kg/day and in
females dosed at 900 mg/kg/day.
Additional Microscopic Findings:
In the spleen, there was a slightly higher incidence of increased hematopoietic cells with a minimal
severity, primarily in males given Omnirad 184 at a doses of 100 mg/kg/day and 900 mg/kg/day. A
slightly higher incidence was seen in females dosed at 900 mg/kg/day only. However, due to the
overall low incidences and because this is a common background finding, it was considered not test i
tem-related.
Other microscopic findings were of the nature commonly observed in this strain and age of rat, or
occurred at a similar incidence in control and treated animals, and, therefore, were considered not to
be test item-related.
Other effects:: no effects observed

Maternal developmental toxicity

Number of abortions:: no effects observed
Pre- and post-implantation loss:: no effects observed
Description (incidence and severity):: F0 and F1 Generations:
There were no test item-related effects on number of corpora lutea, implant counts, pre- or post-implantation loss or total number of pups born at up to 900 mg/kg/day.
Total litter losses by resorption:: no effects observed
Early or late resorptions:: effects observed, non-treatment-related
Description (incidence and severity):: F0 Control Animal 1524F and Animal 4511F given 900 mg/kg/day were terminated on GD 24 as they had failed to produce litters. At necropsy, 1524F had 2 implants (one early resorption) and 4511F was not pregnant.
Dead fetuses:: no effects observed
Changes in pregnancy duration:: no effects observed
Description (incidence and severity):: There were no test item-related effects on male or female mating performance or fertility, or duration of gestation in females, at up to 900 mg/kg/day.
Changes in number of pregnant:: no effects observed
Description (incidence and severity):: F0 control 1520F was found not to be pregnant at scheduled necropsy.
F0 Control Animal 1524F and Animal 4511F given 900 mg/kg/day were terminated on GD 24 as they had failed to produce litters. At necropsy, 1524F had 2 implants (one early resorption) and 4511F was not pregnant.
F0 Animals 1501F, 1502F, 1506F, 1518F, 1521F (control), 2517F (100 mg/kg/day), 350F2 (300 mg/kg/day) and 4523F (900 mg/kg/day) did not have a positive mating sign during pairing and therefore gave birth before their expected GD 21.
The following Cohort 1B females were euthanised on GD 24 as they had failed to produce litters and were found not to be pregnant; 1629F (control), 2624F, 2627F, 2628F and 2637F (100 mg/kg/day) and 3629F (300 mg/kg/day).
Other effects:: no effects observed

Effect levels (maternal animals)

: Key result
Dose descriptor:: NOAEL
Effect level:: 900 mg/kg bw/day
Based on:: test mat.
Basis for effect level:: body weight and weight gain; changes in number of pregnant; changes in pregnancy duration; clinical biochemistry; clinical signs; dead fetuses; early or late resorptions; effects on pregnancy duration; food consumption and compound intake; gross pathology; haematology; histopathology: neoplastic; maternal abnormalities; mortality; necropsy findings; number of abortions; pre and post implantation loss; total litter losses by resorption

Maternal abnormalities

: Key result
Abnormalities:: no effects observed

Results (fetuses)

Fetal body weight changes:: effects observed, treatment-related
Description (incidence and severity):: See tables 5-11.
For animals in Cohorts 1A and 1B, there was a general trend of slightly lower body weight gain (up to
7.0%) for males at 900 mg/kg/day compared to controls, but no test item related-effects for males at
100 or 300 mg/kg/day or females at ≥100 mg/kg/day during pre-pairing, gestation or lactation.
In Cohort 2A and for Surplus animals, body weight gain was variable and did not follow any trend.
Reduction in number of live offspring:: no effects observed
Description (incidence and severity):: F1 and F2 Generations:
Pup numbers and viability on PND 1 to 4 and PND 4 to 21 were comparable to controls at all test item dose levels administered.
Changes in sex ratio:: no effects observed
Description (incidence and severity):: F1 and F2 Generations:
The ratio of male to female pups was similar to controls at all test item dose levels administered.
Changes in litter size and weights:: no effects observed
Description (incidence and severity):: F1 and F2 Generations:
Pup numbers and viability on PND 1 to 4 and PND 4 to 21 were comparable to controls at all test item dose levels administered.
Anogenital distance of all rodent fetuses:: no effects observed
Description (incidence and severity):: F1 and F2 Generations:
There was no effect on anogenital distance or normalised anogenital distance for males or females at up to 900 mg/kg/day.
Changes in postnatal survival:: no effects observed
Description (incidence and severity):: F1 and F2 Generations:
Pup numbers and viability on PND 1 to 4 and PND 4 to 21 were comparable to controls at all test item dose levels administered.
External malformations:: not specified
Skeletal malformations:: not specified
Visceral malformations:: not specified
Other effects:: no effects observed
Description (incidence and severity):: Dam and Litter Observations During Lactation:
There were no test item-related effects noted for the F0 or Cohort 1B dams or their litters during lactation at up to 900 mg/kg/day.

Nipple Retention:
F0 and F1 Generations:
On PND 13, there was no effect on nipple retention in male pups i.e. no nipples were present, at dose levels up to 900 mg/kg/day.

Assessment of Sexual Maturation:
F1 Generation:
There was considered to be no effect on sexual maturation for F1 males or females at up to 900 mg/kg/day.

Acoustic Startle:
F1 Generation:
There were no test item-related effects on maximum response amplitude, average response amplitude or time to maximum response in males or females at up to 900 mg/kg/day.

Motor Activity:
F1 Generation:
For males at 900 mg/kg/day, the number of basic and fine movements were lower than controls by up to 70.1% from 40 to 60 minutes of the 1 hour session; this was 9.6% or 12.7% lower overall for basic or fine movements, respectively. Ambulation values were also lower for the same time period, but this was not confirmed by the overall ambulation values. As there were no clinical findings or detailed functional observations recorded that could have been associated with this reduction in motor activity, the cause of this apparent reduction in motor activity could not be determined.
At 100 or 300 mg/kg/day for males and ≥ 100 mg/kg/day for females, there were no notable effects on overall basic or fine activity or ambulation, compared with control values.

Brain Morphometry Evaluation:
Cohort 2A
No test item-related effects were seen in the brain morphometry parameters.
The length and width of the brain, as measured grossly, were compared between controls and animals at 900 mg/kg/day. The mean values were similar and were considered not to show a test item-relationship.

Cohort 2B
The only statistically significant difference was that the thickness of the cerebral cortex (motor) in males was ~7% less than controls at 900 mg/kg/day. This was considered due to chance and not test item-related, because other parameters were not affected and in females, the thickness of the cerebral cortex (motor) was not statistically significantly less at 900 mg/kg/day compared to the controls (it was only ~5% less).
Other brain morphometry parameters at 900 mg/kg/day were different from the control means, but were within 10% of the controls and not statistically significant, so were considered not test item-related.
The length and width of the brain, as measured grossly, were compared between controls and animals at 900 mg/kg/day. The mean values were similar and were considered not to show a test item-relationship.

Effect levels (fetuses)

: Key result
Dose descriptor:: NOAEL
Effect level:: 900 mg/kg bw/day
Based on:: test mat.
Sex:: male/female
Basis for effect level:: reduction in number of live offspring; changes in sex ratio; fetal/pup body weight changes; changes in litter size and weights; changes in postnatal survival; external malformations; skeletal malformations; visceral malformations

Fetal abnormalities

: Key result
Abnormalities:: no effects observed

Overall developmental toxicity

Developmental effects observed:: no

Any other information on results incl. tables

Table 1 - Summary of Body Weights (g)

F0 Males

Sex: Male		Day(s) Relative to Start Date
Sex: Male		-7	1	8	15	22	29	36
0 mg/kg/day	Mean	124.9	176.6	225.1	268.9	303.1	333	355.5
Group 1	SD	16.6	18.5	21	23.8	24.7	26.3	27.3
	N	25 -	25 -	25 -	25 -	25 -	25 -	25 -

100 mg/kg/day	Mean	123.8	174.3	225.7	270.7	305.6	333.2	355.7
Group 2	SD	16.3	18.8	23.4	25.2	26.4	28.5	30.7
	N	25	25	25	25	25	25	25
	%Diff	-0.9	-1.3	0.3	0.7	0.8	0.1	0.1
300 mg/kg/day	Mean	121	171.9	222.1	268.3	302.8	332.4	355.9
Group 3	SD	15.1	18.9	21	23.1	22.1	24.6	26.8
	N	25	25	25	25	25	25	25
	%Diff	-3.1	-2.7	-1.3	-0.2	-0.1	-0.2	0.1
900 mg/kg/day	Mean	124.9	178.2	230.5	277.9	310.1	334.8	352.2
Group 4	SD	11.6	14.2	18.9	21.9	24.1	25.7	28.3
	N	25	25	25	25	25	25	25
	%Diff	0	0.9	2.4	3.4	2.3	0.5	-0.9

Sex: Male		Day(s) Relative to Start Date
Sex: Male		43	50	57	64	71	78	85
0 mg/kg/day	Mean	374.2	389	406.9	417.8	427.7	428	435.6
Group 1	SD	30.2	31.6	33.7	35	34.9	33.2	34.4
	N	25 -	25 -	25 -	25 -	25 -	25 -	25 -

100 mg/kg/day	Mean	374.4	392.8	408	417.3	423.9	427.8	437.4
Group 2	SD	32.8	34.9	36.1	35.5	36.7	37.4	37.7
	N	25	25	25	25	25	25	25
	%Diff	0.1	1	0.3	-0.1	-0.9	-0.1	0.4
300 mg/kg/day	Mean	373.7	390.5	404.8	415.6	424	426.6	436.5
Group 3	SD	29.8	32.2	33.2	33.8	36.9	36.4	38.4
	N	25	25	25	25	25	25	25
	%Diff	-0.1	0.4	-0.5	-0.5	-0.9	-0.3	0.2
900 mg/kg/day	Mean	365.9	378.8	393.4	403.8	411.4	415.7	423.1
Group 4	SD	29.7	32	33.1	34.7	35.5	34.6	36.7
	N	25	25	25	25	25	25	25
	%Diff	-2.2	-2.6	-3.3	-3.3	-3.8	-2.9	-2.9

Sex: Male		Day(s) Relative to Start Date
Sex: Male		92	99	106	113	120	127	134
0 mg/kg/day	Mean	441.8	453.6	466.3	472.8	483.5	489.2	496.7
Group 1	SD	35.9	36.1	37.8	37.8	38.9	39	41.7
	N	25 -	25 -	25 -	25 -	25 -	25 -	25 -

100 mg/kg/day	Mean	441.6	450.2	462.2	470.4	478	487.7	492.6
Group 2	SD	37.1	37.6	39.7	40.7	41.1	43.8	45.4
	N	25	25	25	25	25	25	25
	%Diff	-0.1	-0.7	-0.9	-0.5	-1.1	-0.3	-0.8
300 mg/kg/day	Mean	446.7	452.6	463.6	475.6	483.9	492.7	496.6
Group 3	SD	40.7	42.3	44.7	47	49.7	50.9	53.1
	N	25	25	25	25	25	25	25
	%Diff	1.1	-0.2	-0.6	0.6	0.1	0.7	0
900 mg/kg/day	Mean	434.1	442.2	449.5	458.4	464.4	475.5	478.6
Group 4	SD	38	39.8	40.3	40.7	40.7	42.5	44.8
	N	25	25	25	25	25	25	25
	%Diff	-1.7	-2.5	-3.6	-3	-3.9	-2.8	-3.6

Sex: Male		Day(s) Relative to Start Date
Sex: Male		137	138	141	142
0 mg/kg/day	Mean	507.9	501.8	493.1	473.4
Group 1	SD	58.2	33.5	36.1	43.3
	N	8 -	6 -	11 -	5 -

100 mg/kg/day	Mean	488	512.6	490.8	477.7
Group 2	SD	46.5	39.6	50.5	63.9
	N	5	7	13	7
	%Diff	-3.9	2.1	-0.5	0.9
300 mg/kg/day	Mean	458	534.4	491	494.8
Group 3	SD	26.4	57.8	46.4	52.9
	N	4	8	13	8
	%Diff	-9.8	6.5	-0.4	4.5
900 mg/kg/day	Mean	473.8	494.5	480.2	471.2
Group 4	SD	41.8	27.5	54.1	65.1
	N	8	4	13	5
	%Diff	-6.7	-1.5	-2.6	-0.5

