Registration Dossier

Administrative data

Description of key information

After dosing rats (50 males and 50 females per dose group) with 0.6, 1.2 or 2.4% Dioctadecyldisulphide (Hostanox SE 10) in diet for 130 weeks increased neutrophil counts, relative weights of liver, spleen and ovaries combined with microscopic changes in these organs were observed. These abnormalities were generally more pronounced in the low and mid dose groups than in the high dose group in both sexes. All effects might be caused by the reported deposition and storage of a unknown compound resulting in inflammatory reactions, characterised by multinucleated giant cells and they are considered to be of secondary nature generated by an overload of the test animals´metabolism/excretion capacity. Therefore, the NOAEL is consiedered to be 0.6% (corrsponding to 300 mg/kg bw/d, considering a diet conversion factor (ppm to mg/kg bw/d) of 20 for older rats).

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
chronic toxicity: oral
Remarks:
combined repeated dose and carcinogenicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
Start of the study: 1976-12-02 Termination of the study: 1979-05-31
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Well performed and reported GLP-study with design equivalent to OECD 452/451.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 452 (Chronic Toxicity Studies)
Deviations:
no
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: obtained from a preceeding reproduction study (with the same test item and dosages; please refer to IUCLID Chapter 7.8.1) with 60 male and 120 female SPF rats (Cpb: WU, Wistar random); these parent rats were obtained from the Central Institute for the Breeding of Laboratory Animals TNO, Zeist, The Netherlands
- Age at study initiation: weaning age (parent animals were also treated with the test substance while reproduction phase)
- Weight at study initiation: males: 52 g; females: 51 g
- Housing: in groups of 5 in suspended stainless steel cages fitted with wire-mesh floors and fronts
- Diet (e.g. ad libitum): CIVO stock diet, ad libitum (before conducting blood glucose-, and urea nitrogen determination, all rats were fasted overnight, and before urine examinations all rats were deprived of food and water for 24 h)
- Water (e.g. ad libitum): water, ad libitum
- Acclimation period: n.a.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23 +/- 1°C
- Humidity (%): 55 - 85%
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12

IN-LIFE DATES: From: 2. Dec. 1976 To: End of May 1979
Route of administration:
oral: feed
Vehicle:
other: CIVO stock diet
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:

DIET PREPARATION
- Rate of preparation of diet (frequency): The test diets were normally prepared in batches of 40 kg once every 4 to 6 weeks, but occasionally batches of 20 kg were prepared.

VEHICLE
- Concentration in diet: 0.6, 1.2, 2.4%

The test substance was thoroughly mixed with CIVE stock diet by means of a mechanical belnder (Lögige type) at levels of 0 (control), 0.6, 1.2 or 2.4%. Levels of nutrients in the stock diet were periodically determined. The contaminants were also periodically determined in stock diets and drinking water. Samples from the feed containers were taken at intervals and sent to Hoechst AG, Frankfurt, for determination of Dioctadecaldisulphide.

Mean test substance concentration in diet:
control: < 0.03%
0.6% group: 0.58%
1.2% group: 1.18%
2.4% group: 2.35%

Since the time interval between sampling the diets and analysis was one to two and a half months, it appears that no appreciable loss of the test substance occurred upon storage.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Results of determination of Dioctadecylsulphide (DOS2) in test diets

Intended % DOS2
in the diet % DOS2 in feed samples in week
45 60 85

0 0.04 0.04 < 0.01
0.6 0.56 0.60 0.57
1.2 1.17 1.24 1.13
2.4 2.28 2.39 2.37

Duration of treatment / exposure:
130 weeks via diet (test animals were pretreated in utero via parent animals and lactation)
Frequency of treatment:
continuously
Remarks:
Doses / Concentrations:
0 %
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
0.6 %
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
1.2 %
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
2.4 %
Basis:
nominal in diet
No. of animals per sex per dose:
50
Control animals:
yes, plain diet
Details on study design:
- Dose selection rationale: This long-term study was preceeded by a reproduction phase which was started at 13 Sept. 1976. This reproduction study with the same test substance and dose levels did not reveal any adevers effects on reproduction performance. Administration of DOS2 at dose levels of 0.1 and 1% to rats for 90 days revealed no treatment-related abnormalities either (Hoechst 1967)

