Bis[(3,4-epoxycyclohexyl)methyl] adipate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

In accordance with column 2 of REACH Annex VIII, information requirement section 8.7.1, the study does not need to be conducted because a pre-natal development toxicity study is available.

Link to relevant study records

Reference

Endpoint:

screening for reproductive / developmental toxicity

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

the study does not need to be conducted because a pre-natal developmental toxicity study is available

Effect on fertility: via oral route

Endpoint conclusion:

no study available

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effects on developmental toxicity

Description of key information

Read-across to structurally similar substance, Varsho (2007)

Based on the results of this study, a dose level of 25 mg/kg/day administered orally to rats was considered to be the no-observed-adverse-effect level (NOAEL) for maternal toxicity and a dose level of 125 mg/kg/day was considered to be the NOAEL for prenatal developmental toxicity.

Link to relevant study records

Reference

Reference 1

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

15 January 2002 to 29 January 2007.

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Justification for type of information:

Read across to material with the same functional groups.

Reason / purpose for cross-reference:

other: read-across target

Qualifier:

according to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)

Principles of method if other than guideline:

Not relevant

GLP compliance:

yes

Limit test:

no

Specific details on test material used for the study:

- Name of test material (as cited in study report): cycloaliphatic epoxy resin ERL-4221
- Physical state: Clear, viscous, colourless liquid.
- Analytical purity: 92.3% - dose levels were adjusted to take acount of this purity
- Purity test date: 26 June 2000
- Lot/batch No.: 87068
- Expiration date of the lot/batch: Not documented
- Stability under test conditions: Stable under conditions outlined by the sponsor.
- Storage condition of test material: room temperature and protected from light.

Species:

rat

Strain:

other: Crl:CD®(SD)IGS BR

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: approximately 70 days old on arrival and circa 84 days old on study initiation
- Weight at study initiation: 223 - 307g
- Housing: All rats were individually housed in clean, wire-mesh cages suspended above cage-board on arrival to the lab and until pairing. The rats were paired for mating in the home cage of the male. Following positive identification of mating, the females were returned to an individual suspended wire-mesh cage. Nesting material was not provided as animals were euthanized before parturition.
- Diet: provided ad libitum.
- Water: Reverse-osmosis purified (on-site) drinking water, delivered by an automatic watering system ad libitum.
- Acclimation period: 14 days

ENVIRONMENTAL CONDITIONS
- Temperature: 21.2 to 22.4 °C
- Humidity: 34.3 to 48.1 %
- Air changes: approximately 10 fresh air changes per hour.
- Photoperiod: 12-hour light/12-hour dark photoperiod

IN-LIFE DATES: From: 15 January 2002 To: 30 April 2002

Route of administration:

oral: gavage

Vehicle:

corn oil

Remarks:

Mazola®

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
For the preparation of test material formulations, the appropriate amount of test material for each group was weighed into tared, calibrated storage containers for weight-to-volume (w/v) mixtures. The vehicle was added in small increments while stirring slowly (not creating a vortex). The containers were occasionally swirled by hand while adding the vehicle. A sufficient amount of vehicle was added to bring the volume to the calibration mark. The formulations were mixed slowly until uniform, using a magnetic stir bar. After uniformity was achieved, formulations were swirled prior to sampling and use for dose administration.

Fresh dosing formulations were prepared daily.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Prior to initial dose administration, samples (10 mL each) were collected from the top, middle and bottom strata of the 5, 25, 125 and 500 mg/kg/day dosing formulations and one sample (10 mL) was collected from the control group for homogeneity determination. Samples (10 mL each) for concentration analysis were collected weekly from each dosing formulation (including the control group). The test material concentration was measured using gas chromatography with a mass selective detector.
Homogeneity and stability of the test material formulations had been established in previous studies which are not summarised here.

Details on mating procedure:

- Impregnation procedure: cohoused
- If cohoused: Each female was placed in a suspended wire mesh cage with a resident male from the same strain and source.
- M/F ratio per cage: Study report indicates the ratio was one male and one female per cage.
- Length of cohabitation: Not documented

- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: copulatory plug and presence of sperm in vaginal smear indicated a positive mating which was referred to as day 0 of pregnancy
- Any other deviations from standard protocol: No

Duration of treatment / exposure:

Rats were treated from Day 6 to Day 19 of gestation

Frequency of treatment:

Once daily

Duration of test:

20 days (from Day 0 of gestation).

Dose / conc.:

5 mg/kg bw/day

Dose / conc.:

25 mg/kg bw/day

Dose / conc.:

125 mg/kg bw/day

Dose / conc.:

500 mg/kg bw/day

No. of animals per sex per dose:

25 female rats per dose group.

