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Carcinogenicity

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Description of key information

There are two key studies for the hydrotrope category substances, both conducted on sodium xylene sulphonate. The key studies are 2-year rat and mouse dermal exposure studies conducted under GLP.  Up to 240 mg (rats) and 727 mg (mice) sodium xylenesulfonate/kg body weight in 50% ethanol were dosed 5 days per week for 104 weeks. There were no treatment related incidences of mononuclear cell leukaemia, neoplasms, or non-neoplastic lesions of the skin and other organs. The increased incidence of epidermal hyperplasia may have been related to exposure to the test substance. The NOAEL for systemic toxicity and carcinogenicity was reported as 240 mg/kg bw/day for rats and 727 mg/kg bw/day for mice. The NOAEL for local effects is considered to be 60 mg/kg bw/day, based on the findings from the rat study.

 

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via dermal route

Link to relevant study records

Referenceopen allclose all

Endpoint:
carcinogenicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
December 20, 1990 to December 18, 1992
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Protocols and results reviewed and accepted by the National Toxicology Program's Board of Scientific Counselor's Reports Review Subcommittee. USA National Institutes of Health
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
Deviations:
not specified
GLP compliance:
yes
Species:
mouse
Strain:
B6C3F1
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS- Source: Simonsen Laboratories, Inc (Gilroy, CA)- Age at study initiation: 7 weeks- Weight at study initiation: no data- Fasting period before study: no data- Housing: individually caged in polycarbonate cages changed once per week and rotated on stainless steel racks once every two weeks. Sani-chip hardwood chips and spun-bonded polyester cage filters. - Diet (e.g. ad libitum): ad libitum- Water (e.g. ad libitum):ad libitum- Acclimation period: 14 daysENVIRONMENTAL CONDITIONS- Temperature (°C): 16.7 to 25.6- Humidity (%): 34 to 69- Air changes (per hr): 10 minimum- Photoperiod (hrs dark / hrs light): 12 / 12IN-LIFE DATES: From: December 20, 1990 To: December 18, 1992
Route of administration:
dermal
Vehicle:
ethanol
Details on exposure:
TEST SITE- Area of exposure: shaved interscapular skin- % coverage: no data- Type of wrap if used: no data - Time intervals for shavings or clipplings: no dataREMOVAL OF TEST SUBSTANCE- Washing (if done): no data- Time after start of exposure: no dataTEST MATERIAL- Amount(s) applied (volume or weight with unit): 46 to 128 microliters- Concentration (if solution): 50% of applied volume. Doses were 0, 182, 364 and 727 mg/kg bw- Constant volume or concentration used: yesVEHICLE- Justification for use and choice of vehicle (if other than water): test material beads up in distilled water- Amount(s) applied (volume or weight with unit): in the 46 to 128 microliters- Concentration (if solution): 50%- Lot/batch no. (if required): no data- Purity: no dataUSE OF RESTRAINERS FOR PREVENTING INGESTION: no data
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Dose formulations were prepared every 2-3 weeks. HPLC at the beginning of the study and every 7-10 weeks thereafter.
Duration of treatment / exposure:
2 years
Frequency of treatment:
5 days per week
Remarks:
Doses / Concentrations:0, 182, 364 and 727 mg/kg bwBasis:analytical conc.
No. of animals per sex per dose:
50
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale: based on 17-day and 14-week range finding studies- Rationale for animal assignment (if not random): random
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes - Time schedule: twice daily- Cage side observations checked not in tableDETAILED CLINICAL OBSERVATIONS: Yes - Time schedule: monthlyDERMAL IRRITATION (if dermal study): Yes - Time schedule for examinations: monthlyBODY WEIGHT: Yes - Time schedule for examinations: weekly through week 13 and montly thereafterFOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): - Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data - Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No dataFOOD EFFICIENCY:- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No dataWATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Not a drinking water studyOPHTHALMOSCOPIC EXAMINATION: No dataHAEMATOLOGY: No dataCLINICAL CHEMISTRY: No dataURINALYSIS: No dataNEUROBEHAVIOURAL EXAMINATION: No dataOTHER:
Sacrifice and pathology:
GROSS PATHOLOGY: Yes (see table 15 ad 16)HISTOPATHOLOGY: Yes (see table 15 and 16)
Statistics:
Kaplan-Meier, logistic regression analysis, life table test, FIsher exact test, Cochran-Armitage trend test, comparison of continuous variables, Dunnett and Williams test, Shirley and Dunn
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
OTHER FINDINGS - epidermal hyperplasia observed in males and females at two highest doses and in female controls.
Relevance of carcinogenic effects / potential:
No evidence of carcinogenic activity
Key result
Dose descriptor:
NOAEL
Effect level:
>= 727 mg/kg bw/day (actual dose received)
Sex:
male/female
Basis for effect level:
other: overall effectsclinical signs; mortality; body weight; gross pathology; histopathology
Remarks on result:
other:
Remarks:
Effect type: other: toxicity and carcinogenicity (migrated information)
Conclusions:
Test substance was found to be non-carcinogenic
Endpoint:
carcinogenicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
November 29, 1990 to November 20, 1992
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Protocols and results reviewed and accepted by the National Toxicology Program's board of Scientific Counselor's Technical Reports Review Subcommittee, USA National Institutes of Health
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
Deviations:
not specified
Principles of method if other than guideline:
