Benzenesulfonic acid, 4-C10-13-sec-alkyl derivs., compds. with 2-propanamine

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

No studies are available on the reproduction toxicity of LAS IPA. The endpoint was addressed with information from LAS Na and IPA. One three generation study with LAS Na after oral exposure, shows no effects on the reproduction parameters. No OECD 421/422 is available for IPA, but a developmental toxicity (OECD 414) is available. This inhalation study shows no effects on reproduction/fertility.

Link to relevant study records

Reference

Reference 1

Endpoint:

three-generation reproductive toxicity

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

Unavailable - original study report dated 1971

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Qualifier:

no guideline available

Principles of method if other than guideline:

- Principle of test: Three-generation reproductive toxicity study
- Short description of test conditions: Na-LAS (chain length distribution C10-14) was fed for 84 days to 4 groups of weanling rats (3 dose levels, plus control), each dose consisting of 50 animals each of both sexes (PO-generation). When the P0 generation was 107-112 days old, 20 females from each dose group were mated with 20 males from the same group and maintained together for 17 days. The first litters of each generation (Fla- and F2a-generation) were sacrificed at 21 days of age. Ten days after the final litter was sacrificed, all females were remated with different males from the same group to obtain the F1b generation. From the Flb-generation, 20 males and females of each group were selected at weaning to continue their respective diets and to be used for further reproduction studies. Reproduction studies on the F1b and F2b generations were started when the rats were 80 to 85 days old, and were continued until the F3b generation was weaned.

GLP compliance:

no

Limit test:

no

Species:

rat

Strain:

other: Charles River

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source:
- Age at study initiation: (P) weanling; (F1) 21 days
- Weight at study initiation: (P) Males: average 59.4-59.9 g; Females: average 57.0-57.3 g; (F1) Males: group weight 183.5-214.2 g; Females: group weight 157.8-193.2 g
- Housing: individual wire bottom cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°F): 76 +/- 3
- Humidity (%): 50 +/- 5
- Photoperiod (hrs dark / hrs light): 12/12 hrs

:

Route of administration:

oral: feed

Vehicle:

not specified

Details on mating procedure:

premating exposure period 84 days

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

2 years ( 3 generations)

Frequency of treatment:

continuous in feed

Details on study schedule:

- F1 parental animals not mated until 80-85 days old
- Selection of parents from F1 generation when pups were 21 days of age.
- Age at mating of the mated animals in the study: 107-112 days old

Dose / conc.:

14 mg/kg bw/day (nominal)

Remarks:

corresponding to 0.02% dose level in diet

Dose / conc.:

70 mg/kg bw/day (nominal)

Remarks:

corresponding to 0.1% dose level in diet

Dose / conc.:

350 mg/kg bw/day (nominal)

Remarks:

corresponding to 0.5% dose level in diet

No. of animals per sex per dose:

50

Control animals:

yes, concurrent no treatment

Details on study design:

Na-LAS (chain length distribution C10-14) was fed for 84 days to 4 groups of weanling rats (3 dose levels, plus control), each dose consisting of 50 animals each of both sexes (P0-generation).  When the P0 generation was 107-112 days old, 20 females from each dose group were mated with 20 males from the same group and maintained together for 17 days.  The first litters of each generation (F1a- and F2a-generation) were sacrificed at 21 days of age.  Ten days after the final litter was sacrificed, all females were remated with different males from the same group to obtain the F1b generation.  From the F1b-generation, 20 males and females of each group were selected at weaning to continue their respective diets and to be used for further reproduction studies.  Reproduction studies on the F1b and F2b generations were started when the rats were 80 to 85 days old, and were continued until the F3b generation was weaned.

Parental animals: Observations and examinations:

DETAILED CLINICAL OBSERVATIONS: Yes

BODY WEIGHT: Yes

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes

Litter observations:

Deformities and number of pups, average body weights, feed consumption, feed efficiency.

Postmortem examinations (parental animals):

Necropsy, body weight, organ to body weight ratios, routine hematology and histology.

Postmortem examinations (offspring):

Necropsy, body weight, organ to body weight ratios, routine hematology and histology.

Reproductive indices:

fertility, gestation, parturition, neonatal viability, lactation, and post-weaning growth

Clinical signs:

no effects observed

Dermal irritation (if dermal study):

not examined

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

No effects to average food consumption were noted in the initial twelve weeks

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:

effects observed, non-treatment-related

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not examined

Reproductive function: oestrous cycle:

not examined

Reproductive function: sperm measures:

not examined

Reproductive performance:

no effects observed

Key result

Dose descriptor:

NOAEL

Effect level:

350 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

reproductive performance

Critical effects observed:

no

Clinical signs:

not specified

Mortality / viability:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

not examined

Haematological findings:

effects observed, non-treatment-related

Description (incidence and severity):

For futher details see "details on results (F1)" section below

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Sexual maturation:

not specified

Anogenital distance (AGD):

not examined

Nipple retention in male pups:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings:

no effects observed

Behaviour (functional findings):

not examined

Developmental immunotoxicity:

not examined

Rats sacrificed at weaning were normal with respect to growth, organ to body weight ratios, gross pathology, and histology, and did not vary from controls. There were a number of statistically significant hematologic values, though these differences were small and did not indicate a trend or pattern.

Key result

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

350 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No adverse effects observed in sacrfied rats at weaning

Critical effects observed:

no

Key result

Dose descriptor:

NOAEL

Generation:

F2

Effect level:

350 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no adverse effects observed

Critical effects observed:

no

Key result

Reproductive effects observed:

no

Conclusions:

No significant effects on reproduction were observed at the highest concentration tested. Based on this results the NOAEL (fertility) was determined to be 350 mg/kg bw/day (corresponding to 0.5% test item in diet).

