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Carcinogenicity

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Description of key information

OECD 453, rat, combined chronic toxicity/carcinogenicity, oral: not carcinogenic
NOAEL = 1125 mg/kg bw/day; LOAEL > 1125 mg/kg bw/day

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records
Reference
Endpoint:
carcinogenicity: oral
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: Comparable to Guideline study with acceptable restrictions.
Reason / purpose:
reference to same study
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
Deviations:
yes
Remarks:
Some examinations like urinalysis are missing.
GLP compliance:
no
Remarks:
Tests were conducted prior to the implementation of GLP (1976-1978).
Species:
rat
Strain:
other: Colworth Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: males: 81.73 g (control group), 82.49 (0.015% dose group), 81.98 g (0.15% dose group), 81.16 g (1.5% dose group); females: 69.36 g (control group), 69.58 (0.015% dose group), 69.40 g (0.15% dose group), 68.80 g (1.5% dose group)
- Housing: rats were individually housed.
- Diet: ad libitum
- Water: ad libitum

IN-LIFE DATES: From: 09 Feb 1976 To: 24 Feb 1978
(The studies were finalised in 1978. Data of both studies were compiled in 1995.)
Route of administration:
oral: feed
Vehicle:
other: plain diet
Details on exposure:
DIET PREPARATION
- Mixing appropriate amounts with a purified diet
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
2 years
Frequency of treatment:
daily, 7 days/week
Post exposure period:
none
Remarks:
Doses / Concentrations:
0.015, 0.15, 1.5%
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
11, 113, 1125 mg/kg bw
Basis:
actual ingested
No. of animals per sex per dose:
45
Control animals:
yes, plain diet
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: animals were inspected daily for signs of ill-health.

BODY WEIGHT: Yes
- Time schedule for examinations: body weights were determined weekly for the first 13 weeks, again at Week 16, and thereafter at intervals of 4 weeks until the end of the study.

FOOD CONSUMPTION: Yes
- Time schedule for examinations: food consumption was determined weekly for the first 13 weeks, again at Week 16, and thereafter at intervals of 4 weeks until the end of the study.
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No, only mean values for each group per week reported

WATER CONSUMPTION: Yes
- Time schedule for examinations: water consumption was determined weekly for the first 13 weeks, again at Week 16, and thereafter at intervals of 4 weeks until the end of the study.

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at study termination and after overnight starvation
- Anaesthetic used for blood collection: Yes
- Animals fasted: Yes, overnight
- How many animals: all surviving animals (244/360 animals)
- Parameters checked: packed cell volume (PCV), haemoglobin, mean cell haemoglobin concentration (MCHC), total leukocytes