Table 2 - Summary of Body Weights (g)

F0 Females - Prior to mating

Sex: Female					Day(s) Relative to Start Date
Sex: Female		-7	1	8	15	22	29	36
0 mg/kg/day	Mean	72.9	110.5	136.4	155.4	173.6	188.9	197.4
Group 1	SD	13.5	13.9	14	13.8	13.3	13.9	14.6
	N	25 -	25 -	25 -	25 -	25 -	25 -	25 -

100 mg/kg/day	Mean	76	114.9	140.8	162	181.1	195.7	206.3
Group 2	SD	10.2	11.1	11.6	13.5	14.4	14.5	16.5
	N	25	25	25	25	25	25	25
	%Diff	4.2	3.9	3.3	4.3	4.3	3.6	4.5
300 mg/kg/day	Mean	74.9	114.2	142.2	162.9	183.5	198.8	209.1*
Group 3	SD	12.4	11.1	10.6	12.3	12.8	14.7	15.6
	N	25	25	25	25	25	25	25
	%Diff	2.8	3.4	4.3	4.9	5.7	5.2	5.9
900 mg/kg/day	Mean	77.2	116.4	147.2*	171.3**	191.6**	208.2**	214.9**
Group 4	SD	14.1	14.3	15.3	17.2	17.4	17.9	18.2
	N	25	25	25	25	25	25	25
	%Diff	5.9	5.3	7.9	10.3	10.3	10.2	8.9

Sex: Female				Day(s) Relative to Start Date
Sex: Female		43	50	57	64	71
0 mg/kg/day	Mean	207.3	214.6	222.2	226.2	230.5
Group 1	SD	14.9	13.1	14.8	14.4	15.6
	N	25 -	25 -	25 -	25 -	25 -

100 mg/kg/day	Mean	216	225.6	229.6	232.8	240.8
Group 2	SD	17.1	18.4	19	20.5	20.5
	N	25	25	25	25	25
	%Diff	4.2	5.2	3.3	2.9	4.5
300 mg/kg/day	Mean	217.2	227.9*	234.7*	238.4	245.9*
Group 3	SD	16.5	18.6	19.4	18.9	19
	N	25	25	25	25	25
	%Diff	4.8	6.2	5.6	5.4	6.7
900 mg/kg/day	Mean	227.0**	233.0**	242.0**	244.5**	250.5**
Group 4	SD	17.2	17.5	18.6	19	19.7
	N	24	24	24	24	24
	%Diff	9.5	8.6	8.9	8.1	8.7

Anova & Dunnett: * = p ≤ 0.05; ** = p ≤ 0.01

Table 3 - Summary of Body Weights (g)

F0 Females - Gestation

Sex: Female			Day(s) Relative to Mating (Litter: A)
Sex: Female		0	7	14	20
0 mg/kg/day	Mean	222.8	246.1	269.9	325.9
Group 1	SD	14.5	13.5	16.3	24
	N	18 -	18 -	18 -	18 -

100 mg/kg/day	Mean	237.2*	259.5	282.3	338.5
Group 2	SD	20.1	20.5	22.9	31.2
	N	24	24	24	24
	%Diff	6.5	5.5	4.6	3.9
300 mg/kg/day	Mean	242.1**	262.4*	284.2	343.6
Group 3	SD	20.5	22.4	24.6	28.1
	N	24	24	24	24
	%Diff	8.6	6.6	5.3	5.4
900 mg/kg/day	Mean	243.7**	264.5*	291.1*	352.5*
Group 4	SD	17.2	21.1	23.4	34.4
	N	22	22	22	22
	%Diff	9.4	7.5	7.9	8.2

Anova & Dunnett: * = p ≤ 0.05; ** = p ≤ 0.01

Table 4 - Summary of Body Weights (g)

F0 Females - Lactation

Group /		1	4	Day	14	21
Sex		1	4	7	14	21
1F	Mean	261.7	274	275.1	282.8	280.1
	SD	19.1	20.8	19.3	21.2	16.6
	N	23	22	23	23	23
	Mean	268.2	280.9	283.3	290.9	288
2F	SD	22.1	22.6	23	23.6	21.7
	N	23	24	24	24	24
	%Diff G1	2.5	2.5	3	2.9	2.8
	Mean	270.8	282.7	285.6	294.8	291
	SD	25.7	25	24.4	23.4	19.9
3F	N	25	25	25	25	25
	%Diff G1	3.5	3.2	3.8	4.2	3.9
	Mean	271.6	286.4	292.2	302.6a	300.1b
4F	SD	23.4	24	24.8	25.7	25.2
	N	22	22	22	22	22
	%Diff G1	3.8	4.5	6.2	7	7.1

Significantly different from control group 1 value :a=p≤0.05,b=p≤0.01 (Dunnett)

Table 5 - Summary of Body Weights (g)

F1 Animals - Cohort 1A

Sex: Male					Day(s) Relative to Start Date
Sex: Male		1 [G]	2 [I]	6 [G]	13 [G]	20 [G]	27 [G]	34 [G]
0 mg/kg/day	Mean	56	-	71.8	119.9	172.1	219.5	269.6
Group 1	SD	5.1	-	8.8	12.2	15.8	19.7	23.4
	N	20 -	-	20 -	20 -	20 -	20 -	20 -
			-
100 mg/kg/day	Mean	56.3	61.0n	70.8	116.4	166.9	213.7	261.2
Group 2	SD	6.6	6.6	9	13.6	16.5	20.5	26.4
	N	19	3 -	18	20	20	20	20
	%Diff	0.7		-1.4	-2.9	-3	-2.6	-3.1
300 mg/kg/day	Mean	57.9	76.0n	76.8	126.3	179.8	227	276.8
Group 3	SD	4.9	-	9.3	14	16.9	19.6	24.9
	N	20	1 -	19	20	20	20	20
	%Diff	3.5		6.9	5.4	4.5	3.4	2.7
900 mg/kg/day	Mean	54.7	59.0n 4.3	70.6	115.8	167.5	212.9	258.5
Group 4	SD	5.5	6 -	8.2	12.5	16.5	21.7	25.5
	N	15		19	20	20	20	20
	%Diff	-2.2		-1.6	-3.4	-2.7	-3	-4.1

[G] - Anova & Dunnett [I] - n - Inappropriate for statistics

Sex: Male					Day(s) Relative to Start Date
Sex: Male		41	48	55	62	68	69	70
0 mg/kg/day	Mean	309.2	343.6	368.2	390.7	408.1	394	405.5
Group 1	SD	26.7	31.5	33	37	40.1	42.2	40.7
	N	20 -	20 -	20 -	20 -	14 -	6 -	20 -

100 mg/kg/day	Mean	300.1	335.3	360.5	382.8	393	408.2	401.6
Group 2	SD	29.4	32.6	35.7	36.5	35.3	42.7	34.3
	N	20	20	20	20	16	6	16
	%Diff	-2.9	-2.4	-2.1	-2	-3.7	3.6	-1
300 mg/kg/day	Mean	317.3	349.4	376.1	396.8	411.1	445.9	411.1
Group 3	SD	28	33	37.6	38.7	46.2	36.6	36.1
	N	20	20	20	20	14	7	19
	%Diff	2.6	1.7	2.1	1.6	0.8	13.2	1.4
900 mg/kg/day	Mean	299.2	325.5	346.4	363.5	386.8	381.7	382.7
Group 4	SD	29	32.1	37.5	40	40.6	48.2	38.9
	N	20	20	20	20	14	11	15
	%Diff	-3.2	-5.3	-5.9	-7	-5.2	-3.1	-5.6

Sex: Male

Day(s) Relative to Start Date

mg/kg/day

Group 1

Mean

100 mg/kg/day

Group 2

Mean

N %Diff

447.0n

69.3

2 -

300 mg/kg/day

Group 3

Mean

N %Diff

900 mg/kg/day

Group 4

Mean

N %Diff

Sex: Female

Day(s) Relative to Start Date

1 [G]

2 [I]

6 [G]

13 [G]

20 [G]

27 [G]

34 [G]

mg/kg/day

Group 1

Mean

52.6

4.9

20 -

66.0

7.8

20 -

103.8

9.7

20 -

136.5

10.7

20 -

157.2

10.2

20 -

176.5

12.3

20 -

100 mg/kg/day

Group 2

Mean

N %Diff

55.3

4.9

5.3

58.0n

3.0

3 -

68.9

5.7

4.5

106.1

9.4

2.2

138.3

11.9

1.3

159.7

14.1

1.6

178.8

16.8

1.3

300 mg/kg/day

Group 3

Mean

N %Diff

55.0

5.0

4.7

71.0n

1 -

69.4

8.9

5.2

105.5

11.3

1.7

138.6

11.6

1.5

160.2

12.3

1.9

179.9

13.8

1.9

900 mg/kg/day

Group 4

Mean

N %Diff

52.1

4.8

-0.8

56.3n 6.0

7 -

66.1

8.2

0.2

103.2

10.6

-0.6

138.6

12.8

1.5

159.9

15.9

1.7

182.0

15.5

3.1

[G] - Anova & Dunnett

Sex: Female

Day(s) Relative to Start Date

41 [G]

48 [G]

55 [G]

62 [G]

68 [G]

69 [G]

70 [I]

mg/kg/day

Group 1

Mean

189.0

12.1

20 -

203.2

14.4

20 -

212.2

15.5

20 -

221.0

18.8

20 -

231.6

18.8

13 -

228.1

18.9

7 -

245.3n

11.0

3 -

100 mg/kg/day

Group 2

Mean

N %Diff

192.4

18.5

1.8

205.7

17.3

1.2

214.1

18.0

0.9

224.2

20.5

1.4

235.2

22.6

1.6

216.7

6.8

-5.0

300 mg/kg/day

Group 3

Mean

N %Diff

194.4

13.6

2.8

206.5

14.6

1.6

216.4

16.9

2.0

226.1

17.7

2.3

231.5

16.3

0.0

242.3

12.6

6.2

220.0n

1 -10.3

900 mg/kg/day

Group 4

Mean

N %Diff

201.6

17.1

6.7

209.2

17.6

3.0

218.0

17.7

2.7

226.5

18.3

2.5

237.5

19.1

2.6

235.6

26.0

3.3

[G] - Anova & Dunnett

Sex: Female

Day(s) Relative to Start Date

71 [G]

72 [I]

73 [G]

74 [G]

mg/kg/day

Group 1

Mean

226.9

16.6

8 -

228.6

21.1

5 -

228.8

17.9

4 -

100 mg/kg/day

Group 2

Mean

N %Diff

228.3

29.4

0.6

223.7n

12.2

3 -

233.8

11.4

2.3

233.8

25.4

2.2

300 mg/kg/day

Group 3

Mean

N %Diff

233.1

15.5

2.7

268.0n

1 -

225.0n

11.3

-1.6

237.7

20.5

3.9

900 mg/kg/day

Group 4

Mean

N %Diff

235.0

23.9

3.6

247.0n

11.3

2 -

232.8

19.2

1.9

235.0n

25.5

2.7

[G] - Anova & Dunnett: n - Inappropriate for statistics

Table 7 - Summary of Body Weights (g)

F1 Animals - Cohort 1B Males

Sex: Male

Day(s) Relative to Start Date

1 [G]

2 [I]

6 [G]

13 [G]

20 [G]

27 [G]

