Nonane-1,9-diol

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

Effects on fertility with read-across substance 1,6-hexandiol

A screening for reproductive / developmental toxicity study was conducted with 1,6-hexanediol (read-across to nonanediol, CAS 3937 -56 -2) in the Wistar rat. Animals (10/sex/group) were dosed orally via gavage at either 0, 100, 400 or 1000 mg/kg bw/d formulated in distilled water (dose volume 10 mL/kg bw). After at least 14 d of treatment, males and females from the same dose group were mated at a ratio of 1:1. After this mating period, the male animals were sacrificed. The females were allowed to litter and rear their pups until day 4 after parturition (p.p). Thereafter, the pups and the F0 generation female parental animals were sacrificed.

1,6-hexanediol had no adverse effects on fertility, on the parturition process or on peri- and postnatal survival of the offspring (up to day 4 p.p).

Clinical signs of toxicity and mortality were unaffected by treatment in F0 parental animals. Reductions in body weight (week 4) and food consumption (weeks 0 – 1 and 3 – 4) were seen in high dose F0 males. Body weight and food consumption values for F0 females were unaffected by treatment.

 

There were no treatment-related effects on reproductive performance (including mating, fertility, gestation index). The mean number of implantation sites, the post-implantation loss values and the mean number of delivered pups/dam were similar for the test article treated groups and the concurrent control group. The observable differences have no biological relevance and/or are not dose-related. The mean number of delivered pups/dam was lowest in the control group. Only spontaneous findings were seen at necropsy (e.g. dilated renal pelvis and acaudia) in very few of the pups examined. These findings occurred exclusively in the low and mid dose groups and therefore were not dose related.

No test article related effects on pup viability/mortality were recorded during the lactation period. The viability index, as an indicator for the viability of the pups during the first 4 days after birth, was similar in all groups as was the mean number of live pups/litter on days 0 and 4 p .p. The observable differences have no biological relevance and/or are not dose-related. Mean body weights/body weight gains were not influenced by the test article administration.

 

Based on the results of this study the NOAELs for parental toxicity, reproductive outcome and offspring toxicity of 1,6-hexanediol when administered orally via gavage during pre-mating, gestation and lactation are as follows:

 

NOAEL for parental toxicity: Males: 400 mg/kg bw/d based on reductions in body weight / body weight gain and food consumption. Females: 1000 mg/kg bw/day, the highest dose tested, based on no adverse effects

NOAEL for reproductive outcome:1000 mg/kg bw/day, the highest dose tested, based on no adverse effects.

NOAEL for offspring toxicity: 1000 mg/kg bw/day, the highest dose tested, based on no adverse effects.

 

The read-across justification is attached in section 13.

 

Extended one generation study in the rat

An oral extended one-generation study in the rat according to OECD 443 guidelines using the test substance nonanediol (CAS 3937-56-2) has been waived based on the lack of adverse effects observed in reproductive organs and tissues.

Link to relevant study records

Reference

Reference 1

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1994-10-17 to 1994-12-20

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)

Version / remarks:

1994

Deviations:

no

Principles of method if other than guideline:

Deficiencies:
The updated OECD 421 (2016) guidance requires evaluation of oestrus cyclicity and sperm parameters were not measured. Developmental observations of pups, in particular nipple retention was not undertaken. Thyroid hormone levels in parental male animals not assessed, and where necessary for parental females and pups. However, the following conclusions can be drawn from existing data to
- reproductive indices in this study from F0 treated animals were comparable to the control group.
- although circulating levels of T4 and TSH were not investigated, thyroid hormone levels have been monitored in the 90 day repeat dose oral toxicity study.
- Up to day 4 p.p, no developmental delays were observed in test article treated animals compared to the control.

Overall it is therefore reasonable to conclude that there is no evidence to suggest that 1,6-hexandiol has any in the developing fetus.

GLP compliance:

yes

Limit test:

no

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Chemical name: 1,6-hexanediol
- CAS no.: 629-11-8
- EC-no.: 211-074-0
- Source and lot/batch No.of test material: BASF / Tank 19
- Molecular weight: 118.175 g/mol
- Purity: 97.0%

Species:

rat

Strain:

Wistar

Details on species / strain selection:

refer to details on test animals and environmental conditions

Sex:

male/female

Details on test animals or test system and environmental conditions:

Age: F0: 10-11 weeks
Weight at dosing: F0: M: 369-414; F: 224-248g
Source: Dr. K. THOMAE GmbH, Biberach an der Riss, Germany
Acclimation period: 5 days
Diet: Kliba maintenance diet rat/mouse/hamster GLP 343 meal, ad libitum
Water: Municipal tap water, ad libitum
Housing: individually (except during mating when females and males were housed 1:1)

Environmental conditions
Temperature: 20-24°C
Humidity: 30-70%
Air changes: Not stated
Photoperiod: 12 hours light/dark

Route of administration:

oral: gavage

Vehicle:

water

Details on exposure:

Four groups of 10 male and 10 female SD rats forming the F0 generation received the test article by oral gavage at dose levels of 0, 100, 400 or 1000 mg/kg bw/d, employing a dose volume of 10 mL/kg bw once daily. After at least 14 d of treatment, males and females from the same dose group were mated at a ratio of 1:1 (refer to Details on mating procedure for more details).

After this mating period, the male animals were sacrificed. The females were allowed to litter and rear their pups until day 4 after parturition (p.p). Thereafter, the pups and the F0 generation female parental animals were sacrificed.

Details on mating procedure:

Each of the male and female animals were mated overnight at a ratio of 1:1 for a maximum of 2 wks. Matings occurred by placing the female in the cage of the male mating partner from ~4pm through until 7-9am the following morning.

A vaginal smear was prepared after each mating and examined for sperm. If sperm was detected, pairing of the animals was discontinued. The day on which sperm were detected was denoted "day 0" and the following day "day 1" p.c. (post coitum).

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Analytical verifications of the stability of the aqueous test article solutions for a period of at least 4 h at room temperature were carried out in a separate study prior to the beginning of this screening study. Under this separate study, homogeneity asessment was undertaken and confirmed.

Homogenetiy was confirmed twice during the study period for verification of the concentrations .

Dose formulations were prepared daily and dosed within time frame of 4 h (period of which stability was confirmed). As homogeneity was confirmed in a separate study, it was considered sufficient to confirm concurrent homogenity visually.

The concentration control analyses of the aqueous solutions of the test article formulations confirmed yields of 100 % - 103 % of the nominal concentrations.

Duration of treatment / exposure:

Parental males: 28 d
Parental females: 50 days
F1 offspring: day 4 after parturition

Frequency of treatment:

Parental anaimals: single oral gavage administered daily

Details on study schedule:

Refer to details on exposure and details on mating procedure

Dose / conc.:

0 mg/kg bw/day (nominal)

Remarks:

(vehilcle distilled water)

Dose / conc.:

100 mg/kg bw/day (nominal)

Dose / conc.:

400 mg/kg bw/day (nominal)

Dose / conc.:

1 000 mg/kg bw/day (nominal)

No. of animals per sex per dose:

10/sex/group

Control animals:

yes, concurrent vehicle

Details on study design:

Refer to details on exposure and details on mating procedure

Parental animals: Observations and examinations:

Parental animals of both sexes were observed for clinical signs and mortality daily. During weighing, each animal was examined for the presence of abnormalities. The nesting, littering, :and lactation behavior of the dams was evaluated, along with the littering behaviour of the dams.
Body weights: determined weekly. For females the following exceptions applied: i) during the mating period the parental females were weighed on the day of positive evidence of sperm (day 0 p .c .) and on days 7, 14 and 20 p.c; ii) females showing no positive evidence of sperm in vaginal smears were weighed weekly during the mating interval . These body weight data were solely used for the calculations of the dose; iii) females with litter were weighed on the day of parturition (day 0 p .p .) and on days 4 and 7 p.p; iv) females without litter were weighed weekly . These body weight data were solely used for the calculations of the dose volume
Food consumption: determined weekly

Oestrous cyclicity (parental animals):

not measured

Sperm parameters (parental animals):

not measured

Litter observations:

Clinical signs of toxicity: as soon as possible post parturition pups were observed for external abnormalities, thereafter daily.
Sex ratio: soon as possible post parturition and also on day 4 post parturition
Body weight: wieghed on the day after bith (day 1 p.p) and on day 4 p.p

Postmortem examinations (parental animals):

Histopathology:
need Appendix III of the report to confirm this

Organ weights:
need Appendix III of the report to confirm this

Postmortem examinations (offspring):

Necropsy:
All surviving pups (after sacrifice on day 4 p.p.), all stillborn pups and those pups that died before schedule, were examined externally, eviscerated and their organs were assessed macroscopically. All pups without any notable findings or abnormalities were discarded after their macroscopic evaluation.

Histopathology:
need Appendix III of the report to confirm this

Statistics:

Dunnett test: food consumption (parental animals), body weights and body weight change (parental animals and pups), number of mating days, duration of gestation, number of implantations, proportion of post-implantation loss and number of pups delivered/litter . For the body weight and the body weight change of the pups the mean weight of each litter was used for the statistical analysis (statistical unit = litter) .

Fisher's exact test: male and female mating index, male and female fertility index, gestation index, females with liveborn, stillborn and with all stillborn pups, pups liveborn, pups stillborn, pups died, pups cannibalized, pups sacrificed moribund, viability index, number of litters with affected pups at necropsy.

Wilcoxon-test: used for a comparison of each dose group with the control for the hypothesis of equal medians. This test was performed one-sided and was used for the proportion of affected pups/litter with necropsy observations.

Reproductive indices:

Males: The mating partners, the number of mating days until vaginal sperm could be detected in the female animals, and the pregnancy status of the female partner were noted for F0 breeding pairs. For the males, mating and fertility indices were calculated according to the following formulas:
- male mating index (%) = (no. of males with confirmed mating / no. of males placed with females) x 100
- male fertility index (%) = (no. of males providing their fertility / no. of males placed with females) x 100

Females: The mating partners, the number of mating days until vaginal sperm could be detected, and pregnancy status were recorded
For the females, mating ; fertility and gestation indices were calculated according to the following formulas:
- female mating index (%) = (no. of females mated / no. of females placed with males) x 100
- female fertility index (%) = (no. of females pregnant / no. of females mated) x 100
- gestation index (%) = (no. of females with live pups on the day of birth / no .of females pregnant) x 100

After sacrifice of the female animals, the implantation sites were counted and the post-implantation loss was calculated for each individual pregnant animal according to the following formula:
- post-implantation loss (%) = ((no. of implantations - no. of pups delivered) / no. of implantations)) x 100

Offspring viability indices:

Pup viability:
Viability index (%) = (no. of live pups on day 4 after birth / no. of liveborn pups on the day of birth) x 100

Sex ratio = (no. of live male or female pups on day 0 and day 4 / no. of live male and female pups on day 0 and day 4) x 100

Clinical signs:

no effects observed

Description (incidence and severity):

There were no differences between treated and control groups in clinical condition

Dermal irritation (if dermal study):

not examined

Mortality:

no mortality observed

Description (incidence):

There were no differences between treated and control groups in mortality

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Body weights and body weight gain (refer to Table CA 7.8.1/01)
Males:
1000 mg/kg bw/d: statistically significant lower mean body weights were seen during the last week (week 4) of the administration period. The mean body weight of these animals was about 5% lower than that of the corresponding control group.

