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Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2000-2001
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP compliant study conducted according to internationally recognised test methods

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
A study to support regulatory submission assessing effects of tri(2-ethylhexyl)trimellitate (TEHTM) upon pre and post-natal development in the rat, with a comparative group receiving di(2-ethylhexyl)phthalate (DEHP) included
Author:
Renaut SD and Whiteley M
Year:
2017
Bibliographic source:
Reproductive Toxicology 74: 59-69, 2017
Reference Type:
publication
Title:
Unnamed
Year:
2010
Report date:
2010
Reference Type:
secondary source
Title:
TEHTM Study for effects on embryo-fetal and pre- and post-natal development in CD rat by oral gavage administration
Author:
Anon.
Year:
2002
Bibliographic source:
EPA TSCATS low detail report

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
no
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Reference substance name:
Tri-(2-ethylhexyl)trimellitate (TEHTM)
IUPAC Name:
Tri-(2-ethylhexyl)trimellitate (TEHTM)
Details on test material:
- Name of test material (as cited in study report): Tri-(2-ethylhexyl)trimellitate (TEHTM)
- Analytical purity: 98.93%

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River (UK) Ltd.
- Age at study initiation: 10 - 11 weeks
- Weight at study initiation: 218 - 266 g
- Fasting period before study: No
- Housing: Individually caged
- Diet (e.g. ad libitum): Pelleted rodent diet, ad libitum
- Water (e.g. ad libitum): Municipal supply, ad libitum
- Acclimation period: Approximately 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 - 23 deg C
- Humidity (%): 40 - 70%
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12 / 12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:

VEHICLE
- Justification for use and choice of vehicle (if other than water): Corn oil
- Concentration in vehicle: 0, 20, 100 and 210 mg/mL
- Amount of vehicle (if gavage): 5 mL/kg bw
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
Homogeneity - Stable for 2 days at 21 deg C and 14 days at 4 deg C
Concentration - Formulations prepared during the first and last weeks of dosing checked with mean achieved concentration ranging from 94.2% to 100.0% of nominal.
Details on mating procedure:
- Impregnation procedure: cohoused
- M/F ratio per cage: 1 / 1
- Verification of same strain and source of both sexes: Yes
- Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as day 0 of pregnancy
- Any other deviations from standard protocol: No
Duration of treatment / exposure:
Gestation days 6-19 (prenatal development)
Gestation day 6 - post-partum day 20 (post-natal development)
Frequency of treatment:
Daily from gestation day 6, except day of parturition for animals allowed to litter
Duration of test:
Approximately 40 days (to lactation day 20)
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (actual dose received)
Dose / conc.:
100 mg/kg bw/day (actual dose received)
Dose / conc.:
500 mg/kg bw/day (actual dose received)
Dose / conc.:
1 050 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
35 females/group - 20 for pre-natal development; 15 for post-natal development
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Random

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes
- Time schedule for examinations: Gestation days 0, 3, 6, 10, 14, 17 and 20, then daily until parturition, and on lactations days 1, 4, 7, 11, 14, 18 and 21.

FOOD CONSUMPTION: Yes
- Time schedule for examinations: Gestation days 6-9, 10-13, 14-17, 18-19; lactations days 1-3, 4-6, 7-10, 11-13

WATER CONSUMPTION: No data

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20 - Organs examined: Evaluation of uterine content. Liver weighed
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes / No / No data
Examinations included:
- Gravid uterus weight: No data
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: No data
Statistics:
ANOVA followed by William’s test, or Kruskal-WaIlis/Hollander & Wolfe followed by Shirley’s test, Steel’s test, Cochran-Armitage, Fisher’s exact test.
Indices:
Implantations
Resorptions
Total implantation loss
Litter size
Litter weight
Sex ratio
Historical control data:
No data

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not examined
Other effects:
no effects observed

Maternal developmental toxicity

Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in pregnancy duration:
no effects observed
Changes in number of pregnant:
no effects observed
Other effects:
no effects observed
Details on maternal toxic effects:
No mortalities or significant clinical signs occurred and treatment had no obvious effect on body weight gain during gestation or lactation. Food consumption during gestation and lactation was unaffected by treatment. Necropsy of dams sacrificed on gestation day 20 revealed no macroscopic changes associated with treatment and all females were pregnant with a live litter. Numbers of corpora lutea, implantations, pre-implantation loss, embryo-foetal survival (as assessed by post-implantation loss) and litter size were unaffected by treatment. Gestation length, litter size and offspring survival were unaffected by treatment. A slightly low group mean survival of offspring (viability index) from lactation day 1 through to weaning amongst females treated at 1050 mg/kg bw/day was the result of one litter which was killed on post-natal day 2 because the pups were cold, unfed and underactive.