Executive summary:

In a three-generation reproduction study Na-LAS (chain length distribution C10-14) was administered to 50 Charles River rats/sex/dose indietat dose levels of 0, 0.02%, 0.1% or 0.5% in diet (equivalent to 0, 14, 70 or 350 mg/kg bw/day, respectively) for 84 days (P0-generation). When the P0 generation was 107-112 days old, 20 females from each dose group were mated with 20 males from the same group and maintained together for 17 days. The first litters of each generation (F1a- and F2a-generation) were sacrificed at 21 days of age. Ten days after the final litter was sacrificed, all females were remated with different males from the same group to obtain the F1b generation. From the F1b-generation, 20 males and females of each group were selected at weaning to continue their respective diets and to be used for further reproduction studies. Reproduction studies on the F1b and F2b generations were started when the rats were 80 to 85 days old and were continued until the F3b generation was weaned.

 

No significant effects were observed at the highest dose tested and the resulting NOAEL for the parental and both offspring generations was 350 mg/kg bw (corresponding to 0.5% test item in diet).Based on these observations the NOAEL (fertility) was derived at 350 mg/kg bw/d (highest dose tested under the conditions of this study).

Reference 2

Endpoint:

three-generation reproductive toxicity

Type of information:

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

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Justification for type of information:

Read-across approach - see read-across justification in section 13.

Reason / purpose for cross-reference:

read-across source

Principles of method if other than guideline:

- Principle of test: Three-generation reproductive toxicity study
- Short description of test conditions: Na-LAS (chain length distribution C10-14) was fed for 84 days to 4 groups of weanling rats (3 dose levels, plus control), each dose consisting of 50 animals each of both sexes (PO-generation). When the P0 generation was 107-112 days old, 20 females from each dose group were mated with 20 males from the same group and maintained together for 17 days. The first litters of each generation (Fla- and F2a-generation) were sacrificed at 21 days of age. Ten days after the final litter was sacrificed, all females were remated with different males from the same group to obtain the F1b generation. From the Flb-generation, 20 males and females of each group were selected at weaning to continue their respective diets and to be used for further reproduction studies. Reproduction studies on the F1b and F2b generations were started when the rats were 80 to 85 days old, and were continued until the F3b generation was weaned.

GLP compliance:

no

Limit test:

no

Species:

rat

Strain:

other: Charles River

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source:
- Age at study initiation: (P) weanling; (F1) 21 days
- Weight at study initiation: (P) Males: average 59.4-59.9 g; Females: average 57.0-57.3 g; (F1) Males: group weight 183.5-214.2 g; Females: group weight 157.8-193.2 g
- Housing: individual wire bottom cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°F): 76 +/- 3
- Humidity (%): 50 +/- 5
- Photoperiod (hrs dark / hrs light): 12/12 hrs

:

Route of administration:

oral: feed

Vehicle:

not specified

Details on mating procedure:

premating exposure period 84 days

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

2 years ( 3 generations)

Frequency of treatment:

continuous in feed

Details on study schedule:

- F1 parental animals not mated until 80-85 days old
- Selection of parents from F1 generation when pups were 21 days of age.
- Age at mating of the mated animals in the study: 107-112 days old

Dose / conc.:

14 mg/kg bw/day (nominal)

Remarks:

corresponding to 0.02% dose level in diet

Dose / conc.:

70 mg/kg bw/day (nominal)

Remarks:

corresponding to 0.1% dose level in diet

Dose / conc.:

350 mg/kg bw/day (nominal)

Remarks:

corresponding to 0.5% dose level in diet

No. of animals per sex per dose:

50

Control animals:

yes, concurrent no treatment

Details on study design:

Na-LAS (chain length distribution C10-14) was fed for 84 days to 4 groups of weanling rats (3 dose levels, plus control), each dose consisting of 50 animals each of both sexes (P0-generation).  When the P0 generation was 107-112 days old, 20 females from each dose group were mated with 20 males from the same group and maintained together for 17 days.  The first litters of each generation (F1a- and F2a-generation) were sacrificed at 21 days of age.  Ten days after the final litter was sacrificed, all females were remated with different males from the same group to obtain the F1b generation.  From the F1b-generation, 20 males and females of each group were selected at weaning to continue their respective diets and to be used for further reproduction studies.  Reproduction studies on the F1b and F2b generations were started when the rats were 80 to 85 days old, and were continued until the F3b generation was weaned.

Parental animals: Observations and examinations:

DETAILED CLINICAL OBSERVATIONS: Yes

BODY WEIGHT: Yes

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes

Litter observations:

Deformities and number of pups, average body weights, feed consumption, feed efficiency.

Postmortem examinations (parental animals):

Necropsy, body weight, organ to body weight ratios, routine hematology and histology.

Postmortem examinations (offspring):

Necropsy, body weight, organ to body weight ratios, routine hematology and histology.

Reproductive indices:

fertility, gestation, parturition, neonatal viability, lactation, and post-weaning growth

Clinical signs:

no effects observed

Dermal irritation (if dermal study):

not examined

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

No effects to average food consumption were noted in the initial twelve weeks

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:

effects observed, non-treatment-related

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not examined

Reproductive function: oestrous cycle:

not examined

Reproductive function: sperm measures:

not examined

Reproductive performance:

no effects observed

Key result

Dose descriptor:

NOAEL

Effect level:

350 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

reproductive performance

Critical effects observed:

no

Clinical signs:

not specified

Mortality / viability:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

not examined

Haematological findings:

effects observed, non-treatment-related

Description (incidence and severity):

For futher details see "details on results (F1)" section below

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Sexual maturation:

not specified

Anogenital distance (AGD):

not examined

Nipple retention in male pups:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings:

no effects observed

Behaviour (functional findings):

not examined

Developmental immunotoxicity:

not examined

Rats sacrificed at weaning were normal with respect to growth, organ to body weight ratios, gross pathology, and histology, and did not vary from controls. There were a number of statistically significant hematologic values, though these differences were small and did not indicate a trend or pattern.

Key result

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

350 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No adverse effects observed in sacrfied rats at weaning

Critical effects observed:

no

Key result

Dose descriptor:

NOAEL

Generation:

F2

Effect level:

350 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no adverse effects observed

Critical effects observed:

no

Key result

Reproductive effects observed:

no

Conclusions:

No significant effects on reproduction were observed at the highest concentration tested. Based on this results the NOAEL (fertility) was determined to be 350 mg/kg bw/day (corresponding to 0.5% test item in diet).