34 [G]

mg/kg/day

Group 1

Mean

54.6

5.4

20 -

70.5

8.5

20 -

116.5

12.0

20 -

167.7

13.3

20 -

212.9

17.3

20 -

261.7

20.9

20 -

100 mg/kg/day

Group 2

Mean

N %Diff

57.4

5.2

5.1

60.0n

8.5

3 -

72.9

8.7

3.5

117.5

14.9

0.8

166.8

20.5

-0.6

211.2

25.9

-0.8

258.5

29.7

-1.2

300 mg/kg/day

Group 3

Mean

N %Diff

56.8

5.7

4.0

70.0n

1 -

74.9

10.8

6.2

124.1

15.9

6.5

175.7

18.3

4.7

222.6

21.4

4.6

271.2

25.8

3.6

900 mg/kg/day

Group 4

Mean

N %Diff

54.5

4.5

-0.1

59.3n 5.9

7 -

69.9

8.7

-0.8

115.4

10.8

-0.9

166.8

12.3

-0.5

212.2

15.2

-0.3

258.6

18.7

-1.2

Sex: Male

Day(s) Relative to Start Date

mg/kg/day

Group 1

Mean

300.5

25.6

20 -

334.6

30.5

20 -

358.4

34.8

20 -

381.5

38.4

20 -

395.5

41.5

20 -

410.3

44.0

20 -

421.2

46.7

20 -

100 mg/kg/day

Group 2

Mean

N %Diff

297.5

32.5

-1.0

330.9

34.9

-1.1

357.3

37.9

-0.3

379.6

39.8

-0.5

399.5

39.4

1.0

414.5

41.7

1.0

429.9

42.0

2.1

300 mg/kg/day

Group 3

Mean

N %Diff

310.2

26.4

3.2

342.6

29.7

2.4

370.5

31.5

3.4

393.0

33.5

3.0

413.3

33.9

4.5

427.1

37.4

4.1

438.9

39.0

4.2

900 mg/kg/day

Group 4

Mean

N %Diff

297.9

23.2

-0.8

324.7

26.1

-2.9

348.3

30.2

-2.8

365.3

33.5

-4.2

383.9

36.0

-2.9

399.6

35.5

-2.6

410.4

40.6

-2.6

Sex: Male

Day(s) Relative to Start Date

104

111

118

125

128

mg/kg/day

Group 1

Mean

431.7

46.1

20 -

434.7

44.9

20 -

441.9

43.5

20 -

453.5

48.3

20 -

464.3

49.9

20 -

473.8

52.6

20 -

484.1

58.9

8 -

100 mg/kg/day

Group 2

Mean

N %Diff

440.9

44.6

2.1

444.3

45.0

2.2

452.5

46.6

2.4

463.5

46.1

2.2

477.7

47.1

2.9

492.3

48.2

3.9

494.2

58.5

2.1

300 mg/kg/day

Group 3

Mean

N %Diff

448.1

41.2

3.8

452.0

38.8

4.0

456.2

39.7

3.2

471.1

40.7

3.9

483.8

43.3

4.2

494.5

45.3

4.4

515.1

42.9

6.4

900 mg/kg/day

Group 4

Mean

N %Diff

415.5

40.8

-3.8

424.9

41.7

-2.3

428.4

41.3

-3.1

442.0

42.1

-2.5

451.7

42.8

-2.7

460.8

41.2

-2.8

463.5

45.3

-4.3

Sex: Male

Day(s) Relative to Start Date

129 [G]

130 [G]

131 [I]

mg/kg/day

Group 1

Mean

465.0

62.2

6 -

475.3

45.0

9 -

100 mg/kg/day

Group 2

Mean

N %Diff

504.9

36.5

8.6

502.0

45.0

5.6

300 mg/kg/day

Group 3

Mean

N %Diff

514.8

41.9

10.7

471.0

41.8

-0.9

485.5n

36.8

4 -

900 mg/kg/day

Group 4

Mean

N %Diff

476.3

43.3

2.4

436.3

10.1

-8.2

529.0n

1 -

Table 8 - Summary of Body Weights (g)

F1 Animals - Cohort 1B Females - Prior to Mating

Sex: Female

Day(s) Relative to Start Date

1 [G]

2 [I]

6 [G]

13 [G]

20 [G]

27 [G]

34 [G]

mg/kg/day

Group 1

Mean

52.6

5.1

20 -

66.2

7.1

20 -

103.6

9.0

20 -

136.1

9.5

20 -

156.9

10.6

20 -

174.8

12.3

20 -

100 mg/kg/day

Group 2

Mean

N %Diff

53.8

7.9

2.4

57.3n

4.0

3 -

66.6

10.4

0.7

103.4

13.9

-0.1

133.7

13.8

-1.7

155.3

14.0

-1.0

173.5

14.1

-0.7

300 mg/kg/day

Group 3

Mean

N %Diff

55.7

4.4

6.0

68.0n

1 -

71.6

7.5

8.3

109.3

8.1

5.5

143.2

9.6

5.3

164.1

10.0

4.6

180.9

11.8

3.5

900 mg/kg/day

Group 4

Mean

N %Diff

51.3

4.3

-2.3

56.3n 6.6

7 -

64.6

7.4

-2.4

102.8

10.3

-0.7

136.6

9.8

0.4

157.6

13.1

0.4

176.8

13.7

1.1

Sex: Female

Day(s) Relative to Start Date

mg/kg/day

Group 1

Mean

189.6

11.3

20 -

204.2

11.0

20 -

210.9

11.8

20 -

218.6

12.6

20 -

227.6

11.8

20 -

232.5

11.5

20 -

236.2

12.5

20 -

100 mg/kg/day

Group 2

Mean

N %Diff

188.1

15.8

-0.8

200.3

15.1

-1.9

209.8

15.4

-0.5

218.7

14.7

0.1

226.3

16.5

-0.6

230.7

18.2

-0.8

232.7

17.3

-1.5

300 mg/kg/day

Group 3

Mean

N %Diff

199.2

12.4

5.1

211.3

13.2

3.5

220.1

14.6

4.4

227.0

15.2

3.9

236.9

15.5

4.1

243.1

16.4

4.5

246.7

17.5

4.5

900 mg/kg/day

Group 4

Mean

N %Diff

195.6

14.1

3.2

203.7

14.7

-0.2

212.2

15.4

0.6

219.5

16.9

0.4

231.0

16.5

1.5

236.4

18.1

1.7

237.4

17.1

0.5

Sex: Female

Day(s) Relative to Start Date

mg/kg/day

Group 1

Mean

240.0

13.4

20 -

100 mg/kg/day

Group 2

Mean

N %Diff

239.6

16.7

-0.2

300 mg/kg/day

Group 3

Mean

N %Diff

251.2

17.1

4.6

900 mg/kg/day

Group 4

Mean

N %Diff

242.7

18.8

1.1

Table 9 - Summary of Body Weights (g)

F1 Animals - Cohort 1B - Gestation

Sex: Female

Day(s) Relative to Mating (Litter: A)

mg/kg/day

Group 1

Mean

241.9

12.7

19 -

261.8

15.3

19 -

284.1

15.0

19 -

337.5

18.9

19 -

100 mg/kg/day

Group 2

Mean

N %Diff

238.8

14.3

-1.3

258.2

14.3

-1.4

277.9

14.9

-2.2

334.6

19.9

-0.9

300 mg/kg/day

Group 3

Mean

N %Diff

253.5

16.6

4.8

271.6

16.9

3.8

291.6

16.6

2.6

348.9

19.3

3.4

900 mg/kg/day

Group 4

Mean

N %Diff

241.1

16.7

-0.3

260.8

20.7

-0.4

278.0

23.3

-2.1

336.5

32.1

-0.3

Table 10 - Summary of Body Weights (g)

F1 Animals - Cohort 1B Females - Lactation

Group /		1	4	Day	14	21
Sex		1	4	7	14	21
1F	Mean	264.2	268.9	276.9	290.6	284.2
	SD	14.4	12.9	14.9	16.8	17.9
	N	18	17	18	18	18
	Mean	262.3	271.3	275.8	288.6	286.3
2F	SD	14.5	15	14.2	16.6	15.4
	N	16	15	16	16	16
	%Diff G1	-0.7	0.9	-0.4	-0.7	0.8
	Mean	278.4a	288.5b	292.6a	306.2a	302.1a
	SD	18.9	16.6	15.7	15.6	16.2
3F	N	19	19	19	19	19
	%Diff G1	5.4	7.3	5.6	5.4	6.3
	Mean	265.9	276.3	283.6	292.4	291.5
4F	SD	21.6	24.5	20.3	21.7	22.9
	N	20	19	20	20	19
	%Diff G1	0.6	2.7	2.4	0.6	2.6

Table 11 - Summary of Body Weights (g)

F1 Animals - Cohort 2A

Sex: Male

Day(s) Relative to Start Date

1 [G]

2 [I]

6 [G]

13 [G]

20 [G]

27 [G]

34 [G]

mg/kg/day

Group 1

Mean

54.6

4.7

10 -

68.4

8.0

10 -

115.1

11.9

10 -

169.5

12.1

10 -

219.4

13.6

10 -

269.5

18.2

10 -

100 mg/kg/day

Group 2

Mean

N %Diff

54.6

5.5

-0.1

59.0n

7.1

2 -

67.0

8.9

-2.0

111.0

12.0

-3.6

160.7

12.0

-5.2

205.3

14.3

-6.4

250.8

18.2

-6.9

300 mg/kg/day

Group 3

Mean

N %Diff

58.5

5.9

7.1

76.0n

1 -

74.7

10.9

9.2

122.9

14.3

6.8

177.1

16.3

4.5

224.4

19.6

2.3

273.9

23.0

1.6

900 mg/kg/day

Group 4

Mean

N %Diff

55.4

3.6

1.5

59.0n 7.1

2 -

67.3

9.2

-1.6

112.4

11.1

-2.3

164.3

12.4

-3.1

211.4

15.1

-3.6

259.5

21.4

-3.7

Sex: Male

Day(s) Relative to Start Date

mg/kg/day

Group 1

Mean

308.0

21.9

10 -

342.0

24.0

10 -

368.4

25.7

10 -

369.8

24.4

4 -

396.8

32.0

5 -

405.0

37.8

3 -

100 mg/kg/day

Group 2

Mean

N %Diff

287.9

19.6

-6.5

320.4

24.2

-6.3

347.9

26.8

-5.6

376.8

42.4

1.9

369.8

20.2

-6.8

360.5

16.2

4 -11.0

300 mg/kg/day

Group 3

Mean

N %Diff

313.5

26.9

1.8

348.1

27.9

1.8

372.8

25.9

1.2

403.3

32.3

9.1

404.0

54.1

1.8

369.5

14.5

-8.8

900 mg/kg/day

Group 4

Mean

N %Diff

298.6

22.8

-3.1

326.5

27.2

-4.5

347.3

31.0

-5.7

362.0

46.0

-2.1

376.9

25.2

-5.0

341.5n 0.7

2 -15.7

Sex: Female

Day(s) Relative to Start Date

1 [G]

2 [I]

6 [G]

13 [G]

20 [G]

27 [G]

34 [G]

mg/kg/day

Group 1

Mean

51.5

4.2

10 -

62.9

6.5

10 -

98.9

9.8

10 -

128.6

9.3

10 -

149.3

8.6

10 -

166.7

9.1

10 -

100 mg/kg/day

Group 2

Mean

N %Diff

54.2

2.9

5.3

54.0n

2.8

2 -

65.4

5.5

4.0

100.5

8.6

1.6

131.3

8.2

2.1

155.1

8.6

3.9

172.1

10.8

3.2

300 mg/kg/day

Group 3

Mean

N %Diff

55.7

7.4

8.2

76.0n

1 -

68.8

10.0

9.3

108.9

13.2

10.1

145.1**

12.9

12.8

167.6**

15.5

12.3

186.0**

18.3

11.6

900 mg/kg/day

Group 4

Mean

N %Diff

53.6

3.7

4.0

57.0n 5.7

2 -

63.2

5.3

0.5

100.5

6.2

1.6

135.7

10.3

5.5

159.2

10.4

6.6

179.3

12.7

7.6

Sex: Female

Day(s) Relative to Start Date

41 [G]

48 [G]

55 [G]

58 [G]

59 [G1]

60 [G]

mg/kg/day

Group 1

Mean

179.8

10.1

10 -

193.9

9.9

10 -

203.7

10.7

10 -

204.8

13.1

4 -

214.0

12.7

5 -

214.3

12.2

3 -

100 mg/kg/day

Group 2

Mean

N %Diff

185.7

12.3

3.3

199.7

13.1

3.0

210.3

14.1

3.2

206.8

12.0

1.0

218.0

20.1

1.9

210.8

12.0

-1.7

300 mg/kg/day

Group 3

Mean

N %Diff

202.3**

20.4

12.5

215.0**

20.3

10.9

223.8*

23.4

9.9

237.2

33.5

15.8

247.0

47.1

15.4

223.5

14.2

4.3

900 mg/kg/day

Group 4

Mean

N %Diff

198.6*

14.7

10.5

210.7*

14.0

8.7

218.6

13.4

7.3

223.0

22.0

8.9

229.9

10.5

7.4

220.7

6.0

3.0

Tables 12. Summary of Clinical Chemistry Values

F0 Animals - Males. Day: 137 Relative to Start Date

Sex: Male

Reporting Biochemistry

AST

(U/L)

