Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records
Reference
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.
Qualifier:
according to
Guideline:
OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
Deviations:
no
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female
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
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
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
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%
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: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
not specified
Reproductive performance:
no effects observed
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.
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.
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
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
Reproductive effects observed:
not specified

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

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
125 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
The available information comprises an adequate and reliable study (Klimisch score 2) from a reference substance with similar structure and intrinsic properties. Read-across is justified based on structural similarity between the source and target substance, the source substance being a product of the hydrolysis of the target substance (refer to endpoint discussion for further details).
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Justification for grouping of substances and read-across

There are no data available on toxicity to reproduction / developmental toxicityof 2-(1-methylethoxy)ethyl acetate (CAS 19234-20-9). In order to fulfil the standard information requirements set out in Annex IX, 8.6, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006, read-across from structurally related substances is conducted.

In accordance with Article 13 (1) of Regulation (EC) No 1907/2006, "information on intrinsic properties of substances may be generated by means other than tests, provided that the conditions set out in Annex XI are met.” In particular for human toxicity, information shall be generated whenever possible by means other than vertebrate animal tests, which includes the use of information from structurally related substances (grouping or read-across).

Having regard to the general rules for grouping of substances and read-across approach laid down in Annex XI, Item 1.5, of Regulation (EC) No 1907/2006, whereby physicochemical, toxicological and ecotoxicological properties may be predicted from data for reference substance(s) by interpolation to other substances on the basis of structural similarity, 2-isopropoxy-ethanol (CAS 109-59-1) and acetic acid (CAS 64-19-7) are selected as reference substances for assessment of the repeated dose toxicity of 2-(1-methylethoxy)ethyl acetate.

The read-across is based on the metabolism of 2-(1-methylethoxy)ethyl acetate, in particular on the fact that the substance undergoes enzymatic ester hydrolysis resulting in the formation of 2-isopropoxy-ethanol and acetic acid. A detailed analogue approach justification is provided in the technical dossier (see IUCLID Section 13).

 

Overview of toxicity to reproduction

CAS #

19234-20-9

109-59-1

64-19-7

Chemical name

2-(1-methyl-ethoxy)ethyl acetate

2-isopropoxy-ethanol

Acetic acid

Molecular weight

146.18

104.15

60.05

Toxicity to reproduction

RA: CAS 109-59-1 and data waiving

Experimental result: NOAEL (fertility) = 125 mg/kg bw/d

--

(a) The substance subject to registration is indicated in bold font.

(b) Reference (read-across) substances are indicated in normal font. Lack of data for a given endpoint is indicated by “--“.

A reproductive and developmental toxicity screening test was conducted under OECD TG421 in compliance with GLP (MHLW, 2003). 2-(1-methylethoxy) ethanol was administered orally by gavage to rats (13 animals/sex/group) at 0 (vehicle control), 8, 30 and 125 mg/kg bw/day. Males were dosed from 14 days before mating to the day before scheduled sacrifice through the mating period (total 48 days). Females were dosed from 14 days before mating to 3 days after delivery through mating and gestation periods (total 41-47 days). Males were sacrificed and necropsied on day 49. Females and all live F1 pups were sacrificed and necropsied on day 4 of lactation. With regard to reproductive toxicity, no treatment-related change was observed in estrous cyclicity and copulation results (indices for copulation index, fertility index, paring days until copulation). Statistically significant prolongation of gestation length was found in the group at 125 mg/kg bw/day. The values expressed in days were 22.3, 22.3, 22.3 and 22.8 for control, 8, 30, and 125 mg/kg bw/day, respectively. Since all pregnant animals delivered on gestation day (GD) 22 or GD23, this was concluded an accidental change and a meaningless significant difference. There were no changes between control and treated groups in gestation index, number of corpora lutea, number of implantation sites and implantation index. No abnormalities were observed in delivery and lactation for dams in each group. Based on these results, NOAEL for reproductive toxicity was considered to be 125 mg/kg bw/day.

