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Administrative data

Description of key information

Alchisor TAL 123 can be characterised according to three constituents: Hydrocarbons C11-C14, n-alkanes, isoalkanes, cyclics, aromatics (2-25%), undecan-1-ol and dodecan-1-ol; however, it should also be noted that Sasol commissioned a 28-day repeated dose oral toxicity study using Alchisor TAL 123 as the test substance (Holalagoudar, 2013), the results of which are used to anchor the read-across approach. 
ORAL: The Alchisor TAL 123 oral toxicity study is the most reliable and relevant study, yielding an oral NOAEL for Alchisor TAL 123 of 1000mg/kg bw.
DERMAL: A study result from Hydrocarbons C11-C14, n-alkanes, isoalkanes, cyclics, aromatics (2-25%) read across rat data will be used for the Alchisor TAL 123 repeat dose dermal endpoint. A systemic NOAEL in this instance is >495mg/kg/day.
INHALATION: A reliable (Klimisch 1) repeat dose rat inhalation toxicity study attributed to the Hydrocarbons C11-C14, n-alkanes, isoalkanes, cyclics, aromatics (2-25%) provides the key study inhalation result from this constituent of Alchisor TAL 123. Consequently following the protective approach as detailed above, an inhalation NOAEC for Alchisor TAL 123 of 690ppm is provided.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEC
3 950 mg/m³
Study duration:
subchronic
Species:
rat

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
495 mg/kg bw/day
Study duration:
subchronic
Species:
rat

Additional information

Alchisor TAL 123 can be characterised according to three constituents: Hydrocarbons C11-C14, n-alkanes, isoalkanes, cyclics, aromatics (2-25%), undecan-1-ol and dodecan-1-ol. As defined in the Read-across Justification Document in section 13, data provided for these constituents when considered together is representative of Alchisor TAL 123 and suitable for assessment purposes. Study data for each constituent has been evaluated. In a protective approach the most sensitive study result from across the three constituents has been identified and used to address the hazard endpoint in question; however, it should also be noted that the registrant commissioned a 28-day repeated dose oral toxicity study using Alchisor TAL 123 as the test substance (Holalagoudar, 2013), the results of which are used to anchor the read-across approach.

 

Oral

Anoral 30 -day subchronic toxicity study report with Hydrocarbons C11-C14, n-alkanes, isoalkanes, cyclics, aromatics (2-25%) along with a combined repeat dose and reproductive/developmental toxicity screening test on dodecan-1-ol is available to address the repeat dose oral toxicity endpoint of Alchsior TAL 123. Key read across data is provided for dodecan-1-ol in the form of a reliable (Klimisch 2) 90 day dietary study with hexan-1-ol. Read across data is provided for undecan-1-ol based on the combined repeat dose and reproductive/developmental toxicity screening test with dodecan-1-ol (Hansen 1992). Adequate reliable data is available for each constituent. Therefore using a protective approach the dataset is a reliable adequate basis for Alchisor TAL assessment purposes.

 

In an oral gavage study BP8313 (representing C9-C14 aliphatics (2-25% aromatics)) was dosed to rats in a corn oil vehicle over 30 days. 5 male and 5 female rats were exposed to dose levels of 0.14, 0.42 and 1.28 ml/kg/day. No mortality was reported. Clinical signs were observed in the majority of rats at the top two dose levels from day 4 of dosing. These clinical signs manifested in the form of salivation, normally for a short period and brown facial staining, which resolved within 24hrs. Plasma glucose levels were depressed in rats at the top dose level. Male rats at this dose level exhibited elevated lymphocyte and platelet numbers and depressed packed cell volume, haemoglobin concentration and erythrocyte counts. Urinary protein concentrations were higher in all male rats in the two higher dose groups, and in 2 males in the lowest dose group. Male rats showed a dosage related increase in liver and kidney weights. Female rats only showed higher liver weight at the highest dose level. Organ specific changes were noted in the kidney. However these kidney changes identified were isolated to 3 male rats in the low dose group and 4 male rats in the mid and high dose groups. These changes specifically related to a slight degeneration of the cells lining the proximal tubules. Tubular cell degeneration, tubular dilation with intra-tubular protein and regeneration were evident. These male-only alterations of the kidneys at all dose levels are known to be species specific and of no-relevance to human hazard assessment. In this study the NOAEL is however restricted to female rats and determined to be 1.28ml/kg/day (1056mg/kg).

                                                                               

The repeat dose toxicity of Dodecanol was assessed in a combined repeats dose reproductivity study; draft OECD 422 (Hansen 1992). Dose levels of 0, 1500, 7500 and 30,000 were selected and 12 rats/sex/dose were exposed to these doses of Dodecanol in their diets. Dietary exposure was continued for 41-45 days in the case of males and 54 days in the case of females. No mortality or clinical signs were reported and food consumption remained the same as controls throughout the study. Haematology and clinical chemistry parameters were assessed in males only. A dose related reduction in white blood cell counts which was significant in top and mid dose males was reported. It should be noted that there were no differences in differential white cell count that explained these observations. There was a significant reduction in plasma triglyceride at the top dose level and a significant reduction in plasma free cholesterol at the intermediate dose level. This reduced cholesterol level was re-analysed after removing 2 outlying values when the statistical significance was lost.  These results may have been confounded by the difference in dietary composition between groups. In this reliable study a NOAEL for systemic toxicity of 2000 mg/kg/day (highest dose tested) was determined in rats in the absence of toxicologically significant effects at any dose level. In addition a 90d dietary study was presented as read across from Alfol 6 (hexan-1-ol) to dodecan-1-ol. In this reliable study, the NOAEL for Alfol 6 in rats following 13 weeks dietary exposure was 1127 mg/kg bw/day for males and 1243 mg/kg bw/day for females (highest doses tested).

