Reaction mass of Disodium decyl(sulphonatophenoxy)benzenesulphonate and Disodium oxybis[decylbenzenesulphonate]

Endpoint summary

Description of key information

Several GLP and non-GLP (pre-GLP) studies containing sufficient data for the interpretation and assessment are available, including rat and dog studies, on the ADPODS category members (refer to full read-across ADPODS category justification document).

These category members differ only in structure and length of their alkyl side chains. The extent of predicted oral absorption and experimental irritation potential between all the category members was similar. Therefore, the substance properties and the structural difference would not affect or change the overall systemic toxicity potential for any of the category members including the registered substance.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

chronic toxicity: oral

Type of information:

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

Adequacy of study:

key study

Study period:

1961-1963

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: This study was conducted prior to GLP and test guidelines, but sufficient data is available for interpretation of results.

Justification for type of information:

Please see read across justification document.

Qualifier:

no guideline followed

Principles of method if other than guideline:

Beagle dogs were divided into matched groups and started on diets containing 0.0 (control), 1.0, 0.5, 0.25, or 0.125% Benax 2A1. Four males and four females comprised each group, except for the 1.0% level, which consisted of two males and four females. The percentage levels given above were approximately equivalent to the administration of 0, 319, 128, 65, and 34 mg/kg/day Benax 2A1, respectively, over the two-year period.

General appearance and behavior, growth, food consumption, hematological values, determinations of serum urea nitrogen content, alkaline phosphatase and transaminase activity and bromsulfophthalein dye retention, final organ and body weights, and gross and microscopic examination of the tissues were conducted.

GLP compliance:

no

Remarks:

pre-GLP

Limit test:

no

Species:

dog

Strain:

Beagle

Sex:

male/female

Details on test animals or test system and environmental conditions:

Male and female beagle hounds of approximately three months of age were obtained from a commercial kennel and housed at the Biochemical Research Laboratory. The pups remained in the laboratory three months prior to the beginning of the experiment, during which time they were vaccinated for distemper, hepatitis, and leptospira. The stock diet for the first two months was Famo Labomtory Chow; it was then changed to Purina Laboratory Chow for the remaining time. Dogs of each sex per level were housed together and had free access to food and water at all times.

On October 17, 1961, the dogs were divided into matched groups.

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

Dogs were divided into matched groups and given diets containing 0.0 (control), 1.0, 0.5, 0.25, or 0.125% Benax 2A1. Four males and four females comprised each group, except for the 1.0% level, which consisted of two males and four females. The percentage levels given above were approximately equivalent to the administration of 0, 319, 128, 65, and 34 mg/kg/day Benax 281, respectively, over the two-year period.

Analytical verification of doses or concentrations:

no

Details on analytical verification of doses or concentrations:

No data

Duration of treatment / exposure:

2 years

Frequency of treatment:

Daily

Remarks:

Doses / Concentrations:
0.0 (control), 1.0, 0.5, 0.25, or 0.125% Benax 2A1
Basis:
nominal in diet

Remarks:

Doses / Concentrations:
0, 319, 128, 65, and 34 mg/kg/day Benax 2A1
Basis:
nominal in diet

No. of animals per sex per dose:

Four males and four females comprised each group, except for the 1.0% level, which consisted of two males and four females.

Control animals:

yes, plain diet

Details on study design:

Beagle dogs were divided into matched groups and started on diets containing 0.0 (control), 1.0, 0.5, 0.25, or 0.125% Benax 2A1. Four males and four females comprised each group, except for the 1.0% level, which consisted of two males and four females. The percentage levels given above were approximately equivalent to the administration of 0, 319, 128, 65, and 34 mg/kg/day Benax 281, respectively, over the two-year period.

Each dog was weighed weekly for the first three months of the experiment and twice a week thereafter. Food consumption was recorded 3 during the first , 12th, and 16th months, and one week out of each month from 18 months to the end of the experiment. Hematological studies and determinations of serum urea nitrogen content and alkaline phosphatase activity were made before the beginning of the experiment and at three, six, nine, 12, 18, and 24 months. Transaminase activity (SGPT) was determined at one and two years and bromsulfophthalein dye retention at one year. Urea nitrogen content and transaminase and alkaline phosphatase activity was determined. Pre-exposure liver biopsies were performed on one dog of each sex per level, as well as at six, 12, and 18 months on the experiment.