Executive summary:

In a three-generation reproduction study Na-LAS (chain length distribution C10-14) was administered to 50 Charles River rats/sex/dose indietat dose levels of 0, 0.02%, 0.1% or 0.5% in diet (equivalent to 0, 14, 70 or 350 mg/kg bw/day, respectively) for 84 days (P0-generation). When the P0 generation was 107-112 days old, 20 females from each dose group were mated with 20 males from the same group and maintained together for 17 days. The first litters of each generation (F1a- and F2a-generation) were sacrificed at 21 days of age. Ten days after the final litter was sacrificed, all females were remated with different males from the same group to obtain the F1b generation. From the F1b-generation, 20 males and females of each group were selected at weaning to continue their respective diets and to be used for further reproduction studies. Reproduction studies on the F1b and F2b generations were started when the rats were 80 to 85 days old and were continued until the F3b generation was weaned.

 

No significant effects were observed at the highest dose tested and the resulting NOAEL for the parental and both offspring generations was 350 mg/kg bw (corresponding to 0.5% test item in diet).Based on these observations the NOAEL (fertility) was derived at 350 mg/kg bw/d (highest dose tested under the conditions of this study).

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

350 mg/kg bw/day

Study duration:

chronic

Species:

rat

Quality of whole database:

Sufficient to address requirements.

Effect on fertility: via inhalation route

Study duration:

subacute

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Since no data exist on the reproduction toxicity of LAS IPA, information on LAS Na and IPA were used to assess the reproductive toxicity potential of the substance.

IPA:

No reproduction toxicity is available with IPA; however, one inhalation pre-natal developmental toxicity OECD 414 study (Kier & Thake, 1988). No effects were observed on reproduction parameters. The NOAELs set in the study were only based on systemic toxicity (maternal toxicity) and hence, they are not relevant for this endpoint. No NOAEL for reproductive effects is set.

LAS Na:

LAS Na (C10 -14; CAS 69669 -44 -9) was fed for 84 days to 4 groups of weanling rats for two years (three generations) at doses of 14, 70, 350 mg/kg bw/day. No significant effects were observed even at the highest dose tested and the resulting NOAEL for the parental and both offspring generations was determined to be 350 mg/kg bw/day (0.5%) (Buehler et al., 1971).

Effects on developmental toxicity

Description of key information

Two studies were performed with LAS Na addressing the developmental toxicity potential of the substance after oral exposure. In these studies marginal teratogenic effects were seen at doses of maternal toxicity. The effect was not considered to be a clear-cut developmental effect and it was associated with maternal toxicity.One inhalation teratology study is available with vapours of isopropylamine. No effects were observed on the development of the foetus/offspring (pre- or post-natally) and the NOAELs set in the study were only based on systemic maternal toxicity; hence, they are not relevant for this endpoint. No NOAEL for developmental effects is set.

Link to relevant study records

Reference

Reference 1

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

Unavailable - study report dated 1971

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Qualifier:

no guideline followed

Principles of method if other than guideline:

- Principle of test: Prenatal developmental toxicity assay in pregnant rats
- Short description of test conditions: After overnight mating, the rats were randomly allocated to five groups which included one control group and four different treatment groups.LAS was prepared daily as a series of graded aqueous solutions. Animals in all groups were dosed orally at the standard volume of 1.0 mL/100 g. Control animals were dosed in a similar manner with distilled water used as the vehicle. The dams were observed daily for signs of toxicity and weighed on days 1, 3, 6, 10, 14, 17 and 20 of pregnancy. On day 20, the rats were killed by CO2 euthanasia.
- Parameters analysed / observed:Ovaries and uterine contents were examined immediately for number of copora lutea, number of viable young, number of resorption sites, litter weight, and fetal abnormalities.

GLP compliance:

no

Limit test:

no

Species:

rat

Strain:

other: Charles River CD strain

Route of administration:

oral: drinking water

Vehicle:

not specified

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

day 6 to day 15 of pregnancy

Frequency of treatment:

daily

Duration of test:

20 days

Dose / conc.:

0 other: mg/kg

Dose / conc.:

0.2 other: mg/kg

Dose / conc.:

2 other: mg/kg

Dose / conc.:

300 other: mg/kg

Dose / conc.:

600 other: mg/kg

No. of animals per sex per dose:

not specified

Control animals:

yes, concurrent no treatment

Details on study design:

After overnight mating, the rats were randomly allocated to five groups which included one control group and four different treatment groups. LAS was prepared daily as a series of graded aqueous solutions. Animals in all groups were dosed orally at the standard volume of 1.0 mL/100 g. Control animals were dosed in a similar manner with distilled water used as the vehicle. The dams were observed daily for signs of toxicity and weighed on days 1, 3, 6, 10, 14, 17 and 20 of pregnancy. On day 20, the rats were killed by CO2 euthanasia. Their ovaries and uterine contents were examined immediately for number of corpora lutea, number of viable young, number of resorption sites, litter weight, and fetal abnormalities.

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Number of corpora lutea: Yes
- Number of early resorptions: Yes / No / No data
- Number of late resorptions: Yes

Fetal examinations:

- External examinations: Yes

Clinical signs:

not specified

Dermal irritation (if dermal study):

not examined

Mortality:

not specified

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Change in bodyweight was not affected by treatment at 0.2, 2.0, and 300 mg/kg, but treatment at 600 mg/kg was associated with retarded weight gain and a transient diarrhea following initiation of treatment.

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

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

not specified

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:

not examined

Gross pathological findings:

not specified

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

not specified

Details on results:

Parent animals were observed daily.Change in bodyweight was not affected by treatment at 0.2, 2.0, and 300 mg/kg, but treatment at 600 mg/kg was associated with retarded weight gain and a transient diarrhea following initiation of treatment

Number of abortions:

not specified

Pre- and post-implantation loss:

not examined

Total litter losses by resorption:

not examined

Early or late resorptions:

no effects observed

Dead fetuses:

not specified

Changes in pregnancy duration:

not specified

Changes in number of pregnant:

no effects observed

Details on maternal toxic effects:

The pregnancy rate was comparable at all dosages.

Key result

Dose descriptor:

NOAEL

Effect level:

300 other: mg/kg

Based on:

test mat.

