Benzenesulfonic acid, 4-C10-13-sec-alkyl derivs., ammonium salts

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

Three-Generation Reproductive Toxicity: NOAEL parental = 350 mg/kg bw/d; NOAEL F1/F2 = 350 mg/kg bw/d; Buehler et al., 1971 (read across from benzenesulfonic acid, 4-C10-13-sec-alkyl derivs. - data on Na-LAS as part of category approach)

Link to relevant study records

Reference

Reference 1

Endpoint:

three-generation reproductive toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1971

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

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

Remarks:

Well documented peer-reviewed publication.

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH
Refer to Section 13.2 for read-across justification document.

Qualifier:

no guideline followed

Principles of method if other than guideline:

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

Remarks:

Study pre-dates GLP

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:

other: LAS was administered in feed (Purina Laboratory Meal) - no documentation of dilution prior to addition to meal

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

Remarks:

Basis:
actual ingested

Dose / conc.:

70 mg/kg bw/day

Remarks:

Basis:
actual ingested

Dose / conc.:

350 mg/kg bw/day

Remarks:

Basis:
actual ingested

No. of animals per sex per dose:

50 males and 50 females per group.

Control animals:

yes, concurrent no treatment

Litter observations:

50 males and 50 females per group.

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

Body weight and weight changes:

no effects observed

Description (incidence and severity):

no effects to body weight were noted in the initial twelve weeks

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

no effects to body weight were noted in the initial twelve weeks

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Other effects:

no effects observed

Description (incidence and severity):

Test substance intake: no effects to average food consumption were noted in the initial twelve weeks

Reproductive function: oestrous cycle:

no effects observed

Reproductive function: sperm measures:

no effects observed

Reproductive performance:

no effects observed

No mortality or clinical signs were observed in parental animals. A statistically significant decrease in liver weights was noted in male rats at the low and mid dose levels at the 8 month sacrifice. As the decreased liver weight was within normal range, was not seen at the highest dose level, nor was seen at the 15 and 24 month sacrifices, it was not considered biologically significant. Body weight gains and organ to body weight ratios were normal. Gross examination revealed no abnormalities attributable to the test substance. General reproduction including fertility, gestation, parturition, neonatal viability, lactation, and post-weaning growth were normal for all test groups and did not vary from controls.

Dose descriptor:

NOAEL

Effect level:

350 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: 0.5 %

Critical effects observed:

no

Clinical signs:

not specified

Mortality / viability:

no mortality observed

Body weight and weight changes:

no effects observed

Sexual maturation:

not specified

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings:

no effects observed

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.

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

350 mg/kg bw/day

Based on:

test mat.

Sex:

male

Basis for effect level:

other: 0.5 %

Critical effects observed:

no

Dose descriptor:

NOAEL

Generation:

F2

Effect level:

350 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: 0.5 %

Reproductive effects observed:

no

Conclusions:

No significant effects on reproduction were observed at the highest concentration tested.

Executive summary:

Na-LAS was fed for 84 days to 4 groups of weanling rats for two years (three generations). 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 (0.5%).

Reference 2

Endpoint:

three-generation reproductive toxicity

Type of information:

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

Adequacy of study:

key study

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH
Refer to Section 13.2 for read-across justification document.

Reason / purpose for cross-reference:

read-across source

Dose descriptor:

NOAEL

Effect level:

350 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: 0.5 %

Critical effects observed:

no

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

350 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: 0.5 %

Critical effects observed:

no

Dose descriptor:

NOAEL

Generation:

F2

Effect level:

350 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: 0.5 %

Critical effects observed:

no

Reproductive effects observed:

no

Conclusions:

No significant effects on reproduction were observed at the highest concentration tested.

Executive summary:

In a one-to-one read-across approach, the substance benzenesulfonic acid, 4-C10-13-sec-alkyl derivs. (data on LAS as part of category approach) is considered appropriate for direct read-across (one-to-one) to benzenesulfonic acid, 4-C10-13-sec-alkyl derivs., ammonium salts (target substance) for the endpoint toxicity to reproduction.  Na-LAS was fed for 84 days to 4 groups of weanling rats for two years (three generations). 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 (0.5%).

In conclusion, The test substance has no adverse effects on reproduction.  A full justification for the read-across approach is presented in IUCLID Section 13.2.

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:

The database consists of a single high quality studies that exceeds the standard tier of data requirements for the registered tonnage band. All studies (key and supporting) are of high quality.