At the end of the two-year period the animals were fasted overnight and weighed before examination at autopsy. The lungs, heart, liver, kidney, spleen, testes, and brain were removed and weighed. Portions of each organ,as well as spinal cord, peripheral nerve, pituitary, thyroid, adrenal, aorta, lymph node, thymus, esophagus, stomach, small and large intestine, pancreas, urinary bladder, ovary, uterus, and skeletal muscle were preserved. The tissues were then sent to the International Research and Development Corporation in Mattawan, Michigan, for preparation of hematoxylin-eosin stained sections and microscopic examination.

Positive control:

Non

Observations and examinations performed and frequency:

Each dog was weighed weekly for the first three months of the experiment and twice a week thereafter. Food consumption was recorded 3 during the first , 12th, and 16th months, and one week out of each month from 18 months to the end of the experiment.

Sacrifice and pathology:

Hematological studies and determinations of serum urea nitrogen content and alkaline phosphatase activity were made before the beginning of the experiment and at three, six, nine, 12, 18, and 24 months. Transaminase activity (SGPT) was determined at one and two years and bromsulfophthalein dye retention at one year. Urea nitrogen content and transaminase and alkaline phosphatase activity was determined. Pre-exposure liver biopsies were performed on one dog of each sex per level, as well as at six, 12, and 18 months on the experiment.

At the end of the two-year period the animals were fasted overnight and weighed before examination at autopsy. The lungs, heart, liver, kidney, spleen, testes, and brain were removed and weighed. Portions of each organ,as well as spinal cord, peripheral nerve, pituitary, thyroid, adrenal, aorta, lymph node, thymus, esophagus, stomach, small and large intestine, pancreas, urinary bladder, ovary, uterus, and skeletal muscle were preserved. The tissues were then sent to the International Research and Development Corporation in Mattawan, Michigan, for preparation of hematoxylin-eosin stained sections and microscopic examination.

Other examinations:

None

Statistics:

No data

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

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:

effects observed, treatment-related

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Details on results:

Benax 2A1 was fed in the diets of male and female beagle hounds for a period of two years at the concentrations of 1.0, 0.5, 0.25, or 0.125%. Food consumption data indicated that the dietary concentrations given above administered the test substance in amounts of 319, 128, 65 and 34 mg/kg/day respectively. No evidence of adverse effect whatsoever was observed in the dogs given the 0.5% dietary level or below as judged by general appearance and behavior, growth, food consumption, hematological values, determinations of serum urea nitrogen content, alkaline phosphstase and transaminase activity, and bromsulfophthalein dye retention, final body and organ weights, and gross and microscopic examination of the tissue.

The two males and four females which received 1.0% Benax 2A1 in their diets showed growth retardation. Because male dog #330 and female dog #343 lost approximately one-third of their original weights, they were sacrificed after 14 months of the experiment. The final weight of the other male was essentially the same as his original weight, while two of the remaining females lost weight and the third gained. The 1.0% level was not readily acceptable to the dogs. Persistent scratching at the feeders was noted during the early months of the experimental period. This was noted to some extent also in the group of dogs receiving the 0.5% level. Food consumption records for the first month reflect this observation in that the unusually high figures in comparison with the controls was due to spillage and wastage. Therefore, it is possible that the growth retardation in the dogs maintained on the diet containing 1.0% Benax 2A1 may be related somewhat to decreased food intake, at least during the early part of the experiment. Intestinal irritation, as evidenced by loose stools and diarrhea which these dogs exhibited for the first 45 days on the experiment, also may have contributed to their failure to gain weight.

Alkaline phosphatase determinations at various intervals throughout the two-year period showed a slight increase in activity in both of the male dogs and in two of the four females on the 1.0% level. However, the determination of two other liver function tests, that of bromsulfophthalein dye retention at approximately one year and transaminase activity at one and two years, gave normal results in comparison with the control values.

An increased liver/body weight ratio was found in the male dog which was sacrificed after 14 months. The organ/body weight ratio of the kidney of the 1.0% male which was carried through to the end of the two-year period was also increased. However, these variations are due to decreased body weights, since there was no increase in the organ weights when considered on the absolute basis in grams.