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: Individual dosages were based on the most recently recorded body weights to provide the correct mg/kg/day dose.
- Rationale for animal assignment (if not random): Not documented
- Other: On gestation day 20, all maternal rats were euthanised by carbon dioxide inhalation and a laparohysterectomy was performed.

Maternal examinations:

CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: All rats were observed twice daily, once in the morning and once in the afternoon, for moribundity and mortality. Individual detailed clinical observations were recorded from days 0 through 20 of gestation (prior to dose administration during the treatment period). Animals were also observed for signs of toxicity approximately 1 hour following dose administration.

BODY WEIGHT: Yes
- Time schedule for examinations: Individual maternal body weights were recorded on gestation days 0 and 6-20 (daily). Group mean body weights were calculated for each of these days. Mean body weight changes were calculated for each corresponding interval and also for gestation days 6-9, 9-12, 12-20, 6-20 and 0-20.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
Individual food consumption was recorded on gestation days 0 and 6-20 (daily). Food intake was reported as g/animal/day and g/kg/day for the corresponding body weight change intervals. On the occasions when food intake could not be measured for one of the days in a given interval (due to spillage, contamination with urine, weighing error, etc.), values were calculated using the appropriate number of days for that interval.

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: The thoracic, abdominal and pelvic cavities were opened by a ventral midline incision and the contents were examined. The uterus and ovaries were excised. The number of corpora lutea on each ovary was recorded. The trimmed uterus was weighed and opened, and the number and location of all in utero foetuses, early and late resorptions and the total number of implantation sites were recorded. The placentae were also examined.

OTHER:
Organ Weights: The liver and kidneys were weighed.
Gravid Uterine Weight: Gravid uterine weight was collected and net body weight and net body weight change were calculated and presented for each gravid female.

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other: The placentae were also examined.

Fetal examinations:

- External examinations: Yes: all per litter, including, eyes, palate and external orifices
- Soft tissue examinations: Yes
- Skeletal examinations: Yes
- Head examinations: Yes: half per litter were placed in Bouin's fixative for subsequent soft tissue examination and the heads from the other half of the litter were examined by a mid-coronal slice.

Statistics:

Analyses were conducted using two-tailed tests for minimum significance levels of 1 and 5 %, comparing each test material-treated group to the control group by sex. Mean maternal body weights (absolute and net), body weight changes (absolute and net) and food consumption, gravid uterine weights, organ weights, numbers of corpora lutea, implantation sites and viable foetuses, and foetal body weights (separately by sex and combined) were subjected to a parametric one-way analysis of variance (ANOVA) to determine intergroup differences. If the ANOVA revealed statistically significant (p<0.05) intergroup variance, Dunnett's test was used to compare the test article-treated groups to the control group.

Mean litter proportions (percent per litter) of prenatal data (viable and nonviable foetuses, early and late resorptions, total resorptions, pre- and pos-timplantation loss, and foetal sex distribution) were subjected to the Kruskal-Wallis nonparametric ANOVA test to determine intergroup differences. If the ANOVA revealed statistically significant (p<0.05) intergroup variance, the Mann-Whitney U-test was used to compare the test material-treated groups to the control group. The same statistical analysis was conducted to evaluate the significance of mean litter proportions of total foetal malformations and developmental variations (external, visceral, skeletal and combined) and of each particular external, visceral and skeletal malformation or variation.

Indices:

No information

Historical control data:

Historical Control Data was documented.

Clinical signs:

not specified

Dermal irritation (if dermal study):

not examined

Mortality:

no mortality observed

Description (incidence):

All animals survived to the scheduled necropsy on gestation day 20.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

- A mean maternal body weight loss (2 g) was observed in the 500 mg/kg/day group during gestation days 6-9 due to a mean body weight loss (11 g) on the first day of dosing (gestation days 6-7). The difference from the control group gain was statistically significant (p<0.01). When the entire treatment period (gestation days 6-20) was evaluated, mean body weight gain in this group (500 mg/kg/day treatment group) was reduced (statistically significant at p<0.05) compared to the control group value which were considered to be test material related.
- A mean body weight loss (6 g) was observed in the 125 mg/kg/day group on the first day of dose administration (gestation days 6-7). However, the loss was followed by a statistically significant (p<0.05) increase in mean body weight gain during gestation days 8-9 compared to that in the control group and the loss was not of sufficient magnitude to affect the mean body weight gain value during gestation days 6-9. Therefore, this transient loss, while attributed to the test material, was not considered to be adverse. No test material-related effects on mean body weights, body weight gains, net body weights, net body weight gains and gravid uterine weights were observed in the 5 and 25 mg/kg/day groups.
- In the 500mg/kg/day treatment group, lower mean body weights and reduced body weight gain and food consumption was observed which at times achieved significance.
- In the 125mg/kg/day treatment group, transient initial mean body weight losses and reduced food consumption were observed, some of which were statistically significant. However, due to the rapid amelioration of the effects, these observations were not considered to have an adverse effect.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