[G]

ALT

(U/L)

[G]

ALP

(U/L)

[G]

GGT

(U/L)

[G1]

(U/L)

[G1]

TBIL

(umol/L)

[G1]

UREA

(mmol/L)

[G]

mg/kg/day

Group 1

Mean

71.4

12.3

10 -

51.0

11.7

10 -

128.5

12.4

10 -

1.5

0.0

10 -

217.1 68.4

10 -

1.25

0.00

10 -

7.35

0.66

10 -

100 mg/kg/day

Group 2

Mean

tCtrl

74.6

10.3

1.04

49.1

12.0

0.96

126.0

25.8

0.98

1.5

0.0

1.00

292.7

163.0

1.35

1.25

0.00

1.00

6.90

0.68

0.94

300 mg/kg/day

Group 3

Mean

tCtrl

60.5 *

4.9

0.85

44.5

7.8

0.87

125.1

32.5

0.97

1.5

0.0

1.00

213.2 70.8

0.98

1.25

0.00

1.00

7.16

0.35

0.97

900 mg/kg/day

Group 4

Mean

tCtrl

61.6 *

5.4

0.86

36.8 14.1

0.72

115.4

28.5

0.90

1.5 0.0

1.00

196.8 60.0

0.91

1.25 0.00

1.00

6.94 0.68

0.94

[G] - Anova & Dunnett: * = p ≤ 0.05
[G1] - Kruskal-Wallis & Dunn

Sex: Male

reporting Biochemistry

CREAT

(umol/L)

[G]

GLUC

(mmol/L)

[G]

CHOL

(mmol/L)

[G]

TRIG

(mmol/L)

[G]

TPROT

(g/L)

[G]

ALB

(g/L)

[G]

GLOB

(g/L)

[G]

mg/kg/day

Group 1

Mean

34.2

3.2

10 -

8.251

0.699

10 -

1.789

0.249

10 -

1.949

0.657

10 -

66.29

1.89

10 -

40.36

1.53

10 -

25.93

2.18

10 -

100 mg/kg/day

Group 2

Mean

N tCtrl

32.1

3.5

0.94

8.778

1.195

1.06

1.853

0.393

1.04

1.933

0.681

0.99

66.09 3.31

1.00

41.22 2.83

1.02

24.87 2.61

0.96

300 mg/kg/day

Group 3

Mean

N tCtrl

29.8 *

2.9

0.87

8.113

0.521

0.98

2.170 *

0.404

1.21

1.594

0.199

0.82

66.67

2.46

1.01

41.93

1.91

1.04

24.74

2.11

0.95

900 mg/kg/day

Group 4

Mean

N tCtrl

31.5

3.6

0.92

8.208 0.634

0.99

2.327 **

0.270

1.30

1.457 0.567

0.75

68.21

2.50

1.03

43.17 *

2.11

1.07

25.04

2.86

0.97

Sex: Male

Reporting Biochemistry

A/G

(ratio) [G]

(mmol/L)

[G]

(mmol/L)

[G]

(mmol/L)

[G]

(mmol/L)

[G]

PHOS

(mmol/L)

[G]

mg/kg/day

Group 1

Mean

1.58

0.18

10 -

2.618

0.059

10 -

141.1

1.3

10 -

4.98

0.29

10 -

103.7

1.2

10 -

1.404

0.193

10 -

100 mg/kg/day

Group 2

Mean

N tCtrl

1.69

0.22

1.07

2.637

0.076

1.01

141.4

1.9

1.00

4.90

0.34

0.98

103.7

1.4

1.00

1.531

0.178

1.09

300 mg/kg/day

Group 3

Mean

N tCtrl

1.71

0.17

1.08

2.654

0.055

1.01

140.3

2.2

0.99

4.97

0.15

1.00

102.3

1.8

0.99

1.545

0.152

1.10

900 mg/kg/day

Group 4

Mean

N tCtrl

1.75 0.28

1.11

2.716 **

0.069

1.04

141.3

1.7

1.00

5.02 0.29

1.01

101.4 **

2.0

0.98

1.591 0.187

1.13

Tables 13. Summary of Clinical Chemistry Values

F0 Animals - Females. Day: 115 Relative to Start Date

Sex: Female

Reporting Biochemistry

AST

(U/L)

[G]

ALT

(U/L)

[G]

ALP

(U/L)

[G]

GGT

(U/L)

[G1]

(U/L)

[G]

TBIL

(umol/L)

[G1]

UREA

(mmol/L)

[G]

mg/kg/day

Group 1

Mean

131.2

28.7

9 -

117.1

17.5

9 -

223.4

49.2

9 -

1.5

0.0

9 -

630.0

384.5

9 -

1.25

0.00

9 -

10.50 1.01

9 -

100 mg/kg/day

Group 2

Mean

tCtrl

105.3

10.9

0.80

110.0

18.4

0.94

200.3

73.8

0.90

1.5

0.0

1.00

356.8

132.6

0.57

1.25

0.00

1.00

10.11 0.94

0.96

300 mg/kg/day

Group 3

Mean

tCtrl

116.1

21.8

0.88

105.7

14.1

0.90

157.1

38.5

0.70

1.5

0.0

1.00

614.7

356.8

0.98

1.25

0.00

1.00

9.38

0.84

0.89

900 mg/kg/day

Group 4

Mean

tCtrl

106.4

25.3

0.81

100.4

21.0

0.86

173.2

49.5

0.78

1.5 0.0

1.00

428.3

244.8

0.68

1.25 0.00

1.00

10.57 1.26

1.01

[G] - Anova & Dunnett
[G1] - Kruskal-Wallis & Dunn

Sex: Female

Reporting Biochemistry

CREAT

(umol/L)

[G]

GLUC

(mmol/L)

[G]

CHOL

(mmol/L)

[G1]

TRIG

(mmol/L)

[G]

TPROT

(g/L)

[G]

ALB

(g/L)

[G]

GLOB

(g/L)

[G]

mg/kg/day

Group 1

Mean

29.4

3.2

9 -

4.740

1.150

9 -

2.828

0.449

9 -

0.589

0.061

9 -

56.30 2.58

9 -

40.21 1.79

9 -

16.09 2.22

9 -

100 mg/kg/day

Group 2

Mean

N tCtrl

24.6 *

4.2

0.84

5.008

0.434

1.06

2.641

0.493

0.93

0.461

0.140

0.78

55.21 2.41

0.98

39.51 2.62

0.98

15.70 0.72

0.98

300 mg/kg/day

Group 3

Mean

N tCtrl

24.0 * 2.5

0.82

4.863

0.808

1.03

2.889

0.655

1.02

0.535

0.177

0.91

56.38 2.85

1.00

40.59 2.45

1.01

16.19 1.63

1.01

900 mg/kg/day

Group 4

Mean

N tCtrl

25.6

4.6

0.87

5.003 0.815

1.06

2.827 0.925

1.00

0.479 0.115

0.81

58.48 3.36

1.04

42.81

2.93

1.06

15.68 1.98

0.97

Sex: Female

Reporting Biochemistry

A/G

(ratio) [G]

(mmol/L)

[G]

(mmol/L)

[G]

(mmol/L)

[G]

(mmol/L)

[G]

PHOS

(mmol/L)

[G]

mg/kg/day

Group 1

Mean

2.53

0.34

9 -

2.680

0.100

9 -

140.7

2.1

9 -

5.12

0.42

9 -

99.8

2.2

9 -

1.708

0.538

9 -

100 mg/kg/day

Group 2

Mean

N tCtrl

2.54

0.23

1.00

2.621

0.139

0.98

140.0

3.5

1.00

5.05

0.57

0.99

100.1

1.9

1.00

1.649

0.518

0.97

300 mg/kg/day

Group 3

Mean

N tCtrl

2.50

0.29

0.99

2.694

0.096

1.01

140.1

1.3

1.00

5.24

0.62

1.02

99.3

1.7

1.00

1.538

0.510

0.90

900 mg/kg/day

Group 4

Mean

N tCtrl

2.78 0.47

1.10

2.781 0.183

1.04

140.1

2.3

1.00

5.19 0.42

1.01

97.8

2.9

0.98

1.949 0.766

1.14

Tables 14. Summary of Clinical Chemistry Values

F1 Animals - Cohort 1A. Day 70 Relative to Start Date

Sex: Male

Reporting Biochemistry

AST

(U/L)

[G]

ALT

(U/L)

[G]

ALP

(U/L)

[G]

GGT

(U/L)

[G1]

(U/L)

[G]

TBIL

(umol/L)

[G1]

UREA

(mmol/L)

[G]

mg/kg/day

Group 1

Mean

68.5

6.0

10 -

57.6

11.4

10 -

153.4

23.5

10 -

1.5

0.0

9 -

239.9

42.0

9 -

1.25

0.00

9 -

7.02

0.68

9 -

100 mg/kg/day

Group 2

Mean

tCtrl

63.0

7.2

0.92

52.0

7.9

0.90

153.5

23.8

1.00

1.5

0.0

1.00

239.2

101.7

1.00

1.25

0.00

1.00

6.32

0.62

0.90

300 mg/kg/day

Group 3

Mean

tCtrl

61.3 *

5.3

0.89

49.9

8.6

0.87

143.2

27.9

0.93

1.5

0.0

1.00

210.5 55.4

0.88

1.25

0.00

1.00

6.84

0.59

0.97

900 mg/kg/day

Group 4

Mean

tCtrl

61.2 *

4.0

0.89

42.5 **

13.0

0.74

141.5

23.9

0.92

1.5 0.0

1.00

174.9 37.4

0.73

1.25 0.00

1.00

7.24 0.85

1.03

[G] - Anova & Dunnett: * = p ≤ 0.05; ** = p ≤ 0.01

[G1] - Kruskal-Wallis & Dunn

Sex: Male

Reporting Biochemistry

CREAT

(umol/L)

[G]

GLUC

(mmol/L)

[G]

CHOL

(mmol/L)

[G]

TRIG

(mmol/L)

[G]

TPROT

(g/L)

[G]

ALB

(g/L)

[G]

GLOB

(g/L)

[G]

mg/kg/day

Group 1

Mean

30.8

4.0

9 -

9.268

0.551

9 -

1.723

0.237

9 -

2.458

1.001

9 -

66.48 1.47

9 -

41.30

1.39

10 -

25.16 1.24

9 -

100 mg/kg/day

Group 2

Mean

N tCtrl

28.1

3.8

0.91

8.529 **

0.254

0.92

1.894

0.316

1.10

2.030

0.674

0.83

66.44

1.28

1.00

41.71

2.18

1.01

24.73

2.00

0.98

300 mg/kg/day

Group 3

Mean

N tCtrl

29.8

2.6

0.97

8.735

0.590

0.94

2.007

0.325

1.16

1.784

0.635

0.73

65.87

2.39

0.99

41.11

2.06

1.00

24.76

2.03

0.98

900 mg/kg/day

Group 4

Mean

N tCtrl

32.6

3.7

1.06

8.617 *

0.503

0.93

2.147 *

0.325

1.25

1.522 0.615

0.62

65.97

1.76

0.99

42.49

1.31

1.03

23.48

1.78

0.93

Sex: Male

Reporting Biochemistry

A/G

(ratio) [G]

(mmol/L)

[G]

(mmol/L)

[G]

(mmol/L)

[G]

(mmol/L)

[G1]

PHOS

(mmol/L)