Hematological values, serum urea nitrogen determinations, and gross and microscopic examination of the tissues gave no indication of any adverse effects in the dogs which received 1.0% Benax 2A1 in their diets when compared with the controls.

Dose descriptor:

NOAEL

Effect level:

128 mg/kg bw/day (nominal)

Sex:

male/female

Basis for effect level:

other: Based on growth retardation, loose stools and diarrhea, and increased alkaline phosphatase observed in dogs given 319 mg/kg/day or 1.0% in diet. Note: 128 mg/kg/day= 0.5% on diet.

Critical effects observed:

not specified

None

Conclusions:

The systemic NOEL in Beagle dogs was determined to be 0.5% or 128 mg DOWFAX 2A1/kg bw/day.

Executive summary:

Male and female beagle hounds were maintained for two years on diets containing 0.5, 0.25, or 0.125% Benax/DOWFAX 2A1 (equivalent to 128, 65, and 34 mg/kg/day) without evidence of adverse effect as judged by general appearance and behavior, growth, food consumption, hematological values, determinations of serum urea nitrogen content, alkaline phosphatase and transaminase activity and bromsulfophthalein dye retention, final organ and body weights, and gross and microscopic examination of the tissues compared to control animals. At the highest dose level (1% or 319 mg/kg/day, study LOAEL), growth was retarded in the male and female dogs fed Benax/DOWFAX 2A1. These dogs also had loose stools and diarrhea for the first 45 days of the experiment; slightly increased alkaline phosphatase activity in both male dogs and in two out of four female dogs; variations in a few organ/body weight ratios with no difference in organ weights when considered on the absolute basis in grams. Hematological determinations, serum urea nitrogen and transaminase values, determination of bromsulfophthalein dye retention, and gross and microscopic examination of the tissues gave no indication of adverse effects when compared with the controls. Based on these effects, the systemic NOEL in Beagle dogs was determined to be 0.5% or 128 mg DOWFAX 2A1/kg bw/day.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

128 mg/kg bw/day

Study duration:

chronic

Species:

dog

Quality of whole database:

acceptable

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 adverse effect observed

Additional information

ORAL STUDIES OVERVIEW:

No repeat-dose studies are available on the registered substance. Data from ADPODS category members are available to satisfy this requirement and derive DNELs (see category document for justification). Chronic dietary dog study with DOWFAX 2A1 category member was used for DNEL deviation (Klimisch=2) as the two ADPODS category members (DOWFAX 3B2 and 2A1) differ only by length of two carbons of the alkyl side chain and thus are closest neighbors within the ADPODS category. In this key study, male and female beagle hounds were maintained for two years on diets containing 0, 34, 65, 128, 319 mg/kg/day DOWFAX 2A1. No evidence of adverse effect was evident at exposure concentrations of equal to or greater than 128 mg/kg/day as judged by general appearance and behavior, growth, food consumption, hematological values, determinations of serum urea nitrogen content, alkaline phosphatase and transaminase activity and bromsulfophthalein dye retention, final organ and body weights, and gross and microscopic examination of the tissues. Growth was decreased in the male and female dogs fed highest dose of 319 mg/kg/day DOWFAX 2A1 (study LOAEL). This test group also had loose stools and diarrhea for the first 45 days of the experiment; slightly increased alkaline phosphatase activity in males and half of females; and variations in a few relative organ/body weight ratios. Based on all these observations, the general systemic toxicity NOAEL (and point of departure for DNEL derivation) for this chronic dog study has been set at 128 mg/kg/day.

 

In the supporting chronic rodent study (Klimisch=2), groups of 30 male and female rats were maintained for a period of two years on diets containing 0, 15, 50, 150, 500 mg DOWFAX 2A1/kg bw/day without evidence of adverse effect as judged by general appearance and behavior, mortality, incidence of tumorous growths, food consumption, hematological studies, serum urea nitrogen and alkaline phosphatase determinations, bone marrow examination, final average body and organ weights, and gross and microscopic examination of the tissues. Study LOAEL was based on depressed growth and statistically significant decrease in the final average body weight at the end of two years seen in female rats fed 500 mg/kg/day DOWFAX 2A1; the general systemic toxicity NOAEL for this study was 150 mg/kg/day.

