Benzenesulfonic acid, 4-C15-16-sec-alkyl derivs.

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records

Reference

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:

see read-across document

Reason / purpose for cross-reference:

read-across source

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.

Key result

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.

Key result

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

350 mg/kg bw/day

Sex:

male/female

Basis for effect level:

other: 0.5%

Key result

Dose descriptor:

NOAEL

Generation:

F2

Effect level:

350 mg/kg bw/day

Sex:

male/female

Basis for effect level:

other: 0.5%

Key result

Reproductive effects observed:

not specified

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%)

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

350 mg/kg bw/day

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Toxicity to reproduction

This key study examined the effects of exposure to LAS (read across) on reproductive toxicity. 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%).

Short description of key information:
The potential for reproductive toxicity of LAS (read across) was examined in a three generation study in rats (two years). 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 LAS/kg bw (0.5%). Two additional long term studies were undertaken to evaluate the potential developmental effects of LAS. The developmental and teratogenic toxicity NOAELs were 300 mg/kg bw/d, which were either at or above the levels that resulted in maternally toxic effects.

Effects on developmental toxicity

Description of key information

The potential for reproductive toxicity of LAS (read across) was examined in a three generation study in rats (two years).

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 LAS/kg bw (0.5%). Two additional long term studies were undertaken to evaluate the potential developmental effects of LAS.

The developmental and teratogenic toxicity NOAELs were 300 mg/kg bw/d, which were either at or above the levels that resulted in maternally toxic effects.

Link to relevant study records

Reference

Reference 1

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:

see read-across document

Reason / purpose for cross-reference:

read-across source

Analytical verification of doses or concentrations:

not specified

Details on maternal toxic effects:

Maternal toxic effects:yes

Details on maternal toxic effects:
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. The pregnancy rate was comparable at all dosages.

Key result

Dose descriptor:

NOAEL

Effect level:

300 other: mg/kg

Basis for effect level:

other: maternal toxicity

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
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

Basis for effect level:

other: teratogenicity

Key result

Abnormalities:

not specified

Key result

Developmental effects observed:

not specified

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.

Conclusions:

NOAEL = 300 mg/kg for both maternal and teratogenicity

Executive summary:

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.

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:

see read-across document

Reason / purpose for cross-reference:

read-across source

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.

Key result

Dose descriptor:

NOAEL

Effect level:

2 mg/kg bw/day

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 doses with maternal toxicity there was an increased foetal loss and reduced litter size due almost entirely to total litter loss, which was considered to be a secondary effect due to the maternal toxicity. The incidences of major malformations was not affected; minor skeletal or visceral anomalies were increased at 300 mg/kg.

Key result

Dose descriptor:

NOAEL

Effect level:

300 mg/kg bw/day

Basis for effect level:

other: teratogenicity

Key result

Abnormalities:

not specified

Key result

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:

subchronic

Species:

mouse

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

Developmental toxicity

Two key studies examined the potential developmental toxicity of LAS (read across). In the first study, female rats were given LAS orally in distilled water from gestation days 6 to 15 during pregnancy. Doses were 0.2, 2.0, 300 and 600 mg/kg. Some effects such as decreased weight gain and transient diarrhea occurred at the highest dose. Pregnancy rates were comparable at all doses. 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. 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 marginal effects the LOAEL is considered to be 600 mg/kg bw/d and the NOAEL is 300 mg/kg bw/d.

In the second study done in the same laboratory (Palmer et al. 1974), pregnant female mice were exposed to LAS via gavage on days 6 -15 of gestation. 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 1-10 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. Increased mortality (35 and 90%, respectively) was observed at these two highest doses. These doses also exhibited retarded weight gain and adverse signs in the necropsy. Based on these effects, the maternal LOAEL is 300 mg/kg and the maternal NOAEL is 2 mg/kg. 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. At the 300 mg/kg 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, mean litter parameters, including litter size and foetal loss, and incidence of major malformations were not statistically different from controls. Minor anomalies, including gross or visceral and skeletal anomalies, were increased. At the 600 mg/kg dose, there were no live births. Based on these data, the developmental NOAEL was 300 mg/kg bw/day and the developmental LOAEL was 600 mg/kg bw/day.