Effect levels (maternal animals)

Key result
Dose descriptor:
NOAEL
Effect level:
1 050 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity

Maternal abnormalities

Abnormalities:
no effects observed

Results (fetuses)

Fetal body weight changes:
no effects observed
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
no effects observed
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed
Other effects:
no effects observed
Details on embryotoxic / teratogenic effects:
Detailed foetal examinations revealed no clear treatment related effects. Sex ratio (% males) was unaffected by treatment and offspring bodyweight was not significantly affected. Values of ano-genital distance were consistent across all treatment groups, including concurrent controls.

Post-natal development
The general condition of maturing pups (F1) animals was unaffected by maternal treatment and body weight gain was unaffected. Offspring auditory and visual function (as assessed by startle response to a sudden noise and pupil closure response of dark-adapted eyes on post-natal day 20) were unaffected by treatment. A number of males from the group treated at a level of 1050 mg/kg bw/day showed a few retained areolar regions but the incidence was very low (10 males from 6 litters with areolar regions visible). No dark areolar regions were noted when affected pups were re-examined at post-natal day 18.
Sexual maturation (vaginal opening) of F1 females revealed no clear adverse effects of maternal treatment. The mean age at completion for animals in the 500 and 1050 mg/kg bw/day treatment groups was marginally later (0.6 and 0.3 days, respectively) than the vehicle control. Sexual maturation of males, as assessed by the start and completion of balano-preputial separation showed no obvious adverse effects of maternal treatment. In the 1050 mg/kg bw/day treatment group, mean age at completion was 0.8 days younger than the vehicle controls and bodyweight was slightly lower. As the mean delay was less than 1 day, and with observations performed once per day, this finding was considered unlikely to reflect a treatment related effect and timing of completion of balano-preputial separation was similar to historical control values.
Necropsy examination of F1 females at approximately 6 weeks of age revealed no findings considered to be related to maternal treatment. Necropsy of F1 males at approximately 15 weeks of age also revealed no findings which were considered to be related to maternal treatment. There was no indication of any reduction in the weights of reproductive organs. Histopathological examination of the left testis from males of all groups and the right testes from the control and the highest (1050mg/kg bw/day) treatment group of the F1 generation revealed no abnormalities.

Effect levels (fetuses)

open allclose all
Key result
Dose descriptor:
NOAEL
Effect level:
1 050 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Lack of significant effects on foetus
Remarks on result:
other: Pre-natal developmental toxicity
Dose descriptor:
NOEL
Effect level:
500 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: retained areolar region PND 13, no longer present PND 18
Remarks on result:
other: Post-natal developmental toxicity
Dose descriptor:
LOAEL
Effect level:
1 050 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: retained areolar region PND 13, no longer present PND 18
Remarks on result:
other: Post-natal developmental toxicity

Fetal abnormalities

Key result
Abnormalities:
no effects observed

Overall developmental toxicity

Key result
Developmental effects observed:
no
Lowest effective dose / conc.:
1 050 mg/kg bw/day (actual dose received)

Any other information on results incl. tables

Post-natal development examinations did not reveal any significant differences relative to controls for survival of offspring, sex ratio, bodyweight or bodyweight gain, auditory startle and pupil closure

responses, age at vaginal opening or preputial separation.

At necropsy, there were no effects attributable to treatment in either females (6 weeks of age) or males (15 weeks of age). Assessment included morphology of the male and female reproductive tract organs, weight of the male reproductive organs or microscopic pathology of the testis.

There was a slight but statistically significant (P<0.05) increase in the number of male animals with retained areolar regions on evaluation at post-natal Day 13 at 1050 mg/kg/day. Affected animals had

only one or two more sites than those in the control group. The areolae present at post-natal Day 13 were no longer present on re-examination on post-natal Day 18. In the absence of any other supporting data, this finding was regarded as being of questionable toxicological significance.

There was a higher incidence of displaced testes in foetuses from the group treated at 1050 mg/kg/day when compared with controls. However, the incidence was within the range of recent historical control data of the test facility for this endpoint. No displaced testes were noted in any of the foetuses undergoing less rigorous examination prior to preparation for skeletal examination. There was no difference in the incidence of non-scrotal testes between males of treatment and control groups at 15 weeks of age.