 

 

Conclusion for toxicity to reproduction

In a reproductive and developmental toxicity screening test, reproductive performance in parental animals was not affected up to 125 mg/kg bw/day. No abnormalities were observed in delivery and lactation for dams in each group. In F1 offspring, no abnormalities were found for the indices of development and growth up to 125 mg/kg bw/day. Based on these results, NOAELs for reproductive and developmental toxicity were considered to be 125 mg/kg bw /day.

In addition, a substance-tailored exposure-driven testing was followed for the hazard assessment of toxicity to reproduction. No significant exposure is expected throughout all relevant exposure scenarios according to Annex XI, section 3.2(a) (i), therefore testing for developmental toxicity is omitted in accordance with Annex VIII column 2 section 8.6.1. The justification is based on an exposure assessment in accordance with section 5 of Annex I.

Further details are given in the endpoint itself , as well as in the chapter "Toxicological information" and in chapter 9 and 10 of the CSR.


Short description of key information:
Based on read-across from 2-isopropoxyethanol (CAS No. 109-59-1):
NOAEL systemic, female = 8 mg/kg bw/d
NOAEL systemic, male = 30 mg/kg bw/d
NOAEL reproduction, male and female = 125 mg/kg bw/d

Justification for selection of Effect on fertility via oral route:
Hazard assessment is conducted by means of read-across from structural analogues/surrogates. The selected study is the most adequate and reliable study based on the identified similarities in structure and intrinsic properties between source and target substance and overall assessment of quality, duration and dose descriptor level (refer to the endpoint discussion for further details).

Effects on developmental toxicity

Description of key information
Based on read-across from 2-isopropoxyethanol (CAS No. 109-59-1):
NOAEL systemic maternal = 8 mg/kg bw/d
NOAEL developmental toxicity = 125 mg/kg bw/d
Link to relevant study records
Reference
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.
Reason / purpose:
reference to same study
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
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
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
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%
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.
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
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.
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.
Abnormalities:
not specified
Developmental effects observed:
not specified

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

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
125 mg/kg bw/day
Quality of whole database:
The available information comprises an adequate and reliable study (Klimisch score 2) from a reference substance with similar structure and intrinsic properties. Read-across is justified based on structural similarity between the source and target substance, the source substance being a product of the hydrolysis of the target substance (refer to endpoint discussion for further details).
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

Justification for grouping of substances and read-across

There are no data available on toxicity to reproduction / developmental toxicityof 2-(1-methylethoxy)ethyl acetate (CAS 19234-20-9). In order to fulfil the standard information requirements set out in Annex IX, 8.6, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006, read-across from structurally related substances is conducted.

In accordance with Article 13 (1) of Regulation (EC) No 1907/2006, "information on intrinsic properties of substances may be generated by means other than tests, provided that the conditions set out in Annex XI are met.” In particular for human toxicity, information shall be generated whenever possible by means other than vertebrate animal tests, which includes the use of information from structurally related substances (grouping or read-across).

Having regard to the general rules for grouping of substances and read-across approach laid down in Annex XI, Item 1.5, of Regulation (EC) No 1907/2006, whereby physicochemical, toxicological and ecotoxicological properties may be predicted from data for reference substance(s) by interpolation to other substances on the basis of structural similarity, 2-isopropoxy-ethanol (CAS 109-59-1) and acetic acid (CAS 64-19-7) are selected as reference substances for assessment of the repeated dose toxicity of 2-(1-methylethoxy)ethyl acetate.

The read-across is based on the metabolism of 2-(1-methylethoxy)ethyl acetate, in particular on the fact that the substance undergoes enzymatic ester hydrolysis resulting in the formation of 2-isopropoxy-ethanol and acetic acid. A detailed analogue approach justification is provided in the technical dossier (see IUCLID Section 13).

