Benzenesulfonic acid, mono-C11-13-branched alkyl derivs., sodium salts

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records

Reference

Endpoint:

three-generation reproductive toxicity

Remarks:

based on test type (migrated information)

Type of information:

migrated information: read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Well documented peer-reviewed publication.

Principles of method if other than guideline:

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:

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

Remarks:

Doses / Concentrations:
0.02, 0.1, 0.5% (14, 70, 350 mg/kg bw d)
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:

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

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

Sex:

male/female

Basis for effect level:

other: 0.5%

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

Sex:

male/female

Basis for effect level:

other: 0.5%

Dose descriptor:

NOAEL

Generation:

F2

Effect level:

350 mg/kg bw/day

Sex:

male/female

Basis for effect level:

other: 0.5%

Reproductive effects observed:

not specified

Conclusions:

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

Executive summary:

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%)

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 single study used for this endpoint was given a reliability rating of 2. However, it is a well-documented study that included many reporduction parameters.

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

No specific studies on sodium salt branched alkylate derivatives (BABS Na salt) were available. However, a study is available on analogue linear alkyl benzene sulfonate (LAS or Na-LAS). The LAS structure is a C10 to C13 linear alkyl chain with a para-substituted benzene sulfonic acid sodium salt group attached at any of the secondary alkyl chain carbon positions. The alkyl chain length averages 11.6. LAS is structurally similar to BABS Na salt, as both are para C11 -C13 alkylbenzene sulfate sodium salts). The primary difference is whether the alkyl chain is linear or branched. Based on similar structures and function, LAS is a good analogue for read-across for instances where data are available on it but not on BABS Na salt.

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.

Short description of key information:

General reproduction in rats including fertility, gestation, parturition, neonatal viability, lactation, and post-weaning growth were normal for all test groups and did not vary from controls.  

Justification for selection of Effect on fertility via oral route:

This study was selected as it is a well-documented three generation rat study that inlcuded general reproduction  parameters including fertility, gestation, parturition, neonatal viability, lactation, and post-weaning growth. The resultant NOAEL value was 350 mg/kg bw/day.

Effects on developmental toxicity

Link to relevant study records

Reference

Endpoint:

developmental toxicity

Type of information:

migrated information: read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Well documented peer-reviewed journal article by researchers at GLP contract testing laboratory.

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:

yes

Remarks:

not stated, but likely GLP

Limit test:

no

Species:

mouse

Strain:

CD-1

Details on test animals or test system and environmental conditions:

Mice were held in plastic containers at standard environmental conditions (20 =/- 1 degrees C, 50 =/- 5% relative humidity) and free access to drinking water and food (Spratt's Laboratory Diet No. 1).

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

Remarks:

Doses / Concentrations:
0.2, 2, 300, 600 mg/kg bw d
Basis:
no data

No. of animals per sex per dose:

20 female mice per dose

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/day) because the likely maximum human intake of detergent from ordinary kitchen use has been estimated at 0.14 mg/kg/day, thus providing factors of 1-2 times the human exposure level. Two further doses were also investigated (300 and 600 mg/kg/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.

Ovaries and uterine content:

Ovaries were examined and the number of corpora lutea counted.

Details on maternal toxic effects:

Maternal toxic effects:yes

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

Dose descriptor:

NOAEL

Effect level:

2 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
At doses with no maternal toxicity, 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 the 600 mg/kg dose, there were no live births.

Dose descriptor:

NOAEL

Effect level:

300 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: teratogenicity

Abnormalities:

not specified

Developmental effects observed:

not specified

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

Conclusions:

Maternal NOAEL = 2 mg/kg bw/day; Teratogenicity NOAEL = 300 mg/kg bw/day

Executive summary:

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.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

300 mg/kg bw/day

Study duration:

subacute

Species:

mouse

Quality of whole database:

Two studies were available on the analogue substance LAS. First LAS key study is a rat study with a reliabilty rating of 2 study (oral in drinking water on gestation days 6-15) with lowest LOEL (delayed ossification LOEL = 600 mg/kg bw/day); NOAEL = 300 mg/kg bw/day. Second key study is mouse RL=2 study (oral in drinking water on gestation days 6-15) with lowest LOEL (increased fetal loss and reduced litter size considered secondary to maternal toxicity; increased minor skeletal or visceral anomalies at 300 mg/kg bw/day); NOAEL for teratogenicity was 300 mg/kg bw/day. Although the studies had the same NOAEL, the second mouse study is considered more conservative as there was higher maternal toxicity.

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

No specific studies on sodium salt branched alkylate derivatives (BABS Na salt) were available. However, a study is available on analogue linear alkyl benzene sulfonate (LAS or Na-LAS). The LAS structure is a C10 to C13 linear alkyl chain with a para-substituted benzene sulfonic acid sodium salt group attached at any of the secondary alkyl chain carbon positions. The alkyl chain length averages 11.6. LAS is structurally similar to BABS Na salt, as both are para C11 -C13 alkylbenzene sulfate sodium salts). The primary difference is whether the alkyl chain is linear or branched. Based on similar structures and function, LAS is a good analogue for read-across for instances where data are available on it but not on BABS Na salt.

Two developmental studies are available. In one developmental study, 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 a the highest dose, but pregnancy rates were comparable at all doses and 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 resultant NOAEL was 300 mg/kg bw/d for both maternal toxicity and teratogenicity. In a second developmental study, pregnant female mice were exposed to LAS via gavage on day 6 to 15 of gestation. Increased mortality was observed at the two highest doses (300 and 600 mg/kg bw/day) but not at the next lowest dose (2 mg/kg bw/day). These doses also exhibited retarded weight gain and adverse signs in 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 bw/day 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 was 300 mg/kg bw/day.

Based on these combined results the NOAEL used for assessment is 300 mg/kg bw/day.

Justification for selection of Effect on developmental toxicity: via oral route:

Two studies were available on the analogue substance LAS.  First LAS key study is a rat study with a reliabilty rating of 2 study (oral in drinking water on gestation days 6-15) with lowest LOEL (delayed ossification LOEL = 600 mg/kg bw/day); NOAEL = 300 mg/kg bw/day.  Second key study is mouse study with a reliability rating of  study (oral in drinking water on gestation days 6-15) with lowest LOEL (increased fet al loss and reduced litter size considered secondary to maternal toxicity; increased minor skeletal or visceral anomalies at 300 mg/kg bw/day); NOAEL = 300 mg/kg bw/day.

Justification for classification or non-classification

A series of reproductive and developmental toxicity studies are available on the analogue substance LAS. The resultant reproductive toxicity NOAEL was 350 mg/kg bw/day and the resultant developmental toxicity NOAEL based on two studies was 300 mg/kg bw/day. Based on the overall lack of significant developmental or reproductive toxicity at doses that were not maternally toxic in the analogues substance, it is expected that BABS Na salt will have a similar profile and therefore would not need to be classified.