Body weight gains of the high dose males were statistically significantly diminished during weeks 2-3 and also, for the weight gain for the total study period (weeks 0- 4). In total, body weight gain was ~49% lower than the concurrent control group.

The lower mean body weights and the depression in body weight gain were deemed to be related to test article administration and were consistent with the reductions in food consumption which occurred in this dose group.

400 and 100 mg/kg bw/d: body weights and body weight gains were unaffected by treatment, with the values similar to the control group

Females:
Body weights/body weight gains from the 100, 400, 1000 mg/kg groups were similar to the control group during premating, gestation and lactation periods.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Food consumption (refer to Table CA 7.8.1/02)
Males:
1000 mg/kg bw/d: food consumption was statistically significantly reduced during study weeks 0- 1 and 3 – 4.
If calculated for the total study period weeks 0- 4), food consumption was 8% lower than the corresponding control value. This was considered to be substance-related, because the slight reductions in food consumption were consistent with lower mean body weights and impaired body weight gains.

400 and 100 mg/kg bw/d: food consumption was unaffected by treatment, with the values similar to the control group

Females:
Food consumption from the 100, 400, 1000 mg/kg groups were similar to the control group during premating, gestation and lactation periods.

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not examined

Other effects:

not examined

Reproductive function: oestrous cycle:

not examined

Reproductive function: sperm measures:

not examined

Reproductive performance:

no effects observed

Description (incidence and severity):

Reproductive performance (refer to Table CA 7.8.1/03)
Males:
For all F0 males of in dose groups 0, 100 and 1000 mg/kg bw/d which were placed with females to generate F0 pups, mating was confirmed; thus, the male mating index for these groups was 100% . Due to the fact that no sperm was detected in the vaginal smear of the female partner of male No . 27 (400 mg/kg bw/d), the male mating index was 90% for the mid dose group. This single incide was deemed unrelated to treatment.

The mean duration until sperm was detected (day 0 p .c .), varied between 2 .6 and 3 .0 days and did not show a clear dose-response relationship . These
values are fully within the expected range of biological variation for the rat strain used.

Females:
The female mating index calculated after the mating period was 100% for dose groups 0, 100 and 1000 mg/kg bw/d. As female No. 127 (400 mg/kg bw/d) showed no sperm in vaginal smear and did not give birth to a litter, the female mating index for dose group 400 mg/kg bw/d was 90%.

Fertility index: all females from test groups becomae pregnant. Therefore a 100% fertility index was calculated for all groups.

Gestation index: gestation was similar in all groups, the gestation ándeA reached 100% in all groups

The mean number of implantation sites, the postimplantation loss values and the mean number of delivered pups/dam were similar for the test article treated groups and the concurrent control group . The observable differences have no biological relevance and/or are not dose-related . The mean number of delivered pups/dam was lowest in the control group .

Key result

Dose descriptor:

NOAEL

Effect level:

ca. 400 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male

Basis for effect level:

body weight and weight gain

food consumption and compound intake

Key result

Dose descriptor:

NOAEL

Effect level:

ca. 1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

female

Basis for effect level:

other: no effects obs. up to the maximum recommended dose tested

Remarks on result:

not determinable due to absence of adverse toxic effects

Clinical signs:

effects observed, non-treatment-related

Description (incidence and severity):

Filiformed tail and acaudia were the only clinical observations which occurred and both were recorded for one low dose pup (#17 from dam #113) . This pup had a filiformed tail at birth and the first day after birth . Thereafter, it lost its malformed tail completely and therefore "acaudia" was observed. These findings are considered to be spontaneous in nature, because no relation to dosing is given

Dermal irritation (if dermal study):

not examined

Mortality / viability:

no mortality observed

Description (incidence and severity):

No test article related effects on pup viability/mortality were recorded during the lactation period. The viability index, as an indicator for the viability of the pups during the first 4 days after birth, was similar in all groups as was the mean number of live pups/litter on days 0 and 4 p.p. The observable differences have no biological relevance and/or are not dose-related.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

refer to Table CA 7.8.1/04
Mean body weights/body weight gains were not influenced by the test article administration. On day 4 p.p., the day of scheduled pup sacrifice, the mean pup body weights for males+females were 9 .6/9.8/9.4/9.8g in the 0/100/400/1000 mg/kg bw/d groups, respectively.

Pup body weight gains between days 1-4 p.p. were also very similar between the groups. The observable differences have no biological relevance and/or are not dose-related.

Food consumption and compound intake (if feeding study):

not examined

Description (incidence and severity):

pups killed day 4 p.p.

Food efficiency:

not examined

Description (incidence and severity):

pups killed day 4 p.p.

Water consumption and compound intake (if drinking water study):

not examined

Description (incidence and severity):

pups killed day 4 p.p.

Ophthalmological findings:

not examined

Description (incidence and severity):

pups killed day 4 p.p.

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Description (incidence and severity):

pups killed day 4 p.p.

Sexual maturation:

not examined

Description (incidence and severity):

pups killed day 4 p.p.

Organ weight findings including organ / body weight ratios:

not examined

Description (incidence and severity):

pups killed day 4 p.p.

Gross pathological findings:

effects observed, non-treatment-related

Description (incidence and severity):

Only spontaneous findings were seen at necropsy (e.g. dilated renal pelvis and acaudia) in very few of the pups examined. These findings occurred exclusively in the low and mid dose groups and therefore were not dose related (refer to Table CA 7.8.1/01/6)

Histopathological findings:

effects observed, non-treatment-related

Description (incidence and severity):

The clinical finding "acaudia" in the low dose pup #17 (from dam #113) was confirmed by the additional examination of the skeleton of this pup according to modified DAWSON's method. The skeletal examination revealed the absence of all caudal vertebrae.

Other effects:

not examined

Description (incidence and severity):

pups killed day 4 p.p.

Behaviour (functional findings):

not examined

Description (incidence and severity):

pups killed day 4 p.p.

Developmental immunotoxicity:

not examined

Description (incidence and severity):

pups killed day 4 p.p.

pups killed day 4 p.p.

Key result

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

ca. 1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Remarks on result:

not determinable due to absence of adverse toxic effects

Reproductive effects observed:

no

Table CA 7.8.1/01-1:
Bodyweight during pre-mating, gestation and lactation (±sd)

Parameter	Dose levels (mg/kg bw/d) [Males]				Dose levels (mg/kg bw/d) [Females]
	0	100	400	1000	0	100	400	1000
Pre-mating
Week 0	392 ±10.16	394 ±6.10	394 ±10.47	396 ±11.61	234 ±4.05	234 ±6.42	236 ±4.94	235 ±7.77
Week 1	401.5 ±14.94	407 ±11.77	409 ±13.13	400 ±14.97	235 ±10.37	235 ±7.26	239 ±7.48	236 ±7.46
Week 2	412 ±15.91	421 ±14.64	420 ±12.77	406 ±17.45	239 ±11.85	241 ±6.02	242 ±9.30	244 ±9.78
Week 3	423 ±11.16	431 ±16.41	432 ±13.3	400 ±19.29	-	-	-	-
Week 4	441 ±12.79	450 ±14.44	450 ±15.16	420 ±22.31*	-	-	-	-
Bwt change Week 0-4	49 ±9.17	56 ±10.63	56 ±14.22	25 ±14.30**	-	-	-	-
Bwt change Week 0-2	-	-	-	-	5.5 ±9.56	7.0 ±9.43	5.8 ±6.59	9.5 ±5.47
Gestation
Day 0	-	-	-	-	251 ±10.60	249 ±5.83	252 ±9.74	252 ±11.90
Day 7	-	-	-	-	276 ±12.19	281 ±7.60	281 ±10.38	281 ±10.58
Day 14	-	-	-	-	311 ±14.04	317 ±10.91	315 ±12.07	313 ±12.53
Day 20	-	-	-	-	380 ±16.83	392 ±20.23	397 ±18.52	390 ±17.10
Bwt change Days 0-20	-	-	-	-	129 ±18.87	144 ±18.87	145 ±12.58	139 ±15.29
Lactation
Day 0	-	-	-	-	300 ±18.62	309 ±9.63	301 ±9.84	299 ±12.36
Day 4	-	-	-	-	313 ±14.07	320 ±10.75	319 ±15.73	306 ±15.93
Day 7	-	-	-	-	306 ±15.38	311 ±13.15	307 ±9.96	303 ±11.32
Bwt change Days 0-7	-	-	-	-	5.8 ±9.49	1.9 ±12.19	6.5 ±9.34	4.4 ±10.58

* p<0.05; ** p <0.01

 

Table CA 7.8.1/01-2:
Food consumption during pre-mating, gestation and lactation (±sd)

Parameter	Dose levels (mg/kg bw/d) [Males]				Dose levels (mg/kg bw/d) [Females]
	0	100	400	1000	0	100	400	1000
Pre-mating
Week 0 to 1	24.6 ±1.64	25.8 ±1.68	25.9 ±1.78	22.6 ±1.80*	17.7 ±1.69	17.9 ±0.89	18.1 ±1.15	17.8 ±1.50
Week 1 to 2	24.2 ±1.35	25.7 ±1.73	25.5 ±1.18	22.9 ±1.89	18.4 ±1.25	18.1 ±1.51	18.0 ±1.68	18.6 ±1.46
Week 3 to 4	25.6 ±1.66	26.5 ±1.38	26.8 ±1.46	23.2 ±1.35**	-	-	-	-
Week 0-4	24.8 ±0.70	26.0 ±0.48	26.0 ±0.67	22.9 ±0.30	-	-	-	-
Week 0-2	-	-	-	-	18.0 ±0.47	18.0 ±0.16	18.0 ±0.09	18.2 ±0.56
Gestation
Day 0 to 7	-	-	-	-	23.2 ±1.23	24.1 ±1.93	23.3 ±1.55	22.8 ±1.12
Day 7 to 14	-	-	-	-	25.8 ±1.46	26.8 ±1.74	25.4 ±1.64	25.4 ±1.70
Day 14 to 20	-	-	-	-	28.3 ±1.46	29.7 ±1.65	28.1 ±1.51	28.2 ±2.17
Day 0 to 20	-	-	-	-	25.8 ±22.51	26.9 ±2.76	25.6 ±2.41	25.5 ±2.70
Lactation
Day 0 to 4	-	-	-	-	37.3 ±3.06	37.1 ±5.75	39.4 ±6.21	37.9 ±4.92
Day 4 to 7	-	-	-	-	29.9 ±2.31	29.6 ±2.87	29.6 ±1.62	29.4 ±2.90
Day 0 to 7	-	-	-	-	33.6 ±5.28	33.4 ±5.32	34.5 ±6.96	33.6 ±5.99

* p<0.05; ** p <0.01

 

Table CA 7.8.1/01-3:
Summary of reproductive performance

Parameter	Dose levels (mg/kg bw/d)
	0	100	400	1000
Males
Males on study	10	10	10	10
Males with confirmed mating (%)	10 (100%)	10 (100%)	9 (90%)	10 (100%)
Males without confirmed mating (%)	0 (0%)	0 (0%)	1 (10%)	0 (0%)
Males proving their fertility (fertility index%)
Females
Females on study	10	10	9	10
Females mated (mating index%)	10 (100%)	10 (100%)	9 (90%)	10 (100%)
Mating days until day 0 p.c.	2.8 ±1.40	2.6 ±1.26	2.78 ±0.97	3.0 ±3.65
- days 1 to 4	10 (100%)	10 (100%)	9 (90%)	9 (90%)
- days 5 to 8	0 (0%)	0 (0%)	0 (0%)	0 (0%)
- days 9 to 14	0 (0%)	0 (0%)	0 (0%)	1 (10%)
Pregnant at delivery (fertility index)	10 (100%)	10 (100%)	9 (100%)	10 (100%)