Basis for effect level:

body weight and weight gain

Remarks on result:

other: maternal toxicity

Remarks:

retarded weight gain and a transient diarrhea observed at high dose level

Abnormalities:

no effects observed

Fetal body weight changes:

effects observed, non-treatment-related

Description (incidence and severity):

Mean pup weights were statistically higher at 0.2, 2.0 and 300 mg/kg.

Reduction in number of live offspring:

no effects observed

Changes in sex ratio:

not examined

Changes in litter size and weights:

no effects observed

Changes in postnatal survival:

not examined

External malformations:

no effects observed

Skeletal malformations:

effects observed, treatment-related

Description (incidence and severity):

The distribution of skeletal variants were not statistically significant with the exception of a marginal retardation of sternebral ossification at 600 mg/kg.

Visceral malformations:

no effects observed

Description (incidence and severity):

The incidence of minor visceral anomalies was unaffected by treatment at any dosage.

Details on embryotoxic / teratogenic effects:

- Pregnancy/litter data: The litter parameters assessed included litter size, fetal loss and litter weight. These parameters were not significantly affected by any dosage. Mean pup weights were statistically higher at 0.2, 2.0 and 300 mg/kg.
- Embryonic and fetal development were assessed by the incidence of major malformations. The incidence of minor visceral anomalies was unaffected by treatment at any dosage. The distribution of skeletal variants were not statistically significant with the exception of a marginal retardation of sternebral ossification at 600 mg/kg.

Key result

Dose descriptor:

NOAEL

Effect level:

300 other: mg/kg

Based on:

test mat.

Sex:

male/female

Basis for effect level:

skeletal malformations

Remarks on result:

other: teratogenicity

Remarks:

marginal retardation of sternebral ossification

Abnormalities:

no effects observed

Developmental effects observed:

no

Conclusions:

Female rats were given LAS orally in distilled water from gestation days 6 to 15 during pregnancy. Some effects such as decreased weight gain and transient diarrhea occurred at the highest dose. Pregnancy rates were comparable at all doses. Litter parameters were not significantly affected at any dose. No significant differences were observed in visceral anomalies or skeletal variants, with the exception of a marginal retardation of sternabral ossification at the highest dose. Based on these results the maternal and developmental NOAELs were therefore determined to 300 mg/kg.

Executive summary:

In a developmental toxicity study LAS was administrated pregnant Charles River CD rats/does in water at dose levels of 0, 0.2, 2, 300 or 600 mg/kg from days 6 through 15 of gestation. The number of animals tested was not specified in the study.

The parent animals were observed daily. Body weight change was not affected by treatment at 0.2, 2.0 and 300 mg/kg, but treatment at 600 mg/kg was associated with delayed weight gain and transient diarrhoea after the start of treatment. Pregnancy rates were comparable at all doses. Litter parameters evaluated were litter size, fetal loss and litter weight. These parameters were not significantly affected by any of the doses. Mean pup weights were statistically higher at 0.2, 2.0 and 300 mg/kg. In addition, embryonic and fetal development was assessed by the incidence of major malformations. The incidence of minor visceral anomalies was not affected by the treatment at any dose. The distribution of skeletal variants was not statistically significant except for a marginal delay in sternal ossification at 600 mg/kg. Based on these observations the maternal and the developmental NOAELs are therefore determined to be 300 mg/kg.

Reference 2

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

Unavailable - publication dated 1975

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Qualifier:

no guideline followed

Principles of method if other than guideline:

Twenty female mice were administered 0.2, 2.0, 300 or 600 mg/kg bw of LAS by gavage at days 6-15 of gestation. All animals were sacrificed on day 17 of pregnancy.

GLP compliance:

not specified

Limit test:

no

Species:

mouse

Strain:

CD-1

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Housing: In plastic containers
- Diet: ad libitum
- Water: ad libitum (Spratt's Laboratory Diet No. 1)

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 ± 1
- Humidity (%): 50 ± 5% relative humidity

Route of administration:

oral: gavage

Vehicle:

not specified

Details on exposure:

Dosing commenced on day 6 after confirmation of mating by detection of the vaginal plug.
Exposure continued until day 15 of gestation.

Analytical verification of doses or concentrations:

not specified

Details on mating procedure:

Male and female mice were housed five per cage in opaque plastic cages until natural mating occurred.

Duration of treatment / exposure:

days 6 - 15 of pregnancy

Frequency of treatment:

daily

Duration of test:

sacrifice at day 17 of pregnancy

Dose / conc.:

0 mg/kg bw/day (nominal)

Dose / conc.:

0.2 mg/kg bw/day (nominal)

Dose / conc.:

2 mg/kg bw/day (nominal)

Dose / conc.:

300 mg/kg bw/day (nominal)

Dose / conc.:

600 mg/kg bw/day (nominal)

No. of animals per sex per dose:

20 females

Control animals:

yes, concurrent no treatment

Details on study design:

Two doses were chosen to form the basis for safety evaluation (0.2 and 2.0 mg/kg bw/day) because the likely maximum human intake of detergent from ordinary kitchen use has been estimated at 0.14 mg/kg bw/day, thus providing factors of 1-2 times the human exposure level. Two further doses were also investigated (300 and 600 mg/kg bw/day) based on previous toxicity data suggesting that these would impair maternal survival and result in obvious adverse effects.

Maternal examinations:

All animals were observed daily for signs of malreaction and were weighed regularly throughout gestation. All animals that died, and survivors at termination, were dissected and examined for macroscopic changes.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: All animals were weighed regularly throughout gestation

POST-MORTEM EXAMINATIONS: Yes
All animals that died, and survivors at termination, were dissected and examined for macroscopic changes.

Ovaries and uterine content:

The ovaries was examined after termination: Yes
Examinations included:
- Number of corpora lutea: Yes
- Number of implantation: Yes
:

Fetal examinations:

- External examinations: Yes

Clinical signs:

not specified

Dermal irritation (if dermal study):

not examined

Mortality:

mortality observed, treatment-related

Description (incidence):

Treatment at 300 and 600 mg/kg bw/day was associated with increased mortality (35% and 90% respectively).

