Registration Dossier

Diss Factsheets

Toxicological information

Toxicity to reproduction

Currently viewing:

Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Remarks:
based on test type (migrated information)
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
GLP-Guideline study, tested with the source substance 2-(1-Methylethoxy)ethanol (CAS No. 109-59-1). According to the ECHA guidance document “Practical guide 6: How to report read-across and categories (March 2010)”, the reliability was changed from RL1 to RL2 to reflect the fact that this study was conducted on a read-across substance.

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
2003
Reference Type:
secondary source
Title:
SIDS Initial Assessment Report For SIAM 28 Paris, France, 15-17 April 2009, Chemical Name: 2-(1-methylethoxy)ethanol, CAS Number: 109-59-1
Author:
OECD SIDS
Year:
2009
Bibliographic source:
http://webnet.oecd.org/Hpv/UI/SIDS_Details.aspx?id=C1C0D516-D068-4A01-B34D-7C61F59A21D1

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
Deviations:
no
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Reference substance name:
2-isopropoxyethanol
EC Number:
203-685-6
EC Name:
2-isopropoxyethanol
Cas Number:
109-59-1
IUPAC Name:
2-isopropoxyethanol
Details on test material:
- Name of test material (as cited in study report): 2-(1-Methylethoxy)ethanol
- Molecular formula (if other than submission substance): C5H12O2
- Molecular weight: 104.15
- Analytical purity :>/= 99. 5%
- Impurities (identity and concentrations): water (<0.1 %)
- Lot No.: 30321- Stability under test conditions: The stability of test material was identified by analysis of the remainder.
- Storage condition of test material: at room temperature

Test animals

Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Japan, Inc. Atsugi
- Fasting period before study: 18 h
- Housing: animals were housed individually in metallic cages with wire mesh bottoms.
- Diet: ad libitum
- Water: ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-25
- Humidity (%): 40-75
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on mating procedure:
- M/F ratio per cage: 1/1
- Length of cohabitation: 2 weeks
- Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as Day 0 of pregnancy
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
Males: 48 days
Females: from 14 days prior to mating, during mating and 3 days of lactation (41-47 days)
Frequency of treatment:
daily, 7 days/week
Doses / concentrations
Remarks:
Doses / Concentrations:
8, 30 and 125 mg/kg bw/day
Basis:
actual ingested
No. of animals per sex per dose:
13
Control animals:
yes, concurrent vehicle

Examinations

Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: All males and females were observed once per day every day during before administration period, twice per day every day during the administration period.
DETAILED CLINICAL OBSERVATIONS: No
BODY WEIGHT: Yes
- Time schedule for examinations:
Male: On administration days 1, 8, 15, 22, 29, 36, 43 and autopsy day.
Female: On administration days 1, 8, 15 and 22, After confirmation of mating, on gestation days 0, 7, 14 and 20, and after delivery, lactation days 0 and 4 and autopsy day. In females mating, on administration days 36, 43, 50 and autopsy day.
FOOD CONSUMPTION: Yes
- Food consumption:
Male: On administration days 1-2, 8-9, 15-16, 36-37 and 43-44.
Female: Before mating, on administration days 1-2, 8-9 and 14-15, and after confirmation of mating, on gestation days 0-1, 7-8, 14-15 and 20-21, and after delivery, lactation days 3-4.
WATER CONSUMPTION: No
Oestrous cyclicity (parental animals):
The estrous cycles in all female were determined daily by vaginal smears from acclimation period to mating.
Sperm parameters (parental animals):
Parameters examined in P male parental generations:testis weight, epididymis weight
Litter observations:
PARAMETERS EXAMINED
The following parameters were examined in F1 offspring: number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioral abnormalities.

GROSS EXAMINATION OF DEAD PUPS:
external and internal abnormalities; possible cause of death was determined for found dead.
Postmortem examinations (parental animals):
Male animals were sacrificed and necropsied on day following day 48, and the organs were removed for spleen, testis, epididymis, ventral prostate, coagulation gland and seminal vesicle. Of these, spleen, testis, epididymis were weighed. All females delivered were sacrificed and necropsied on day 4 of lactation, and the organs were removed for spleen, ovary, uterus and vagina. Spleen was weighed. The numbers of uterine implantation sites and corpora lutea were counted and implantation index was calculated. Histopathological examination was conducted for testis and epididymis of all male specimens and for ovary of all female specimens in the control and high dose groups.
Postmortem examinations (offspring):
Live pups were weighed on day 0 and 4 of lactation, and were necropsied on day 4 of lactation
Statistics:
Statistical analyses were conducted by Mann-Whitney U-test, Fischer’s exact probability test, Dunnett’s test, and Kruskal-Wallis rank sum test.
Reproductive indices:
Copulation index = (Number of copulated pairs/Number of mated pairs) x 100%
Fertility index = (Number of pregnant animals/Number of copulated pairs) x 100%
Offspring viability indices:
Delivery index = (Number of pups born/Number of implantation sites) x 100%
Birth index = (Number of live pups on day 0/ Number of implantation sites) x 100%
Live birth index = (Number of live pups on day 0/ Number of pups born) x 100%
Sex ratio on day 0 = (Number of male pups/ Number of female pups) x 100%
Viability index = (Number of live pups on day 4/ Number of live pups on day 0) x 100%

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
effects observed, treatment-related
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Other effects:
no effects observed

