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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
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.
Cross-reference
Reason / purpose:
reference to same study

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, 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:
other: OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
no
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
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 (if other than submission substance): 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 the room temperature

Test animals

Species:
rat
Strain:
Crj: CD(SD)
Details on test animals 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
Analytical verification of doses or concentrations:
yes
Details on mating procedure:
- M/F ratio per cage: 1:1
- Length of cohabitation: up to 2 weeks
- Proof of pregnancy: vaginal plug or sperm in vaginal smear referred to as day 0 of pregnancy
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
No. of animals per sex per dose:
13
Control animals:
yes, concurrent vehicle

Examinations

Maternal 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
POST-MORTEM EXAMINATIONS: Yes
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.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Number of corpora lutea: Yes
- Number of implantations: Yes
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: No
- Skeletal examinations: No
- Head examinations: No
Statistics:
Statistical analyses were conducted by Mann-Whitney U-test, Fischer’s exact probability test, Dunnett’s test, and Kruskal-Wallis rank sum test.
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: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes. Remark: haematuria

Details on maternal toxic effects:
As a clinical sign, reddish urine (hematuria) was observed after approximately 4 hrs after dosing on the first administration day. 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 hematuria was found after day 2. Absolute and relative weights of spleen were increased in male and female groups at 125 mg/kg bw/day.

Effect levels (maternal animals)

Dose descriptor:
NOEL
Remarks:
systemic
Effect level:
8 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: haematuria

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
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 and sex ratio on postnatal day 4.

Effect levels (fetuses)

Dose descriptor:
NOEL
Remarks:
developmental
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 developmental parameters up to the highest dose tested.

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

Table 1. 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