Body weight and weight changes:

effects observed, non-treatment-related

Description (incidence and severity):

At 300 mg/kg bw/day weight gain was retarded only during the first four days. No assessment could be made at 600 mg/kg bw/day, due to the high mortality rate.

Food consumption and compound intake (if feeding study):

not examined

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:

not specified

Gross pathological findings:

effects observed, non-treatment-related

Description (incidence and severity):

Necropsy revealed an ubiquitous occurrence of tympanites, sometimes associated with gastritis.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Number of abortions:

not examined

Pre- and post-implantation loss:

no effects observed

Total litter losses by resorption:

not specified

Early or late resorptions:

not specified

Dead fetuses:

not specified

Changes in pregnancy duration:

not examined

Changes in number of pregnant:

no effects observed

Details on maternal toxic effects:

Among parent animals, treatment at 300 and 600 mg/kg bw/day was associated with increased mortality (35% and 90% respectively).At 300 mg/kg bw/day weight gain was retarded only during the first four days. No assessment could be made at 600 mg/kg bw/day, due to the high mortality rate.Necropsy revealed an ubiquitous occurrence of tympanites, sometimes associated with gastritis. Pregnancy rate was essentially comparable for all groups.

Key result

Dose descriptor:

NOAEL

Effect level:

2 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

mortality

Remarks on result:

other: maternal toxicity

Remarks:

increased mortality at 300 and 600 mg/kg bw/day.

Abnormalities:

no effects observed

Fetal body weight changes:

no effects observed

Reduction in number of live offspring:

effects observed, non-treatment-related

Description (incidence and severity):

At the 300 mg/kg bw/day dose, the incidence of total litter loss was 20%; this was attributed to the high maternal toxicity observed at this dose.

Changes in sex ratio:

not specified

Changes in litter size and weights:

effects observed, non-treatment-related

Description (incidence and severity):

For further details see "details on embryotoxic / teratogenic effects" section below.

Changes in postnatal survival:

not examined

External malformations:

effects observed, non-treatment-related

Description (incidence and severity):

Minor anomalies, including gross anomalies were increased.

Skeletal malformations:

effects observed, non-treatment-related

Description (incidence and severity):

Minor anomalies, including skeletal anomalies were increased.

Visceral malformations:

effects observed, non-treatment-related

Description (incidence and severity):

Minor anomalies, including visceral anomalies were increased.

Details on embryotoxic / teratogenic effects:

At doses with no maternal toxicity (0.2 and 2.0 mg/kg bw/day), no differences were observed among the dose group and the control group with respect to number of litters, viable young, litter weight, foetal weight, embryonic deaths, implantations and post implantation embryonic loss.At these doses the incidences of major malformations and minor abnormalities were not affected.
At the 300 mg/kg bw/day dose, the incidence of total liter loss was 20%; this was attributed to the high maternal toxicity observed at this dose.Among the nine animals with viable young at this dose, mean litter parameters, including litter size and fetal loss, and incidence of major malformations were not statistically different from controls. Minor anomilies, including gross or visceral and skeletal anomalies were increased. At 600 mg/kg there were no live births due to the high maternal mortality rate at this dose.

Key result

Dose descriptor:

NOAEL

Effect level:

300 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

skeletal malformations

visceral malformations

Remarks on result:

other: Since, there were no live fetuses at 600 mg/kg bw/day due to the high maternal mortality rate, 300 mg/kg bw/day was considered as the highest dose tested.

Abnormalities:

no effects observed

Developmental effects observed:

no

The maternal NOAEL of 2 mg/kg bw d is considered very conservative because the range (2-300 mg/kg bw/day) was too wide, especially considering the repeated dose toxicity studies (section 7.5.1) which give much higher NOAEL values.

Conclusions:

Pregnant female mice were exposed to LAS via gavage on days 6 -15 of gestation. Increased mortality was observed at the two highest doses (300 and 600 mg/kg bw/day). These doses also exhibited retarded weight gain and adverse signs in the necropsy. Pregnancy rate was comparable, however, for all groups. At doses without maternal toxicity, no differences were observed in any parameters. Based on these observations the maternal NOAEL is 2 mg/kg bw/day, however because of the very wide range between the 2 mg/kg and 300 mg/kg bw/day doses, the maternal NOAEL of 2 mg/kg bw/day must be considered very conservative. The NOAEL for teratogenicity is considered to 300 mg/kg bw/day.

Executive summary:

In a developmental toxicity study LAS was administrated to 20 pregnant CD-1 mice/does by gavage at dose levels of 0, 0.2, 2, 300 or 600 mg/kg bw/day from days 6 through 15 of gestation. All animals were sacrificed on day 17 of gestation.

Among parent animals, treatment at 300 and 600 mg/kg bw/day was associated with increased mortality (35% and 90% respectively). At 300 mg/kg bw/day weight gain was retarded only during the first four days. No assessment could be made at 600 mg/kg bw/day, due to the high mortality rate. Necropsy revealed an ubiquitous occurrence of tympanites, sometimes associated with gastritis. However, pregnancy rate was essentially comparable for all groups. Based on these observations the maternal NOAEL is 2 mg/kg bw/day, because of the very wide range between the 2 mg/kg and 300 mg/kg bw/day doses, the maternal NOAEL of 2 mg/kg bw/day must be considered very conservative.

At doses without maternal toxicity (0.2 and 2.0 mg/kg bw/day), no treatment-related effects on developmental parameters were observed in the treated and control groups. These parameters included number of litters, viable young, litter weight, fetal weight, embryonic deaths, implantation and post-implantation embryonic losses. At these doses the incidences of major malformations and minor abnormalities were also not affected. At 300 mg/kg bw/day, the incidence of total litter loss was 20%; this was attributed to the high maternal toxicity observed at this dose. Among the nine animals with viable pups at 300 mg/kg bw/day, mean litter parameters, including litter size and fetal loss, and the incidence of major malformations were not statistically different from controls. Minor anomalies, including gross or visceral and skeletal anomalies, were increased. At 600 mg/kg there were no live births due to the high maternal mortality rate at this dose. Therefore, based on these observations the developmental NOAEL is 300 mg/kg bw/day.

Reference 3

Endpoint:

developmental toxicity

Type of information:

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

Adequacy of study:

weight of evidence

Justification for type of information:

Read-across approach - see read-across justification in section 13.