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
not specified
Reproductive performance:
no effects observed

Details on results (P0)

No deaths were observed in both sex groups. As a clinical sign, reddish urine (haematuria) was observed after approximately 4 hrs after dosing on the first administration day. Seven males and all females in the group at 125 mg/kg bw/day, and one female in the group at 30 mg/kg bw/day showed reddish urine until before administration of the next day. No haematuria was found after day 2. In body weight during administration period, no change was observed in both sex groups. In food intake significantly low value was found on days 1-2 in male group at 125 mg/kg bw/day, however, no change was observed in other groups. In necropsy findings, enlargement of spleen was observed in 2 male animals at 125 mg/kg bw/day. Except for this, there were no dose-related changes in any organ. In organ weight, there were no change in testis and epididymis between control and treated groups. Absolute and relative weights of spleen were increased in male and female groups at 125 mg/kg bw/day.In histopathological findings, in spleen of two males enlargement of spleen was observed at necropsy, extramedullary haematopoiesis and deposition of brown pigment were recognized. No dose related histopathological changes were found in testis and epididymis in males and ovary in females.No treatment-related change was observed in estrous cycle. As a result of mating, no treatment-related change was observed in copulation and fertility indexes. There were no changes in paring days until copulation or mean times of oestrous during the mating period between control and treated groups.Gestation length was significantly prolonged at 125 mg/kg, however, all pregnant animals delivered on gestation day (GD) 22 or GD 23, and therefore it was considered as an accidental change and a meaningless significant difference by the author. No treatment-related effect was observed in gestation index. There were no treatment-related changes in number of corpora lutea, number of implantation sites or implantation index. No abnormalities were observed in delivery and lactation conditions in dams of each group.The treatment did not affect the indices of birth index, number of pups born, delivery index, number of live pups, live birth index, number of live pups on day 4 of lactation, viability index or sex ratio on postnatal day 4.

Effect levels (P0)

open allclose all
Dose descriptor:
NOAEL
Remarks:
systemic
Effect level:
8 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: haematuria
Dose descriptor:
NOAEL
Remarks:
systemic
Effect level:
30 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: haematuria
Dose descriptor:
NOAEL
Remarks:
reproduction
Effect level:
125 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No test substance related effects were observed any reproductive parameters up to the highest dose tested.

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Sexual maturation:
no effects observed
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
no effects observed
Histopathological findings:
not specified

Effect levels (F1)

Dose descriptor:
NOAEL
Remarks:
developmental
Generation:
F1
Effect level:
125 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no adverse effects observed

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

Table 1. Results on reproductive performance.

Dose (mg/kg bw/day)

Control

8

30

125

Number of females examined

13

13

13

13

Mean length of estrous cycle [days]

4.0 ± 0.0

4.0 ± 0.0

4.0 ± 0.1

4.1 ± 0.4

Number of animals showing each type of cycle during pre-treatment period

13

13

12

13

Changes of oestrous cycle after treatment

13

13

12

12

Mean times of oestrous during mating

1.0 ± 0.0

1.0 ± 0.0

1.0 ± 0.0

1.1 ± 0.3

Number of mated pairs

13

13

13

13

Copulation indexin %

100.0

100.0

100.0

100.0

Number of pregnant animals

13

12

12

13

Fertility indexin %

100.0

92.3

92.3

100.0

Paring days until copulation

2.5 ± 1.1

2.4 ± 1.0

2.5 ± 1.1

2.5 ± 1.5

Number of pregnant females with live pups

13

12

12

13

Gestation index %

100.0

100.0

100.0

100.0

Gestation length in days

22.3 ± 0.5

22.3 ± 0.5

22.3 ± 0.5

22.8 ± 0.4*

Number of corpora lutea

15.0 ± 1.9

15.4 ± 1.9

14.8 ± 1.2

15.9 ± 2.4

Number of implantation sites

14.7 ± 2.0

14.8 ± 1.8

13.9 ± 2.4

14.9 ± 2.7

*: p <0.05, **: p<0.01

Table 2. Developmental parameters of offspring.

Dose (mg/kg bw/day)

Control

8

30

125

Day 0 of lactation

Number of pups born

13.8 ± 1.9

13.9 ± 2.49

13.2 ± 2.4

13.3 ± 3.2

Delivery index (%)

94.3 ± 4.3

93.9 ± 7.3

94.4 ± 6.4

88.3 ± 12.0

Number of live pups

13.8 ± 1.9

13.9 ± 2.4

12.9 ± 2.4

13.2 ± 3.1

Birth index (%)

94.3 ± 4.3

93.9 ± 7.3

92.7 ± 6.8

87.8 ± 11.6

Live birth index (%)

100.0 ± 0.0

100.0 ± 0.0

98.2 ± 4.4

99.5 ± 1.6

Sex ratio on Day 0 (%)

49.72 ± 16.0

54.4 ± 15.7

48.7 ± 15.8

49.3 ± 10.8

Day 4 of lactation

Number of live pups

13.8 ± 2.0

13.9 ± 2.4

12.6 ± 2.4

13.2 ± 3.0

Viability index (%)

99.4 ± 2.1

100.0± 0.0

97.6 ± 6.3

99.5 ± 1.6

Sex ratio on Day 4

49.5 ± 15.8

54.4 ± 15.7

49.3 ± 16.6

49.5 ± 10.6

Applicant's summary and conclusion

Categories Display