The incidence of renal cavitation was higher controls in foetuses that were macroscopically assessed prior to skeletal examination. Again, this finding was within the range of recent historical control values,

and was not found during examination of foetuses by the more rigorous serial sectioning technique.

The incidence of effects in the testes and kidneys appear to be related to the low incidence of these findings in the concurrent control group compared to the range of historical control values. The observed

incidences of these findings in treated groups were within the range of historical controls from recent studies at the test facility and they were not supported by complimentary observations made in foetuses

or offspring. They were therefore considered not to be related to treatment.

Body weight gain (g) of dams during gestation and lactation - Group mean data

 

 

 

Treatment

 

 

Control

100 mg/kg

500 mg/kg

1050 mg/kg

Bodyweight on GD 0

Mean

246

246

246

247

 

SD

10

9

9

9

 

n

34

35

35

34

Bodyweight gain GD 6–20

Mean

138

134

136

142

 

SD

19

17

16

24

 

n

34

35

35

34

Bodyweight gain adjusted for gravid

Mean

50.8

47.6

43.6

50.0

uterus weight (g) GD 6–20

SD

13.4

12.3

10.1

17.5

 

n

18

20

20

20

Bodyweight on lactation day 1

Mean

335

320

322

319

 

SD

26

26

24

17

 

n

14

15

15

13

Bodyweight gain lactation day 1–21

Mean

27

34

38

38

 

SD

17

14

18

13

 

n

14

15

15

13

 

 

Food consumption (g/animal/day) of dams during gestation and lactation - Group mean data

 

 

 

 Treatment 

 

 

Control

100 mg/kg

500 mg/kg

1050 mg/kg

Gestation days 6–9

Mean

29

27

28

29

 

SD

3

3

4

3

 

n

34

35

35

34

Gestation days 10–13

Mean

31

29

29

30

 

SD

3

3

5

3

 

n

34

35

35

34

Gestation days 14–17

Mean

32

31

31

32

 

SD

3

3

4

4

 

n

34

35

35

34

Gestation days 18–19

Mean

29

29

28

30

 

SD

3

3

3

4

 

n

34

35

35

34

Lactation days 1–3

Mean

38

37

36

37

 

SD

3

6

4

7

 

n

14

15

15

13

Lactation days 4–6

Mean

58

56

56

58

 

SD

6

8

4

6

 

n

14

15

15

13

Lactation days 7–10

Mean

74

72

72

73

 

SD

6

9

5

6

 

n

14

15

15

13

Lactation days 11–13

Mean

83

79

80

82

 

SD

7

10

5

7

 

n

14

15

15

13

 

 

Pre-natal developmental toxicity - Litter data, foetal and litter weight on GD 20 - Group mean data

 

 

 

Treatment 

 

 

Control

100 mg/kg

500 mg/kg

1050 mg/kg

Implantations

Mean

15.4

15.6

16.1

16.4

 

SD

2.0

1.9

1.7

2.1

 

n

20

20

20

20

Total resorptions

Mean

0.8

0.8

0.3

0.5

 

n

20

20

20

20

Sex ratio

Mean

54.8

55.2

52.3

50.9

 

n

20

20

20

20

Post-implantation loss (%)

Mean

5.2

5.2

1.8

2.9

 

n

20

20

20

20

Litter size (total live young)

Mean

14.7

14.8

15.8

15.9

 

SD

2.3

2.2

1.7

1.9

 

n

20

20

20

20

Overall fetal weight (g)

Mean

3.83

3.89

3.88

3.80

 

SD

0.24

0.15

0.20

0.15

 

n

20

20

20

20

Litter weight (g)

Mean

56.01

57.54

61.18

60.39

 

SD

9.21

8.27

6.90

7.37

 

n

20

20

20

20

Anogenital distance (mm) for males

Mean

4.24

4.30

4.33

4.28

 

SD

0.17

0.15

0.20

0.17

 

n

20

20

20

20

AGD/cube root of male foetal weight

Mean

2.69

2.71

2.73

2.72

 

SD

0.10

0.08

0.11

0.10

 

n

20

20

20

20

 

 

Pre-natal developmental toxicity - Foetal visceral examination - Group incidence

 

 

Foetuses 

 

Litters

Treatment:

Control

100 mg/kg

500 mg/kg

1050 mg/kg

 

Control

100 mg/kg

500 mg/kg

1050 mg/kg

Total Number examined

146

151

160

159

 

20

20

20

20

Total Number affected

22

28

25

28

 