Positive control:
No
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
The animals were observed at intervals for signs of illness and tumours. All signs if ill-health or toxicity with any changes in behaviour were recorded, together with the progression of such abnormalities. Animals which were ill were caged individually. They were returned to their cage if condition improved or killed if conditions deteriorated.

BODY WEIGHT: Yes
Individual body weights were recorded at the end of weeks 0, 1, 2, 3, 4, 6, 8, 10 and 12 and once every 4 weeks thereafter.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)/FOOD EFFICIENCY:
Food intake (g/rat/day) of 20 rats/sex/group was determined during the first four weeks and in weeks 11 and 12, 23 and 24, 35 and 36, 47, 59 and 60, 71 and 72, 83 and 84 and 95 and 96. From the body weight gain and the total amount of food consumed in the first four weeks, the food efficiency (g body weight gain per g food) was calculated.

HAEMATOLOGY: Yes
- Time schedule for collection of blood: weeks 13, 26, 52, 78, 102 and 127
- Animals fasted: Yes (please refer to "Details on test animals and environmental conditions")
- How many animals: 10/sex/group

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: weeks 26, 52 and 102
- Animals fasted: Yes (please refer to "Details on test animals and environmental conditions")
- How many animals: 10/sex/group

URINALYSIS: Yes
- Time schedule for collection of urine: weeks 13, 26, 52, 78 and 102
- Animals fasted: Yes, urine was collectedd during the last 16 hours of a 24-hour period of deprivation from food and water

Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Statistics:
Body weights, results of hematological-, blood chemical-, and urine analysis, and relative organ weights were analysed by the Student t-test. Mortality figures and incidence of neoplastic and non-neoplastic lesions were evaluated by Chi square test.
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
mortality in males slightliy higher at 2.4% diet
Mortality:
mortality observed, treatment-related
Description (incidence):
mortality in males slightliy higher at 2.4% diet
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
decreased
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
decreased red blood cell count, increase in total white cells
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
increased relative weights of liver, spleen and ovaries
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
abnormalities in spleen and mesenteric lymph nodes
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
changes in liver, spleen, ovaries, adrenals, bone marrow (sternum) and mesenteric lymph nodes
Histopathological findings: neoplastic:
no effects observed
Details on results:
Clinical signs:
There were no overt signs of reaction to DOS2. After 18 months ageing symptoms developed in all groups.

Mortality:
Mortality in males receiving DOS2 was slightly higher than in controls during the last six months of the study. No such difference occurred in females.

Body weights/food effeciency:
Statistically significantly lower body weights were observed in males at 0.6% from week 40 onwards, at 1.2% from week 60 onwards and at 2.4% from week 80 onwards. In females lower body weights were observed at all dose levels from week 20 onwards. The differences with the controls were less pronounced in the top-dose group than in the lower dose groups. It should be noticed that at the initiation of the study the mean body weights of males of the 0.6% group and females of both the 0.6% and the 1.2% group were already lower than in controls. Moreover, body weights in all test groups were similar to the corresponding control values in the period of rapid growth.

No treatment-related differences in food intake or food efficienc were observed between the groups.

Hematology:
Decreased values for hemoglobin content, packed cell volume and red blood cell count were observed in the treated groups of both sexes. The decreases, which were generally inversely dose-related, did not aggravate in the curse of time. Only slight to marked increases in neutrophilic cells were observed in the test groups in both sexes. The differences with the controls were often most pronounced in the lowest dose group.

Blood chemistry:
Enzyme activities or levels of Glucoes, Urea and Protein of the blood did not show any treatment-related effects.