In a supporting subchronic rodent study (Klimisch=2), rats were administered 0, 0.01, 0.03, 0.1, 0.3 and 1.0 % DOWFAX 2A1 in the diet for 90 days. Livers of male rats at the 1% level showed central lobular necrosis of the parenchymal cells, and fatty degeneration and early, but slight fibrosis with some slight bile duct epithelium proliferation in the portal areas. At 1% dose level, females showed decreased growth together and similar histopathology to males, as well as statistically significant increase in the average liver and kidney weights. Based on the above findings the study NOAEL was 0.3% in the diet.

 

In another supporting subchronic study (Klimisch=2), dogs were administered 0, 40, 131 or 350 mg/kg/day DOWFAX 2A1 in the diet for 95 days. The dogs in the 350 mg/kg/day dose group dogs consumed 73% of the food quantity compared to the control group. The corresponding decrease in body gain weight and relative organ weights was proportional to the decrease in food consumption in comparison with the controls. However, there was no difference in absolute organ weights when compared with the controls. There was an increase in the serum alkaline phosphatase values in the highest intake group without accompanying pathological changes in the liver nor any significant difference in the liver/body weight ratio when compared with the controls. Based on the above findings the study NOAEL was 131 mg/kg/day.

 

In the 2003 GLP OECD422 screen with another category member (Klimisch=1), groups of 12 male and 12 female CD rats were administered DOWFAX 8390 surfactant 7 days/week, by gavage at dose levels of 0, 25, 75, and 250 mg/kg/day. Gavage administration of 250 mg DOWFAX 8390/kg/day resulted in increased incidences of soft/decreased feces (males only), accompanied by slightly increased prothrombin times (males only), increased serum ALT, and increased serum AST (females only) levels. At 75 mg/kg/day, prothrombin times were increased in males only. Urinalysis in the males revealed a slight increase in urine pH at all dose levels thought to be associated with the properties of the test material and/or its metabolites. There were no treatment-related effects on body weights, body weight gains, feed consumption, detailed clinical observations, neurological end points, reproductive/developmental end points, organ weights, or histopathology at any dose level tested. No toxicologically significant effects occurred in the 25 mg/kg/day group (systemic study NOAEL) following bolus administration of DOWFAX 8390.

 

In a supporting subchronic rodent study with DOWXAF 8390 (Klimisch=2), rats were given 0, 50, 100, 200 or 600 mg of substance daily in the diet for 90-91 days. Increased kidney weights accompanied by microscopic observations were observed only at the highest dose levels. The kidney morphology and function were not different from control rats at the two groups with lower material intake. The SGPT activity was increased at all dose levels in the male rats in the absence of any histological or other biochemical evidence of liver damage. No other alterations/effects were observed at any dose level. The subchronic study NOAEL was 200 mg/kg/day for rats.

 

In another supporting subchronic dog study with DOWXAF 8390 (Klimisch=2), dogs were given 0, 50, 100 or 200 mg/kg/day material in the diet for 90 days. Increased kidney and liver weights in male and female dogs, without associated histological alterations, were seen at the high dose level. Thus, no significant toxicological effects were observed among any of the groups of dogs administered DOWFAX 8390. The subchronic study NOAEL was 200 mg/kg/day for dogs.

 

 

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:  Longest repeat dose study with DOWFAX 2A1 category member of close alkyl chain length was chosen that also established the lowest study NOAEL within the dietary ADPODS dataset. All durations of exposure to this category of materials have showed similar effects in test animals.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Longest repeat dose study with DOWFAX 2A1 with lowest NOAEL. All durations of exposure to test material showing similar effects in test animals.

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:
sufficient data available on the registered substance for assessment.

Justification for selection of repeated dose toxicity dermal - local effects endpoint:
sufficient data available on the registered substance for assessment.

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

Justification for classification or non-classification

Non-classification for the registered substance (Reaction mass of Disodium decyl(sulphonatophenoxy)benzenesulphonate and Disodium oxybis[decylbenzenesulphonate]) is based on the chronic NOAEL of 128 mg/kg/day of a category member in accordance with the CLP.