50 male and 50 female F344/N rats (at 6 weeks old) were administered dermal applications of 0, 60, 120 or 240 mg sodium xylenefulfonate/kg body weight in 50% ethanol. Doses were applied 5 days per week for 104 weeks to the clipped interscapular skin at volumes of 85 to 357 microliters. Volumes were adjusted for the weights of the animals throughout the study. Animals were housed individually and fed and given water ad libitum. Cages were changed weekly and racks were rotated every 2 weeks. All animals were observed twice daily and clinical findings were recorded monthly. Body weights were recorded weekly for 13 weeks, then monthly thereafter. All animals were necropsied and a complete histopathological examination was performed. All organs and tissues including skin were examined for grossly visible lesions. Major tissues were examined microscopically and slides were evaluated by an independent quality laboratory in addition to the study laboratory pathologist. The study was conducted under GLPs. The studywas conducted from November 29, 1990 to November 20, 1992 at the Battelle Columbus Laboratories. The temperature was 20-24.4 degrees centigrade; the humidity was 35-70%; the room air was changed 10 times per hour minimum; and the photoperiod was 12 hours light and 12 hours dark.NTP Technical Report on the Toxicology and Carcinogenesis Studies of Technical Grade Sodium Xylenesulfonate in F344/N Rats and B6C3F1 Mice. NTP TR 464, June 1998. The study reliability is Klimisch 1.
GLP compliance:
yes
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS- Source: Simonsen Laboratories, Inc (Gilroy, CA)- Age at study initiation: 7 weeks- Weight at study initiation: no data- Fasting period before study: no data- Housing: housed individually in polycarbonate cages; changed every week and stainless steel racks rotated every 2 weeks. Heat-treated hardwood chips and spun-bonded polyester cage filters - Diet (e.g. ad libitum): ad libitum- Water (e.g. ad libitum):ad libitum- Acclimation period: 14 daysENVIRONMENTAL CONDITIONS- Temperature (°C): 20-24.4- Humidity (%): 35-70- Air changes (per hr): 10 per day minimum- Photoperiod (hrs dark / hrs light): 12 / 12IN-LIFE DATES: From: November 29, 1990 To: November 20, 1992
Route of administration:
dermal
Vehicle:
ethanol
Details on exposure:
TEST SITE- Area of exposure: shaved interscapular skin- % coverage: no data- Type of wrap if used: no data- Time intervals for shavings or clipplings: no dataREMOVAL OF TEST SUBSTANCE- Washing (if done): no data- Time after start of exposure: no dataTEST MATERIAL- Amount(s) applied (volume or weight with unit): 85 to 357 microliters (volume adjusted for weights during the study)- Concentration (if solution): 50% of applied volume; doses were 0, 60, 120 and 240 mg/kg bw- Constant volume or concentration used: yesVEHICLE- Justification for use and choice of vehicle (if other than water): beading of test substance in distilled water- Amount(s) applied (volume or weight with unit): as part of the 85-357 microliters- Concentration (if solution): 50%- Lot/batch no. (if required): no data- Purity: no dataUSE OF RESTRAINERS FOR PREVENTING INGESTION:no data
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
HPLC at the beginning of the study and then every 7 to 10 weeks
Duration of treatment / exposure:
2 years
Frequency of treatment:
5 days per week
Post exposure period:
no data
Remarks:
Doses / Concentrations:0, 60, 120 and 240 mg/kg bwBasis:analytical conc.
No. of animals per sex per dose:
50
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale: based on 17 day and 14 week range finding studies- Rationale for animal assignment (if not random): random
Positive control:
no data
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes - Time schedule: twice daily- Cage side observations checked in table were not included. DETAILED CLINICAL OBSERVATIONS: Yes- Time schedule: monthlyDERMAL IRRITATION (if dermal study): Yes - Time schedule for examinations: monthlyBODY WEIGHT: Yes- Time schedule for examinations: weekly through week 13, monthly thereafterFOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): - Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes / No / No data - Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes / No / No dataFOOD EFFICIENCY:- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No dataWATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Not a drinking water studyOPHTHALMOSCOPIC EXAMINATION: No dataHAEMATOLOGY: No dataCLINICAL CHEMISTRY: No dataURINALYSIS: No dataNEUROBEHAVIOURAL EXAMINATION: No dataOTHER:
Sacrifice and pathology:
GROSS PATHOLOGY: Yes (see table 8)HISTOPATHOLOGY: Yes (see appendix A4 and B4)
Statistics:
Kaplan-Meier, logistic regression analysis, life table test, FIsher exact test, Cochran-Armitage trend test, comparison of continuous variables, Dunnett and Williams test, Shirley and Dunn
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
OTHER FINDINGS - epidermal hyperplasia at the site of treatment in several females at the two hightest doses and in one control animal
Relevance of carcinogenic effects / potential:
No evidence of carcinogenic activity.
Key result
Dose descriptor:
NOAEL
Effect level:
>= 240 mg/kg bw/day (actual dose received)
Sex:
male/female
Basis for effect level:
other: overall effectsclinical signs; mortality; body weight; gross pathology; organ weights; histopathology
Remarks on result:
other:
Remarks:
Effect type: other: toxicity and carcinogenicity (migrated information)
Dose descriptor:
NOAEL
Effect level:
>= 60 mg/kg bw/day
Sex:
female
Basis for effect level:
other: Epidermal hyperplasia
Remarks on result:
other:
Remarks:
Effect type: other: local effects on skin (migrated information)
Conclusions:
Test substance was found to be non-carcinogenic
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
240 mg/kg bw/day
Study duration:
chronic
Species:
rat
Quality of whole database:
Sufficient to meet requirements.
System:
other: skin