Kidney function/Urinalysis:
No indication of kidney damage was noticed in the volume, specific gravity or Glutamic-oxalacetic Transaminase activity of the urine. Urine composition was essentially normal.

Relative Organ weights:
There were increases in the relative weight of the liver, spleen and ovaries of all treatment groups. The increases showed a negative correlation with the feeding level of the test item.

Gross examination:
Macroscopic examination revealed some abnormalities in the spleen and mesenteric lymph nodes, such as enlargement and hemorrhages in treated animals. Microscopic examination of these organs indicated that these gross changes were treatment-related.

Microscopy:
Treatment-related histopathological changes were found in the liver, spleen, ovaries, adrenals, bone marrow (sternum) and mesenteric lymph nodes. The changes consisted of accumulations of a crystalline material, usually accompanied by multinucleated giant cells. The mesenteric lymph nodes were most heavily involved and are considered to be the major target organs. The abnormalities observed were more pronounced in the low- and mid-dose groups than in the high dose group.

Neoplasic lesion:
The incidence of hemangio-endotheliomas in mesenteric lymph nodes was increased in each of the test groups. The increases were considered to be related to treatment although a positive dose-response relationship was absent.





Dose descriptor:
NOAEL
Effect level:
0.6 other: % in diet
Sex:
male/female
Basis for effect level:
other: based on secondary effects generated by an overload of the animals´ metabolism/excretion capacity
Critical effects observed:
not specified
Conclusions:
After dosing rats (50 males and 50 females per dose group) with 0.6, 1.2 or 2.4% Dioctadecyldisulphide (Hostanox SE 10) in diet for 130 weeks increased neutrophil counts, relative weights of liver, spleen and ovaries combined with microscopic changes in these organs were observed. These abnormalities were generally more pronounced in the low and mid dose groups than in the high dose group in both sexes. All effects might be caused by the reported deposition and storage of a unknown compound resulting in inflammatory reactions, characterised by multinucleated giant cells and they are considered to be of secondary nature generated by an overload of the test animals´metabolism/excretion capacity. Therefore, the NOAEL is consiedered to be 0.6% (corrsponding to 300 mg/kg bw/d, considering a diet conversion factor (ppm to mg/kg bw/d) of 20 for older rats).
Executive summary:

Each 50 male and 50 female rats were fed with the test substance at dietary levels of 0, 0.6, 1.2 and 2.4 % for 130 weeks. During the treatment period animals were at least monthly observed for general health, mortality, food consumption and body weight development. Blood and urine samples were taken at treatment weeks 13, 26, 78, 102 and 127 for hematological and biochemical investigations. After 130 weeks of feeding the surviving animals were killed and were subjected to macroscopic and microscopic investigations for non-neoplastic as well as for neoplastic lesions.

From the treatment week 112 onwards the mortality in males of high dose was significantly increased compared to controls. No such difference occurred in other groups of males or in females.

From the treatment week 20 onward significantly decreased body weights of treated animals from all dose groups were observed compared to control values, with a more pronounced difference in animals of the low and mid dose groups.

No difference was observed for food consumption for treated and control animals.

Evident decreases for hemoglobin, packed cell volume and red blood count were found in females of all dose groups at the treatment week of 78 and 102. Additionally, increases in the neutrophil counts were observed for treated males and females almost all along the animal treatment period, partially accompanied with increased white blood cell counts.

Upon necropsy, increased organ weights were found for liver, spleen and gonads for all treated groups, whereas the increases for low or mid dose groups were more evident than for high dose groups. For spleen and mesenteric lymph nodes, enlargement and discoloration were found additionally, again the high dose group less severely affected than the mid- or low dose groups.

Non-neoplastic histopathological changes were found in the liver, spleen, ovaries, adrenals, bone marrow (sternum) and mesenteric lymph nodes. The changes consisted of accumulation of crystalline materials, usually accompanied by multinucleated giant cells. The abnormalities observed were more pronounced in the low and mid dose groups than in the high-dose group.