[G]

mg/kg/day

Group 1

Mean

1.64

0.10

9 -

2.592

0.033

9 -

141.0

0.8

10 -

5.09

0.30

10 -

100.5

0.5

10 -

1.747

0.191

9 -

100 mg/kg/day

Group 2

Mean

N tCtrl

1.70

0.19

1.03

2.620

0.064

1.01

142.0

1.2

1.01

5.12

0.30

1.01

101.7 *

0.8

1.01

2.034 **

0.122

1.16

300 mg/kg/day

Group 3

Mean

N tCtrl

1.67

0.19

1.02

2.626

0.074

1.01

141.1

1.5

1.00

4.99

0.20

0.98

101.3

1.2

1.01

1.968 **

0.179

1.13

900 mg/kg/day

Group 4

Mean

N tCtrl

1.83 0.17

1.11

2.657 0.064

1.02

141.6

2.0

1.00

4.95 0.18

0.97

99.9

1.6

0.99

2.065 **

0.116

1.18

Sex: Female

Reporting Biochemistry

AST

(U/L)

[G]

ALT

(U/L)

[G]

ALP

(U/L)

[G]

GGT

(U/L)

[G1]

(U/L)

[G]

TBIL

(umol/L)

[G1]

UREA

(mmol/L)

[G]

mg/kg/day

Group 1

Mean

78.0

10.7

7 -

55.9

14.4

7 -

100.6

26.1

7 -

1.5

0.0

7 -

295.7

114.0

7 -

1.25

0.00

7 -

8.09

1.15

7 -

100 mg/kg/day

Group 2

Mean

tCtrl

71.9

7.5

0.92

54.6

17.9

0.98

93.2

23.3

0.93

1.5

0.0

1.00

242.9

83.5

0.82

1.25

0.00

1.00

7.43

0.78

0.92

300 mg/kg/day

Group 3

Mean

tCtrl

68.3

6.1

0.88

49.9

13.2

0.89

94.3

24.1

0.94

1.5

0.0

1.00

259.2 98.3

0.88

1.25

0.00

1.00

7.70

0.89

0.95

900 mg/kg/day

Group 4

Mean

tCtrl

73.7

9.9

0.94

59.8 26.8

1.07

135.4

38.1

1.35

2.2 1.5

1.47

296.8

105.5

1.00

1.25 0.00

1.00

7.66 1.24

0.95

Sex: Female

Reporting Biochemistry

CREAT

(umol/L)

[G]

GLUC

(mmol/L)

[G]

CHOL

(mmol/L)

[G]

TRIG

(mmol/L)

[G]

TPROT

(g/L)

[G]

ALB

(g/L)

[G]

GLOB

(g/L)

[G]

mg/kg/day

Group 1

Mean

34.0

3.5

7 -

8.577

0.866

7 -

1.589

0.267

7 -

1.421

0.304

7 -

65.96 2.49

7 -

45.56 2.60

7 -

20.40 2.41

7 -

100 mg/kg/day

Group 2

Mean

N tCtrl

34.8

4.5

1.02

7.801

0.566

0.91

1.512

0.297

0.95

1.021

0.261

0.72

67.76 2.46

1.03

46.70 1.56

1.03

21.06 1.80

1.03

300 mg/kg/day

Group 3

Mean

N tCtrl

32.7

4.0

0.96

8.161

0.464

0.95

1.647

0.235

1.04

1.268

0.529

0.89

68.21

2.48

1.03

46.77

2.62

1.03

21.44

2.18

1.05

900 mg/kg/day

Group 4

Mean

N tCtrl

32.4

4.5

0.95

8.082 0.391

0.94

1.913 *

0.234

1.20

0.978 0.268

0.69

67.82

2.61

1.03

46.97

2.19

1.03

20.85

1.87

1.02

Sex: Female

Reporting Biochemistry

A/G

(ratio) [G]

(mmol/L)

[G]

(mmol/L)

[G]

(mmol/L)

[G]

(mmol/L)

[G]

PHOS

(mmol/L)

[G]

mg/kg/day

Group 1

Mean

2.27

0.35

7 -

2.574

0.035

7 -

140.3

1.1

7 -

4.43

0.42

7 -

103.6

1.4

7 -

1.227

0.104

7 -

100 mg/kg/day

Group 2

Mean

N tCtrl

2.24

0.21

0.99

2.581

0.060

1.00

140.2

1.2

1.00

4.78

0.29

1.08

102.9

1.2

0.99

1.436

0.206

1.17

300 mg/kg/day

Group 3

Mean

N tCtrl

2.18

0.30

0.96

2.591

0.053

1.01

140.6

0.8

1.00

4.45

0.20

1.00

104.1

1.3

1.01

1.379

0.205

1.12

900 mg/kg/day

Group 4

Mean

N tCtrl

2.30 0.28

1.01

2.664 **

0.039

1.03

140.4

1.1

1.00

4.86 *

0.27

1.10

102.2

0.9

0.99

1.312 0.263

1.07

Table 15. Summary of Coagulation Values

F0 Animals – Males, Day: 137 Relative to Start Date

Sex: Male

Reporting Coagulation

(sec)

[G]

APTT

(sec)

[G]

FIB

(g/L)

[G]

mg/kg/day

Group 1

Mean

10.55

0.20

10 -

13.51

1.35

10 -

2.278

0.177 10 .

100 mg/kg/day

Group 2

Mean

N tCtrl

10.43

0.15

0.99

12.52

1.72

0.93

2.282

0.122

1.00

300 mg/kg/day

Group 3

Mean

N tCtrl

10.30 **

0.14

0.98

12.35

1.14

0.91

2.286

0.185

1.00

900 mg/kg/day

Group 4

Mean

N tCtrl

10.26 **

0.12

0.97

11.77

1.51

0.87

2.454 *

0.114

1.08

[G] - Anova & Dunnett: * = p ≤ 0.05; ** = p ≤ 0.01

Table 16. Summary of Coagulation Values

F0 Animals – Females, Day: 115 Relative to Start Date

Sex: Female

Reporting Coagulation

(sec)

[G]

APTT

(sec)

[G]

FIB

(g/L)

[G]

mg/kg/day

Group 1

Mean

10.19

0.21

9 -

11.17

1.22

9 -

1.713

0.292 9 .

100 mg/kg/day

Group 2

Mean

N tCtrl

10.48

0.34

1.03

12.17

1.55

1.09

1.612

0.157

0.94

300 mg/kg/day

Group 3

Mean

N tCtrl

10.27

0.32

1.01

11.82

1.49

1.06

1.743

0.316

1.02

900 mg/kg/day

Group 4

Mean

N tCtrl

10.39

0.73

1.02

11.16

2.64

1.00

1.682 0.425

0.98

[G] - Anova & Dunnett

Table 17. Summary of Coagulation Values

F1 Animals - Cohort 1A, Day: 70 Relative to Start Date

Sex: Male

Reporting Coagulation

(sec)

[G]

APTT

(sec)

[G]

FIB

(g/L)

[G]

mg/kg/day

Group 1

Mean

10.50

0.14

9 -

12.27

1.80

9 -

2.580

0.172 9 .

100 mg/kg/day

Group 2

Mean

N tCtrl

10.40

0.11

0.99

12.79

2.10

1.04

2.516

0.141

0.98

300 mg/kg/day

Group 3

Mean

N tCtrl

10.34 *

0.14

0.98

12.09

2.30

0.99

2.655

0.219

1.03

900 mg/kg/day

Group 4

Mean

N tCtrl

10.33 *

0.05

0.98

11.51

2.25

0.94

2.707 0.250

1.05

[G] - Anova & Dunnett: * = p ≤ 0.05

Sex: Female

Reporting Coagulation

(sec)

[G]

APTT

(sec)

[G]

FIB

(g/L)

[G]

mg/kg/day

Group 1

Mean

10.31

0.26

9 -

12.21

1.52

8 -

2.116

0.251 9 .

100 mg/kg/day

Group 2

Mean

N tCtrl

10.17

0.17

0.99

12.33

1.57

1.01

2.128

0.172

1.01

300 mg/kg/day

Group 3

Mean

N tCtrl

10.15

0.14

0.98

11.65

0.99

0.95

2.186

0.194

1.03

900 mg/kg/day

Group 4

Mean

N tCtrl

10.02 **

0.17

0.97

11.71

1.65

0.96

2.182 0.099

1.03

[G] - Anova & Dunnett: ** = p ≤ 0.01

Table 18. Summary of Hematology Values

F0 Animals – Males Day: 137 Relative to Start Date

Sex: Male

Reporting Hematology

WBC

(10^9/L)

[G]

NEUT

(10^9/L)

[G]

LYMPH

(10^9/L)

[G1]

MONO

(10^9/L)

[G]

EOS

(10^9/L)

[G]

BASO

(10^9/L)

[G1]

LUC

(10^9/L)

[G1]

mg/kg/day

Group 1

Mean

4.651

0.478

10 -

0.961

0.257

10 -

3.480

0.289

10 -

0.065

0.014

10 -

0.116

0.046

10 -

0.008

0.004

10 -

0.019

0.006

10 -

100 mg/kg/day

Group 2

Mean

N tCtrl

4.340

0.805

0.93

0.769

0.202

0.80

3.390

0.784

0.97

0.062

0.018

0.95

0.096

0.024

0.83

0.006

0.005

0.75

0.016

0.008

0.84

300 mg/kg/day

Group 3

Mean

N tCtrl

4.469

0.783

0.96

0.687 *

0.169

0.71

3.605

0.697

1.04

0.057

0.021

0.88

0.089

0.023

0.77

0.010

0.000

1.25

0.019

0.007

1.00

900 mg/kg/day

Group 4

Mean

N tCtrl

5.192 0.960

1.12

0.854 0.199

0.89

4.126 0.908

1.19

0.079 0.028

1.22

0.092 0.040

0.79

0.009 0.006

1.13

0.027 0.013

1.42

[G] - Anova & Dunnett: * = p ≤ 0.05

[G1] - Kruskal-Wallis & Dunn

Sex: Male

Reporting Hematology

RBC

(10^12/L)

[G]

HGB

(g/L)

[G]

HCT

(L/L)

[G]

MCV

(fL)

[G]

MCH

(pg)

[G]

MCHC

(g/L)

[G]

RDWG

(%)

[G]

mg/kg/day

Group 1

Mean

8.813

0.449

10 -

153.6

4.7

10 .

0.4464

0.0164

10 -

50.68

1.37

10 -

17.43

0.57

10 -

343.9

7.0

10 -

11.88

0.31

10 -

100 mg/kg/day

Group 2

Mean

N tCtrl

8.630

0.303

0.98

150.7

6.5

0.98

0.4441

0.0155

0.99

51.52

2.26

1.02

17.46

1.03

1.00

338.9

7.5

0.99

12.00

0.48

1.01

300 mg/kg/day

Group 3

Mean

N tCtrl

8.572

0.317

0.97

149.6

5.2

0.97

0.4388

0.0129

0.98

51.25

1.89

1.01

17.47

0.71

1.00

341.1

6.6

0.99

12.01

0.52

1.01

900 mg/kg/day

Group 4

Mean

N tCtrl

8.573 0.220

0.97

147.4

5.4

0.96

0.4364 0.0139

0.98

50.92

1.39

1.00

17.17

0.55

0.99

337.5

4.5

0.98

12.16

0.48

1.02

Sex: Male

Reporting Hematology

PLT

(10^9/L)

[G]

RETIC

(10^9/L)

[G]

mg/kg/day

Group 1

Mean

781.6

146.2

10 -

155.83

19.62

10 -

100 mg/kg/day

Group 2

Mean

N tCtrl

765.3

76.5

0.98

142.51

41.33

0.91

300 mg/kg/day

Group 3

Mean

N tCtrl

760.4

92.6

0.97

160.37

18.17

1.03

900 mg/kg/day

Group 4

Mean

N tCtrl

883.4

160.3

1.13

171.47

21.32

1.10

Table 19. Summary of Hematology Values

F0 Animals – Females Day: 115 Relative to Start Date

Sex: Female

Reporting Hematology

WBC

(10^9/L)

[G]

NEUT

(10^9/L)

[G]

LYMPH

(10^9/L)

[G]

MONO

(10^9/L)

[G]

EOS

(10^9/L)

[G]

BASO

(10^9/L)

[G]

LUC

(10^9/L)

[G]

mg/kg/day

Group 1

Mean

5.168

1.072

8 -

1.669

0.559

8 -

3.265

0.790

8 -

0.109

0.031

8 -

0.095

0.038

8 -

0.011

0.006

8 -

0.023

0.009

8 -

100 mg/kg/day

Group 2

Mean

N tCtrl

5.529

0.603

1.07

1.737

0.408

1.04

3.564

0.620

1.09

0.113

0.025

1.04

0.077

0.039

0.81

0.012

0.008

1.07

0.025

0.010

1.11

300 mg/kg/day

Group 3

Mean

N tCtrl

5.866

1.252

1.14

1.903

0.424

1.14

3.694

0.894

1.13

0.143

0.060

1.31

0.091

0.038

0.96

0.013

0.007

1.16

0.026

0.013

1.16

900 mg/kg/day

Group 4

Mean

N tCtrl

5.570 0.802

1.08

1.762 0.315

1.06

3.555 0.672

1.09

0.144 0.051

1.32

0.073 0.013

0.77

0.008 0.004

0.71

0.028 0.011

1.24

Sex: Female

Reporting Hematology

RBC

(10^12/L)

[G]

HGB

(g/L)

[G]

HCT

(L/L)

[G]

MCV

(fL)

[G]

MCH

(pg)

[G]

MCHC

(g/L)

[G]

RDWG

(%)

[G]

mg/kg/day

Group 1

Mean

7.958

0.449

8 -

157.3

3.4

8 .