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

In a one-to-one read-across approach, the substance benzenesulfonic acid, 4-C10-13-sec-alkyl derivs. (data on LAS as part of category approach) is considered appropriate for direct read-across (one-to-one) to benzenesulfonic acid, 4-C10-13-sec-alkyl derivs., ammonium salts (target substance) for the endpoint toxicity to reproduction.  Na-LAS was fed for 84 days to 4 groups of weanling rats for two years (three generations). 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 (0.5%).

In conclusion, The test substance has no adverse effects on reproduction.  A full justification for the read-across approach is presented in IUCLID Section 13.2.

The key study (Buehler et al., 1971) examined the potential reproductive toxicity of Na-LAS (read across). Na-LAS was given in the feed at doses of 0.02, 0.1, and 0.5% (14, 70, and 350 mg/kg bw d) for 84 days to four groups of weanling rats and evaluated for two years (three generations). 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 (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 F1band F2b-generations were started when the rats were 80 to 85 days old, and were continued until the F3b-generation was weaned. All 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. Overall, no significant effects were observed at the highest dose tested and the resulting NOAEL for the parental and both offspring generations was the highest dose tested, i.e., 350 mg/kg bw (0.5%).

Effects on developmental toxicity

Description of key information

Maternal NOAEL = 300 mg/kg bw/d, Developmental NOAEL = 600 mg/kg bw/d

Link to relevant study records

Reference

Reference 1

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1975

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

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

Remarks:

Well documented peer-reviewed journal article

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH
Refer to Section 13.2 for read-across justification document.

Qualifier:

no guideline followed

Principles of method if other than guideline:

Twenty female rats 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 20 of pregnancy.

GLP compliance:

no

Remarks:

Study pre-dated GLP

Limit test:

no

Species:

rat

Strain:

other: CD

Details on test animals or test system and environmental conditions:

Source: Charles River Breeding Laboratories, Wilmingoton, Mass., USA.
Rats were housed 5 per cage in opaque plastic cages, and maintained under environmental conditions of 20 +/- 1°C and 50 +/- 5% RH. All animals were allowed free access to drinking water and food (Spratt’s Laboratory Diet No. 1).

Route of administration:

oral: gavage

Vehicle:

not specified

Details on exposure:

For administration each material was prepared daily as a series of graded aqueous solutions so that within each study animals in all groups were dosed orally by intragastric intubation at a standard volume. Control animals were dosed with water.

Duration of treatment / exposure:

days 6 - 15 of pregnancy

Frequency of treatment:

Daily

Dose / conc.:

0.2 mg/kg bw/day

Dose / conc.:

2 mg/kg bw/day

Dose / conc.:

300 mg/kg bw/day

Dose / conc.:

600 mg/kg bw/day

No. of animals per sex per dose:

20 female rats per dose

Control animals:

yes, concurrent no treatment

Maternal examinations:

The day of mating as judged by the detection of the vaginal plug in rats was considered day 0; dosing commenced on day 6 and continued daily up to and including day 15.
Throughout the experiment 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.
At termination (days 20) rats were euthanised by carbon dioxide euthanasia. The uteri were immediately dissected and the contents examined to determine the numbers of {a) implantations, (b) viable young, (c) embryonic deaths (abortion or resorption sites).

Ovaries and uterine content:

Ovaries were examined and the number of corpora lutea counted.

Fetal examinations:

Viable young were weighed and carefully examined for external abnormalities. Following weighing and examination for external malformations, one third of the foetuses were fixed in Bouin's fluid for subsequent free hand sectioning to detect visceral anomalies, and the remaining two thirds fixed in alcohol for subsequent dissection and examination followed by clearing, alizarin staining and skeletal examination.

Statistics:

In assessing results group mean values were calculated from the individual litter data in two ways. Mean A: includes all surviving animals showing evidence of implantation, including those with total litter loss. Mean B: includes only animals bearing viable young at termination.
Mean B has more meaning when only the occasional animal shows total litter loss, Mean A provides a better index when several animals show total litter loss.
Differences in mean values were statistically analysed by non-parametric methods (Wilcoxon test) since litter values rarely, if ever, follow a normal (Gaussian) distribution; in all analyses the litter was considered as the basic sample unit.

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Toxic effects were generally associated with a principal disturbance of the gastrointestinal tract.

