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

Endpoint summary

Description of key information

In a combined repeated dose oral toxicity study with a reproduction/developmental screening study in rats with HCl MIPA, a NOAEL for general systemic toxicity of 300 mg/kw bw/day was established for males, based on some indications for a mild anemic process. For females, the NOAEL was 1000 mg/kg bw/day, the highest dose tested. For DIPA, a sub-chronic oral toxicity study was performed in rats. NOAELs of 100 mg/kw bw/day for males and 500 mg/kg bw/day for females were established. Three repeated-dose toxicity oral studies are available for LAS Na. The lowest LOAEL is from the 6-month rat study (Yoneyama et al., 1972) with a LOAEL of 115 mg/kg bw.  The highest NOAEL below this LOAEL is from the 9-month rat study (Yoneyama et al., 1976) with NOAEL = 85 mg/kg bw, based on histological changes seen in the kidney. Based on the data from all the studies, a NOAEL of 85 mg/kg bw is proposed, which was derived from a 9- month oral study and corresponds to the NOAEL, which is closest to the lowest available oral LOAEL of 115 mg/kg bw.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: oral

Type of information:

migrated 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:

other: This study is assigned a reliability score of 2 because the original report was not available for review. However, the study was evaluated by IPCS prior to inclusion in their criteria document.

Qualifier:

no guideline followed

Principles of method if other than guideline:

Male and female rats were exposed to Na-LAS in drinking water daily for 9 months.

GLP compliance:

no

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Route of administration:

oral: drinking water

Vehicle:

not specified

Details on oral exposure:

LAS was provided daily in drinking water.

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

nine months

Frequency of treatment:

daily in drinking water

Remarks:

Doses / Concentrations:
85, 145, 430 mg/kg bw d. (0.07, 0.2, 0.6%)
Basis:
nominal in water

No. of animals per sex per dose:

Information as cited in IPCS document. 8-9 animals of each sex per dose group.

Control animals:

yes, concurrent no treatment

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Food efficiency:

not specified

Ophthalmological findings:

not specified

Haematological findings:

no effects observed

Clinical biochemistry findings:

effects observed, treatment-related

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Details on results:

Body weight gain was suppressed in the male 0.6% group. Hematological examination revealed no significant change in any of the experimental groups, but a dose-related decrease in cholesterol level was seen in males. Significant decreases in the activities of glutamate-oxalate transaminase and lactate dehydrogenase were seen in males at 0.2% and a dose-related increase in the activity of gluatamate-oxalate transaminase in females. A significant decrease in renal Na,K-ATPase was seen in the group given 0.2%. No organ weight changes were observed. The intake of LAS was 50 mg/kg bw/day in the male 0.07% group and 120 mg/kg bw/day in the female group. The values for the 0.2% group were 120 and 170 mg/kg bw/day for males and females, respectively.

Dose descriptor:

NOAEL

Effect level:

85 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: activities of glutamate-oxalate transaminase and lactate dehydrogenase and renal Na,K-ATPase

Dose descriptor:

LOAEL

Effect level:

145 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Significant decreases in the activities of glutamate-oxalate transaminase and lactate dehydrogenase in males. A significant decrease in renal Na,K-ATPase in males and females.

Critical effects observed:

not specified

Conclusions:

NOAEL = 85 mg/kg bw/day; LOAEL = 145 mg/kg bw/day

Executive summary:

Male and female rats were exposed to Na-LAS in drinking water daily for 9 months. Body weight was suppressed in the highest dose group only. Significant decreases in transaminase activity and renal Na,K-ATPase was seen in the 0.2% group. The resultant LOAEL and NOAEL values were 145 and 85 mg/kg bw/day, respectively. The NOAEL represents the highest NOAEL below the lowest LOAEL.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

85 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Oral

No information is available on the repeated dose toxicity of LAS MIPA. The endpoint was addressed with data from LAS Na, HCl MIPA and DIPA.

MIPA:

In a combined repeated dose oral toxicity study with a reproduction/developmental screening study, rats were administerd hydrochloride salt of MIPA at 0, 100, 300 or 1000 mg/kg bw by oral gavage for 28 days(BASF AG, 2008). Results revealed slightly, but statistically significant reduced hemoglobin and hematocrit values, which are indicative of a mild anemic process, in high dose males. Other (minor) clinical and pathological findings were incidental and not dose-related. Thus, the NOAELs for general, systemic toxicity were established 300 mg/kg bw for males and 1000 mg/kg bw for females, respectively.