 

Table CA 7.8.1/01-4:
Pup bodyweights and body weight changes(g) (±sd)

Parameter	Dose levels (mg/kg bw/d) [Males]				Dose levels (mg/kg bw/d) [Females]
	0	100	400	1000	0	100	400	1000
Day 1	6.8 ±0.43	6.8 ±0.45	6.5 ±0.53	6.7 ±0.43	6.4 ±0.38	6.4 ±0.52	6.4 ±0.53	6.5 ±0.48
Day 4	9.9 ±0.73	10.0 ±0.96	9.5 ±0.93	10.0 ±0.82	9.4 ±0.60	9.8 ±0.98	9.4 ±0.92	9.8 ±0.91
Days 1 to 4	3.2 ±0.37	3.2 ±0.56	3.0 ±0.49	3.2 ±050	3.1 ±0.34	3.1 ±0.66	3.1 ±0.48	3.2 ±0.71

 

Table CA 7.8.1/01-5:
Summary of litter data

Parameter	Dose levels (mg/kg bw/d)
	0	100	400	1000
Implantation sites (total / mean ±SD)	148 /14.8 ±2.10	161 / 16.1 ±1.97	150 / 16.7 ±2.07	164 / 16.4 ±1.90
Post-implantation loss (total / mean ±SD)	17 / 17.1 ±1.49	29 / 2.9 ±2.23	11 / 11.2 ±1.56	20 / 2.0 ±1.76
Duration of gestation (days)	22.0 ±0.00	2.19 ±0.32	22.1 ±0.33	22.1 ±0.32
Females with liveborn (gestation index %)	10 (100%)	10 (100%)	9 (100%)	10 (100%)
- with stillborn pups	0 (0%)	3 (30%)	1 (11%)	0 (0%)
- will all stillborn	0 (0%)	0 (0%)	0 (0%)	0 (0%)
Litters with liveborn pups (%)	10 (100%)	10 (100%)	9 (100%)	10 (100%)
Litters with stillborn pups (%)	0 (0%)	3 (30%)	1 (11%)	0 (0%)
Pups delivered (total / mean ±SD)	131 / 13.1 ±2.13	132 / 13.2 ±3.08	139 / 15.4 ±2.13	144 / 14.4 ±2.22
Pups liveborn	131 (100%)	129 (98%)	132 (97%)	144 (100%)
Pups stillborn	0 (0%)	3 (2.3%)	4 (2.9%)	0 (0%)
Pups died	2 (1.5%)	1 (0.8%)	7 (5.0%)	5 (3.5%)
Pups cannibalised	2 (1.5%)	1 (0.8%)	1 (0.7%)	1 (0.7%)
Pups dead day 0	0 (0%)	0 (0%)	1 (0.7%)	1 (0.7%)
Pups dead days 1 to 4	4 (3.1%)	2 (1.6%)	7 (5.2%)	5 (3.5%)
Pups surviving days 0 to 4 (viability index %)	127 (7%)	127 (98%)	127 (94%)	138 (96%)
Live pups/litter day 0 (total / mean ±SD)	131 / 13.1 ±2.13	129 / 12.9 ±3.03	135 / 15.0 ±1.94	144 / 14.4 ±2.22
Live pups/litter day 4 (total / mean ±SD)	127 / 1.27 ±1.77	127 / 12.7 ±2.98	127 / 14.1 ±2.32	138 / 13.8 ±2.57
Sex ratio: day 0 %live males, % live females	M: 44.3%, F: 55.7%	M: 55.8%, F: 44.2%	M: 54.8%, F: 45.2%	M: 47.2%, F: 52.8%
Sex ratio: day 4 %live males, % live females	M: 44.9%, F: 55.1%	M: 55.9%, F: 44.1%	M: 55.9%, F: 44.1%	M: 47.8%, F: 52.2%

  

Table CA 7.8.1/01-6:
Pup necropsy observations

Parameter	Dose levels (mg/kg bw/d)
	0	100	400	1000
Litter evaluated	10	10	9	10
Pups evaluated	129	131	138	143
- Live	129	128	134	143
Dilated renal pelvis - Pup incidence (%) - Litter incidence (%) - Affected pups/litter (mean%)	0 (0%) 0 (0%) 0 ±0.0	5 (3.8%) 2 (20%) 3.1 ±7.92	1 (0.7%) 1 (11%) 0.7 ±2.08	0 (0%) 0 (0%) 0 ±0.0
Acaudia - Pup incidence (%) - Litter incidence (%) - Affected pups/litter (mean%)	0 (0%) 0 (0%) 0 ±0.0	1 (0.8%) 1 (10%) 0.6 ±1.86	0 (0%) 0 (0%) 0 ±0.0	0 (0%) 0 (0%) 0 ±0.0
Total pup necropsy - Pup incidence (%) - Litter incidence (%) - Affected pups/litter (mean%)	0 (0%) 0 (0%) 0 ±0.0	6 (4.6%) 3 (30%) 3.7 ±7.88	1 (0.7%) 1 (11%) 0.7 ±2.08	0 (0%) 0 (0%) 0 ±0.0

 

Conclusions:

Based on the results of this study the NOAELs for parental toxicity, reproductive outcome and offspring toxicity of 1,6-hexanediol when administered orally via gavage during pre-mating, gestation and lactation are as follows:

NOAEL for parental toxicity: Males: 400 mg/kg bw/d based on reductions in body weight / body weight gain and food consumption. Females: 1000 mg/kg bw/day, the highest dose tested, based on no adverse effects
NOAEL for reproductive outcome: 1000 mg/kg bw/day, the highest dose tested, based on no adverse effects.
NOAEL for offspring toxicity: 1000 mg/kg bw/day, the highest dose tested, based on no adverse effects

Executive summary:

A screening for reproductive / developmental toxicity study was conducted with 1,6-hexanediol in the Wistar rat. Animals (10/sex/group) were dosed orally via gavage at either 0, 100, 400 or 1000 mg/kg bw/d formulated in distilled water (dose volume 10 mL/kg bw). After at least 14 d of treatment, males and females from the same dose group were mated at a ratio of 1:1. After this mating period, the male animals were sacrificed. The females were allowed to litter and rear their pups until day 4 after parturition (p.p). Thereafter, the pups and the F0 generation female parental animals were sacrificed.

1,6-hexanediol had no adverse effects on fertility, on the parturition process or on peri- and postnatal survival of the offspring (up to day 4 p.p).

Clinical signs of toxicity and mortality were unaffected by treatment in F0 parental animals. Reductions in body weight (week 4) and food consumption (weeks 0 – 1 and 3 – 4) were seen in high dose F0 males. Body weight and food consumption values for F0 females were unaffected by treatment.

There were no treatment-related effects on reproductive performance (including mating, fertility, gestation index). The mean number of implantation sites, the post-implantation loss values and the mean number of delivered pups/dam were similar for the test article treated groups and the concurrent control group. The observable differences have no biological relevance and/or are not dose-related. The mean number of delivered pups/dam was lowest in the control group. Only spontaneous findings were seen at necropsy (e.g. dilated renal pelvis and acaudia) in very few of the pups examined. These findings occurred exclusively in the low and mid dose groups and therefore were not dose related.

No test article related effects on pup viability/mortality were recorded during the lactation period. The viability index, as an indicator for the viability of the pups during the first 4 days after birth, was similar in all groups as was the mean number of live pups/litter on days 0 and 4 p .p. The observable differences have no biological relevance and/or are not dose-related. Mean body weights/body weight gains were not influenced by the test article administration.

Based on the results of this study the NOAELs for parental toxicity, reproductive outcome and offspring toxicity of 1,6-hexanediol when administered orally via gavage during pre-mating, gestation and lactation are as follows:

NOAEL for parental toxicity: Males: 400 mg/kg bw/d based on reductions in body weight / body weight gain and food consumption. Females: 1000 mg/kg bw/day, the highest dose tested, based on no adverse effects

NOAEL for reproductive outcome:1000 mg/kg bw/day, the highest dose tested, based on no adverse effects.

NOAEL for offspring toxicity: 1000 mg/kg bw/day, the highest dose tested, based on no adverse effects.

Reference 2

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

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

Adequacy of study:

key study

Justification for type of information:

The read across justification is attached in section 13.

Reason / purpose for cross-reference:

read-across source

Clinical signs:

no effects observed

Description (incidence and severity):

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Dermal irritation (if dermal study):

not examined

Description (incidence and severity):

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Mortality:

no mortality observed

Description (incidence):

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Food efficiency:

not examined

Description (incidence and severity):

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Water consumption and compound intake (if drinking water study):

not examined

Description (incidence and severity):

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Ophthalmological findings:

not examined

Description (incidence and severity):

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Haematological findings:

not examined

Description (incidence and severity):

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Clinical biochemistry findings:

not examined

Description (incidence and severity):

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Urinalysis findings:

not examined

Description (incidence and severity):

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Behaviour (functional findings):

not examined

Description (incidence and severity):

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Histopathological findings: neoplastic:

not examined

Description (incidence and severity):

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Other effects:

no effects observed

Description (incidence and severity):

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Reproductive function: oestrous cycle:

not examined

Description (incidence and severity):

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Reproductive function: sperm measures:

not examined

Description (incidence and severity):

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Reproductive performance:

no effects observed

Description (incidence and severity):

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Key result

Dose descriptor:

NOAEL

Effect level:

ca. 400 mg/kg bw/day

Based on:

other: Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Sex:

male

Basis for effect level:

other: Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Remarks on result:

other: Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Key result

Dose descriptor:

NOAEL

Effect level:

ca. 1 000 mg/kg bw/day

Based on:

other: Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Sex:

female

Basis for effect level:

other: Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Remarks on result:

other: Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Clinical signs:

not examined

Description (incidence and severity):

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Dermal irritation (if dermal study):

not examined

Description (incidence and severity):

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Mortality:

not examined

Description (incidence):

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Body weight and weight changes:

not examined

Description (incidence and severity):

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Food consumption and compound intake (if feeding study):

not examined

Description (incidence and severity):

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Food efficiency:

not examined

Description (incidence and severity):

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Water consumption and compound intake (if drinking water study):

not examined

Description (incidence and severity):

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Ophthalmological findings:

not examined

Description (incidence and severity):

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Haematological findings:

not examined

Description (incidence and severity):

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Clinical biochemistry findings:

not examined

Description (incidence and severity):

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Urinalysis findings:

not examined

Description (incidence and severity):

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Behaviour (functional findings):

not examined

Description (incidence and severity):

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Immunological findings:

not examined

Description (incidence and severity):

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Organ weight findings including organ / body weight ratios:

not examined

Description (incidence and severity):

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Gross pathological findings:

not examined

Description (incidence and severity):

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Neuropathological findings:

not examined

Description (incidence and severity):

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Histopathological findings: non-neoplastic:

not examined

Description (incidence and severity):

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Histopathological findings: neoplastic:

not examined

Description (incidence and severity):

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Other effects:

not examined

Description (incidence and severity):

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Details on results:

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Reproductive function: oestrous cycle:

not examined

Description (incidence and severity):

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Reproductive function: sperm measures:

not examined

Description (incidence and severity):

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Reproductive performance:

not examined

Description (incidence and severity):

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Clinical signs:

effects observed, non-treatment-related

Description (incidence and severity):

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Dermal irritation (if dermal study):

not examined

Description (incidence and severity):

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Mortality / viability:

no mortality observed

Description (incidence and severity):

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Food consumption and compound intake (if feeding study):

not examined

Description (incidence and severity):

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Food efficiency:

not examined

Description (incidence and severity):

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Water consumption and compound intake (if drinking water study):

not examined

Description (incidence and severity):

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Ophthalmological findings:

not examined

Description (incidence and severity):

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Haematological findings:

not examined

Description (incidence and severity):

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Clinical biochemistry findings:

not examined

Description (incidence and severity):

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Urinalysis findings:

not examined

Description (incidence and severity):

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Sexual maturation:

not examined

Description (incidence and severity):

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Organ weight findings including organ / body weight ratios:

not examined

Description (incidence and severity):

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Gross pathological findings:

effects observed, non-treatment-related

Description (incidence and severity):

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Histopathological findings:

effects observed, non-treatment-related

Description (incidence and severity):

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Other effects:

not examined

Description (incidence and severity):

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Behaviour (functional findings):

not examined

Description (incidence and severity):

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Developmental immunotoxicity:

not examined

Description (incidence and severity):

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Key result

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

ca. 1 000 mg/kg bw/day

Based on:

other: Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Sex:

male/female

Basis for effect level:

other: Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Remarks on result:

other: Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Clinical signs:

not examined

Description (incidence and severity):

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Dermal irritation (if dermal study):

not examined

Description (incidence and severity):

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Mortality / viability:

not examined

Description (incidence and severity):

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Body weight and weight changes:

not examined

Description (incidence and severity):

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Food consumption and compound intake (if feeding study):

not examined

Description (incidence and severity):

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Food efficiency:

not examined

Description (incidence and severity):

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Water consumption and compound intake (if drinking water study):

not examined

Description (incidence and severity):

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Ophthalmological findings:

not examined

Description (incidence and severity):

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Haematological findings:

not examined

Description (incidence and severity):

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Clinical biochemistry findings:

not examined

Description (incidence and severity):

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Urinalysis findings:

not examined

Description (incidence and severity):

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Sexual maturation:

not examined

Description (incidence and severity):

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Organ weight findings including organ / body weight ratios:

not examined

Description (incidence and severity):

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Gross pathological findings:

not examined

Description (incidence and severity):

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Histopathological findings:

not examined

Description (incidence and severity):

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Other effects:

not examined

Description (incidence and severity):

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Behaviour (functional findings):

not examined

Description (incidence and severity):

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Developmental immunotoxicity:

not examined

Description (incidence and severity):

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Reproductive effects observed:

no

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Conclusions:

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Executive summary:

Refer to Key_Source_Toxicity to reproduction_1995_RL2. The read across justification is attached in section 13.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

400 mg/kg bw/day

Study duration:

subacute

Species:

rat

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Effects on developmental toxicity

Description of key information

Effects on develepment toxicity with read-across substances 1,6-hexandiol (source 1) and 1,2 -hexanediol (source 2)

1,6 -Hexanediol

1,6-Hexanediol (source 1, read-across to nonanediol, CAS 3937 -56 -2) was daily administered by oral gavage at dose levels of 0, 100, 400 or 1000 mg/kg bw/d, to groups of 25 time-mated Wistar rats from day 6 to day 19 of gestation (GD) inclusive. On day 20 of gestation all rats were subjected to a caesarean section and macroscopic examination of the organs in the thoracic and abdominal cavities. The number of implantations, resorptions (early and late), corpora lutea, and uteri were determined, as well as placental weight, number of live and dead foetuses, litter and sex ratios. Live foetuses were individually weighed as well as their placenta and the foetuses were examined for external anomalies, soft tissue changes (half of the fetuses) and skeletal changes (remaining fetuses).

 

Treatment at dosages up to 1000 mg/kg bw/d was well tolerated by the pregnant females and was not associated with any effects on clinical condition, bodyweight, bodyweight change, food intake or necropsy observations.

 

There were no effects at dosages up to 1000 mg/kg/day on embryofoetal survival, growth and development.

 

The daily administration of 1,6 -hexanediol during the period of organogenesis, at dose levels up to 1000 mg/kg bw/d, was not associated with any adverse effect on the pregnant rat or on the developing conceptus. The maternal NOAEL was 1000 mg/kg bw/d (the maximum recommended dose for sub-acute toxicity studies, in accordance with current guideline requirements).

 

The NOAEL for developmental toxicity was set at 1000 mg/kg bw/d, the maximum dose tested. There were no indications of teratogenic potential at doses up to 1000 mg/kg bw/d (the maximum recommended dose for sub-acute toxicity studies).

1,2 -Hexanediol

SYM05/841129 (1,2 -hexanediol, source 2, read-across to nonanediol, CAS 3937 -56 -2) was daily administered by oral gavage at dose levels of 0, 30, 100 or 300 mg/kg bw/d, to groups of 24 time-mated SD rats from day 5 to day 19 of gestation (GD) inclusive. The dose levels were selected based on a dose range finding study, reported under CA 7.8.2/01. The maximum dose (300 mg/kg bw/d) was deemed to be a maximum tolerated dose On day 20 of gestation all rats were subjected to a caesarean section and macroscopic examination of the organs in the thoracic and abdominal cavities. The number of implantations, resorptions (early and late), corpora lutea, and uteri were determined, as well as placental weight, number of live and dead fetuses, litter and sex ratios. Live foetuses were individually weighed as well as their placenta and the foetuses were examined for external anomalies, soft tissue changes (half of the fetuses) and skeletal changes (remaining fetuses).

 

Treatment at dosages up to 300 mg/kg bw/d was well tolerated by the pregnant females and was not associated with any effects on clinical condition, bodyweight, bodyweight change, food intake or necropsy observations.

 

There were no effects at dosages up to 300 mg/kg/day on embryofoetal survival, growth and development.

 

The daily administration of SYM05/841129 during the period of organogenesis, at dose levels up to 300 mg/kg bw/d, was not associated with any adverse effect on the pregnant rat or on the developing conceptus. The maternal NOAEL was 300 mg/kg bw/d (deemed to be the maximum tolerated dose), the maximum dose tested.

 

The NOAEL for developmental toxicity was set at 300 mg/kg bw/d, the maximum dose tested. There were no indications of teratogenic potential at doses up to 300 mg/kg bw/d (a dosedeemed to be the maximum tolerated dose for maternal animals).

The read-across justification is attached in section 13.

Link to relevant study records

Reference

Reference 1

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2006-01-18 to 2006-05-10

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Version / remarks:

2001

Deviations:

no

GLP compliance:

yes

Limit test:

no

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Chemical name: 1,2-hexanediol
- CAS no.: 6920-22-5
- EC-no.: 230-029-6
- Source and lot/batch No.of test material: Symirise GmbH & Co. Ltd / lot 2
- Purity: 99.7%

Species:

rat

Strain:

Sprague-Dawley

Details on test animals or test system and environmental conditions:

Age: not given, but based on weight range ~7-9 weeks of age
Weight at dosing: F: 194-292 g
Source: Charles River U.K. Ltd, Margate, Kent, UK
Acclimation period: 4 days
Diet: Certified Rodent diet PMI 5002, BCM IPS Ltd, UK, ad libitum
Water: Municipal water supply, ad libitum
Housing: 4-5/cage of the same sex, then housed individually upon assignment to the study
Temperature: 19-23°C
Humidity: 40-70%
Air changes: 15 changes/hour
Photoperiod: 12 hours light/dark

Route of administration:

oral: gavage

Vehicle:

water

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Stability data (generated under CA 7.8.2/01) confirmed the test article formulations to be stable for at least 14 days. Analysis of weekly formulations show concentrations to be within ±% of nominal
concentration.

Details on mating procedure:

refer to details on study design

Duration of treatment / exposure:

14 days / oral

Frequency of treatment:

daily

Duration of test:

15 days

Dose / conc.:

0 mg/kg bw/day

Dose / conc.:

30 mg/kg bw/day

Dose / conc.:

100 mg/kg bw/day

Dose / conc.:

300 mg/kg bw/day

No. of animals per sex per dose:

24/gp

Control animals:

yes, concurrent vehicle

Details on study design:

Four groups of 96 pregnant female SD rats received the test article via oral gavage at concentrations of 0, 30, 100, 300 mg/kg bw/d from day 5 of gestation to day 19 post-partum (pp) using a dose volume of 5 mL/kg. On day 20 of gestation, dams were subjected to caesarean section and macroscopic examination. The number of implantations, resorptions (early and late), corpora lutea, and uteri were determined, as well as placental weight, number of live and dead fetuses, litter and sex ratios. Live foetuses were individually weighed as well as their placenta and the foetuses were examined for external anomalies, soft tissue changes (half of the fetuses) and skeletal changes (remaining fetuses).

Maternal examinations:

Clinical signs of toxicity: observed once daily, in the morning throughout gestation and, additionally 1 h after dosing throughout the dosing period
Mortality: twice daily during the normal working week and once daily at weekends
Bodyweight: weighed on Day 3, Days 5 to 8, Day 11, Day 14, Day 17 and Day 20 of gestation
Food consumption: recorded for discrete periods throughout the study on Day 3 to 5, Day 5 to 8, Day 8 to 11, Day 11 to 14, Day 14 to 17 and Day 17 to 20 of gestation
Necropsy: On day 20 of gestation, dams were subjected to caesarean section and macroscopic examination.

Ovaries and uterine content:

The number of implantations, resorptions (early and late), corpora lutea, and uteri were determined. Pregnancy status, no. of copora lutea, gravid uterus weight, number position and type of intra-uterine implantation were recorded as well as placental weight.

Fetal examinations:

Number of live and dead fetuses, litter and sex ratios. Live foetuses were individually weighed as well as foetuses examined for external anomalies. Foetuses were transferred to 90% industrial methylated spirits (IMS) in distilled water and examined for visceral anomalies under a low power binocular microscope. The remaining foetuses were identified using colour coded wires and placed in 70% IMS in distilled water. The foetuses were eviscerated, processed and the skeletons stained with alizarin red. The foetuses were examined for skeletal development and anomalies.

Statistics:

Bodyweight, bodyweight change and food consumption: Bartlett' s test for homogeneity of variance and one way analysis of variance, followed by Dunnet's multiple comparison test or, if unequal variances were observed, an alternative multiple comparison test.

Litter data and litter, placental and foetal weights: Kruskal-Wallis non-parametric analysis of variance; and a subsequent pairwise analysis of control value against treated values

Indices:

Percentage pre-implantation loss was calculated as:
(no. of corpora lutea - no. of implantations) / no.of copora lutea x 100

Percentage post-implantation loss was calculated as:
(no. of implantations - no. of live foetuses) / no.of implantations x 100

Historical control data:

no historical control data provided

Clinical signs:

no effects observed

Description (incidence and severity):

No test article related effects were observed.

Mortality:

no mortality observed

Description (incidence):

All animals survived to the scheduled necropsy

Body weight and weight changes:

no effects observed

Description (incidence and severity):

No test article related effects were observed.

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

No test article related effects were observed.