- In the 500mg/kg/day treatment group, lower mean body weights and reduced body weight gain and food consumption was observed which at times achieved significance.
- In the 125mg/kg/day treatment group, transient initial mean body weight losses and reduced food consumption were observed, some of which were statistically significant. However, due to the rapid amelioration of the effects, these observations were not considered to have an adverse effect.

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

Increased mean kidney weight were observed in both the 500mg/kg/day and 125 mg/kg/day treatment groups.

Gross pathological findings:

not specified

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Other effects:

not examined

Number of abortions:

not specified

Pre- and post-implantation loss:

no effects observed

Description (incidence and severity):

- Mean numbers of corpora lutea and implantation sites in all groups, including the control group, were similar.

Total litter losses by resorption:

not specified

Early or late resorptions:

not specified

Dead fetuses:

no effects observed

Description (incidence and severity):

- Intrauterine growth and survival in the 5, 25 and 125 mg/kg/day groups were unaffected by test material administration.

Changes in pregnancy duration:

not examined

Changes in number of pregnant:

not specified

Other effects:

not examined

Key result

Dose descriptor:

NOAEL

Effect level:

25 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

body weight and weight gain

food consumption and compound intake

organ weights and organ / body weight ratios

Abnormalities:

not specified

Fetal body weight changes:

not specified

Description (incidence and severity):

- In the 500 mg/kg/day treatment group, a statistically significant reduced mean foetal body weight was observed.

Reduction in number of live offspring:

not specified

Changes in sex ratio:

not specified

Changes in litter size and weights:

not specified

Changes in postnatal survival:

not specified

External malformations:

effects observed, non-treatment-related

Description (incidence and severity):

One foetus in the 25 mg/kg/day and two foetuses in the 125 mg/kg/day groups had external malformations. The foetus in the 25 mg/kg/day group had bilateral anophthalmia, consisting skeletally of orbits that appeared smaller than normal. In the 125mg/kg/day treatment group, one foetus had anasarca while the 2nd foetus had a conjoined twin (two complete oedematous foetuses were joined along the ventral surface from the neck to the umbilicus). These malformations were considered spontaneous since no external malformations were observed in the 500 mg/kg/day group.

Skeletal malformations:

effects observed, treatment-related

Description (incidence and severity):

- There were no skeletal malformations observed in foetuses in this study. However, in the 500mg/kg/day group, the mean litter proportion of cervical centrum no. 1 ossified (11.7 %) in this group was reduced (statistically significant at p<0.01) compared to the control group value (25.7 %). While this value was considered to be within the range of the historical control data, it indicated evidence of developmental delay in conjunction with reduced mean foetal body weights. The mean litter proportions for unossified sternebra(e) nos. 5 and/or 6 (26.4 %) and unossified sternebra(e) nos. 1, 2, 3 and/or 4 (1.6 %) were increased in the 500 mg/kg/day group compared to the control group values (7.6 and 0.3 %, respectively). These values were also above the maximum values in the historical control data (21.4 and 1.0 %, respectively). These skeletal variations were also attributed to the test material as further indication of developmental delay. Other skeletal developmental variations also occurred in all dose groups, however, no relationship to the test material was evident.

Visceral malformations:

effects observed, non-treatment-related

Description (incidence and severity):

Soft tissue malformations were observed in two foetuses in the 125 mg/kg/day group. One foetus had a retroesophageal aortic arch in addition to an enlarged aorta. In the 2nd foetus, situs inversus was observed. These malformations were considered to be spontaneous since no soft tissue malformations were observed in the 500 mg/kg/day group. Several foetuses also displayed soft tissue findings that were not classified as malformations or developmental variations and were not included.

Other effects:

not examined

Key result

Dose descriptor:

NOAEL

Effect level:

125 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

fetal/pup body weight changes

skeletal malformations

Key result

Developmental effects observed:

yes

Lowest effective dose / conc.:

500 mg/kg bw/day

Treatment related:

yes

Relation to maternal toxicity:

developmental effects as a secondary non-specific consequence of maternal toxicity effects

Dose response relationship:

yes

Relevant for humans:

not specified

5, 25, 125 and 500 mg/kg bw/day doses were administered for 20 days from day 0 of gestation.  