0.4679

0.0124

8 -

58.88 2.37

8 -

19.80 0.92

8 -

336.4 5.2

8 -

12.00 1.06

8 -

100 mg/kg/day

Group 2

Mean

tCtrl

7.678

0.380

0.96

153.3

5.2

0.97

0.4515

0.0208

0.97

58.86

1.56

1.00

19.99

0.77

1.01

339.8

8.3

1.01

11.84

0.79

0.99

300 mg/kg/day

Group 3

Mean

tCtrl

7.466

0.606

0.94

152.7

5.1

0.97

0.4468

0.0194

0.95

59.99 2.69

1.02

20.48 1.21

1.03

341.6 7.1 9

1.02

11.82

0.97

0.99

900 mg/kg/day

Group 4

Mean

tCtrl

7.528 0.566

0.95

151.3

8.8

0.96

0.4428 0.0316

0.95

58.85

1.83

1.00

20.10

1.07

1.02

341.5 10.8

1.02

12.17

1.05

1.01

Sex: Female

Reporting Hematology

PLT

(10^9/L)

[G]

RETIC

(10^9/L)

[G]

mg/kg/day

Group 1

Mean

894.6

119.2

8 -

177.99

20.44

8 -

100 mg/kg/day

Group 2

Mean

N tCtrl

794.3

132.8

0.89

178.18

31.61

1.00

300 mg/kg/day

Group 3

Mean

N tCtrl

872.4

121.5

0.98

161.09

22.77

0.91

900 mg/kg/day

Group 4

Mean

N tCtrl

833.4

177.2

0.93

173.25

30.61

0.97

Table 20. Summary of Hematology Values

F1 Animals – Cohort 1A. Day 70 Relative to Start Date

Sex: Male

Reporting Hematology

WBC

(10^9/L)

[G]

NEUT

(10^9/L)

[G]

LYMPH

(10^9/L)

[G]

MONO

(10^9/L)

[G]

EOS

(10^9/L)

[G]

BASO

(10^9/L)

[G1]

LUC

(10^9/L)

[G1]

mg/kg/day

Group 1

Mean

6.989

1.038

10 -

0.930

0.183

10 -

5.762

0.940

10 -

0.121

0.043

10 -

0.108

0.036

10 -

0.008

0.009

10 -

0.059

0.018

10 -

100 mg/kg/day

Group 2

Mean

N tCtrl

7.203

0.765

1.03

0.970

0.322

1.04

5.976

0.743

1.04

0.099

0.031

0.82

0.091

0.031

0.84

0.011

0.006

1.38

0.054

0.023

0.92

300 mg/kg/day

Group 3

Mean

N tCtrl

7.256

0.780

1.04

0.993

0.193

1.07

6.050

0.666

1.05

0.086

0.030

0.71

0.074

0.023

0.69

0.007

0.005

0.88

0.047

0.009

0.80

900 mg/kg/day

Group 4

Mean

N tCtrl

8.090 *

0.978

1.16

1.081 0.253

1.16

6.736 1.071

1.17

0.115 0.030

0.95

0.080 0.032

0.74

0.011 0.006

1.38

0.064 0.023

1.08

[G] - Anova & Dunnett: * = p ≤ 0.05

[G1] - Kruskal-Wallis & Dunn

Sex: Male

Reporting Hematology

RBC

(10^12/L)

[G]

HGB

(g/L)

[G]

HCT

(L/L)

[G]

MCV

(fL)

[G]

MCH

(pg)

[G]

MCHC

(g/L)

[G]

RDWG

(%)

[G]

mg/kg/day

Group 1

Mean

9.078

0.461

10 -

163.2

4.9

10 .

0.4747

0.0207

10 -

52.33

1.52

10 -

17.99

0.90

10 -

343.7 10.9

10 -

11.47

0.49

10 -

100 mg/kg/day

Group 2

Mean

N tCtrl

8.551 *

0.488

0.94

156.9 *

5.4

0.96

0.4471 **

0.0181

0.94

52.33

2.09

1.00

18.37

0.87

1.02

350.8

6.2

1.02

11.59

0.52

1.01

300 mg/kg/day

Group 3

Mean

N tCtrl

8.522 **

0.298

0.94

157.1 *

4.1

0.96

0.4519 *

0.0171

0.95

53.06

1.54

1.01

18.44

0.54

1.03

347.7

7.0

1.01

11.63

0.51

1.01

900 mg/kg/day

Group 4

Mean

N tCtrl

8.340 **

0.285

0.92

154.7 **

4.4

0.95

0.4456 **

0.0166

0.94

53.45

1.51

1.02

18.56

0.67

1.03

347.4

7.6

1.01

11.84

0.32

1.03

[G] - Anova & Dunnett: * = p ≤ 0.05; ** = p ≤ 0.01

Sex: Male

Reporting Hematology

PLT

(10^9/L)

[G]

RETIC

(10^9/L)

[G]

mg/kg/day

Group 1

Mean

763.2

131.0

10 -

193.85

15.23

10 -

100 mg/kg/day

Group 2

Mean

N tCtrl

876.8

89.5

1.15

171.56

23.85

0.89

300 mg/kg/day

Group 3

Mean

N tCtrl

899.7

76.1

1.18

198.49

23.89

1.02

900 mg/kg/day

Group 4

Mean

N tCtrl

823.3

144.5

1.08

208.78

30.71

1.08

Sex: Female

Reporting Hematology

WBC

(10^9/L)

[G]

NEUT

(10^9/L)

[G1]

LYMPH

(10^9/L)

[G]

MONO

(10^9/L)

[G1]

EOS

(10^9/L)

[G]

BASO

(10^9/L)

[G]

LUC

(10^9/L)

[G]

mg/kg/day

Group 1

Mean

5.104

1.013

9 -

0.587

0.094

9 -

4.321

0.997

9 -

0.070

0.018

9 -

0.081

0.019

9 -

0.003

0.005

9 -

0.038

0.010

9 -

100 mg/kg/day

Group 2

Mean

N tCtrl

5.207

1.111

1.02

0.671

0.142

1.14

4.371

1.058

1.01

0.053

0.017

0.76

0.074

0.028

0.92

0.004

0.005

1.33

0.029

0.014

0.76

300 mg/kg/day

Group 3

Mean

N tCtrl

4.656

0.870

0.91

0.708

0.238

1.21

3.780

0.791

0.87

0.060

0.021

0.86

0.067

0.020

0.83

0.003

0.005

0.90

0.034

0.008

0.90

900 mg/kg/day

Group 4

Mean

N tCtrl

5.515 1.387

1.08

0.681 0.323

1.16

4.640 1.417

1.07

0.076 0.039

1.09

0.079 0.031

0.97

0.004 0.005

1.20

0.037 0.014

0.98

[G] - Anova & Dunnett

[G1] - Kruskal-Wallis & Dunn

Sex: Female

Reporting Hematology

RBC

(10^12/L)

[G]

HGB

(g/L)

[G]

HCT

(L/L)

[G]

MCV

(fL)

[G]

MCH

(pg)

[G]

MCHC

(g/L)

[G]

RDWG

(%)

[G]

mg/kg/day

Group 1

Mean

7.842

0.436

9 -

151.6

5.3

9 .

0.4248

0.0164

9 -

54.23 1.82

9 -

19.38 0.95

9 -

356.8 8.1

9 -

10.70 0.38

9 -

100 mg/kg/day

Group 2

Mean

N tCtrl

7.868

0.225

1.00

148.8

6.5

0.98

0.4244

0.0173

1.00

53.91 1.31

0.99

18.89 0.64

0.97

350.7 8.5 9

0.98

10.91 0.36

1.02

300 mg/kg/day

Group 3

Mean

N tCtrl

7.867

0.362

1.00

149.7

5.4

0.99

0.4244

0.0143

1.00

54.01

2.25

1.00

19.06

0.93

0.98

352.6

4.3

0.99

10.68

0.35

1.00

900 mg/kg/day

Group 4

Mean

N tCtrl

7.744 0.368

0.99

144.3

5.5

0.95

0.4116 0.0156

0.97

53.20

1.94

0.98

18.64

0.75

0.96

350.5

6.8

0.98

10.82

0.33

1.01

Sex: Female

Reporting Hematology

PLT

(10^9/L)

[G]

RETIC

(10^9/L)

[G1]

mg/kg/day

Group 1

Mean

833.0

141.8

9 -

183.07

34.30

9 -

100 mg/kg/day

Group 2

Mean

N tCtrl

801.3

145.2

0.96

178.02

22.41

0.97

300 mg/kg/day

Group 3

Mean

N tCtrl

796.3

97.2

0.96

185.18

28.61

1.01

900 mg/kg/day

Group 4

Mean

N tCtrl

910.6

58.3

1.09

177.80

38.40

0.97

Table 21. Summary of Reproductive Performance

F0 Females

Sex: Female

Day(s) Relative to Pairing (Litter: A

)

0 mg/kg/day

Group 1

100 mg/kg/day

Group 2

300 mg/kg/day

Group 3

900 mg/kg/day

Group 4

Group Size - Females

N+ve

Mean

%Diff

N+ve

N+ve %

% ProA

5.3

5.1

76.0

24.0

100.0

25/25

3.2

2.5

-39.4

96.0

4.0

100.0

25/25

2.7

2.6

-49.2

96.0

4.0

100.0

25/25

3.0

2.7

-43.2

95.8

4.2

100.0

24/24

Paired - Females

Mated Females

Pre-coital Interval (Days)

Confirmed Mating Days 1-7

Confirmed Mating Days 8-14

Female Mating Index

Mated Females - Pregnant or Not Pregnant with confirmed mating date (by sperm or plug).

Table 22. Summary of Reproductive Performance

F1 Animals - Cohort 1B Females

Sex: Female

Day(s) Relative to Pairing (Litter: A

)

0 mg/kg/day

Group 1

100 mg/kg/day

Group 2

300 mg/kg/day

Group 3

900 mg/kg/day

Group 4

Group Size - Females

N+ve

Mean

%Diff

N+ve

N+ve %

% ProA

2.7

1.0

100.0

0.0

100.0

20/20

3.9

3.7

45.3

90.0

10.0

100.0

20/20

3.5

2.7 20

32.1

95.0

5.0

100.0

20/20

2.5

1.2 20

-7.5

100.0

0.0

100.0

20/20

Paired - Females

Mated Females

Pre-coital Interval (Days)

Confirmed Mating Days 1-7

Confirmed Mating Days 8-14

Female Mating Index

Mated Females - Pregnant or Not Pregnant with confirmed mating date (by sperm or plug).