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

No test article related effects (refer to Table CA 7.8.2/02-1)

Gross pathological findings:

no effects observed

Description (incidence and severity):

No treatment-related macroscopic abnormalities were seen at post mortem examination for animals that were killed at the end of the study.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Other effects:

not examined

Details on results:

no evidence of maternal toxicity up to the maximum dose level, deemed to be a maximum tolerated dose based on the dose range finder reported under CA 7.8.2/01

Number of abortions:

no effects observed

Description (incidence and severity):

No test article related effects were observed (refer to Table CA 7.8.2/02-2)

Pre- and post-implantation loss:

no effects observed

Description (incidence and severity):

No test article related effects were observed (refer to Table CA 7.8.2/02-3)

Total litter losses by resorption:

no effects observed

Description (incidence and severity):

Litters were unaffected by maternal treatment (refer to Table CA 7.8.2/02-3)

Early or late resorptions:

no effects observed

Description (incidence and severity):

Early and late resorptions were unaffected by maternal treatment (refer to Table CA 7.8.2/02-3)

Dead fetuses:

no effects observed

Description (incidence and severity):

The mean number of live young were unaffected by maternal treatment up to a maximum dose of 300 mg/kg bw/day (refer to Table CA 7.8.2/02-3)

Changes in pregnancy duration:

no effects observed

Description (incidence and severity):

No test article related effect observed (refer to Table CA 7.8.2/02-2)

Changes in number of pregnant:

no effects observed

Description (incidence and severity):

No test article related effect observed (refer to Table CA 7.8.2/02-2)

Other effects:

no effects observed

Details on maternal toxic effects:

The administration of SYM05/841129 at dose levels up to 300 mg/kg bw/d (deemed to a maximum tolerated dose) caused resulted in no maternal toxicity

Key result

Dose descriptor:

NOAEL

Effect level:

> 300 mg/kg bw/day

Based on:

test mat.

Remarks on result:

not determinable due to absence of adverse toxic effects

Abnormalities:

no effects observed

Fetal body weight changes:

no effects observed

Description (incidence and severity):

Placental and foetal weights at were unaffected by maternal treatment up to 300 mg/kg bw/day (deemed to be a maximum tolerated dose) (refer to Table CA 7.8.2/02-3)

Reduction in number of live offspring:

no effects observed

Description (incidence and severity):

The mean number of live young were unaffected by maternal treatment up to 300 mg/kg bw/day (deemed to be a maximum tolerated dose) (refer to Table CA 7.8.2/02-3)

Changes in sex ratio:

no effects observed

Description (incidence and severity):

Sex ratio were unaffected by maternal treatment up to 300 mg/kg bw/day (deemed to be a maximum tolerated dose) (refer to Table CA 7.8.2/02-3)

Changes in litter size and weights:

no effects observed

Description (incidence and severity):

Litter size and weights at all dose levels were essentially similar to control and were considered to have been unaffected by maternal treatment (refer to Table CA 7.8.2/02-3)

Changes in postnatal survival:

no effects observed

Description (incidence and severity):

Post natal surivial was unaffected by maternal treatment up to 300 mg/kg bw/day (deemed to be a maximum tolerated dose) (refer to Table CA 7.8.2/02-3)

External malformations:

no effects observed

Description (incidence and severity):

Neither the type, distribution nor incidence of foetal findings observed during extemal examination at necropsy indicated any adverse effect of maternal treatment on foetal growth or development at 30, 100 or 300 mg/kg/day.

Skeletal malformations:

no effects observed

Description (incidence and severity):

Neither the type, distribution nor incidence of foetal findings observed during skeletal examinations indicated any adverse effect of maternal treatment on foetal growth or development at 30, 100 or 300 mg/kg/day (refer to Table CA 7.8.2/02-4 and Table CA 7.8.2/02-5).

Visceral malformations:

no effects observed

Description (incidence and severity):

Neither the type, distribution nor incidence of foetal findings observed during detailed visceral examinations indicated any adverse effect of maternal treatment on foetal growth or development at 30, 100 or 300 mg/kg/day (refer to Table CA 7.8.2/02-6)

Other effects:

no effects observed

Details on embryotoxic / teratogenic effects:

No effects were observed on foetal growth or development in the offspring of animals treated with up to 300 mg/kg bw/day

Key result

Dose descriptor:

NOAEL

Effect level:

> 300 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No effects were observed on foetal growth or development

Remarks on result:

other:

Abnormalities:

no effects observed

Description (incidence and severity):

No effects were observed on foetal growth or development

Key result

Developmental effects observed:

no

Lowest effective dose / conc.:

300 mg/kg bw/day

Table CA 7.8.2/02-1:
Bodyweight during gestation and gravid uterus weight at termination (±sd)

Parameter	Dose level (mg/kg bw/d)
	0	30	100	300
GD 3	250 ±26	252 ±20	248 ±19	249 ±22
GD 5	262 ±25	263 ±21	263 ±20	263 ±23
GD 6	266 ±26	267 ±21	267 ±22	266 ±23
GD 7	270 ±28	272 ±23	273 ±22	271 ±23
GD 8	275 ±28	277 ±21	278 ±21	276 ±23
GD 11	294 ±31	298 ±24	299 ±25	297 ±26
GD 14	312 ±33	318 ±26	320 ±28	315 ±27
GD 17	344±39	349 ±31	351 ±34	344 ±30
GD 20	387 ±46	396 ±35	396 ±40	388 ±34
Gravid uterus weight (g)	78.87 ±1906	79.31 ±10.59	79.02 ±14.55	74.63 ±16.29
Adjusted terminal bwt (g)	308 ±33	316 ±30	317 ±32	313 ±27

 

Table CA 7.8.2/02-2:
Summary of female performance

Parameter	Dose level (mg/kg bw/d)
	0	30	100	300
Initial group size	24	24	24	24
No. not pregnant	0	0	0	0
No. pregnant	24	24	24	24
No. killedin extremis	0	0	0	0
With live young at day 20	24	24	24	24

 

Table CA 7.8.2/02-3:
Litter data on day 20 of gestation – group mean values (±sd)

Parameter	Dose level (mg/kg bw/d)
	0	30	100	300
Number of Corpora Lutea	15.6 ±3.1	15.3 ±1.6	16.0 ±3.1	14.9 ±2.5
No. of live implants [m; f; total]	5.8 ±2.6; 6.5 ±1.9; 12.3 ±3.3	6.1 ±1.9; 6.3 ±1.8; 12.4 ±1.7	6.3 ±2.5; 6.1 ±2.1; 12. ±2.1	5.8 ±2.3; 5.9 ±2.7; 11.7 ±2.8
% male foetuses	46.23 ±12.76	49.31 ±12.94	50.00 ±17.84	50.29 ±18.19
No. of embryonic/foetal deaths [early; late; total]	0.3 ±0.6; 0.1 ±0.6; 0.4 ±0.8	0.5 ±1.1; 0.0 ±0.0; 0.5 ±1.1	0.3 ±0.4; 0.1 ±0.3; 0.3 ±0.5	0.3 ±0.8; 0.1 ±0.3; 0.4 ±0.8
Implantation loss % [pre; post]	17.8 ±14.9 5.1 ±12.9	16.3 ±9.1; 3.1 ±8.4	19.2 ±14.1; 2.5 ±3.7	19.6 ±3.0; 12.9 ±6.5
Mean foetal weight (g) [M; F]	4.14 ±0.36; 3.86 ±0.32	4.20 ±0.23; 3.98 ±0.24	4.24 ±0.34; 3.97 ±0.31	4.10 ±0.23; 3.82 ±0.49
Mean foetal weight (g)	3.99 ±0.30	4.09 ±0.22	4.10 ±0.30	3.99 ±0.21
Mean placental weight (g)	0.63 ±0.28	0.57 ±0.05	0.57 ±0.07	0.56 ±0.05
Total litter weight (g)	48.81 ±12.24	50.18 ±6.67	50.45 ±7.69	46.49 ±11.15
Total placental weight (g)	7.15 ±1.63	6.96 ±1.06	7.06 ±1.46	6.51 ±1.42

 

Table CA 7.8.2/02-4:
Foetal skeletal development – group incidence

Parameter (foetal occurrence / litter occurrence [% group mean/litter])		Dose level (mg/kg bw/d)
		0	30	100	300
		No. of foetuses / litters examined
		141/24	140/24	142/24	132/24
Number of ribs	3/3 13/13 14/13	0/0 [-%] 140/24 [100%] 0/0 [-%]	0/0 [-%] 138/24 [100%] 0/0 [-%]	1/1 [0.7%] 140/24 [98.8%] 1/1 [0.7%]	0/0 [-%] 129/24 [100%] 0/0 [-%]
Number of fully ossified sternebrae	<4 4 >4	0/0 [-%] 17/8 [10.1%] 124/24 [89.9%]	1/1 [0.7%] 14/10 [10.4%] 124/24 [88.9%]	0/0 [-%] 14/8 [8.8%] 127/24 [91.2%]	0/0 [-%] 10/8 [8.5%] 122/24 [91.5%]
Number of post lumbar vertebral centra	<7 =7	3/3 [1.8%] 136/24 [98.2%]	1/1 [0.6%] 138/24 [99.4%]	2/2 [1.5%] 139/24 [98.5%]	2/2 [1.2%] 129/24 [98.8%]
Number of post lumbar vertebral arches	<5 =5	13/9 [8.1%] 126/24 [91.9%]	9/6 [6.8%] 130/24 [93.2%]	14/8 [10.1%] 127/24 [89.9%]	12/8 [8.2%] 119/24 [91.8%]
Number of metacarpals	<6 6 =6	1/1 [1.0%] 39/16 [29.0%] 101/22 [70.0%]	0/0 [-%] 29/12 [22.3%] 111/23 [77.7%]	0/0 [-%] 37/14 [24.9%] 104/23 [75.1%]	1/1 [0.4% 24/11 [16.8%] 107/24 [82.5%]
Number of metatarsals	6 >6	4/2 [7.3%] 137/23 [92.7%]	0/0 [-%] 139/24 [100%]	1/1 [0.7%] 141/24 [99.3]	1/1 [0.7%] 129/24 [99.3%]
Fontanelle	Sm Med Lg	6/3 [3.4%] 118/24 [85.5%] 17/9 [12.2%]	6/4 [3.8%] 120/24 [85.7%] 14/10 [11.2%]	8/4 [6.1%] 115/23 [81.2%] 19/9 [12.7%]	5.4 [4.1%] 116/24 [87.9%] 11/6 [8.0%]

 