At 500 mg/kg bw/day the maternal effects noted included - lower mean body weights (including a mean body weight loss from gestation days 6-7) and reduced body weight gain and food consumption; increased mean kidney weight. Necropsy revealed depressed renal cortex in one female at 125 and two females at 500 mg/kg bw/day and dilated renal pelvis in one control female. No treatment relationship was established. Maternal organ weights – mean kidney weights for 125 and 500 mg/kg bw/day groups were 9.6 and 12 % higher than controls.

At 125 mg/kg bw/day the maternal effects observed included - Transient, initial mean body weight losses and reduced food consumption and increased mean kidney weight.

No test material-related effects were observed in the 5 and 25 mg/kg/day groups.

No maternal deaths occurred at any dose level. No adverse clinical signs of reaction to treatment at 5 to 500 mg/kg bw/day.

Test material-related developmental effects were noted in the 500 mg/kg/day group - Reduced mean foetal body weight and increased skeletal developmental variations (reduced mean litter proportion of cervical centrum no. 1 ossified and increased mean litter proportions of unossified sternebrae). Mean foetal weight at 500 mg/kg bw/day reduced below minimum for historical database.

No foetal effects were observed at the maternally toxic level of 125 mg/kg bw/day, or at lower doses. Intrauterine growth and survival was unaffected at 125 mg/kg bw/day.

No maternal effects noted at 5 or 25 mg/kg bw/day

No foetal effects evident at 5 or 25 mg/kg bw/day

No foetal malformations at any dose level 5-500 mg/kg bw/day

No developmental variations observed at 5, 25 or 125 mg/kg bw/day

Overall bodyweight gain in high dose dams was significantly reduced – an initial weight loss in GD 6-9 and then reduced weight gain GD 18-20. While it is unlikely the reduced gains on days 18-20 would have affected foetal development the initial weight loss in this group may have affected the intrauterine foetal growth/development. No such effects were evident in the dams dosed at 125 mg/kg bw.

 

Skeletal developmental variations – in the 500 mg/kg bw group – limited to cervical centrum no 1 ossified, the mean litter proportion was reduced - 11.7% compared with 25 % in controls. While these percentages were within the lab background range, it was considered the variation, in conjunction with reduced foetal bodyweight, was evidence of delayed development induced by the test material. The mean litter proportion for unossified sternebrae nos 5 and 6 (26.4 %) was increased compared with controls (7.6 %) and higher than the lab background upper range (21.4 %) Similarly unossified sternebrae 1,2,3 and 4 incidence/proportion was increased (1.6 %) compared with controls (0.3 %) and historic background (1 %). These sternebral changes were also considered indicative of delayed development at the high dose level.

  

It was concluded that the maternal NOAEL is 25 mg/kg based on increased kidney weight at 125 mg/kg bw/day.

The prenatal developmental NOAEL is 125 mg/kg based on observations of skeletal variations indicative of delayed development at 500 mg/kg bw/day only.

Conclusions:

Based on the results of this study, a dose level of 25 mg/kg/day administered by oral gavage to rats was considered to be the no-observed-adverse-effect level (NOAEL) for maternal toxicity and a dose level of 125 mg/kg/day was considered the NOAEL for prenatal developmental toxicity.

Executive summary:

The prenatal developmental toxicity of the test material was investigated in accordance with the standardised guidelines OECD 414 and EPA OPPTS 870.3700, under GLP conditions.

In the study conducted by Varsho (2007), the test material was evaluated for its potential to act as a maternal and/or developmental toxicant. The test material was administered in the vehicle (corn oil) via oral gavage to four groups of 25 female Crl:CD®(SD)IGS BR rats. The rats were dosed once daily from gestation days 6 through 19 at concentration levels of 5, 25, 125 and 500 mg/kg/day. The control group received the vehicle on the same dosing regimen. All animals were observed twice daily for appearance and behaviour. Clinical observations, body weights and food consumption were recorded at appropriate intervals. On gestation day 20, a laparohysterectomy was performed on all females. The uteri, placentae and ovaries were examined, and the numbers of foetuses, early and late resorptions, total implantations and corpora lutea were recorded. Gravid uterine weights were recorded, and net body weights and net body weight changes were calculated. The foetuses were weighed, sexed and examined for external, visceral and skeletal malformations and developmental variations.