Justification for classification or non-classification

There was no evidence of carcinogenic activity in two dermal carcinogenicity studies in rats and mice. Therefore there is no justification for hazard classification.

Additional information

50 male and 50 female rats and mice were administered dermal applications of up to 240 mg (rats) and 727 mg (mice) sodium xylenefulfonate/kg body weight in 50% ethanol. Doses were applied 5 days per week for 104 weeks to the clipped interscapular skin at volumes adjusted for the weights of the animals throughout the study. Animals were housed individually and fed and given water ad libitum. Cages were changed weekly and racks were rotated every 2 weeks. All animals were observed twice daily and clinical findings were recorded monthly. Body weights were recorded weekly for 13 weeks, then monthly thereafter. All animals were necropsied and a complete histopathological examination was performed. All organs and tissues including skin were examined for grossly visible lesions. Major tissues were examined microscopically and slides were evaluated by an independent quality laboratory in addition to the study laboratory pathologist. The study was conducted under GLPs from late 1990 to late 1992 at the Battelle Columbus Laboratories. NTP Technical Report on the Toxicology and Carcinogenesis Studies of Technical Grade Sodium Xylenesulfonate in F344/N Rats and B6C3F1 Mice. NTP TR 464, June 1998. The study reliability is Klimisch 1.

Survival of the dosed males and females was similar to that of the control groups and consistent with historical controls.

Mean body weights of dosed males and females were similar to those of the controls throughout and there were no clinical findings considered treatment related in males. In female rats, clinical findings were limited to irritation at the site of application in one control, in 4 at 120 mg/kg bw and in 2 at 240 mg/kg bw. In mice, clinical finding were limited to irritation of the site of application in female controls, and males and females at the 364 and 727 mg/kg bw doses. There were no treatment related incidences of mononuclear cell leukaemia, neoplasms, or non-neoplastic lesions of the skin and other organs. The increased incidence of epidermal hyperplasia may have been related to exposure to the test substance.


Justification for selection of carcinogenicity via dermal route endpoint:
The NOAEL (systemic and local) were lowest in the rat study.