15

15

13

14

Ventricular septal defect, small

1

1

-

-

 

1

1

-

-

Kidney(s) rudimentary/absent papilla

1

2

1

-

 

1

1

1

-

Testis(es) displaced

4

3

3

9

 

3

3

3

6

 

 

Pre-natal developmental toxicity - Foetal skeletal examination - Group incidence

 

 

Foetuses 

 

Litters 

Treatment:

Control

100 mg/kg

500 mg/kg

1050 mg/kg

 

Control

100 mg/kg

500 mg/kg

1050 mg/kg

Total Number examined

147

145

156

159

 

20

20

20

20

thoracic (1 or 2 elements)

1

2

1

-

 

1

2

1

-

Incomplete ossification, sternebrae 5th and/or 6th

66

77

62

81

 

18

18

15

20

Incomplete ossification, other

3

1

1

4

 

3

1

1

3

Number with 13/14 or 14/14 ribs

19

31

22

18

 

9

11

10

13

Complete 14th rib

1

-

-

-

 

1

-

-

-

Cervical rib

1

-

-

1

 

1

-

-

1

 

 

Prenatal developmental toxicity - Gestation length, litter data, survival indices and sex ratio – Incidence and group mean data

 

 

 

Treatment 

 

 

Control

100 mg/kg

500 mg/kg

1050 mg/kg

Number (%) of females with a

21.5 days

0

0

3 (20)

1 (7)

gestation length of:

22 days

7 (50)

6 (40)

8 (53)

6 (43)

 

22.5 days

7 (50)

8 (53)

4 (27)

6 (43)

 

23 days

0

1 (7)

0

1 (7)

 

23.5 days

0

0

0

0

No.post-partumimplantation sites

Mean

15.6

15.4

15.7

16.0

 

SD

1.9

2.0

1.6

1.7

 

n

14

15

15

14

Total litter size

Mean

14.6 (14)

14.5 (15)

14.9 (15)

15.1 (14)

 

SD

2.1

2.0

1.5

1.6

 

n

14

15

15

14

Live litter size at weaning on Day 21 of age

Mean

14.3 (14)

14.3 (15)

14.7 (15)

14.7 (13)

 

SD

2.1

2.0

1.4

1.5

 

n

14

15

15

13

Sex ratio (%M) on Day 1 of age

Mean

47.1

49.1

52.2

49.0

 

SD

11.7

15.7

7.4

14.6

 

n

14

15

15

14

Post-implantation survival (%)

 

93.2

93.9

95.0

94.8

 

n

14

15

15

14

Live birth index (%)

 

99.1

100.0

99.6

98.5

 

n

14

15

15

14

Viability index (%) Day 21

 

99.0

99.1

99.2

90.7

 

n

14

15

15

14

 

 

Postnatal developmental toxicity - Body weight (g) - Group mean data

 

 

Treatment 

 

 

Control

100 mg/kg

500 mg/kg

1050 mg/kg

Males:

 

 

 

 

 

Offspring body weight (g) on PND 1

Mean

6.9

6.8

6.5

6.7

 

SD

0.6

0.4

0.6

0.7

 

n

14

15

15

14

Offspring body weight (g) on PND 21

Mean

47.1

44.7

42.2

44.3

 

SD

6.0

4.3

4.5

5.9

 

n

14

15

15

13

Offspring body weight gain (g) PND 1-21

Mean

40.2

37.8

35.7

37.5

 

SD

5.7

4.1

4.2

5.6

 

n

14

15

15

13

Females:

 

 

 

 

 

Offspring body weight (g) on PND 1

Mean

6.4

6.5

6.3

6.3

 

SD

0.7

0.4

0.6

0.7

 

n

14

15

15

14

Offspring body weight (g) on PND 21

Mean

44.5

43.1

40.7

42.6

 

SD

6.2

3.9

4.1

5.9

 

n

14

15

15

13

Offspring body weight gain (g) PND 1-21

Mean

38.1

36.6

34.5

36.2

 

SD

5.8

3.7

3.9

5.6

 

n

14

15

15

13

 

 

Postnatal developmental toxicity - incidences of auditory and visual function of pups - Group mean data

 

Treatment 

 

Control

100 mg/kg

500 mg/kg

1050 mg/kg

Number of offspring (litters):

 

 

 

 

Number examined

200 (14)

215 (15)

221 (15)

191 (13)

Normal auditory startle reflex

200 (14)

215 (15)

221 (15)

191 (13)

Normal pupil closure responsea

199 (14)

212 (15)

220 (15)