Reason / purpose for cross-reference:

read-across source

Principles of method if other than guideline:

- Principle of test: Prenatal developmental toxicity assay in pregnant rats
- Short description of test conditions: After overnight mating, the rats were randomly allocated to five groups which included one control group and four different treatment groups.LAS was prepared daily as a series of graded aqueous solutions. Animals in all groups were dosed orally at the standard volume of 1.0 mL/100 g. Control animals were dosed in a similar manner with distilled water used as the vehicle. The dams were observed daily for signs of toxicity and weighed on days 1, 3, 6, 10, 14, 17 and 20 of pregnancy. On day 20, the rats were killed by CO2 euthanasia.
- Parameters analysed / observed:Ovaries and uterine contents were examined immediately for number of copora lutea, number of viable young, number of resorption sites, litter weight, and fetal abnormalities.

GLP compliance:

no

Limit test:

no

Species:

rat

Strain:

other: Charles River CD strain

Route of administration:

oral: drinking water

Vehicle:

not specified

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

day 6 to day 15 of pregnancy

Frequency of treatment:

daily

Duration of test:

20 days

Dose / conc.:

0 other: mg/kg

Dose / conc.:

0.2 other: mg/kg

Dose / conc.:

2 other: mg/kg

Dose / conc.:

300 other: mg/kg

Dose / conc.:

600 other: mg/kg

No. of animals per sex per dose:

not specified

Control animals:

yes, concurrent no treatment

Details on study design:

After overnight mating, the rats were randomly allocated to five groups which included one control group and four different treatment groups. LAS was prepared daily as a series of graded aqueous solutions. Animals in all groups were dosed orally at the standard volume of 1.0 mL/100 g. Control animals were dosed in a similar manner with distilled water used as the vehicle. The dams were observed daily for signs of toxicity and weighed on days 1, 3, 6, 10, 14, 17 and 20 of pregnancy. On day 20, the rats were killed by CO2 euthanasia. Their ovaries and uterine contents were examined immediately for number of corpora lutea, number of viable young, number of resorption sites, litter weight, and fetal abnormalities.

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Number of corpora lutea: Yes
- Number of early resorptions: Yes / No / No data
- Number of late resorptions: Yes

Fetal examinations:

- External examinations: Yes

Clinical signs:

not specified

Dermal irritation (if dermal study):

not examined

Mortality:

not specified

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Change in bodyweight was not affected by treatment at 0.2, 2.0, and 300 mg/kg, but treatment at 600 mg/kg was associated with retarded weight gain and a transient diarrhea following initiation of treatment.

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

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

not specified

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:

not examined

Gross pathological findings:

not specified

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

not specified

Details on results:

Parent animals were observed daily.Change in bodyweight was not affected by treatment at 0.2, 2.0, and 300 mg/kg, but treatment at 600 mg/kg was associated with retarded weight gain and a transient diarrhea following initiation of treatment

Number of abortions:

not specified

Pre- and post-implantation loss:

not examined

Total litter losses by resorption:

not examined

Early or late resorptions:

no effects observed

Dead fetuses:

not specified

Changes in pregnancy duration:

not specified

Changes in number of pregnant:

no effects observed

Details on maternal toxic effects:

The pregnancy rate was comparable at all dosages.

Key result

Dose descriptor:

NOAEL

Effect level:

300 other: mg/kg

Based on:

test mat.

Basis for effect level:

body weight and weight gain

Remarks on result:

other: maternal toxicity

Remarks:

retarded weight gain and a transient diarrhea observed at high dose level

Abnormalities:

no effects observed

Fetal body weight changes:

effects observed, non-treatment-related

Description (incidence and severity):

Mean pup weights were statistically higher at 0.2, 2.0 and 300 mg/kg.

Reduction in number of live offspring:

no effects observed

Changes in sex ratio:

not examined

Changes in litter size and weights:

no effects observed

Changes in postnatal survival:

not examined

External malformations:

no effects observed

Skeletal malformations:

effects observed, treatment-related

Description (incidence and severity):

The distribution of skeletal variants were not statistically significant with the exception of a marginal retardation of sternebral ossification at 600 mg/kg.

Visceral malformations:

no effects observed

Description (incidence and severity):

The incidence of minor visceral anomalies was unaffected by treatment at any dosage.

Details on embryotoxic / teratogenic effects:

- Pregnancy/litter data: The litter parameters assessed included litter size, fetal loss and litter weight. These parameters were not significantly affected by any dosage. Mean pup weights were statistically higher at 0.2, 2.0 and 300 mg/kg.
- Embryonic and fetal development were assessed by the incidence of major malformations. The incidence of minor visceral anomalies was unaffected by treatment at any dosage. The distribution of skeletal variants were not statistically significant with the exception of a marginal retardation of sternebral ossification at 600 mg/kg.

Key result

Dose descriptor:

NOAEL

Effect level:

300 other: mg/kg

Based on:

test mat.

Sex:

male/female

Basis for effect level:

skeletal malformations

Remarks on result:

other: teratogenicity

Remarks:

marginal retardation of sternebral ossification

Abnormalities:

no effects observed

Developmental effects observed:

no

Conclusions:

Female rats were given LAS orally in distilled water from gestation days 6 to 15 during pregnancy. Some effects such as decreased weight gain and transient diarrhea occurred at the highest dose. Pregnancy rates were comparable at all doses. Litter parameters were not significantly affected at any dose. No significant differences were observed in visceral anomalies or skeletal variants, with the exception of a marginal retardation of sternabral ossification at the highest dose. Based on these results the maternal and developmental NOAELs were therefore determined to 300 mg/kg.

Executive summary:

In a developmental toxicity study LAS was administrated pregnant Charles River CD rats/does in water at dose levels of 0, 0.2, 2, 300 or 600 mg/kg from days 6 through 15 of gestation. The number of animals tested was not specified in the study.