Mortality:

mortality observed, treatment-related

Description (incidence):

a single mortality was observed at 600 mg/kg bw/d. No evidence was offered as to whether this was related to test item dosing or an isolated incident.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Significant body weight gain reduction was seen at 600 mg/kg bw/d.

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

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

not specified

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:

not specified

Gross pathological findings:

not specified

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Number of abortions:

no effects observed

Pre- and post-implantation loss:

no effects observed

Total litter losses by resorption:

not specified

Early or late resorptions:

not specified

Dead fetuses:

no effects observed

Changes in pregnancy duration:

not specified

Changes in number of pregnant:

no effects observed

Other effects:

no effects observed

Details on maternal toxic effects:

Body weight gain was retarded in the highest dose group from the start of dosing and showed partial recovery toward the end of the dosing period. One animal died in this group but it could not be conclusively related to treatment. The toxic effects were associated with disturbance of the gastrointestinal tract.

Dose descriptor:

NOAEL

Effect level:

300 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

body weight and weight gain

Abnormalities:

no effects observed

Fetal body weight changes:

no effects observed

Reduction in number of live offspring:

no effects observed

Changes in sex ratio:

not specified

Changes in litter size and weights:

no effects observed

Changes in postnatal survival:

no effects observed

External malformations:

no effects observed

Skeletal malformations:

no effects observed

Visceral malformations:

no effects observed

Other effects:

no effects observed

Details on embryotoxic / teratogenic effects:

No differences were observed among dose groups and the control group with respect to number of litters, viable young, litter weight, foetal weight, embryonic deaths, implantations, corpora lutea, pre- and post implantation embryonic loss, major malformations, minor visceral or embryonic loss, major malformations, minor visceral or skeletal anomalies or incidence of pups with extra ribs.

Dose descriptor:

NOAEL

Effect level:

>= 600 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Remarks on result:

not determinable due to adverse toxic effects at highest dose / concentration tested

Abnormalities:

no effects observed

Developmental effects observed:

no

Summary of adult performance

Observation	Number of animals at dosage
mg/kg bw/d	0	0.2	2	300	600
Mated	20	20	20	20	20
Died	0	0	0	0	1
Non-pregnant	5	5	2	4	3
Total litter loss	0	1	0	0	0
With viable young	15	14	18	16	16
Bodyweight change	-	-	-	-	Retarded weight gain

Group mean incidence of major malformations and minor anomalies

Dosage	Number of Young									Incidence of pups with extra ribs *
	Major malformations			Minor anomalies
	Examined	Affected		Gross or visceral			Skeletal			Mean %
(mg/kg)		Total number	Mean %	Examined	Total Number Affected	Mean % Affected	Examined	Total Number Affected	Mean % Affected	Cervical	Lumbar
0	149	0	0	33	1	2.2	116	2	2.0		18.6
0.2	137	0	0	26	0	0	111	2	1.7		33.1
2	147	0	0	22	0	0	125	5	3.5		21.3
300	153	1	0.6	30	0	0	122	4	3.6		12.9
600 (M)	166	0	0	34	1	6.7	132	2	1.8		15.3

* Young showing major malformations excluded

(M) denotes minor maternal toxicity

Group Litter Data

						Embryonic Loss (%)
Dosage (mg/kg)	Number of Litters	Litter Size and Viable Young	Embryonic Deaths	Implantations	Corpora Lutea	Pre-Implantation	Post-Implantation	Litter Weight (g)	Foetal Weight (g)
0	15	9.9	0.3	10.3	12.5	18.1	2.8	36.15	3.66
0.2	14	9.8	0.6	10.4	12.8	18.4	6.1	37.14	3.84 (a)
2	18	8.2	0.6	8.8	13.9	36.9	5.9	31.62	3.94 (b)
300	16	9.6	0.4	10.0	12.4	15.6	3.6	35.72	3.78
600 (M)	16	10.4	0.4	10.8	13.9	20.3	3.1	37.49	3.64

Differences from controls statistically significant at Wilcoxon test (a) P < 0.05; (b) P < 0.001

(M) denotes minor maternal toxicity

Conclusions:

Based on the results of the study, the maternal NOAEL = 300 mg/kg bw/d and the developmental NOAEL = 600 mg/kg bw/d.

Executive summary:

Pregnant female rats (20 animals per group) were exposed to LAS via gavage on days 6 -15 of gestation.

Maternal toxicity:


Body weight gain was retarded in the highest dose group from the start of dosing and showed partial recovery toward the end of the dosing period. One animal died in this group but it could not be conclusively related to treatment. The toxic effects were associated with disturbance of the gastrointestinal tract. Pregnancy rate was comparable at all dosages.