All females survived to the scheduled necropsy. In the 500 mg/kg/day group, maternal animals had lower mean body weights (including a mean body weight loss from gestation days 6-7) and reduced body weight gain and food consumption (occasionally statistically significant) and also had an increased mean kidney weight which was statistically significant. In the same dose group, a statistically significant reduced mean foetal body weight was also observed and increased skeletal developmental variations (reduced mean litter proportion of cervical centrum no. 1 ossified [statistically significant] and increased mean litter proportions of unossified sternebrae [not statistically significant]) were also observed.

In the 125 mg/kg/day treatment group, a statistically significant increased mean kidney weight was observed in maternal animals. In addition to this, transient, initial mean body weight losses and reduced food consumption (some statistically significant). These observations were not considered to be adverse due to the rapid amelioration of the effects.

Based on the results of this study, a dose level of 25 mg/kg/day administered orally to rats was considered to be the no-observed-adverse-effect level (NOAEL) for maternal toxicity and a dose level of 125 mg/kg/day was considered to be the NOAEL for prenatal developmental toxicity.

Reference 2

Endpoint:

developmental toxicity

Type of information:

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

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study conducted on read-across material

Justification for type of information:

Read across to material with the same functional groups.

Reason / purpose for cross-reference:

read-across source

Key result

Dose descriptor:

NOAEL

Effect level:

25 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

body weight and weight gain

food consumption and compound intake

organ weights and organ / body weight ratios

Abnormalities:

not specified

Key result

Dose descriptor:

NOAEL

Effect level:

125 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

fetal/pup body weight changes

skeletal malformations

Key result

Developmental effects observed:

yes

Lowest effective dose / conc.:

500 mg/kg bw/day

Treatment related:

yes

Relation to maternal toxicity:

developmental effects as a secondary non-specific consequence of maternal toxicity effects

Dose response relationship:

yes

Relevant for humans:

not specified

Effect on developmental toxicity: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

125 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

Additional information

Read-across to structurally similar substance, Varsho (2007)

The prenatal developmental toxicity of the test material was investigated in accordance with the standardised guidelines OECD 414 and EPA OPPTS 870.3700, under GLP conditions.

In the study conducted by Varsho (2007), the test material was evaluated for its potential to act as a maternal and/or developmental toxicant. The test material was administered in the vehicle (corn oil) via oral gavage to four groups of 25 female Crl:CD®(SD)IGS BR rats. The rats were dosed once daily from gestation days 6 through 19 at concentration levels of 5, 25, 125 and 500 mg/kg/day. The control group received the vehicle on the same dosing regimen. All animals were observed twice daily for appearance and behaviour. Clinical observations, body weights and food consumption were recorded at appropriate intervals. On gestation day 20, a laparohysterectomy was performed on all females. The uteri, placentae and ovaries were examined, and the numbers of foetuses, early and late resorptions, total implantations and corpora lutea were recorded. Gravid uterine weights were recorded, and net body weights and net body weight changes were calculated. The foetuses were weighed, sexed and examined for external, visceral and skeletal malformations and developmental variations.

All females survived to the scheduled necropsy. In the 500 mg/kg/day group, maternal animals had lower mean body weights (including a mean body weight loss from gestation days 6-7) and reduced body weight gain and food consumption (occasionally statistically significant) and also had an increased mean kidney weight which was statistically significant. In the same dose group, a statistically significant reduced mean foetal body weight was also observed and increased skeletal developmental variations (reduced mean litter proportion of cervical centrum no. 1 ossified [statistically significant] and increased mean litter proportions of unossified sternebrae [not statistically significant]) were also observed.

In the 125 mg/kg/day treatment group, a statistically significant increased mean kidney weight was observed in maternal animals. In addition to this, transient, initial mean body weight losses and reduced food consumption (some statistically significant). These observations were not considered to be adverse due to the rapid amelioration of the effects.

Based on the results of this study, a dose level of 25 mg/kg/day administered orally to rats was considered to be the no-observed-adverse-effect level (NOAEL) for maternal toxicity and a dose level of 125 mg/kg/day was considered to be the NOAEL for prenatal developmental toxicity.

Justification for classification or non-classification

Based on the results of the developmental toxicity/teratogenicity study, the read-across test material, is not toxic to the developing foetus at dose levels that are not maternally toxic.

There are no effects apparent on pre-natal growth or development at dose levels up to 125 mg/kg bw/day which exceeds the 25 mg/kg bw/day maternal no effect level. No classification is required in accordance with Directive 7/548/EEC, as amended, in respect to developmental toxicity.

In the absence of foetal developmental effects, there are no indications that maternal effects had any adverse outcome on the developing conceptus and consequently no classification is required in accordance with Regulation 1272/2008.