Treatment related neoplastic changes were found in animals of low and mid dose groups. Eight males in low dose group and three and five females in low and mid dose groups respectively exhibited hemangio-endotheliomas in the mesenteric lymph nodes, whereas no or only one animal in both, high and control group showed comparable changes. Since the incidence of hemangiomas in mesenteric lymph nodes of both male and female Wistar rats was well within the range of controls for Wistar-derived rat strains, the development of hemangiomas at this single site was considered to be unrelated to the administration of Hostanox SE 10. This was strenghtened by the absence of an increase in any other tumor type in treated rats following lifetime exposure to massive amounts of compounds, as well as a lack of genotoxic potential and reproductive toxicity of Hostanox SE 10, and the complete absence of any evidence of vascular endothelial cell proliferation in dogs with similar compound-associated foreign material in their tissues after two years (please refer to "WoE_2 year oral toxicity (diet)_dog_Hoechst_1980).

The result obtained from this chronic study in Wistar rats reflects the effect of phagocytic cells attempting to engulf amd dispose of the test substance, and constituted the expected response of dosing animals with large amounts of foreign material over a very long period of time. Therefore, the changes observed are considered to be secondary effects (inflammation, fibrosis etc.) generated by an overload of the animals´capacity to metabolize/excrete the substance. With regard to the apparent inverse dose-response relationship for many of the observed effects, it was noted that mortality was directly related to the dose, indicating that there were symptoms of greater toxicity at the high dose. It is supposed, that there may have been a higher degree of fibrosis, due to destruction of normal tissue, in the high dose group that could have led ultimately to the increased mortality and, in essence, masked the effects that were noted at lower doses.

Based on the above mentioned considerations (observation of secondary effects due to overload effects) the NOAEL of Hostanox SE 10 is considered to be 0.6% (corresponding to 600 mg/kg bw/d; assuming a mean food intake of 10 g/100 g bw/d).

Based on the findings mentioned above the NOAEL could not be established in this study.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
300 mg/kg bw/day
Study duration:
chronic
Species:
rat
Quality of whole database:
reliable without restriction

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: inhalation
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: inhalation
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: dermal
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Each 50 male and 50 female rats were fed with the test substance at dietary levels of 0, 0.6, 1.2 and 2.4 % for 130 weeks. During the treatment period animals were at least monthly observed for general health, mortality, food consumption and body weight development. Blood and urine samples were taken at treatment weeks 13, 26, 78, 102 and 127 for hematological and biochemical investigations. After 130 weeks of feeding the surviving animals were killed and were subjected to macroscopic and microscopic investigations for non-neoplastic as well as for neoplastic lesions.

From the treatment week 112 onwards the mortality in males of high dose was significantly increased compared to controls. No such difference occurred in other groups of males or in females.

From the treatment week 20 onward significantly decreased body weights of treated animals from all dose groups were observed compared to control values, with a more pronounced difference in animals of the low and mid dose groups.

No difference was observed for food consumption for treated and control animals.

Evident decreases for hemoglobin, packed cell volume and red blood count were found in females of all dose groups at the treatment week of 78 and 102. Additionally, increases in the neutrophil counts were observed for treated males and females almost all along the animal treatment period, partially accompanied with increased white blood cell counts.

Upon necropsy, increased organ weights were found for liver, spleen and gonads for all treated groups, whereas the increases for low or mid dose groups were more evident than for high dose groups. For spleen and mesenteric lymph nodes, enlargement and discoloration were found additionally, again the high dose group less severely affected than the mid- or low dose groups.

Non-neoplastic histopathological changes were found in the liver, spleen, ovaries, adrenals, bone marrow (sternum) and mesenteric lymph nodes. The changes consisted of accumulation of crystalline materials, usually accompanied by multinucleated giant cells. The abnormalities observed were more pronounced in the low and mid dose groups than in the high-dose group.