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at study termination and after overnight starvation
- Animals fasted: Yes
- How many animals: all surviving animals (244/360 animals)
- Parameters checked: sodium, potassium, chloride, calcium, magnesium, urea, glucose, total cholesterol, triglycerides, creatinine, aspartate transaminase (ASAT), alanine transaminase (ALAT), lactate dehydrogenase, hydroxybutyrate dehydrogenase, alkaline phosphatase, pseudo cholinesterase
Sacrifice and pathology:
GROSS PATHOLOGY: Yes, a full post-mortem examination was performed in all animals (survivors and decedents), including physical examination of the external body surface, all orifices, cranial cavity, meningeal surface of the brain, the neck, the thoracic, abdominal and pelvic cavities with their associated organs and tissues and the carcass; organ weights of heart, liver, spleen kidneys, testes, adrenals and brain were determined in all surviving animals.
HISTOPATHOLOGY: Yes, in all animals; histopathological examination was performed in heart, liver, spleen kidneys, testes, adrenals, brain, aorta, eyes, intestine, kidneys, lacrimal glands, liver, lungs, lymph nodes, mammary gland, muscle, ovaries, pancreas, pituitary, prostate, salivary gland, seminal vesicles, spleen, stomach, testes, thyroids, thymus, tongue, urinary bladder and uterus
Other examinations:
Animals dying or killed during the test received a full post-mortem examination at which tissues were taken for histological examination. Animals surviving to the end of the test were starved overnight and blood was taken under anaesthesia for haematology and biochemical measurements after which the animals were killed and a number of organs (heart, liver, spleen kidneys, testes, adrenals and brain) were removed and weighed. These organs and a range of other tissues from each rat were preserved for histological examination. Histological examination was undertaken on stained tissue sections from all animals fed the control diet and each dietary level of the test substances.
Statistics:
For all relevant parameters, except those for pathology, mean values were calculated.
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
1.5% in the diet: reduced weight gain in rats (particularly males) compared to controls (non-adverse)
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
1.5% in the diet: reduced food consumption in rats (particularly males) compared to controls (non-adverse)
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Description (incidence and severity):
1.5% in the diet: reduced water consumption in males and females compared to controls (non-adverse)
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
1.5% in the diet: reduced total white cell count in females (non-adverse)
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
1.5% in the diet: increased activity of ALAT, AP and urea in males (non-adverse); decreased activities of lactate dehydrogenase and hydroxybutyrate dehydrogenase in females (non-adverse)
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
1.5% in the diet: reduction in the relative organ weights of spleen, heart, kidneys and adrenals in males; increased testes weights in males; increased liver weights in male and female (non-adverse)
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
1.5% in the diet: hepatic enlargement in males and females
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
1.5% in the diet: major changes in liver and spleen; minor changes in kidney, heart
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY
No adverse effects on survival were observed after treatment with the test substance. Of the 360 rats involved, 244 (67.8%) survived to the termination of the study. Survival was highest in rats receiving the highest dose level of 1.5% (78.9%) and lowest in those fed 0.15% of the test substance in the diet (60%). Neoplasia was the most common cause of death in animals which died during the study, but death from this cause was or from any other illness was not enhance by feeding with the test substance.

BODY WEIGHT AND WEIGHT GAIN
Weight gain was poorer for the rats fed at the highest dose level (1.5%), particularly the male animals, when compared to controls.

FOOD CONSUMPTION
Reduced food consumption compared to controls was observed at the highest dose level (1.5%), especially for males, which is consistent with the observed decrease in body weight gain in these animals.

WATER CONSUMPTION
During the study, a lower water consumption compared to controls was noted in both sexes at the highest dose level (1.5%).

HAEMATOLOGY
The only effect on haematological parameters was a reduction in the total white cell count for females receiving the test substance at a dietary dose level of 1.5% (highest dose).

CLINICAL CHEMISTRY (see Tables 1 under “Any other information on results incl. tables”)
The activities of alanine aminotransferase (ALAT) and alkaline phosphatase (AP) were increased in the blood of male rats of the highest dose group (1.5%), as also was the urea level. In contrast, the activities of lactate dehydrogenase and hydroxybutyrate dehydrogenase were lower for female rats of this dose group. The increased incidence of multifocal sublobular hepatic necrosis, which is occasionally observed in the liver of aging rats, was probably responsible for the elevated activity of ALAT in males of the high dose group. The increase in AP activity at the high dose group was rather associated with the hepatic parenchymal hypertrophy resulting from the physiological adaptive response to the increased metabolic demand.

ORGAN WEIGHTS (see Tables 2 under “Any other information on results incl. tables”)
A reduction in the relative organ weights of spleen, heart, kidneys and adrenals was observed for male rats at dietary levels of 1.5%, while absolute and relative testes weights in males were increased at this dose level. Much heavier adrenal weights were found for female rats fed the same dose levels, but this was considered to be due to some experimental error. The main treatment-related effect comprised an increase in absolute and relative liver weights in both male and female rats at the highest dose level.