Teratogenicity:


No differences were observed among dose groups and the control group with respect to number of litters, viable young, litter weight, foetal weight, embryonic deaths, implantations, corpora lutea, pre- and post implantation embryonic loss, major malformations, minor visceral or embryonic loss, major malformations, minor visceral or skeletal anomalies or incidence of pups with extra ribs.

Based on the results of the study, the maternal NOAEL = 300 mg/kg bw/d and the developmental NOAEL = 600 mg/kg bw/d.

Reference 2

Endpoint:

developmental toxicity

Type of information:

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

Adequacy of study:

key study

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH
Refer to Section 13.2 for read-across justification document.

Reason / purpose for cross-reference:

read-across source

Dose descriptor:

NOAEL

Effect level:

300 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

body weight and weight gain

Abnormalities:

no effects observed

Dose descriptor:

NOAEL

Effect level:

>= 600 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Remarks on result:

not determinable due to adverse toxic effects at highest dose / concentration tested

Abnormalities:

no effects observed

Developmental effects observed:

no

Conclusions:

Based on the results of the study, the maternal NOAEL = 300 mg/kg bw/d and the developmental NOAEL = 600 mg/kg bw/d.

Executive summary:

In a one-to-one read-across approach, the substance benzenesulfonic acid, 4-C10-13-sec-alkyl derivs. (data on LAS as part of category approach) is considered appropriate for direct read-across (one-to-one) to benzenesulfonic acid, 4-C10-13-sec-alkyl derivs., ammonium salts (target substance) for the endpoint developmental toxicity.

Pregnant female rats (20 animals per group) were exposed to LAS via gavage on days 6 -15 of gestation.

Maternal toxicity:


Body weight gain was retarded in the highest dose group from the start of dosing and showed partial recovery toward the end of the dosing period. One animal died in this group but it could not be conclusively related to treatment. The toxic effects were associated with disturbance of the gastrointestinal tract. Pregnancy rate was comparable at all dosages.

Teratogenicity:


No differences were observed among dose groups and the control group with respect to number of litters, viable young, litter weight, foetal weight, embryonic deaths, implantations, corpora lutea, pre- and post implantation embryonic loss, major malformations, minor visceral or embryonic loss, major malformations, minor visceral or skeletal anomalies or incidence of pups with extra ribs.

Based on the results of the study, the maternal NOAEL = 300 mg/kg bw/d and the developmental NOAEL = 600 mg/kg bw/d.

A full justification for the read-across approach is presented in IUCLID Section 13.2.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

300 mg/kg bw/day

Study duration:

chronic

Species:

rat

Quality of whole database:

The database consists of high quality studies on the rat and mouse, that exceeds the standard data requirements for the registered tonnage band. All studies (key and supporting) are of high quality.

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

In a one-to-one read-across approach, the substance benzenesulfonic acid, 4-C10-13-sec-alkyl derivs. (data on LAS as part of category approach) is considered appropriate for direct read-across (one-to-one) to benzenesulfonic acid, 4-C10-13-sec-alkyl derivs., ammonium salts (target substance) for the endpoint developmental toxicity.

Pregnant female rats (20 animals per group) were exposed to LAS via gavage on days 6 -15 of gestation.

Maternal toxicity:


Body weight gain was retarded in the highest dose group from the start of dosing and showed partial recovery toward the end of the dosing period. One animal died in this group but it could not be conclusively related to treatment. The toxic effects were associated with disturbance of the gastrointestinal tract. Pregnancy rate was comparable at all dosages.

Teratogenicity:

No differences were observed among dose groups and the control group with respect to number of litters, viable young, litter weight, foetal weight, embryonic deaths, implantations, corpora lutea, pre- and post implantation embryonic loss, major malformations, minor visceral or embryonic loss, major malformations, minor visceral or skeletal anomalies or incidence of pups with extra ribs.

Based on the results of the study, the maternal NOAEL = 300 mg/kg bw/d and the developmental NOAEL = 600 mg/kg bw/d.

A full justification for the read-across approach is presented in IUCLID Section 13.2.

Mode of Action Analysis / Human Relevance Framework

Not applicable, no reproductive or developmental toxicity was observed in any of the presented studies.

Justification for classification or non-classification

The substance does not meet the criteria for classification in accordance with Regulation (EC) No 1272/2008.