Treatment related neoplastic changes were found in animals of low and mid dose groups. Eight males in low dose group and three and five females in low and mid dose groups respectively exhibited hemangio-endotheliomas in the mesenteric lymph nodes, whereas no or only one animal in both, high and control group showed comparable changes. Since the incidence of hemangiomas in mesenteric lymph nodes of both male and female Wistar rats was well within the range of controls for Wistar-derived rat strains, the development of hemangiomas at this single site was considered to be unrelated to the administration of Hostanox SE 10. This was strenghtened by the absence of an increase in any other tumor type in treated rats following lifetime exposure to massive amounts of compounds, as well as a lack of genotoxic potential and reproductive toxicity of Hostanox SE 10, and the complete absence of any evidence of vascular endothelial cell proliferation in dogs with similar compound-associated foreign material in their tissues after two years (please refer to "WoE_2 year oral toxicity (diet)_dog_Hoechst_1980).

The result obtained from this chronic study in Wistar rats reflects the effect of phagocytic cells attempting to engulf amd dispose of the test substance, and constituted the expected response of dosing animals with large amounts of foreign material over a very long period of time. Therefore, the changes observed are considered to be secondary effects (inflammation, fibrosis etc.) generated by an overload of the animals´capacity to metabolize/excrete the substance. With regard to the apparent inverse dose-response relationship for many of the observed effects, it was noted that mortality was directly related to the dose, indicating that there were symptoms of greater toxicity at the high dose. It is supposed, that there may have been a higher degree of fibrosis, due to destruction of normal tissue, in the high dose group that could have led ultimately to the increased mortality and, in essence, masked the effects that were noted at lower doses.

Based on the above mentioned considerations (observation of secondary effects due to overload effects) the NOAEL of Hostanox SE 10 is considered to be 0.6% (corresponding to 300 mg/kg bw/d; considering a diet conversion factor (ppm to mg/kg bw/d) of 20 for older rats).

 

The oral administration of Distearyldisulfid (Hostanox SE 10) to rats at doses of 1 and 0.1 % in diet (corresponding to 1000 and 100 mg/kg bw/d, respectively) for 90 days resulted in no treatment-related deaths, no clinical signs, changes in hematology, urinalysis and histopathology. The body weight gain of the 0.1 % dosed animals was decreased. Animals of the 1 % dose group were unaffected.
Based on the results of this study, the no-observed-adverse-effect-level (NOAEL) for the test item, Distearyldisulfid (Hostanox SE 10), was considered to be 1% in diet (corresponding to 1000 mg/kg bw/d).

Each 6 male and 6 female dogs were fed with the test substance at dietary levels of 0, 6000, 12000 or 25000 ppm for 2 years. During the treatment period animals were for general health, mortality, food consumption and body weight development. Blood and urine samples were taken at treatment after 3, 6, 12, 18 months and before end of dosing for hematological and biochemical investigations. After 2 years of feeding the surviving animals were killed and were subjected to macroscopic and microscopic investigations.
With exception of changes in lymph nodes, liver and adrenals no effects were observed. In summary, the feeding of large doses Hostanox SE 10 to beagle dogs resulted in a consistent foreign body granulomatous reaction associated with the accumulation of eosinophilic amorphous or crystalline material in the cytoplasm of the inflammatory cells. The foreign material was most likely compound-associated and was phagocytised as would be expected by the cells of the reticuloendothelial system in the lymph nodes, adrenal glands and liver. In none of these tissues there was any histopathologic evidence of angiomatous hyperplasia or hemangioma observed in the mesenteric lymph nodes.
The result obtained from this chronic study in Beagle dogs reflects the effect of phagocytic cells attempting to engulf and dispose of the test substance, and constituted the expected response of dosing animals with large amounts of foreign material over a very long period of time. Therefore, the changes observed are considered to be secondary effects (inflammation, fibrosis etc.) generated by an overload of the animals´capacity to metabolize/excrete the substance. The assumption is strengthened by the absence of any dose-response relationship for many of the observed effects.
Based on the above mentioned considerations (observation of secondary effects due to overload effects) the NOAEL of Hostanox SE 10 is considered to be 6000 ppm (corresponding to 390 mg/kg bw/d (males) and 340 mg/kg bw/ (females)).