Table CA 7.8.2/02-5:
Foetal skeletal findings – group incidence

Parameter (foetal occurrence / litter occurrence [% group mean/litter])	Dose level (mg/kg bw/d)
	0	30	100	300
	No. of foetuses / litters examined
	141/24	140/24	142/24	132/24
HEAD/NECK
- Incomplete ossification of one cranial bone	39/19 [25.3%]	34/15 [23.9%]	33/15 [22.1%]	33/19 [27.0%]
- Incomplete ossification of more than one cranial bone	27/17 [18.9%]	23/13 [19.2%]	36/15 [25.6%]	17/8 [14.1%]
- Irregular ossification of one cranial bone	20/13 [13.5%]	15/9 [11.4%]	18/11 [12.3%]	25/16 [17.5%]
- Incomplete ossification of one facial bone	1/1 [0.5%]	1/1 [0.8%]	1/1 [0.5%]	1/1 [0.7%]
- Incomplete ossification of more than one facial bone	0/0 [-%]	0/0 [-%]	0/0 [-%]	1/1 [0.8%]
- No ossification of hyoid	23/12 [17.7%]	15/11 [10.1%]	27/13 [17.9%]	23/13 [17.1%]
- Incomplete ossification of hyoid	1/1 [0.5%]	0/0 [-%]	1/1 [0.6%]	0/0 [-%]
- Hyoid bipartite	1/1 [0.7%]	0/0 [-%]	0/0 [-%]	0/0 [-%]
-Irregular ossification of more than one cranial bone	1/1 [0.5%]	4/3 [2.95%]	5/4 [3.4%]	2/1 [1.0%]
- No ossification of more than one cranial bone	0/0 [-%]	0/0 [-%]	0/0 [-%]	1/1 [3.0%]
STERNEBRAE (1-4)
- 5^thsternebra not ossified	0/0 [-%]	0/0 [-%]	1/1 [0.8%]	0/0 [-%]
- Incomplete ossification of one sternebra	0/0 [-%]	1/1 [0.6%]	0/0 [-%]	2/2 [1.3%]
- No ossification of one sternebra	0/0 [-%]	0/0 [-%]	1/1 [0.7%]	1/1 [0.7%]
- No ossification of more than one sternebrae	0/0 [-%]	0/0 [-%]	0/0 [-%]	0/0 [-%]
- No ossification of vertebrae or ribs below 3^rdthoracic	0/0 [-%]	0/0 [-%]	0/1/1 [0.7%]	0/0 [-%]
- Incomplete ossification of more than one sternebrae	0/0 [-%]	0/0 [-%]	0/0 [-%]	1/1 [5.9%]
RIBS
-All ribs rudimentary	0/0 [-%]	0/0 [-%]	1/1 [0.7%]	0/0 [-%]
- Bilateral/unilateral wavy 13^thrib(s)	2/2 [1.1%]	2/2 [1.4%]	5/4 [3.3%]	2/1 [1.2%]
- Bilateral/unilateral short 13^thrib(s)	2/2 [1.1%]	4/3 [3.3%]	3/2 [2.0%]	6/6 [4.2%]
- Bilateral/unilateral wavy rib(s))	2/2 [1.1%]	1/1 [0.7%]	0/0 [-%]	0/0 [-%]
- Bilateral/unilateral thickened rib(s)	0/0 [-%]	1/1 [0.7%]	0/0 [-%]	0/0 [-%]
- Bilateral/unilateral rudimentary 14^thrib(s)	0/0 [-%]	0/0 [-%]	1/1 [0.8%]	0/0 [-%]
VERTEBRAE
-One thoracic vertebral centre semi-bipartite	16/11 [10.9%]	11/9 [7.9%]	11/9 [8.5%]	12/8 [7.6%]
- More than onr thoracic vertebral centre semi-bipartite	1/1 [0.7%]	1/1 [1.0%]	4/2 [3.8%]	9/5 [7.9%]
- One thoracic vertebral centre bipartite	2/2 [1.1%]	4./3 [3.3%]	4/3 [2.2%]	7/6 [5.0]
- More than one thoracic vertebral centre bipartite	1/1 [0.7%]	0/0 [-%]	1/1 [0.7%]	0/0 [-%]
- One lumbar vertebral centre semi-bipartite	0/0 [-%]	0/0 [-%]	1/1 [1.0%]	2/1 [1.4%]
OTHER
- Pubisnot ossified	0/0 [-%]	0/0 [-%]	0/0 [-%]	1/1 [0.7%]
- Ilia and ischia close together	0/0 [-%]	0/0 [-%]	1/1 [0.7%]	0/0 [-%]
- Upwards pelvic shift	0/0 [-%]	0/0 [-%]	0/0 [-%]	1/1 [0.7%]
TOTAL	91/21 [64.5%]	79/22 [56.4%]	99/24 [70.4%]	93/24 [69.7%]

 

Table CA 7.8.2/02-6:
Foetal visceral findings – group incidence

Parameter (foetal occurrence / litter occurrence [% group mean/litter])	Dose level (mg/kg bw/d)
	0	30	100	300
	No. of foetuses / litters examined
	154/24	156/24	155/24	148/24
- 3^rdventricle dilated	4/4 [2.3%]	0/0 [-%]	1/1 [0.7%]	0/0 [-%]
- eye lens - ovoid	4/4 [2.2%]	2/2 [1.2%]	2/2 [1.2%]	1/1 [0.7%]
- Small cleft in palate proximal to mouth	0/0 [-%]	0/0 [-%]	1/1 [0.6%]	0/0 [-%]
- undescended lobe(s) of thymus	6/5 [7.6%]	3/3 [1.7%]	5/5 [2.9%]	2/2 [1.5%]
- thyroid small	0/0 [-%]	0/0 [-%]	0/0 [-%]	0/0 [-%]
- small lobe of thyroid	1/1 [0.5%]	0/0 [-%]	0/0 [-%]	0/0 [-%]
- pericardial oedema	0/0 [-%]	0/0 [-%]	0/0 [-%]	1/1 [0.5%]
- blood in pericardial sac	0/0 [-%]	1/1 [0.6%]	0/0 [-%]	0/0 [-%]
- partial persistant truncus arteriosas	1/1 [0.5%]	0/0 [-%]	0/0 [-%]	0/0 [-%]
- high interventricular septal defect	1/1 [0.5%]	0/0 [-%]	0/0 [-%]	1/1 [1.0%]
- No brachiocephalic trunk — common carotid and subclavian exit from aorta	1/1 [0.5%]	0/0 [-%]	0/0 [-%]	1/1 [1.0%]
-Retro oesophageal subclavian artery	0/0 [-%]	0/0 [-%]	1/1 [0.6%]	0/0 [-%]
- Heart malrotated	0/0 [-%]	0/0 [-%]	0/0 [-%]	1/1 [1.0%]
- Area of haemorrhage an diaphragm	0/0 [-%]	0/0 [-%]	1/1 [0.7%]	0/0 [-%]
- Small inguinal hernia — small protrusion in abdominal wall	0/0 [-%]	0/0 [-%]	0/0 [-%]	1/1 [0.6%]
- Blood in abdomen	0/0 [-%]	0/0 [-%]	1/1 [0.6%]	1/1 [0.6%]
- Small renal papilla	13/11 [7.9%]	15/8 [9.5%]	16/11 [10.1%]	1/1 [0.6%]
- increased renal pelvic cavitation	0/0 [-%]	4/3 [2.4%]	2/1 [0.9%]	10/5 [6.7%]
- No development of renal papilla	1/1 [0.5%]	3/2 [1.9%]	0/0 [-%]	6/5 [4.5%]
- Adrenal dark	1/1 [0.5%]	0/0 [-%]	0/0 [-%]	0/0 [-%]
- extra lobulation of median lobe of liver	1/1 [0.5%]	3/2 [1.9%]	0/0 [-%]	0/0 [-%]
- dilated ureter	7/7 [8.1%]	11/7 [7.1%]	7/5 [4.1%]	8/5 [5.6%]
- kinked ureter	7/6 [7.6%]	9/6 [5.4%]	11/6 [6.5%]	7/4 [4.9]
- dilated lateral ventricle	1/1 [0.5%]	0/0 [-%]	0/0 [-%]	0/0 [-%]
TOTAL	25/15 [18.6%]	23/10 [14.6%]	26/15 [16.2%]	19/13 [13.0%]

 

Conclusions:

The daily administration of SYM05/841129 during the period of organogenesis, at dose levels up to 300 mg/kg bw/d, was not associated with any adverse effect on the pregnant rat or on the developing conceptus. The maternal NOAEL was 300 mg/kg bw/d (deemed to be the maximum tolerated dose), the maximum dose tested.

The NOAEL for developmental toxicity was set at 300 mg/kg bw/d, the maximum dose tested. There were no indications of teratogenic potential at doses up to 300 mg/kg bw/d (a dosedeemed to be the maximum tolerated dose for maternal animals).

Executive summary:

SYM05/841129 was daily administered by oral gavage at dose levels of 0, 30, 100 or 300 mg/kg bw/d, to groups of 24 time-mated SD rats from day 5 to day 19 of gestation (GD) inclusive. The dose levels were selected based on a dose range finding study, reported under CA 7.8.2/01. The maximum dose (300 mg/kg bw/d) was deemed to be a maximum tolerated dose On day 20 of gestation all rats were subjected to a caesarean section and macroscopic examination of the organs in the thoracic and abdominal cavities. The number of implantations, resorptions (early and late), corpora lutea, and uteri were determined, as well as placental weight, number of live and dead fetuses, litter and sex ratios. Live foetuses were individually weighed as well as their placenta and the foetuses were examined for external anomalies, soft tissue changes (half of the fetuses) and skeletal changes (remaining fetuses).

 

Treatment at dosages up to 300 mg/kg bw/d was well tolerated by the pregnant females and was not associated with any effects on clinical condition, bodyweight, bodyweight change, food intake or necropsy observations.

 

There were no effects at dosages up to 300 mg/kg/day on embryofoetal survival, growth and development.

 

The daily administration of SYM05/841129 during the period of organogenesis, at dose levels up to 300 mg/kg bw/d, was not associated with any adverse effect on the pregnant rat or on the developing conceptus. The maternal NOAEL was 300 mg/kg bw/d (deemed to be the maximum tolerated dose), the maximum dose tested.

 

The NOAEL for developmental toxicity was set at 300 mg/kg bw/d, the maximum dose tested. There were no indications of teratogenic potential at doses up to 300 mg/kg bw/d (a dosedeemed to be the maximum tolerated dose for maternal animals).

Reference 2

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2013-08-27 to 2014-04-24

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Version / remarks:

2001

Deviations:

no

Principles of method if other than guideline:

Deficiencies: Test article administered from GD 6-19, with sacrifice on GD 20 (guideline requirements: at least from GD 5 – GD 19). Therefore the concerns are that the first day organogenesis has not been addressed, in accordance with the guideline requirements. Deficiencies considered to be minor. In accordance with the Witschi rat stages, implantation is on GD 6. The study is however still considered acceptable and adequately addresses this endpoint

GLP compliance:

yes

Limit test:

no

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Chemical name: 1,6-hexanediol
- CAS no.: 629-11-8
- EC-no.: 211-074-0
- Source and lot/batch No.of test material: BASF SE / 000STD77L0
- Expiration date of the lot/batch: 22 January 2014
- Purity: 95.9%

Species:

rat

Strain:

Wistar

Details on test animals or test system and environmental conditions:

Age: 10-12 weeks
Weight at dosing: F: 146-187 g
Source: Charles River Laboratories, Research Models and Services, Germany GmbH
Acclimation period: 5 days
Diet: Kliba maintenance diet mouse/rat, Kaiseraugst, Switzerland, ad libitum
Water: Municipal water supply, ad libitum
Housing: Individually upon assignment to the study
Temperature: 20-24°C
Humidity: 30-70%
Air changes: 15 changes/hour
Photoperiod: 12 hours light/dark

Route of administration:

oral: gavage

Vehicle:

water

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Stability data confirmed the test article formulations to be stable for at least 7 days. Analysis of weekly formulations show concentrations to be within ±7% of nominal concentration.