 

Overview of developmental toxicity

CAS #

19234-20-9

109-59-1

64-19-7

Chemical name

2-(1-methyl-ethoxy)ethyl acetate

2-isopropoxy-ethanol

Acetic acid

Molecular weight

146.18

104.15

60.05

Developmental toxicity

RA: CAS 109-59-1 and CAS 64-19-7 and data waiving

Experimental result: NOAEL (development) = 125 mg/kg bw/d

Experimental result: NOAEL = 1600 mg/kg bw/d

(a) The substance subject to registration is indicated in bold font.

(b) Reference (read-across) substances are indicated in normal font.

 

A reproductive and developmental toxicity screening test was conducted under OECD TG421 in compliance with GLP (MHLW, 2003). 2-(1-methylethoxy) ethanol was administered orally by gavage to rats (13 animals/sex/group) at 0 (vehicle control), 8, 30 and 125 mg/kg bw/day. Males were dosed from 14 days before mating to the day before scheduled sacrifice through the mating period (total 48 days). Females were dosed from 14 days before mating to 3 days after delivery through mating and gestation periods (total 41-47 days). Males were sacrificed and necropsied on day 49. Females and all live F1 pups were sacrificed and necropsied on day 4 of lactation. There were no changes between control and treated groups in gestation index, number of corpora lutea, number of implantation sites and implantation index. No abnormalities were observed in delivery and lactation for dams in each group. The treatment did not affect the indices for development and growth of F1 pups (birth index, live 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, sex ratio on postnatal day 4, and morphological examinations). Based on these results, NOAEL for developmental toxicity was considered to be 125 mg/kg bw/day.

A developmental toxicity study was conducted similar to EU Method B.31 (MHLW, 2003). Acetic acid was administered orally by gavage to 25 pregnant rats, 25 pregnant mice or 12 pregnant rabbits for 10 consecutive days (days 6-15 of gestation) with doses of 0, 16, 74.3, 345 and 1600 mg/kg bw/day. Females and all live F1 pups were subjected to caesarean section where they were sacrificed on day 20 (rats), 17 (mice), or 20 (rabbits). The administration of up to 1600 mg/kg bw/d of the test material to rats, mice or rabbits had no clearly discernible effect on nidation or on maternal or foetal survival. The number ab abnormalities seen either in soft or skeletal tissues of the test group did not differ from the number of occurring spontaneously in the sham-treated controls. Based on these results, NOAEL for developmental toxicity was considered to be 1600 mg/kg bw/day.

 

Conclusion for developmental toxicity

In a reproductive and developmental toxicity screening test, reproductive performance in parental animals was not affected up to 125 mg/kg bw/day 2-(1-methylethoxy) ethanol. No abnormalities were observed in delivery and lactation for dams in each group. In F1 offspring, no abnormalities were found for the indices of development and growth up to 125 mg/kg bw/day (highest dose tested). Based on these results, NOAELs for reproductive and developmental toxicity were considered to be 125 mg/kg bw /day.

In a developmental toxicity study the NOAEL for developmental toxicity of Acetic acid was considered to be 1600 mg/kg bw/day (highest dose tested).

In addition, a substance-tailored exposure-driven testing was followed for the hazard assessment of developmental toxicity. No significant exposure is expected throughout all relevant exposure scenarios according to Annex XI, section 3.2(a) (i), therefore testing for developmental toxicity is omitted in accordance with Annex VIII column 2 section 8.6.1. The justification is based on an exposure assessment in accordance with section 5 of Annex I.

Further details are given in the endpoint itself, as well as in the chapter "Toxicological information" and in chapter 9 and 10 of the CSR.


Justification for selection of Effect on developmental toxicity: via oral route:
Hazard assessment is conducted by means of read-across from structural analogues/surrogates. The selected study is the most adequate and reliable study based on the identified similarities in structure and intrinsic properties between source and target substance and overall assessment of quality, duration and dose descriptor level (refer to the endpoint discussion for further details).

Justification for classification or non-classification

Based on the available data on toxicity to reproduction/developmental toxicity of the breakdown products of hydrolysis, the data is insufficient for classification and labelling according to the classification criteria of Regulation (EC) 1272/2008 or Directive 67/548/EEC, and therefore the conclusion is data lacking