After dosing dogs (2 males and 2 females) with 12000 ppm Dioctadecyldisulphide (Hostanox SE 10) in diet for 90 days increased no clinical/neurological changes as well macroscopical/microscopical effects were observed. The NOEL is set at 12000 ppm substance in diet corresponding to 641.5 mg/kg bw/d (males, highest dose tested) and 557 mg/kg bw/d (females, highest dose tested), respectively.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
This study was chosen as key study due to the test system employed. The rat is the commonly excepted and best examined species for risk assessment and inter-species extrapolation purposes. This study is fully reliable.

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
In accordance with column 2 of REACH Annexes VIII and IX, the repeated dose toxicity study, as required in section 8.6.1 of Annex VIII and in section 8.6.2 of Annex IX, does not need to use the inhalation route because exposure of human via inhalation, especially in a higher extent than via oral application as performed in the animal studies, is considered unlikely taking into account the vapour pressure/physical form of the substance, intended use pattern (embedded in polymeric matrices) and the occupational health surveillance data.

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:
In accordance with column 2 of REACH Annexes VIII and IX, the repeated dose toxicity study, as required in section 8.6.1 of Annex VIII and in section 8.6.2 of Annex IX, does not need to use the inhalation route because exposure of human via inhalation, especially in a higher extent than via oral application as performed in the animal studies, is considered unlikely taking into account the vapour pressure/physical form of the substance, intended use pattern (embedded in polymeric matrices) and the occupational health surveillance data.

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:
In accordance with column 2 of REACH Annexes VIII and IX, the repeated dose toxicity study, as required in section 8.6.1 of Annex VIII and in section 8.6.2 of Annex IX, does not need to use the dermal route because
- no primary systemic effects or other evidence of absorption were observed in skin and eye irritation studies in rabbits as well as in the local lymph node assay in mice
- due to the combination of its polar character (Sulfur bridge in molecule center) and the long extent of the alkyl chain it is unlikely that higher amounts than tested in a repeated oral toxicity study will be systemically available via the intact skin barrier.

Justification for selection of repeated dose toxicity dermal - local effects endpoint:
In accordance with column 2 of REACH Annexes VIII and IX, the repeated dose toxicity study, as required in section 8.6.1 of Annex VIII and in section 8.6.2 of Annex IX, does not need to use the dermal route because
- no primary systemic effects or other evidence of absorption were observed in skin and eye irritation studies in rabbits as well as in the local lymph node assay in mice
- due to the combination of its polar character (Sulfur bridge in molecule center) and the long extent of the alkyl chain it is unlikely that higher amounts than tested in a repeated oral toxicity study will be systemically available via the intact skin barrier.

Repeated dose toxicity: via oral route - systemic effects (target organ) cardiovascular / hematological: lymph nodes; cardiovascular / hematological: spleen; digestive: liver

Justification for classification or non-classification

Due to the NOAEL of 300 mg/kg bw/day in a study equivalent to OECD 451/452 combined chronic toxicity/carcinogenicity study in rats with Dioctadecyl disulphide does not have to be classified regarding systemic and target organ toxicity after repeated exposure according to the criteria laid down in the EU Dangerous Substances Directive (67/548/EEC) and in the EU Classification Labelling and Packaging Regulation (1272/2008/EC).
This study was chosen as key study due to the test system employed. The rat is the commonly excepted and best examined species for risk assessment and inter-species extrapolation purposes.