DIPA:

No sub-chronic oral toxicity studies are available for MIPA. Based on the category approach and read-across, the 90-day oral toxicity study for DIPA (OECD 408) is assumed to cover this endpoint. In this 90-day toxicity study, Fischer 344 rats (10/sex/dose) were administered DIPA at 0, 100, 500 or 1000 mg/kg bw/day via their drinking water (Dow, 2003). Rats given 1000 mg/kg bw/day drank less water than lower dose groups, with a corresponding decrement in food consumption and body weight. Urine specific gravity increased, and urine volume decreased for this group as well; both were considered to be related to reduced water intake. Serum cholesterol was slightly increased, and serum phosphorous was slightly decreased in the main study group at 1000 mg/kg-bw/day; neither effect was noted in the recovery group. Changes in albumin in treated groups were also observed. Absolute and relative kidney weights were increased, males were affected to a larger degree. After the 28-day recovery, the changes in kidney weights were approximately one half that present at the end of the dosing period and slight renal tubule degeneration with regeneration was seen at the end of recovery in the 1000 mg/kg bw/day group. The only effect found in the 500 mg/kg bw/day group was increased absolute and relative kidney weights for males and females, without any histopathologic correlate. Absolute kidney weights were increased in the 100 mg/kg bw/day male group, but these rats weighed more than the controls, and the relative kidney weights were not statistically different than controls. NOAELs of 100 and 500 mg/kw bw/day were established for males and females, respectively.

LAS Na:

Male and female rats were exposed to LAS Na (125, 250, 500 mg/kg bw/day) orally by gavage daily for 28 days. The results showed suppressed body weight gain, differences in some serum biochemical measures when compared to the controls, and decreased (spleen, heart, thymus) or increased (liver) organ weights in the animals of the highest dose level. The resultant LOAEL and NOAEL values were 250 and 125 mg/kg bw/day, respectively (Ito et al., 1978).

In a 6-month toxicity test male and female rats were exposed to LAS Na (CAS 69669-44-9) in the diet daily:40, 115, 340, 1030 mg/kg bw/day. Diarrhea, suppressed growth, increased cecal weight, and degeneration of renal tubes characterized the highest dose group. Similar but less severe signs were seen in other doses with the exception of the lowest dose of 0.07%, which showed no adverse effects related to exposure to LAS. The resultant LOAEL and NOAEL values were 115 and 40 mg/kg bw/day, respectively (Yoneyama et al., 1972).

In a 9-month toxicity study male and female rats were exposed to LAS Na (CAS 69669-44-9; 85, 145, 430 mg/kg bw/day) in drinking water daily. Body weight was suppressed in the highest dose. Significant decreases in transaminase activity and renal Na,K-ATPase was seen in the second group. The resultant LOAEL and NOAEL values were 145 and 85 mg/kg bw/day, respectively (Yoneyama et al., 1976).

Dermal and Inhalation

No dermal or inhalation repeated-dose toxicity studies are available for LAS MIPA. The effects of repeated exposure were addressed with the use of the oral studies and they are considered sufficient to cover these endpoints.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:

The endpoint was addressed with data from LAS Na, HCl MIPA, and DIPA. There are three repeated dose oral toxicity studies with LAS Na.  The lowest LOAEL is from the 6-month rat study (Yoneyama et al., 1972) with a LOAEL of 115 mg/kg bw.  The highest NOAEL below this LOAEL is from the 9-month rat study (Yoneyama et al., 1976) with NOAEL = 85 mg/kg bw, based on histological changes seen in the kidney. In view of the available information it is not possible to determine which single study among those is the most reliable or appropriate for the determination of a NOAEL. Therefore, based on the data from all the studies, a NOAEL of 85 mg/kg bw is proposed, which was derived from a 9- month oral study and corresponds to the NOAEL, which is closest to the lowest available oral LOAEL of 115 mg/kg bw.The NOAELs observed in the repeated dose studies with HCl MIPA (28 days) and DIPA (90 days) were 300 and 100 mg/kg bw, respectively. In the 28 day study anemic effects were seen in male animals. In the 90 day study with DIPA, absolute and relative kidney weights were significantly increased; nonetheless, these kidney effects were not accompanied by any histological changes in the kidney, in the whole dosing regimen. It can therefore be stated that the two substances, LAS Na and DIPA, although they both give rise to effects on the kidney, they induce effects with different mechanisms and modes of action. Consequently, there is no need to derive a NOAEL based on considerations of combination toxicity - the lowest NOAEL observed, since NOAELs presuppose absence of effects, is protective for all MoAs.  On this basis, the NOAEL of 85 mg/kg bw for Las Na, is also a safe level for LAS MIPA. The same holds for the anemic effects observed in the study with HCl MIPA, at a much higher dose level of 300 mg/kg bw (NOAEL: 300 mg/kg bw). Based on this reasoning the NOAEL= 85 mg/kg bw/day is proposed.

Repeated dose toxicity: via oral route - systemic effects (target organ) digestive: cecum; urogenital: kidneys

Justification for classification or non-classification

Based on the results of the repeated dose toxicity studies, LAS MIPA does not warrant for a STOT classification according to (CLP) Regulation (EC) No. 1272/2008. Although adverse effects have been seen after repeated exposures of animals to HCl MIPA, DIPA, and LAS Na, these were seen at dose levels above the classification criterion limit of 100 mg/kg bw (lowest LOAEL observed for LAS Na was 115 mg/kg bw).