GROSS PATHOLOGY (see Tables 3 under “Any other information on results incl. tables”)
Liver:
Diffuse hepatic enlargement was observed in 10 rats fed 0-0.15% of the test substance in the diet. However, this macroscopic feature was identified in 12 animals of the high dose group (1.5% in the diet), thus being treatment-related. In contrast, the incidence of raised areas, nodules and masse in the groups fed 0 and 0.015% in the diet (in total: 16 and 20 animals, respectively) was greater than in the 0.15 and 1.5% test groups (in total: 12 and 11 animals, respectively).

Thymus:
Macroscopic nodules/masses were recorded in 28 rats fed 0-0.15% of the test substance in the diet. In contrast, these lesions were identified only in one animals of the high dose group (1.5% in the diet).

Pancreas:
Nodules/masses were observed in 8 rats fed 0-0.15% in the diet. Similar lesions were observed in 8 animals fed a dietary dose level of 1.5%.

Kidney:
Diffuse granularity/pitting was recorded in 74 male rats fed 0-0.15% of the test substance in the diet. In 23 of these animals, the lesions wre graded moderate or severe. In contrast, in the males of the high dose group (1.5% in the diet), only 11 cases of renal granularity/pitting were identified and in only 4 cases the lesions were rated moderate or severe.

HISTOPATHOLOGY: NON-NEOPLASTIC (see Tables 3 under “Any other information on results incl. tables”)
Liver:
The most significant treatment-related changes in the liver involved the increases in the incidence and severity of parenchymal hypertrophy, focal coagulative and/or haemorrhagic necrosis and pigmented lipid granuloma.
Zonal (periportal) or diffuse parenchymal hypertrophy was observed in 21 males and 33 females fed a dietary concentration of 1.5% of the test substance (high dose group). In contrast, this feature was only observed in 3 rats fed 0.015 and 0.15% of the test substance in the diet. The hepatic parenchymal hypertrophy in animals of the high dose group correlated with the observed increase in liver weight at this dose group. However, this histopathological finding was considered to probably represent a physiological adaptive respond to increased metabolic demand after treatment with the test substance.
Sublobular foci of coagulative and/or haemorrhagic necrosis were observed in the livers of 22 rats fed dietary concentrations of 0-0.15%, whereas these lesions were recorded in 19 animals of the high dose group. Granulomata, composed of vacuolated macrophage aggregates containing fine particles of a dark pigment (pigmented lipid granuloma) were located between cords of hepatocytes and around portal tracts. These lesions were present in the livers of small numbers of females fed 0, 0.015 and 0.15% of the test substance in the diet and in one male control animals. However, in the high dose group, lesions were present in the livers of 19 rats. The focal coagulative/haemorrhagic necrosis and the lipid granuloma were considered to be lesions, which occasionally occur in the livers of ageing rats of one or both sexes. Sublobular foci of hepatic necrosis may be attributable to enteric bacterial infection while lipid granuloma may represent the aggregation, within Kupffer cells, of enzymatically digestible debris normally retained in mesenteric macrophages and macrophage syncytia.
The incidence and/or severity of a few other histopathological changes in the liver (e.g. portal bailer stasis) were altered in the high dose group, but not considered to be of biological relevance due to the fact that these lesions only occurred in one sex of the animals.
Hepatic extramedullary erythropoiesis was, however, observed less frequently in the high dose group compared to groups fed 0-0.15% of the test substance in the diet.

Spleen:
The severity of splenic extramedullary erythropoiesis was reduced in females fed the high dose (1.5% in the diet) when compared to dose fed 0-0.15% of the test substance in the diet. Likewise, in females of the high dose group, the incidence of myelopoiesis and stem cell hyperplasia was reduced. In contrast, in females of the high dose group, the severity of red pulp hemosiderin deposition was greater than in animals of the same sex fed 0-0.15% of the test substance in the diet.

Kidney:
A reduced severity and/or incidence of chronic nephropathy and pelvic nephrocalcinosis were observed among rats fed the high dose (1.5% in the diet).

