Triisononyl benzene-1,2,4-tricarboxylate

Developmental toxicity / teratogenicity

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

Reference

Reference 1

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 2

Reference Type:

publication

Title:

Unnamed

Year:

2010

Report date:

2010

Reference 3

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

Test material information

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 / concentrations

Doses / concentrations 1

Dose / conc.:

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

Doses / concentrations 2

Dose / conc.:

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

Doses / concentrations 3

Dose / conc.:

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

Doses / concentrations 4

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)

1

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

2

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

3

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