190 (13)

Pupils failed to dilate

1 (1)

-

-

-

Opacity in right eye; unable to assess pupil response

-

3 (1)

-

-

Eyes closed in response to light; unable to assess

-

-

-

1 (1)

 

 

Post-natal developmental toxicity - Nipple regression for male offspring at PND 13/14 - Group data

 

 

 Treatment 

 

Control

100 mg/kg

500 mg/kg

1050 mg/kg

Total number of offspring

96

104

114

92

 

No. areolar regions visible PND 13/14

 

% pups with areolar regions visible

0

97.9

97.1

98.2

89.1

1

1.0

1.0

0.9

5.4

2

0.0

0.0

0.0

4.3

3

0.0

0.0

0.0

0.0

4

1.0

1.9

0.9

1.1

5

0.0

0.0

0.0

0.0

6

0.0

0.0

0.0

0.0

7 or more

0.0

0.0

0.0

0.0

No. of male offspring with areolar regions visible

2

3

2

10

No. litters affected

2

2

2

6 *

 

 

Post-natal developmental toxicity - Post-weaning body weight (g) - Group mean data

 

 

Treatment 

 

 

Control

100 mg/kg

500 mg/kg

1050 mg/kg

Males:

 

 

 

 

 

Body weight on Day 1 of the F1 generation @

Mean

93

89

85**

86**

 

SD

17

16

15

13

 

n

96

104

114

91

Bodyweight gain during Weeks:

 

 

 

 

 

1 - 3

Mean

121

120

120

118

 

SD

11

14

11

12

 

n

96

104

114

91

1 - 4

Mean

186

184

182

181

 

SD

16

18

15

16

 

n

96

104

114

91

1 - 12

Mean

451

451

450

443

 

SD

55

48

41

42

 

n

96

104

114

91

Females:

 

 

 

 

 

Body weight on Day 1 of the F1 generation @

Mean

82

80

78

80

 

SD

16

12

12

12

 

n

104

111

107

100

Body weight gain during Weeks:

 

 

 

 

 

1 - 3

Mean

79

83*

8

82*

 

SD

9

10

8

6

 

n

104

111

107

100

 

@ = Day 1 corresponds to approximately 4 weeks of age (post-natal day 25-30)

 

 

Post-natal developmental toxicity - Sexual maturation - Group mean data

 

 

 

 Treatment 

 

 

Control

100 mg/kg

500 mg/kg

1050 mg/kg

Females - Vaginal opening:

 

 

 

 

 

Age at completion (days)

Mean

33.8

33.7

34.4*

34.1*

 

SD

1.9

1.8

1.8

1.9

 

n

104

111

107

100

Body weight at completion (g)

Mean

108.4

109.3

108.9

109.1

 

SD

12.3

10.3

12.3

13.4

 

n

104

111

107

100

Males - Balano preputial separation:

 

 

 

 

 

Age at start (days)

Mean

36.5

37.3

37.4**

36.8

 

SD

1.0

1.1

1.7

1.2

 

n

96

104

114

91

Body weight at start (g)

Mean

153.4

157.0

152.6

148.4 *

 

SD

15.2

16.4

15.1

16.1

 

n

96

104

114

91

Age at completion (days)

Mean

45.0

45.1

44.8

44.2 *

 

SD

2.4

1.8

2.1

2.4

 

n

96

104

114

91

Body weight at completion (g)

Mean

231.3

226.5

218.6**

215.0**

 

SD

27.6

22.6

18.6

20.5

 

n

95

104

114

91

 

 

Post-natal developmental toxicity - Macroscopic findings - Group incidence

 

 

 

Treatment 

 

 

Control

100 mg/kg

500 mg/kg

1050 mg/kg

Males:

 

 

 

 

 

Number of animals examined

 

96

104

114

91

Testis left:

inguinal

1

0

0

0

 

abdominal

1

0

0

0

 

small

1

2

4

1

 

blue

0

2

1

1

 

flaccid

0

2

1

1

Testis right:

inguinal

2

0

0

1

 

abdominal

0

1

0

0

 

small

1

1

5

0

 

blue

0

1

2

0

 

flaccid

0

1

1

0

Epididymis left:

small

1

2

4

1

Epididymis right:

small

1

1

5

0

Prostate:

small

1

2

0

1

Females:

 

 

 

 

 

Number of animals examined

 

104

111

107

100

Uterus and cervix:

 

-

-

-

-

Vagina:

 

-

-

-

-

 

 