Details on mating procedure:

refer to details on study design

Duration of treatment / exposure:

14 days / oral

Frequency of treatment:

daily

Duration of test:

14 days

Dose / conc.:

0 mg/kg bw/day

Dose / conc.:

100 mg/kg bw/day

Dose / conc.:

400 mg/kg bw/day

Dose / conc.:

1 000 mg/kg bw/day

No. of animals per sex per dose:

25/gp

Control animals:

yes, concurrent vehicle

Details on study design:

Four groups of 100 pregnant female Wistar rats received the test article via oral gavage at concentrations of 0, 100, 400, 1000 mg/kg bw/d from day 6 of gestation to day 19 post-partum (pp) using a dose volume of 10 mL/kg. On day 20 of gestation, dams were subjected to caesarean section and macroscopic examination. The number of implantations, resorptions (early and late), corpora lutea, and uteri were determined, as well as placental weight, number of live and dead fetuses, litter and sex ratios. Live foetuses were individually weighed as well as their placenta and the foetuses were examined for external anomalies, soft tissue changes (half of the fetuses) and skeletal changes (remaining fetuses).

Maternal examinations:

Clinical signs of toxicity: observed once daily, in the morning throughout gestation and throughout the dosing period
Mortality: twice daily during the normal working week and once daily at weekends
Bodyweight: weighed on GD 0, 1, 3, 6, 8, 10, 13, 15, 17, 19 and 20.
Food consumption: recorded for the intervals GD 0-1, 1-3, 3-6, 6-8, 8-10, 10-13, 13-15, 15-17, 17-19 and 19-20
Necropsy: On day 20 of gestation, dams were subjected to caesarean section and macroscopic examination.

Ovaries and uterine content:

The number of implantations, resorptions (early and late), corpora lutea, and uteri were determined. Pregnancy status, no. of copora lutea, gravid uterus weight, number position and type of intra-uterine implantation were recorded as well as placental weight.

Fetal examinations:

Number of live and dead fetuses, litter and sex ratios. Live foetuses were individually weighed as well as foetuses examined for external anomalies. Half of the foetuses were eviscerated, skinned and fixed in ethanol and then stained according to a modified method of Kimmel and Trammell and examined for visceral anomalies under a low power binocular microscope. The remaining foetuses were placed in Harrison’s fluid for fixation and examined for any visceral findings according to the method of Barrow and Taylor.

Statistics:

Simultaneous comparison of all dose groups with the control group using the Dunnett-test (2-sided) for the hypothesis of equal means: Food consumption, body weight / weight change / weight gain, carcass weight, weight of unopened uterus, no. of corpora lutea, no. of implantations, no. of resorptions, no. of live fetuses, proportions of preimplantation loss, proportions of post-implantation loss, proportions of resorptions, proportion of live fetuses in each litter, litter mean fetal body weight, litter mean placental weight

Pairwise comparison of each dose group with the control group using Fisher's Exact test (1-sided) for the hypothesis of equal proportions: Female mortality, females pregnant, at terminal sacrifice, no. of litters with fetal findings

Pairwise comparison of each dose group with the control group using the Wilcoxon-test (1-sided) for the hypothesis of equal medians: Proportions of fetuses with malformations, variations and/or unclassified observations in each litter

Indices:

Conception rate was calculated as:
(no. of pregnant animals / no. of fertilised animals) x 100

Percentage pre-implantation loss was calculated as:
(no. of corpora lutea - no. of implantations) / no.of copora lutea x 100

Percentage post-implantation loss was calculated as:
(no. of implantations - no. of live foetuses) / no.of implantations x 100

Historical control data:

Historical control data provided (Jan 2009 - Feb 2014)

Clinical signs:

no effects observed

Description (incidence and severity):

No test article related effects were observed.

Mortality:

no mortality observed

Description (incidence):

All animals survived to the scheduled necropsy

Body weight and weight changes:

no effects observed

Description (incidence and severity):

No test article related effects were observed (refer to Table CA Table CA 7.8.2/03-1).

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

No test article related effects were observed.

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Description (incidence and severity):

No test article related effects (refer to Table CA 7.8.2/03-1)

Gross pathological findings:

no effects observed

Description (incidence and severity):

No treatment-related macroscopic abnormalities were seen at post mortem examination for animals that were killed at the end of the study.

Neuropathological findings:

not examined

Description (incidence and severity):

n/a

Histopathological findings: non-neoplastic:

not examined

Description (incidence and severity):

n/a

Histopathological findings: neoplastic:

not examined

Description (incidence and severity):

n/a

Other effects:

not examined

Description (incidence and severity):

n/a

Details on results:

No evidence of maternal toxicity when tested up tp the maximum recommended dose for sub acute toxicity studies, in accordance with current guideline requirements.

Number of abortions:

no effects observed

Description (incidence and severity):

No test article related effects were observed (refer to Table CA 7.8.2/03-2)

Pre- and post-implantation loss:

no effects observed

Description (incidence and severity):

No test article related effects were observed (refer to Table CA 7.8.2/03-3)

Total litter losses by resorption:

no effects observed

Description (incidence and severity):

Litters were unaffected by maternal treatment (refer to Table CA 7.8.2/03-3)

Early or late resorptions:

no effects observed

Description (incidence and severity):

Early and late resorptions were unaffected by maternal treatment (refer to Table CA 7.8.2/03-3)

Dead fetuses:

no effects observed

Description (incidence and severity):

The mean number of live young were unaffected by maternal treatment up to 1000 mg/kg bw/d (refer to Table CA 7.8.2/03-3)

Changes in pregnancy duration:

no effects observed

Description (incidence and severity):

No test article related effect observed (refer to Table CA 7.8.2/03-2)

Changes in number of pregnant:

no effects observed

Description (incidence and severity):

No test article related effect observed (refer to Table CA 7.8.2/03-2)

Other effects:

no effects observed

Details on maternal toxic effects:

The administration of 1,6-hexanediol at dose levels up to 1000 mg/kg bw/d (the maximum recommended dose for sub acute toxicity studies, in accordance with current guideline requirements) resulted in no maternal toxicity

Key result

Dose descriptor:

NOAEL

Effect level:

> 1 000 mg/kg bw/day

Based on:

test mat.

Remarks on result:

not determinable due to absence of adverse toxic effects

Abnormalities:

no effects observed

Fetal body weight changes:

no effects observed

Description (incidence and severity):

Placental and foetal weights at were unaffected by maternal treatment up to 1000 mg/kg bw/day (the maximum recommended dose for sub acute toxicity studies, in accordance with current guideline requirements) (refer to Table CA 7.8.2/03-3)

Reduction in number of live offspring:

no effects observed

Description (incidence and severity):

The mean number of live young were unaffected by maternal treatment up to 1000 mg/kg bw/day (the maximum recommended dose for sub acute toxicity studies, in accordance with current guideline requirements) (refer to Table CA 7.8.2/03-3)

Changes in sex ratio:

no effects observed

Description (incidence and severity):

Sex ratio were unaffected by maternal treatment up to 1000 mg/kg bw/day (the maximum recommended dose for sub acute toxicity studies, in accordance with current guideline requirements) (refer to Table CA 7.8.2/03-3)

Changes in litter size and weights:

no effects observed

Description (incidence and severity):

Litter size and weights at all dose levels were essentially similar to control and were considered to have been unaffected by maternal treatment (refer to Table CA 7.8.2/03-3)

Changes in postnatal survival:

no effects observed

Description (incidence and severity):

Post natal surivial was unaffected by maternal treatment up to 1000 mg/kg bw/day (deemed to be a maximum tolerated dose) (refer to Table CA 7.8.2/03-2 and Table CA 7.8.2/03-3)

External malformations:

no effects observed

Description (incidence and severity):

MALFORMATIONS:
External malformations were recorded for two fetuses of the control and three test article treated groups each (1 foetus from 100 mg/kg bw/d; 2 foetuses from 1000 mg/kg bw/d) had more than one malformation affecting the head. The total incidence of external malformations in treated animals did not differ significantly from the control group and was comparable to the historical control data (Table CA 7.8.2/03-4 and Table CA 7.8.2/03-5).

VARIATIONS:
No external variations were recorded.

Skeletal malformations:

no effects observed

Description (incidence and severity):

MALFORMATIONS:
Some skeletal malformations were detected in single foetuses of test article treated groups 100, 400 and 1000 mg/kg bw/d affecting the skull, vertebral column, sternum, ribs, fore- and hindlimbs and the pelvic girdle (Table CA 7.8.2/03-6 and Table CA 7.8.2/03-7). The incidences of these malformations were neither statistically significantly different from control nor dose-dependent and therefore were not considered biologically relevant. Most of these findings occured in the historical control data.

VARIATIONS:
For all test article treated groups, skeletal variations of different bone structures were observed, with or without effects on corresponding cartilages. The observed skeletal variations were related to several parts of foetal skeleton and appeared without a relation to dosing (Table CA 7.8.2/03-6 and Table CA 7.8.2/03-7). Variations that were both statistically significantly increase and outside the historical control range were limited to supernumeracy of the thoracic vertebra, observed in the low dose group (100 mg/kg bw/d). This however was not deemed to be test article related as the variations were note related to dose.

CARTILAGE OBSERVATIONS:
Some isolated cartilage findings without impact on the respective bony structures, which were designated as unclassified cartilage observations, occurred in all test article treated groups (Table CA 7.8.2/03-8). The observed unclassified cartilage findings were related to the skull, the vertebral column, the sternum and ribs and did not show any relation to dosing.

Visceral malformations:

no effects observed

Description (incidence and severity):

MALFORMATIONS:
Neither the type, distribution nor incidence of foetal findings observed during detailed visceral examinations indicated any adverse effect of maternal treatment on foetal growth or development at 300, 100 or 30 mg/kg/day (refer to Table CA 7.8.2/03-9 and Table CA 7.8.2/03-10).

VARIATIONS:
Some soft tissue variations were detected in all test article treated including the control group and included short innominate, dilated renal pelvis and dilated ureter. These variations were neither statistically significantly different from control nor dose-dependent and therefore, not considered biologically relevant (refer to Table CA 7.8.2/03-9 and Table CA 7.8.2/03-10).