Heart:
A reduced severity and/or incidence of arterial medial hypertrophy was observed among rats fed the high dose (1.5% in the diet).

HISTOPATHOLOGY: NEOPLASTIC
The total number of tumour and the number of tumour bearing rats was reduced for rats fed 1.5% of the test substance in the diet (high dose) and this was largely due to a decrease in liver and lymphoreticular tumours, while the tumour incidence in male rats of the same dose group did not differ from the incidence of control rats. The former consisted of more benign tumours and fewer malignant tumours than for controls. The total numer of pancreatic tumours was increaesd in males of the high dose group, but this was due to a slight increase in both exocrine and islet tumours; when each tumour type was considered separately, the increase in this incidence had no biological significance.
Relevance of carcinogenic effects / potential:
The material was not tumorigenic at the any dose level, including the highest dose of 1.5%.
Dose descriptor:
NOEL
Effect level:
> 1 125 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No neoplasm observed.
Remarks on result:
other: Effect type: carcinogenicity (migrated information)

Table 1. Serum analysis – Changes in biochemical parameters in male rats over the 2-year treatment period (mean values)

Dietary level of the test substance (%)

Urea

(mmol/L)

ALAT

(U(L)

AP

(U/L)

1.5

7.076

58.0

824.3

0.15

5.279

40.0

506.8

0.015

5.204

36.7

568.2

0.0 (control)

5.933

34.9

520.0

 

Table 2. Mean absolute and relative organ weights of male rats after the 2-year treatment period

Dietary level of the test substance (%)

Final body weight (g)

Heart (g)

Liver (g)

Spleen (g)

Kidneys (g)

Adrenals (g)

Testes (g)

Abs.

Rel.

Abs.

Rel.

Abs.

Rel.

Abs.

Rel.

Abs.

Rel.

Abs.

Rel.

1.5

474.6

1.322

0.280

15.579

3.290

0.865

0.183

3.711

0.787

0.04333

0.00936

3.540

0.766

0.15

473.3

1.437

0.306

13.120

2.776

0.910

0.194

3.952

0.841

0.04126

0.00882

3.168

0.672

0.015

477.6

1.412

0.296

13.760

2.896

0.898

0.188

3.962

0.834

0.03787

0.00800

3.149

0.664

0.0 (control)

471.5

1.530

0.326

13.713

2.917

1.103

0.238

4.112

0.878

0.04807

0.01024

3.204

0.683

Table 3. Pathology. Summary of biologically significant treatment-induced effects observed in rats fed 0-1.5% dietary concentrations of the test substance for up to 2 years

Findings

0.015% in the diet

0.15% in the diet

1.55% in the diet

Male

Female

Male

Female

Male

Female

Macroscopic pathology

Liver: diffuse enlargement

        raised areas/nodules/masses

-

-

-

-

-

-

-

Thymus: nodules/masses

-

-

-

-

-

Pancreas: nodules/masses

-

-

-

-

-

Kidneys: granularity/pitting

-

-

-

-

-

Histopathology

Liver: zonal, diffuse parenchymal hypertrophy

        pigmented lipid granulomata

        focal coagulative/haemorrhagic necrosis

-

-

-

-

-

-

-

-

-

-

-

-

-

-

Spleen: erythropoiesis

           myelopoiesis

           stem cell hyperplasia

           hemosiderin deposition

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

 

↑ or ↓: increase or decrease in incidence/severity of features;

-: no change in in incidence/severity

 