Post-natal developmental toxicity - Organ weight (g) of males - Group mean data

 

 

 

 Treatment 

 

 

Control

100 mg/kg

500 mg/kg

1050 mg/kg

Terminal bodyweight (g)

Mean

547.7

543.0

538.0

532.4*

 

SD

59.2

52.6

46.0

48.7

 

n

96

104

114

91

Absolute organ weights:

Testes

Mean

3.51

3.48

3.36 b

3.48

 

SD

0.38

0.32

0.30

0.31

 

n

96

104

114

91

Epididymides

Mean

1.126

1.146

1.113

1.167**

 

SD

0.101

0.110

0.101

0.080

 

n

96

104

114

91

Prostate

Mean

0.647

0.610

0.619

0.612

 

SD

0.296

0.155

0.151

0.131

 

n

96

104

114

91

Seminal vesicles

Mean

2.205

2.355**

2.300**

2.376 **

 

SD

0.267

0.298

0.282

0.292

 

n

96

104

114

91

Relative (to body weight) organ weights (%):

Testes

Mean

0.648

0.645

0.628

0.658

 

SD

0.092

0.071

0.069

0.069

 

n

96

104

114

91

Epididymides

Mean

0.2075

0.2129

0.2078

0.2206

 

SD

0.0247

0.0282

0.0204

0.0204

 

n

96

104

114

91

Prostate

Mean

0.1185

0.1132

0.1152

0.1158

 

SD

0.0499

0.0299

0.0273

0.0264

 

n

96

104

114

91

Seminal vesicles

Mean

0.4054

0.4365**

0.4297**

0.4496**

 

SD

0.0529

0.0609

0.0571

0.0661

 

n

96

104

114

91

 

 

Post-natal developmental toxicity - Microscopic pathology in the testis of males - Group incidence

 

 

Treatment

 

Treatment 

 

Control

100 mg/kg

500 mg/kg

1050 mg/kg

 

Control

100 mg/kg

500 mg/kg

1050 mg/kg

 

 Left testis: 

 

Right testis: 

Number of animals examined

96

104

114

91

 

96

 

 

91

Degeneration of tubular germinal epithelium

2

4

3

4

 

3

 

 

3

Rete tubular dilatation

24

25

33

16

 

22

 

 

16

Multinucleate giant cells

1

4

5

1

 

0

 

 

0

Interstitial cell hyperplasia

0

0

1

2

 

1

 

 

0

Interstitial oedema

1

2

0

0

 

0

 

 

0

Seminiferous tubular dilatation

0

1

0

0

 

0

 

 

3

Seminiferous tubular mineralisation

0

0

1

0

 

0

 

 

0

Aplasia

0

0

0

1

 

0

 

 

0

Capsular thickening

0

0

0

1

 

0

 

 

0

Perivascular lymphocyte infiltration

0

1

0

0

 

0

 

 

0

Seminiferous tubular vacuolation

0

0

2

0

 

0

 

 

2

Ectopic seminiferous tubules within tunica albuginea

1

0

0

0

 

0

 

 

0

Interstitial inflammatory infiltrate

0

0

0

0

 

0

 

 

0

 

 

Key to tables

GD = Gestation day

LD = Lactation day

PND = Post-natal day

* = p < 0.05: Significantly different from controls

** = p < 0.01: Significantly different from controls

 

Applicant's summary and conclusion

Conclusions:
A developmental toxicity study in the rat, extended to permit an assessment of post-natal development, found no treatment-related effects indicative of maternal toxicity. No effects on offspring body weights or litter viability were observed. No developmental (teratogenic) effects were observed and there were no effects upon sexual maturation or development of the reproductive tract in male or female offspring that were attributed to treatment.

NOEL maternal toxicity: 1050 mg/kg/day
NOEL pre-natal developmental toxicity: 1050 mg/kg/day
NOEL post-natal evaluation of offspring: 500 mg/kg/day; LOAEL: 1050 mg/kg/day
Executive summary:

A developmental toxicity study in the rat, extended to permit an assessment of post-natal development, found no treatment-related effects indicative of maternal toxicity. No effects on offspring body weights or litter viability were observed. No developmental (teratogenic) effects were observed and there were no effects upon sexual maturation or development of the reproductive tract in male or female offspring that were attributed to treatment.

NOEL maternal toxicity: 1050 mg/kg/day

NOEL pre-natal developmental toxicity: 1050 mg/kg/day

NOEL post-natal evaluation of offspring: 500 mg/kg/day; LOAEL: 1050 mg/kg/day