Table 23. Mating Performance and Fertility

F0 Animals

Number of Nights to Positive Mating Sign	Group/Dose Level (mg/kg/day)
	1 (0)	2 (100)	3 (300)	4 (900)
	Number of Animals (Number of these not becoming pregnant)
1	6(1)*	4	8	7(1)
2	2	5	6	5
3	6	8	7	3
4	5	7	3	8
No clear indication of mating	6(1)	1	1	1
Mean number of nights to positive mating sign	2.5	2.8	2.2	2.5
Number passing one estrus	0	0	0	0
Number of males paired	25	25	25	24
Number of siring males	24	25	25	23
Male Mating Index	0.96	1.00	1.00	1.00
Male Fertility Index	1.00	1.00	1.00	0.96
Male Pregnancy Index	0.96	1.00	1.00	0.96
Female Mating Index	0.96	1.00	1.00	1.00
Female Fertility Index	1.00	1.00	1.00	0.96
Female Pregnancy Index	0.96	1.00	1.00	0.96

*Includes Animal 1524 that had 2 implant sites (no live or dead pups)

Table 24. Mating Performance and Fertility

F1 Animals

Number of Nights to Positive Mating Sign	Group/Dose Level (mg/kg/day)
	1 (0)	2 (100)	3 (300)	4 (900)
	Number of Animals (Number of these not becoming pregnant)
1	3	5	2	7
2	5	2	4	2
3	9	5(2)	8	6
4	2	5	4	5
5	1(1)	1	0	0
6	0	0	1	0
No clear indication of mating	0	2(2)	1(1)	0
Mean number of nights to positive mating sign	2.7	2.7	2.9	2.5
Number passing one estrus	0	1	1	0
Number of males paired	20	20	20	20
Number of siring males	19	16	19	20
Male Mating Index	1.00	0.90	0.95	1.00
Male Fertility Index	0.95	0.89	0.95	1.00
Male Pregnancy Index	0.95	0.80	0.95	1.00
Female Mating Index	1.00	0.90	0.95	1.00
Female Fertility Index	0.95	0.89	0.95	1.00
Female Pregnancy Index	0.95	0.80	0.95	1.00

Table 25. Summary of Duration of Gestation and Overall Litter Performance

F0 Animals

F0 Generation	Group/Dose Level (mg/kg/day)
F0 Generation	1	2	3	4
	(0)	(100)	(300)	(900)
Number Pregnant	24	25	25	23
Duration of Gestation (Days) 21	1	1	0	0
22	17	17	23	20
23	0	6	1	2
No clear indication of mating	6	1	1	1
Mean Duration	21.9	22.2	22.0	22.1
Number of females producing a live litter	23	25	25	23
Gestation index as %	96	100	100	100
Mean number of implant sites per pregnancy ± standard deviation	12.0 ± 3.4	12.5 ± 2.4	12.6 ± 1.9	12.9 ± 1.6
Mean total number of pups born per litter ± standard deviation	11.0 ± 3.0	11.2 ± 2.3	11.0 ± 2.5	11.0 ± 3.3
Mean number of live pups per litter ± standard deviation: Lactation Day 1	11.0 ± 3.0	11.1 ± 2.2	10.9 ± 2.6	11.1 ± 2.6
Lactation Day 4	10.9 ± 3.1	11.2 ± 2.2	10.9 ± 2.6	11.0 ± 2.7
Lactation Day 4^a	7.7 ± 1.1	7.9 ± 0.4	7.8 ± 0.7	7.7 ± 0.9
Lactation Day 7	7.7 ± 1.1	7.9 ± 0.4	7.8± 0.7	7.7 ± 0.9
Lactation Day 14	7.7 ± 1.1	7.9 ± 0.4	7.8 ± 0.7	7.7 ± 0.9
Lactation Day 21	7.7 ± 1.1	7.9 ± 0.4	7.8 ± 0.7	7.7 ± 0.9
Number of males on Lactation Day 1 (%)	120 (47)	135 (49)	145 (53)	116 (47)
Number of females on Lactation Day 1 (%)	134 (53)	143 (51)	127 (47)	129 (53)

^aAfter cull of pups on PND 4 to standardise the size of the litter

Table 26. Summary of Duration of Gestation and Overall Litter Performance

F1 Animals

F1 Generation	Group/Dose Level (mg/kg/day)
F1 Generation	1	2	3	4
	(0)	(100)	(300)	(900)
Number Pregnant	19	16	19	20
Duration of Gestation (Days) 21	1	3	1	1
22	15	9	17	18
23	3	4	1	1
Mean Duration	22.1	22.1	22.0	22.0
Number of females producing a live litter	19	16	19	20
Gestation index as %	100	100	100	100
Mean number of implant sites per pregnancy ± standard deviation	12.6 ± 1.7	12.3 ± 2.3	13.0 ± 1.6	12.5 ± 2.3
Mean total number of pups born per litter ± standard deviation*	11.6 ± 1.9	11.1 ± 2.8	10.5 ± 2.8	11.3 ± 2.2
Mean number of live pups per litter ± standard deviation*: Lactation Day 1	11.3 ± 2.2	11.1 ± 3.0	10.4 ± 2.7	11.1 ± 2.1
Lactation Day 4	11.3 ± 2.2	11.0 ± 2.9	10.3 ± 2.8	11.0 ± 2.1
Lactation Day 4^a	7.9 ± 0.5	7.7 ± 0.9	7.6 ± 1.2	7.9 ± 0.5
Lactation Day 7	7.9 ± 0.5	7.7 ± 0.9	7.6 ± 1.2	7.9 ± 0.5
Lactation Day 14	7.9 ± 0.5	7.7 ± 0.9	7.6 ± 1.2	7.9 ± 0.5
Lactation Day 21	7.9 ± 0.5	7.7 ± 0.9	7.6 ± 1.2	7.8 ± 0.5
Number of males on Lactation Day 1 (%)	96 (47)	96 (54)	93 (49)	100 (45)
Number of females on Lactation Day 1 (%)	108 (53)	81 (46)	96 (51)	121 (55)

^aAfter cull of pups on PND 4 to standardise the size of the litter

* Excludes Animal 1628 that had a total litter loss

Table 27. Summary of Urinalysis Values

F0 Animals - Males
Day: 131 Relative to Start Date

Sex: Male			Reporting Urinalysis
		VOLUME	SPECIFIC	URINE pH
		(mL)	GRAVITY	[G]
		[G]	[G1]
0 mg/kg/day	Mean	4.32	1.0152	7.5
Group 1	SD	2.94	0.0089	0.94
	N	10	10 -	10 -
		-
100 mg/kg/day	Mean	5.64	1.0135	8
Group 2	SD	2.99	0.0052	0.62
	N	10	10	10
	tCtrl	1.31	1	1.07
300 mg/kg/day	Mean	4.22	1.0215	8.15
Group 3	SD	2.11	0.0086	0.63
	N	10	10	10
	tCtrl	0.98	1.01	1.09
900 mg/kg/day	Mean	5.25	1.0300 **	7.35 0.71
Group 4	SD	2.39	0.0133	10
	N	10	10	0.98
	tCtrl	1.22	1.01

Table 28. Summary of Urinalysis Values

F0 Animals - Females
Day: 108 Relative to Start Date

Sex: Female			Reporting Urinalysis
		VOLUME	SPECIFIC	URINE pH
		(mL)	GRAVITY	[G1]
		[G]	[G]
0 mg/kg/day	Mean	4.85	1.0188	8.6
Group 1	SD	2.33	0.0052	0.32
	N	10 -	10 -	10 -

100 mg/kg/day	Mean	5.23	1.0192	8.45
Group 2	SD	2.96	0.0069	0.16
	N	10	10	10
	tCtrl	1.08	1	0.98
300 mg/kg/day	Mean	6.01	1.0199	8.2
Group 3	SD	1.68	0.0039	0.42
	N	10	10	10
	tCtrl	1.24	1	0.95
900 mg/kg/day	Mean	7.05 2.58	1.0218 0.0051	8.05 *
Group 4	SD	10	10	0.72
	N	1.45	1	10
	tCtrl			0.94

[G] - Anova & Dunnett
[G1] - Kruskal-Wallis & Dunn: * = p ≤ 0.05

Table 29. Summary of Urinalysis Values

F1 Animals - Cohort 1A
Day: 60 Relative to Start Date

Sex: Male			Reporting urinalysis
		VOLUME	SPECIFIC	URINE pH
		(mL)	GRAVITY	[G]
		[G]	[G]
0 mg/kg/day	Mean	2.67	1.0182	8.11
Group 1	SD	1.87	0.0078	0.6
	N	10 -	10 -	9 -

100 mg/kg/day	Mean	3.07	1.0168	7.9
Group 2	SD	0.95	0.0123	0.61
	N	10	10	10
	tCtrl	1.15	1	0.97
300 mg/kg/day	Mean	1.96	1.0302 *	7.11 ** 0.70
Group 3	SD	1.25	0.0118	9
	N	10	10	0.88
	tCtrl	0.73	1.01
900 mg/kg/day	Mean	2.94 1.43	1.0346 **	6.25 **
Group 4	SD	10	0.0091	0.42
	N	1.1	10	10
	tCtrl		1.02	0.77

Day: 60 Relative to Start Date

Sex: Female

Reporting Urinalysi

VOLUME

(mL)

[G]

SPECIFIC

GRAVITY

[G]

URINE pH

[G]

mg/kg/day

Group 1

Mean

1.88

1.25

10 -

1.0226

0.0117

10 -

7.00

0.94

9 -

100 mg/kg/day

Group 2

Mean

N tCtrl

3.20

2.88

1.70

1.0161

0.0086

0.99

7.15

0.91

1.02

300 mg/kg/day

Group 3

Mean

N tCtrl

1.33

1.08

0.71

1.0333

0.0118

1.01

6.61

0.55

0.94

900 mg/kg/day

Group 4

Mean

N tCtrl

2.61 1.55

1.39

1.0267 0.0087

1.00

6.44 0.68

0.92

[G] - Anova & Dunnett

Applicant's summary and conclusion

Conclusions:

The administration of Omnirad 184 once daily (or twice daily 3 hours apart on some occasions) via
oral gavage was well tolerated in Han Wistar rats at dose levels of up to 900 mg/kg/day with no
test item-related deaths. There were occasional observations of decreased activity, abnormal, un
coordinated gait and low carriage for F0 animals at 900 mg/kg/day and for F0 and F1 animals, dose le
vel-related salivation and/or ploughing. F0 and F1 males at 900 mg/kg/day had slightly lower body we
ight gain, and F0 and F1 females a slightly higher dose level-related body weight gain at ≥ 100 mg/kg/
day. Food consumption was generally slightly higher for males and females at ≥ 100 mg/kg/day. Ther
e were no test item-related effects on F0 and F1 generation fertility, mating or reproduction, or F1 and
F2 generation pup numbers, survival or development. For males at 900 mg/kg/day, motor activity
was 9.6% or 12.7% lower overall for basic or fine movements, respectively, but this was not confirme
d by overall ambulation values, or any associated clinical findings, detailed functional observations or
brain morphometry values for Cohort 2A. Triglyceride values were lower for F0 males given ≥300 mg/
kg/day, F0 females and F1 animals given ≥100 mg/kg/day, and cholesterol values higher for F0 male
s only at ≥300 mg/kg/day and F1 animals at 900 mg/kg/day. There were slightly higher TSH levels
(up to 3.1-fold of controls) on the morning of necropsy in F0 and F1 adult males given 300 or 900 mg/kg/day. There were no test item-related effects on haematology, coagulation, urinalysis, T4 values
or the immune cell populations analysed for immunophenotyping, at up to 900 mg/kg/day. Target
organ effects were observed at dose levels of ≥100 mg/kg/day and consisted of centrilobular hypertro
phy in the liver and stomach mucosal hyperplasia of the glandular region. Higher liver and/or kidney
weights were seen in both sexes. In neurological investigations, there were no test item-related brain
weight differences, gross or histological findings or effects on the brain dimensions. There were no
histological findings in the reproductive tissues of the females that had not been observed to litter tha
t would have caused reduced fertility. The NOAEL (No Observed Adverse Effect Level) for F0 and F1
adult toxicity, male and female fertility and reproduction was considered to be 900 mg/kg/day as the i
n-life and pathological findings were considered not to be adverse. For F1 and F2 developmental para
meters, the NOAEL was considered to be 900 mg/kg/day as there were no test item-related effects on
the pup numbers, survival or development.

Executive summary:

The objective of this study was to determine the potential toxicity of the chemical Omnirad 184, when given by oral gavage to adult rats and their offspring. This study was designed to provide an evaluation of reproduction and development as well as a thorough evaluation of systemic toxicity in pregnant and lactating females and their offspring. Detailed examination of key developmental endpoints, such as offspring viability, neonatal health, developmental status at birth, physical and functional development until adulthood, nervous and immune system development was expected to identify any specific target organs in the offspring. In addition, the study provided information about the effects of Omnirad 184 on the integrity and performance of the adult male and female reproductive systems and a neurobehavioural assessment of the F1 generation.