The parent animals were observed daily. Body weight change was not affected by treatment at 0.2, 2.0 and 300 mg/kg, but treatment at 600 mg/kg was associated with delayed weight gain and transient diarrhoea after the start of treatment. Pregnancy rates were comparable at all doses. Litter parameters evaluated were litter size, fetal loss and litter weight. These parameters were not significantly affected by any of the doses. Mean pup weights were statistically higher at 0.2, 2.0 and 300 mg/kg. In addition, embryonic and fetal development was assessed by the incidence of major malformations. The incidence of minor visceral anomalies was not affected by the treatment at any dose. The distribution of skeletal variants was not statistically significant except for a marginal delay in sternal ossification at 600 mg/kg. Based on these observations the maternal and the developmental NOAELs are therefore determined to be 300 mg/kg.

Reference 4

Endpoint:

developmental toxicity

Type of information:

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

Adequacy of study:

weight of evidence

Justification for type of information:

Read-across approach - see read-across justification in section 13.

Reason / purpose for cross-reference:

read-across source

Principles of method if other than guideline:

Twenty female mice were administered 0.2, 2.0, 300 or 600 mg/kg bw of LAS by gavage at days 6-15 of gestation. All animals were sacrificed on day 17 of pregnancy.

GLP compliance:

not specified

Limit test:

no

Species:

mouse

Strain:

CD-1

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Housing: In plastic containers
- Diet: ad libitum
- Water: ad libitum (Spratt's Laboratory Diet No. 1)

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 ± 1
- Humidity (%): 50 ± 5% relative humidity

Route of administration:

oral: gavage

Vehicle:

not specified

Details on exposure:

Dosing commenced on day 6 after confirmation of mating by detection of the vaginal plug.
Exposure continued until day 15 of gestation.

Analytical verification of doses or concentrations:

not specified

Details on mating procedure:

Male and female mice were housed five per cage in opaque plastic cages until natural mating occurred.

Duration of treatment / exposure:

days 6 - 15 of pregnancy

Frequency of treatment:

daily

Duration of test:

sacrifice at day 17 of pregnancy

Dose / conc.:

0 mg/kg bw/day (nominal)

Dose / conc.:

0.2 mg/kg bw/day (nominal)

Dose / conc.:

2 mg/kg bw/day (nominal)

Dose / conc.:

300 mg/kg bw/day (nominal)

Dose / conc.:

600 mg/kg bw/day (nominal)

No. of animals per sex per dose:

20 females

Control animals:

yes, concurrent no treatment

Details on study design:

Two doses were chosen to form the basis for safety evaluation (0.2 and 2.0 mg/kg bw/day) because the likely maximum human intake of detergent from ordinary kitchen use has been estimated at 0.14 mg/kg bw/day, thus providing factors of 1-2 times the human exposure level. Two further doses were also investigated (300 and 600 mg/kg bw/day) based on previous toxicity data suggesting that these would impair maternal survival and result in obvious adverse effects.

Maternal examinations:

All animals were observed daily for signs of malreaction and were weighed regularly throughout gestation. All animals that died, and survivors at termination, were dissected and examined for macroscopic changes.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: All animals were weighed regularly throughout gestation

POST-MORTEM EXAMINATIONS: Yes
All animals that died, and survivors at termination, were dissected and examined for macroscopic changes.

Ovaries and uterine content:

The ovaries was examined after termination: Yes
Examinations included:
- Number of corpora lutea: Yes
- Number of implantation: Yes
:

Fetal examinations:

- External examinations: Yes

Clinical signs:

not specified

Dermal irritation (if dermal study):

not examined

Mortality:

mortality observed, treatment-related

Description (incidence):

Treatment at 300 and 600 mg/kg bw/day was associated with increased mortality (35% and 90% respectively).

Body weight and weight changes:

effects observed, non-treatment-related

Description (incidence and severity):

At 300 mg/kg bw/day weight gain was retarded only during the first four days. No assessment could be made at 600 mg/kg bw/day, due to the high mortality rate.

Food consumption and compound intake (if feeding study):

not examined

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:

not specified

Gross pathological findings:

effects observed, non-treatment-related

Description (incidence and severity):

Necropsy revealed an ubiquitous occurrence of tympanites, sometimes associated with gastritis.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Number of abortions:

not examined

Pre- and post-implantation loss:

no effects observed

Total litter losses by resorption:

not specified

Early or late resorptions:

not specified

Dead fetuses:

not specified

Changes in pregnancy duration:

not examined

Changes in number of pregnant:

no effects observed

Details on maternal toxic effects:

Among parent animals, treatment at 300 and 600 mg/kg bw/day was associated with increased mortality (35% and 90% respectively).At 300 mg/kg bw/day weight gain was retarded only during the first four days. No assessment could be made at 600 mg/kg bw/day, due to the high mortality rate.Necropsy revealed an ubiquitous occurrence of tympanites, sometimes associated with gastritis. Pregnancy rate was essentially comparable for all groups.

Key result

Dose descriptor:

NOAEL

Effect level:

2 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

mortality

Remarks on result:

other: maternal toxicity

Remarks:

increased mortality at 300 and 600 mg/kg bw/day.

Abnormalities:

no effects observed

Fetal body weight changes:

no effects observed

Reduction in number of live offspring:

effects observed, non-treatment-related

Description (incidence and severity):

At the 300 mg/kg bw/day dose, the incidence of total litter loss was 20%; this was attributed to the high maternal toxicity observed at this dose.

Changes in sex ratio:

not specified

Changes in litter size and weights:

effects observed, non-treatment-related

Description (incidence and severity):

For further details see "details on embryotoxic / teratogenic effects" section below.

Changes in postnatal survival:

not examined

External malformations:

effects observed, non-treatment-related

Description (incidence and severity):

Minor anomalies, including gross anomalies were increased.

Skeletal malformations:

effects observed, non-treatment-related

Description (incidence and severity):

Minor anomalies, including skeletal anomalies were increased.

Visceral malformations:

effects observed, non-treatment-related

Description (incidence and severity):

Minor anomalies, including visceral anomalies were increased.