The test materials used in the individual studies were prepared by two different production methods (high conversion bleached or HCB; and low conversion, unbleached or LCU). They differed slightly in chain length distribution, the latter having a slightly higher proportion of the C15AS. In both studies, the test material was dosed at 0, 0.015, 0.15 and 1.5% in the diet. There was no increase in tumor incidence, nor any impact on tumor type in either study. For both studies, approximately 70% of animals survived to study termination. Mortality was similar across dosage groups and controls. Animals in the 1.5% dose groups in both studies exhibited reduced food and water consumption, and slower growth rates. Within these high dose groups, there was a decreased number of total tumors and tumor-bearing animals. Elevated serum GPT, LDH and AP were observed in high dose males. Increased absolute liver weights and liver to body weight ratios, hypertrophy of the hepatic parenchyma, increased relative testicular weights, reduced incidence and severity of chronic nephropathy and nephrocalcinosis, and reduced arterial medial hypertrophy were among the findings at the higher dose levels. Absoulte values reported within this entry are for the high conversion bleached material.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 125 mg/kg bw/day
Study duration:
chronic
Species:
rat

Carcinogenicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

The possibility of a read-across to other alkyl sulfates in accordance with Regulation (EC) No 1907/2006 Annex XI 1.5. Grouping of substances and read-across approach was assessed. In Annex XI 1.5 it is given that a read-across approach is possible for substances, whose physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity. The AS reported within the AS category show structural similarity. The most important common structural feature of the category members is the presence of a predominantly linear aliphatic hydrocarbon chain with a polar sulfate group, neutralized with a counter ion. This structural feature confers the surfactant properties of the alkyl sulfates. The surfactant property of the members of the AS category in turn represent the predominant attribute in mediating effects on mammalian health. Therefore, the AS of the AS category have similar physicochemical, environmental and toxicological properties, validating the read across approach within the category. The approach of grouping different AS for the evaluation of their effects on human health and the environment was also made by the OECD in the SIDS initial assessment profile [1] and by a voluntary industry programme carrying out Human and Environmental Risk Assessments (HERA [2]), further supporting the read across approach between structurally related AS.

A detailed justification for grouping of alkyl sulfates into a category is provided separately. Please refer for more details on the read-across also to the document “AS Category Approach Justification” attached in section 13 of IUCLID.

A reliable combined chronic toxicity/carcinogenicity study was conducted with C12 -15 AS Na (CAS 68890-70-0). For two combined chronic toxicity/carcinogenicity studies similar to OECD Guideline 453 C12-15 AS Na (CAS 68890-70-0) was prepared by two different production methods (high conversion bleached or HCB; and low conversion, unbleached or LCU). The substances of these different production methods differed slightly in chain length distribution, the latter having a slightly higher proportion of the C15AS Na. In both studies, the test material was dosed at 0, 0.015, 0.15 and 1.5% in the diet. There was no increase in tumour incidence, nor any impact on tumour type in either study. For both studies, approximately 70% of animals survived to study termination. Mortality was similar across dosage groups and controls. Animals in the 1.5% dose groups in both studies exhibited reduced food and water consumption, and slower growth rates. Within these high dose groups, there were a decreased number of total tumours and tumour-bearing animals.

Other pathological findings are summarized in the Section Repeated dose toxicity. Increased absolute liver weights and liver to body weight ratios, hypertrophy of the hepatic parenchyma, increased relative testicular weights, reduced incidence and severity of chronic nephropathy and nephrocalcinosis, and reduced arterial medial hypertrophy were among the findings at the higher dose levels.

Alkyl sulfates (AS) show a consistent absence of mutagenic activity when tested in in-vitro and in-vivo tests. Neither AS nor its metabolites possess electrophilic functional groups or functional groups associated with mutagenic activity. Taken together with the results of the carcinogenicity studies, AS are considered as non-carcinogenic.

 

[1] SIDS initial assessment profile, (2007); http://www.aciscience.org/docs/Alkyl_Sulfates_Final_SIAP.pdf

[2] (HERA Draft report, 2002); http://www.heraproject.com/files/3-HH-04-%20HERA%20AS%20HH%20web%20wd.pdf


Justification for selection of carcinogenicity via oral route endpoint:
The reliable OECD Guideline study was chosen.

Justification for classification or non-classification

The available data on carcinogenicity do not meet the criteria for classification according to Regulation (EC) 1272/2008 and are therefore conclusive but not sufficient for classification.