The study design was as follows:

Text Table 1 Experimental Design – F0 Animals

Group No.	Treatment	Dose Level (mg/kg/day)	Dose Volume^a (mL/kg)	Dose Conc. (mg/mL)	Corrected Dose Conc. (mg/mL)	Corrected Dose Levels (mg/kg/day)	Number of Animals
Group No.	Treatment	Dose Level (mg/kg/day)	Dose Volume^a (mL/kg)	Dose Conc. (mg/mL)	Corrected Dose Conc. (mg/mL)	Corrected Dose Levels (mg/kg/day)	Males	Females
1	Control	0	10	0	0	0	25	25
2	Omnirad 184	100	10	10	10.03	100	25	25
3	Omnirad 184	300	10	30	30.09	301	25	25
4	Omnirad 184	900	10	90	90.27	903	25	25

Text Table 2 Experimental Design – F1 Unselected PND (Post Natal Day) 21 Pups

Group No.^a	Number of Animals^b
Group No.^a	Males	Females
1	10	10
2	10	10
3	10	10
4	10	10

^aUnselected pups were not dosed, group number refers to dam group number.

^bThese pups had TSH and T4 blood sampling and necropsy procedures.

Text Table 3 Experimental Design – Cohort 1A (Reproductive)

Group No.	Treatment	Dose Level (mg/kg/day)	Dose Volume^a (mL/kg)	Dose Conc. (mg/mL)	Corrected Dose Conc. (mg/mL)	Corrected Dose Levels (mg/kg/day)	Number of Animals
Group No.	Treatment	Dose Level (mg/kg/day)	Dose Volume^a (mL/kg)	Dose Conc. (mg/mL)	Corrected Dose Conc. (mg/mL)	Corrected Dose Levels (mg/kg/day)	Males	Females
1	Control	0	10	0	0	0	20	20
2	Omnirad 184	100	10	10	10.03	100	20	20
3	Omnirad 184	300	10	30	30.09	301	20	21^d
4	Omnirad 184	900^bc	10^bc	90^bc	90.27	903	20	20

Control/vehicle = 0.5% (w/v) CMC medium viscosity and 0.1% (w/v) Tween 80 in Milli-Q water
Conc. = concentration

Text Table 4 Experimental Design – Surplus F1 Animals

Group No.	Treatment	Dose Level (mg/kg/day)	Dose Volume^a (mL/kg)	Dose Conc. (mg/mL)	Corrected Dose Conc. (mg/mL)	Corrected Dose Levels (mg/kg/day)	Number of Animals
Group No.	Treatment	Dose Level (mg/kg/day)	Dose Volume^a (mL/kg)	Dose Conc. (mg/mL)	Corrected Dose Conc. (mg/mL)	Corrected Dose Levels (mg/kg/day)	Males	Females
1	Control	0	10	0	0	0	10	10
2	Omnirad 184	100	10	10	10.03	100	10	10
3	Omnirad 184	300	10	30	30.09	301	10	10
4	Omnirad 184	900^bc	10^bc	90^bc	90.27	903	10	10

^aDose was based on the most recent body weight measurement.

^b From 19 Aug 2021, F1 Group 4 animals were dosed twice daily (approximately 3 hours apart) at 10 mL/kg and 450 mg/kg (45 mg/mL), equivalent to 900 mg/kg/day.

Text Table 5 Experimental Design – Cohort 1B (Reproductive)

Group No.	Treatment	Dose Level (mg/kg/day)	Dose Volume^a (mL/kg)	Dose Conc. (mg/mL)	Corrected Dose Conc. (mg/mL)	Corrected Dose Levels (mg/kg/day)	Number of Animals
Group No.	Treatment	Dose Level (mg/kg/day)	Dose Volume^a (mL/kg)	Dose Conc. (mg/mL)	Corrected Dose Conc. (mg/mL)	Corrected Dose Levels (mg/kg/day)	Males	Females
1	Control	0	10	0	0	0	20	20
2	Omnirad 184	100	10	10	10.03	100	20	20
3	Omnirad 184	300	10	30	30.09	301	20	20
4	Omnirad 184	900^bc	10^bc	90^bc	90.27	903	20	20

^aDose was based on the most recent body weight measurement.

^b From 19 Aug 2021, F1 Group 4 animals were dosed twice daily (approximately 3 hours apart) at 10 mL/kg and 450 mg/kg (45 mg/mL), equivalent to 900 mg/kg/day.

Text Table 6 Experimental Design – F2 Unselected PND 21 Pups

Group No.^a	Number of Animals^b
Group No.^a	Males	Females
1	10	10
2	10	10
3	10	10
4	10	10

^aUnselected pups were not dosed, group number refers to dam group number.

^bThese pups had TSH and T4 blood sampling and necropsy procedures.

Text Table 7 Experimental Design – Cohort 2A (Neurobehavioural)

Group No.	Treatment	Dose Level (mg/kg/day)	Dose Volume^a (mL/kg)	Dose Conc. (mg/mL)	Corrected Dose Conc. (mg/mL)	Corrected Dose Levels (mg/kg/day)	Number of Animals
Group No.	Treatment	Dose Level (mg/kg/day)	Dose Volume^a (mL/kg)	Dose Conc. (mg/mL)	Corrected Dose Conc. (mg/mL)	Corrected Dose Levels (mg/kg/day)	Males	Females
1	Control	0	10	0	0	0	10	10
2	Omnirad 184	100	10	10	10.03	100	10	10
3	Omnirad 184	300	10	30	30.09	301	10	10
4	Omnirad 184	900^bc	10^bc	90^bc	90.27	903	10	10

^aDose was based on the most recent body weight measurement.

^b From 19 Aug 2021, F1 Group 4 animals were dosed twice daily (approximately 3 hours apart) at 10 mL/kg and 450 mg/kg (45 mg/mL), equivalent to 900 mg/kg/day.

Text Table 8 Experimental Design – Cohort 2B (Neuropathology)^a

Group No.	Number of Animals
Group No.	Males	Females
1	10	10
2	10	10
3	10	10
4	10	10

^aCohort 2B were not dosed as they were terminated on PND 21/22.

None of the unscheduled deaths in any generation were considered to be test item-related.

There were no test item-related effects on F0 and F1 generation fertility, mating or reproduction, or F1 and F2 generation pup numbers, survival or development.

There were no test item-related organ weight differences in a limited list of tissues in F1 and F2 pups that were euthanised at PND 21 without active dosing.

There were no test item-related gross findings in the entire study, and there were only 6 premature deaths, all of which were considered not test item-related.

There were no histological findings in the reproductive tissues of the females that had not been observed to litter that would have caused reduced fertility.

In conclusion, administration of Omnirad 184 by once daily (or twice daily 3 hours apart on some occasions) oral gavage was well tolerated in Han Wistar rats at dose levels of up to 900 mg/kg/day with no test item-related deaths. There were occasional observations of decreased activity, abnormal, uncoordinated gait and low carriage for F0 animals at 900 mg/kg/day and for F0 and F1 animals, dose level-related salivation and/or ploughing. F0 and F1 males at 900 mg/kg/day had slightly lower body weight gain, and F0 and F1 females a slightly higher dose level-related body weight gain at ≥ 100 mg/kg/day. Food consumption was generally slightly higher for males and females at ≥ 100 mg/kg/day. There were no test item-related effects on F0 and F1 generation fertility, mating or reproduction, or F1 and F2 generation pup numbers, survival or development. For males at 900 mg/kg/day, motor activity was 9.6% or 12.7% lower overall for basic or fine movements, respectively, but this was not confirmed by overall ambulation values, or any associated clinical findings, detailed functional observations or brain morphometry values for Cohort 2A. Triglyceride values were lower for F0 males given ≥300 mg/kg/day, F0 females and F1 animals given ≥100 mg/kg/day, and cholesterol values higher for F0 males only at ≥300 mg/kg/day and F1 animals at 900 mg/kg/day. There were slightly higher TSH levels (up to 3.1-fold of controls) on the morning of necropsy in F0 and F1 adult males given 300 or 900 mg/kg/day. There were no test item-related effects on haematology, coagulation, urinalysis, T4 values or the immune cell populations analysed for immunophenotyping, at up to 900 mg/kg/day. Target organ effects were observed at dose levels of ≥100 mg/kg/day and consisted of centrilobular hypertrophy in the liver and stomach mucosal hyperplasia of the glandular region. Higher liver and/or kidney weights were seen in both sexes. In neurological investigations, there were no test item-related brain weight differences, gross or histological findings or effects on the brain dimensions. There were no histological findings in the reproductive tissues of the females that had not been observed to litter that would have caused reduced fertility. The NOAEL (No Observed Adverse Effect Level) for F0 and F1 adult toxicity, male and female fertility and reproduction was considered to be 900 mg/kg/day as the in-life and pathological findings were considered not to be adverse. For F1 and F2 developmental parameters, the NOAEL was considered to be 900 mg/kg/day as there were no test item-related effects on the pup numbers, survival or development.

Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.

Registration Dossier

Registration Dossier

Data platform availability banner - registered substances factsheets

Diss Factsheets

2-hydroxy-2-methylpropiophenone

Developmental toxicity / teratogenicity

Administrative data

Cross-reference

Reference

Table 1 - Summary of Body Weights (g)

F0 Males

Table 2 - Summary of Body Weights (g)

F0 Females - Prior to mating

Table 3 - Summary of Body Weights (g)

F0 Females - Gestation

Table 4 - Summary of Body Weights (g)

F0 Females - Lactation

Table 5 - Summary of Body Weights (g)

F1 Animals - Cohort 1A

Table 7 - Summary of Body Weights (g)

F1 Animals - Cohort 1B Males

Table 8 - Summary of Body Weights (g)

F1 Animals - Cohort 1B Females - Prior to Mating

Table 9 - Summary of Body Weights (g)

F1 Animals - Cohort 1B - Gestation

Table 10 - Summary of Body Weights (g)

F1 Animals - Cohort 1B Females - Lactation

Table 11 - Summary of Body Weights (g)

F1 Animals - Cohort 2A

Tables 12. Summary of Clinical Chemistry Values

F0 Animals - Males. Day: 137 Relative to Start Date

Tables 13. Summary of Clinical Chemistry Values

F0 Animals - Females. Day: 115 Relative to Start Date

Tables 14. Summary of Clinical Chemistry Values

F1 Animals - Cohort 1A. Day 70 Relative to Start Date

Table 15. Summary of Coagulation Values

F0 Animals – Males, Day: 137 Relative to Start Date

Table 16. Summary of Coagulation Values

F0 Animals – Females, Day: 115 Relative to Start Date

Table 17. Summary of Coagulation Values

F1 Animals - Cohort 1A, Day: 70 Relative to Start Date

Table 18. Summary of Hematology Values

F0 Animals – Males Day: 137 Relative to Start Date

Table 19. Summary of Hematology Values

F0 Animals – Females Day: 115 Relative to Start Date

Table 20. Summary of Hematology Values

F1 Animals – Cohort 1A. Day 70 Relative to Start Date

Table 21. Summary of Reproductive Performance

F0 Females

Table 22. Summary of Reproductive Performance

F1 Animals - Cohort 1B Females

Table 23. Mating Performance and Fertility

F0 Animals

Table 24. Mating Performance and Fertility

F1 Animals

Table 25. Summary of Duration of Gestation and Overall Litter Performance

F0 Animals

Table 26. Summary of Duration of Gestation and Overall Litter Performance

F1 Animals

Table 27. Summary of Urinalysis Values

Table 28. Summary of Urinalysis Values

Table 29. Summary of Urinalysis Values

Data source

Reference

Materials and methods

Test guidelineopen allclose all

Test guideline 1

Test guideline 2

Test material

Test material information

Constituent 1

Test animals

Administration / exposure

Doses / concentrationsopen allclose all

Doses / concentrations 1

Doses / concentrations 2

Doses / concentrations 3

Doses / concentrations 4

Examinations

Results and discussion

Test guidelineopen all close all

Doses / concentrationsopen all close all