Details on embryotoxic / teratogenic effects:

At doses with no maternal toxicity (0.2 and 2.0 mg/kg bw/day), no differences were observed among the dose group and the control group with respect to number of litters, viable young, litter weight, foetal weight, embryonic deaths, implantations and post implantation embryonic loss.At these doses the incidences of major malformations and minor abnormalities were not affected.
At the 300 mg/kg bw/day dose, the incidence of total liter loss was 20%; this was attributed to the high maternal toxicity observed at this dose.Among the nine animals with viable young at this dose, mean litter parameters, including litter size and fetal loss, and incidence of major malformations were not statistically different from controls. Minor anomilies, including gross or visceral and skeletal anomalies were increased. At 600 mg/kg there were no live births due to the high maternal mortality rate at this dose.

Key result

Dose descriptor:

NOAEL

Effect level:

300 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

skeletal malformations

visceral malformations

Remarks on result:

other: Since, there were no live fetuses at 600 mg/kg bw/day due to the high maternal mortality rate, 300 mg/kg bw/day was considered as the highest dose tested.

Abnormalities:

no effects observed

Developmental effects observed:

no

The maternal NOAEL of 2 mg/kg bw d is considered very conservative because the range (2-300 mg/kg bw/day) was too wide, especially considering the repeated dose toxicity studies (section 7.5.1) which give much higher NOAEL values.

Conclusions:

Pregnant female mice were exposed to LAS via gavage on days 6 -15 of gestation. Increased mortality was observed at the two highest doses (300 and 600 mg/kg bw/day). These doses also exhibited retarded weight gain and adverse signs in the necropsy. Pregnancy rate was comparable, however, for all groups. At doses without maternal toxicity, no differences were observed in any parameters. Based on these observations the maternal NOAEL is 2 mg/kg bw/day, however because of the very wide range between the 2 mg/kg and 300 mg/kg bw/day doses, the maternal NOAEL of 2 mg/kg bw/day must be considered very conservative. The NOAEL for teratogenicity is considered to 300 mg/kg bw/day.

Executive summary:

In a developmental toxicity study LAS was administrated to 20 pregnant CD-1 mice/does by gavage at dose levels of 0, 0.2, 2, 300 or 600 mg/kg bw/day from days 6 through 15 of gestation. All animals were sacrificed on day 17 of gestation.

Among parent animals, treatment at 300 and 600 mg/kg bw/day was associated with increased mortality (35% and 90% respectively). At 300 mg/kg bw/day weight gain was retarded only during the first four days. No assessment could be made at 600 mg/kg bw/day, due to the high mortality rate. Necropsy revealed an ubiquitous occurrence of tympanites, sometimes associated with gastritis. However, pregnancy rate was essentially comparable for all groups. Based on these observations the maternal NOAEL is 2 mg/kg bw/day, because of the very wide range between the 2 mg/kg and 300 mg/kg bw/day doses, the maternal NOAEL of 2 mg/kg bw/day must be considered very conservative.

At doses without maternal toxicity (0.2 and 2.0 mg/kg bw/day), no treatment-related effects on developmental parameters were observed in the treated and control groups. These parameters included number of litters, viable young, litter weight, fetal weight, embryonic deaths, implantation and post-implantation embryonic losses. At these doses the incidences of major malformations and minor abnormalities were also not affected. At 300 mg/kg bw/day, the incidence of total litter loss was 20%; this was attributed to the high maternal toxicity observed at this dose. Among the nine animals with viable pups at 300 mg/kg bw/day, mean litter parameters, including litter size and fetal loss, and the incidence of major malformations were not statistically different from controls. Minor anomalies, including gross or visceral and skeletal anomalies, were increased. At 600 mg/kg there were no live births due to the high maternal mortality rate at this dose. Therefore, based on these observations the developmental NOAEL is 300 mg/kg bw/day.

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

Quality of whole database:

Sufficient to address requirements

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

No data exist on the developmental toxicity of LAS IPA, therefore, information on LAS Na and IPA were used to address this requirement.

IPA:

In a GLP, similar to Guidelines study (Kier & Thake, 1988) female rats were exposed to IPA vapours, whole body, during gestation, at concentrations of 50, 499 or 1000 mg IPA/m3. The substance did not induce embryotoxic, fetotoxic or teratogenic effects, although slight maternal toxicity was observed at the 499 mg/m3 exposure level and substantial maternal toxicity was observed at 1000 mg/m3.

LAS Na:

Pregnant female mice were exposed to LAS via gavage on days 6 -15 of gestation. Increased mortality was observed at the two highest doses (300 and 600 mg/kg bw/day). These doses also exhibited retarded weight gain and adverse signs in the necropsy. Pregnancy was comparable, however, for all groups. At doses without maternal toxicity, no differences were observed in any parameters. Because of the very wide range between the 2 mg/kg and 300 mg/kg doses, the maternal NOAEL of 2 mg/kg bw/day must be considered very conservative. The NOAEL for teratogenicity was 300 mg/kg bw/day (Palmer et al., 1971)

Pregnant female rats were given LAS orally in distilled water from gestation days 6 to 15 at doses of 0.2, 2, 300, 600 mg/kg bw/day. Some effects such as decreased weight gain and transient diarrhea occurred at the highest dose. Pregnancy rates were comparable at all doses. Litter parameters were not significantly affected at any dose. No significant differences were observed in visceral anomalies or skeletal variants, with the exception of a marginal retardation of sternabral ossification at the highest dose. The NOAEL was set at 300 mg/kg bw/day both for maternal toxicity and teratogenicity (Palmer et al., 1975).

Based on the results of the aforementioned studies LAS IPA is not considered to be a developmental toxicant.

Justification for selection of Effect on developmental toxicity: via oral route:
Only studies with LAS Na are available via the oral route. In these studies marginal teratogenic effects were seen at doses of maternal toxicity. The effect was not considered to be a clear-cut developmental effect and it was associated with maternal toxicity. No NOAEL for developmental effects is set.

Justification for selection of Effect on developmental toxicity: via inhalation route:
One inhalation study is available with vapours of isopropylamine. No effects were observed on the development of the foetus/offspring (pre- or post-natally) and the NOAELs set in the study were only based on systemic maternal toxicity; hence, they are not relevant for this endpoint. No NOAEL for developmental effects is set.

Justification for classification or non-classification

Based on the available data, for LAS Na and IPA, LAS IPA does not need to be classified for effects on fertility and developmental toxicity according to Regulation (EC) No. 1272/2008.