Other effects:

no effects observed

Details on embryotoxic / teratogenic effects:

No effects were observed on foetal growth or development in the offspring of animals treated with up to 1000 mg/kg bw/d (the maximum recommended dose for sub acute toxicity studies, in accordance with current guideline requirements)

Key result

Dose descriptor:

NOAEL

Effect level:

> 1 000 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No effects were observed on foetal growth or development

Remarks on result:

other:

Abnormalities:

no effects observed

Description (incidence and severity):

No effects were observed on foetal growth or development

Key result

Developmental effects observed:

no

Lowest effective dose / conc.:

1 000 mg/kg bw/day

Table CA 7.8.2/03-1:
Bodyweight during gestation and gravid uterus weight at termination (±sd)

Parameter	Dose level (mg/kg bw/d)
	0	100	400	1000
GD 0	161 ±10.99	162 ±9.70	162 ±9.61	161 ±8.85
GD 1	174 ±10.90	174 ±11.55	174 ±12.00	171 ±9.29
GD 3	181 ±10.51	181 ±9.31	182 ±12.47	182 ±10.06
GD 6	192 ±12.32	192 ±10.00	193 ±13.03	192 ±10.03
GD 8	202 ±12.18	201 ±10.64	202 ±19.28	199 ±10.22
GD 10	212 ±13.14	211 ±10.76	214 ±14.25	209 ±10.54
GD 13	230 ±13.98	226 ±11.58	231 ±15.23	225 ±10.95
GD 15	243 ±15.83	239 ±12.47	242 ±16.51	236 ±11.48
GD 17	261 ±17.05	258 ±16.13	262 ±18.04	255 ±11.64
GD 19	284 ±19.55	279 ±17.15	283 ±20.06	276 ±12.59
GD 20	297 ±20.92	292 ±18.64	297 ±19.70	289 ±13.95
Gravid uterus weight	58.4 ±9.92	55.2 ±7.03	58.0 ±7.62	53.9 ±7.37

 

Table CA 7.8.2/03-2:
Summary of female performance

Parameter	Dose level (mg/kg bw/d)
	0	100	400	1000
Initial group size	25	25	25	25
No. not pregnant	1	0	0	1
No. pregnant	24	25	25	24
No. killed in extremis	0	0	0	0
With live young at day 20	24	25	25	24

 

Table CA 7.8.2/03-3:
Litter data on day 20 of gestation – group mean values (±sd)

Parameter	Dose level (mg/kg bw/d)
	0	100	400	1000
No. of Corpora Lutea	11.43 ±1.40	11.1 ±1.01	11.6 ±1.04	11.1 ±1.42
No. of live implants [m; f; total]	5.3 ±1.54; 5.1 ±2.00; 10.3 ±1.90	5.0 ±1.90; 5.1 ±1.75; 10.0 ±1.34	5.6 ±1.80; 4.8 ±1.55; 10.4 ±1.53	4.6 ±1.81; 5.4 ±2.24; 9.7 ±1.43
% male foetuses	50.8	49.4	54.0	47.6
No. of embryonic/foetal deaths [early; late; total]	0.8 ±1.18; 0.0 ±0.2; 0.8 ±1.17	0.5 ±0.65; 0.1 ±0.28; 0.6 ±0.65	0.8 ±1.13; 0.0 ±0.00; 0.8 ±1.13	0.9 ±0.88; 0.3 ±0.53; 1.2 ±1.01
Implantation loss % [pre; post]	1.4 ±3.76; 7.7 ±10.89	4.0 ±9.92; 5.6 ±6.08	3.5 ±6.03; 6.7 ±9.65	2.1 ±5.08; 10.6 ±9.45
Mean foetal weight (g) [M; F]	3.7 ±0.15; 3.5 ±0.11	3.6 ±0.20; 3.4 ±0.23	3.6 ±0.25; 3.4 ±0.23	3.6 ±0.23 3.3 ±0.21
Mean foetal weight (g)	3.6 ±0.13	3.5 ±0.5	3.5 ±0.21	3.5 ±0.23
Mean placental weight (g)	0.45 ±0.036	0.43 ±0.034	0.45 ±0.048	0.46 ±0.050

 

Table CA 7.8.2/03-4:
External foetal malformations – group incidence

Parameter	Dose level (mg/kg bw/d)
	0	100	400	1000
	No. of foetuses / litters examined
	248/24	251/25	261/25	233/24
Foetal incidence (%)	2 (0.8)	1 (0.4)	0.0	2 (0.9)
Litter incidence (%)	2 (8.3)	1 (4.0)	0.0	2 (8.3)
Mean % affected foetuses/litter	0.7	0.4	0.0	0.8

 

Table CA 7.8.2/03-5:
External foetal malformations – individual incidences

Parameter	Dose level (mg/kg bw/d)
	0	100	400	1000
External malformations (Dam #; Foetus #, sex)
Malrotated limb	9; 11, M	-	-	78; 08,F
Umbilical hernia	17; 11,M	-	-	-
Mandibular micrognathia, aglossia, cleft palate	-	43; 03,F	-	-
Mandibular micrognathia, aglossia	77; 04,M	-	-	-

 

Table CA 7.8.2/03-6:
Foetal skeletal development – group incidence

Parameter	Dose level (mg/kg bw/d)
	0	100	400	1000
	No. of foetuses / litters examined
	129/24	133/25	135/25	121/24
Skeletal malformations
Foetal incidence (%)	0.0	3(2.3)	2 (1.5)	2 (1.7)
Litter incidence (%)	0.0	2 (8.0)	2 (8.0)	2 (8.3)
Mean % affected foetuses/litter	0.0	2.1	1.5	1.4
Skeletal variations
Foetal incidence (%)	127 (88)	132 (99)	134 (99)	121 (100)
Litter incidence (%)	24 (100)	25 (100)	25 (100)	24 (100)
Mean % affected foetuses/litter	98.1	99.3	99.2	100

 

Table CA 7.8.2/03-7:
Foetal skeletal findings – individual incidences

Parameter	Dose level (mg/kg bw/d)
	0	100	400	1000
	Skeletal malformations (Dam #; Foetus #, sex)
Severely malformed skull bones	-	43; 03,F	-	-
Misshapen basisphenoid, cleft sternum, shortened humerus, shortened femur, shortened ilium	-	46; 10,M 46; 12,F	-	-
Shortened humerus	-	-	60; 01,M; 64; 07,F	-
Absent lumbar vertebra, branched rib	-	-	-	-
Severely malformed skull bones, severely malformed vertebral column	-	-	-	77; 04,M
Malpositioned and bipartite sternebra	-	-	-	84; 05,F
Skeletal variations (expressed as mean percentage of affected foetuses/litter)
Incomplete ossification of skull; unchanged cartilage	5.1	12.5*	8.8	5.5
Historical control data: Mean% (range): 8.8 (0.8 – 21.4)
Supernumerary thoracic vertebra	3.4	10.0*	6.5	4.2
Historical control data: Mean% (range): 3.9 (0.8 – 8.0)
Incomplete ossification of sacral arch; cartilage present	0.0	3.3*	0.8	0.0
Historical control data: Mean% (range): 1.7 (0.0 – 8.1)
Supernumerary rib (14^th); cartilage present	3.4	7.9	8.1	11.2
Historical control data: Mean% (range): 5.7 (1.4 – 11.7)

* p=0.05 Wilcoxon

 

Table CA 7.8.2/03-8:
Foetal skeletal findings – unclassified cartilage observations

Parameter	Dose level (mg/kg bw/d)
	0	100	400	1000
	No. of foetuses / litters examined
	129/24	133/25	135/25	121/24
Foetal incidence (%)	107 (83)	115 (86)	116 (86)	91 (75)
Litter incidence (%)	24 (100)	25 (100)	25 (100)	23 (96)
Mean % affected foetuses/litter	83.3	86.1	86.3	72.6

 

Table CA 7.8.2/03-9:
Foetal visceral findings – group incidence

Parameter	Dose level (mg/kg bw/d)
	0	100	400	1000
Soft tissue malformations
Foetal incidence (%)	0.0	0.0	0.0	2 (1.8)
Litter incidence (%)	0.0	0.0	0.0	2 (8.3)
Mean % affected foetuses/litter	0.0	0.0	0.0	1.7
Soft tissue variations
Foetal incidence (%)	6 (5.0)	2 (1.7)	4 (3.2)	1 (0.9)
Litter incidence (%)	6 (25)	2 (8.0)	4 (16)	1 (4.2)
Mean % affected foetuses/litter	5.2	1.6	3.8	0.8

 

Table CA 7.8.2/03-8:
Total foetal external, soft tissue and skeletal observations

Parameter	Dose level (mg/kg bw/d)
	0	100	400	1000
Total foetal malformations
Foetal incidence (%)	2 (0.0)	3 (1.2)	2 (0.8)	5 (2.1)
Litter incidence (%)	2 (8.3)	2 (8.0)	2 (8.0)	5 (21)
Mean % affected foetuses/litter	0.7	1.2	0.7	2.1
Total foetal variations
Foetal incidence (%)	133 (54)	134 (53)	138 (53)	122 (52)
Litter incidence (%)	24 (100)	25 (100)	25 (100)	24 (100)
Mean % affected foetuses/litter	53.7	53.4	53.2	52.2

 

Conclusions:

The daily administration of 1,6-hexanediol during the period of organogenesis, at dose levels up to 1000 mg/kg bw/d, was not associated with any adverse effect on the pregnant rat or on the developing conceptus. The maternal NOAEL was 1000 mg/kg bw/d (the maximum recommended dose for sub-acute toxicity studies, in accordance with current guideline requirements).

The NOAEL for developmental toxicity was set at 1000 mg/kg bw/d, the maximum dose tested. There were no indications of teratogenic potential at doses up to 1000 mg/kg bw/d (the maximum recommended dose for sub-acute toxicity studies).

Executive summary:

1,6 -hexanediol was daily administered by oral gavage at dose levels of 0, 100, 400 or 1000 mg/kg bw/d, to groups of 25 time-mated Wistar rats from day 6 to day 19 of gestation (GD) inclusive. On day 20 of gestation all rats were subjected to a caesarean section and macroscopic examination of the organs in the thoracic and abdominal cavities. The number of implantations, resorptions (early and late), corpora lutea, and uteri were determined, as well as placental weight, number of live and dead foetuses, litter and sex ratios. Live foetuses were individually weighed as well as their placenta and the foetuses were examined for external anomalies, soft tissue changes (half of the fetuses) and skeletal changes (remaining fetuses).

 

Treatment at dosages up to 1000 mg/kg bw/d was well tolerated by the pregnant females and was not associated with any effects on clinical condition, bodyweight, bodyweight change, food intake or necropsy observations.

 

There were no effects at dosages up to 1000 mg/kg/day on embryofoetal survival, growth and development.

 

The daily administration of 1,6 -hexanediol during the period of organogenesis, at dose levels up to 1000 mg/kg bw/d, was not associated with any adverse effect on the pregnant rat or on the developing conceptus. The maternal NOAEL was 1000 mg/kg bw/d (the maximum recommended dose for sub-acute toxicity studies, in accordance with current guideline requirements).

 

The NOAEL for developmental toxicity was set at 1000 mg/kg bw/d, the maximum dose tested. There were no indications of teratogenic potential at doses up to 1000 mg/kg bw/d (the maximum recommended dose for sub-acute toxicity studies).

Reference 3

Endpoint:

developmental toxicity

Type of information:

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

Adequacy of study:

key study

Justification for type of information:

The read across justification is attached in section 13.

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Key result

Dose descriptor:

NOAEL

Remarks:

The read across justification is attached in section 13.

Effect level:

ca. 0 other: The read across justification is attached in section 13.

Basis for effect level:

other: The read across justification is attached in section 13.

Remarks on result:

other: The read across justification is attached in section 13.

Key result

Dose descriptor:

NOAEL

Effect level:

ca. 0 other: The read across justification is attached in section 13.

Basis for effect level:

other: The read across justification is attached in section 13.

Remarks on result:

other: The read across justification is attached in section 13.

Developmental effects observed:

no

The read across justification is attached in section 13.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

300 mg/kg bw/day

Study duration:

subacute

Species:

rat

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Justification for classification or non-classification

Comparison with the CLP criteria

There was no indication that the read-across substances 1,6 -hexanediol (source 1) and/or 1,2 -hexanediol (source 2) had any negative effects on reproduction or development in rats based on the results of the studies conducted according to OECD 421 and 414. The target 1,9 -nonanediol is, therefore, proposed to be also devoid of any potential to cause any negative effects with respect to reproduction and development.

 

The criteria for classification for reprotoxicity were not met, therefore no reprotoxicity classification is proposed.