                                                                               

Within the scope of these studies, evidence of repeat dose organ toxicity is restricted to the kidneys (DHC Solvent Chemie GmbH, 1984) in the case of exposure to BP8313. Although being dose related this type of renal pathology is specific to male rats due to an alpha2u-globulin-mediated process that is not relevant to humans. A NOAEL has been reported in this instance (for female rats) at 1.28ml/kg/day (equivalent to 1056mg/kg bw).

 

The registrant commissioned a 28-Day Repeated Dose Oral Toxicity study with Alchisor TAL 123 (Holalagoudar, 2013) in male and female Wistar rats with dose levels of 100, 500, and 1000 mg/kg/day to assess the possible health hazards that could arise from repeated exposure via oral administration. The test item was administered daily in graduated doses to 3 groups of test animals, one dose level per group for a treatment period of 28 days. Animals of an additional control group were handled identically as the dose groups but received cotton seed oil, the vehicle used in this study. The 4 groups were comprised of 5 male and 5 female Wistar rats. Daily oral treatment with Alchisor TAL 123 did not lead to mortality, did not affect body weight development or food consumption and did not lead to alterations in parameters of clinical pathology. Histopathological liver changes and associated thyroid gland changes were minor in degree and restricted to the 1000 mg/kg/day dose group. Kidney changes, reflecting α2-microglobulin nephropathy, do not have relevance for man. Based on the type of histological liver changes and their reversibility shown in 8/10 animals in the recovery group, in the absence of clinical signs and clinical pathology changes, the liver findings are considered as non-adverse and minor adaptive change. The no observed adverse effect level (NOAEL) is therefore considered to be 1000 mg/ kg body weight /day.

A reliable sub-chronic oral toxicity study with BP8313 (representing C9-C14 aliphatics (2-25% aromatics)) provides the most sensitive study result for constituents of Alchisor TAL 123; however, since the Alchisor TAL 123 oral toxicity study is the most reliable and relevant study, the oral NOAEL is determined to be 1000 mg/kg/day.

                                                               

Inhalation

Two repeat dose inhalation studies are available for the C9-C14 aliphatics (2-25% aromatics). In addition read across information is presented for Stoddard solvent and mineral spirits in support of the C9-C14 aliphatic (2-25% aromatics) constituent category. No repeat dose inhalation studies were available for either undecan-1-ol or dodecan-1-ol. Consequently the most sensitive study result from the C9-C14 aliphatics (2-25% aromatics) study reports will be used for the Alchisor TAL 123 repeat dose inhalation endpoint.

In a repeated dose study (Shell Research Ltd 1980) where C9-12 Aliphatics (2-25% Aromatics) were administered via inhalation, no signs of toxicity were observed at the maximum concentration of 1293 ppm in female rats. Female rats had significant body weight reduction at the highest dose tested. Based on these observations, the repeat inhalation NOAEL is = 690 ppm for C9-14 Aliphatics (2-25% Aromatics). Similarly to the oral findings, renal damage was observed in male rats at all dose levels. This type of renal pathology is specific to male rats due to an alpha2u-globulin-mediated process that is not relevant to humans.

 

A second reliable guideline comparable (OECD 413) inhalation study was conducted in rats (ExxonMobil 1979). Groups of 35 rats were exposed to a test atmosphere containing 100 or 300ppm MRD-78-25 (C9-C12 aliphatics (2-25% aromatics)) for 6hrs/day 5days per week for 12 weeks.10 rats/sex from each group were sacrificed at week 4 and week 8.No mortality was reported throughout the study. Males in the 300ppm dose group had increased mean total leukocyte values at week 12. Alterations in haemocrit, haemoglobin levels and some clinical chemistry parameters were recorded within the study but where disregarded as being unrelated to treatment and having little biological significance. A NOAEC for female rats was determined to be 300ppm.

 

This study examined the subchronic toxicity of MRD-78-25 to rats via inhalation. Groups of 35 rats per sex were exposed to 0, 100, or 300 ppm of test substance vapors. Exposure was 6 hrs/day, 5 days/week, for 12 weeks. Animals were observed for clinical signs daily, and weighed weekly. At the end of the study, all surviving animals were sacrificed. After sacrifice, hematological, clinical chemistry, and histopathological parameters were examined. There was no treatment related mortality during the study, and no treatment related body weight effects. For male rats, the LOAEC was 100 ppm via inhalation. This value is based on kidney effects due to a alpha2u-globulin-mediated process that is not regarded as relevant to humans that are not relevant to humans. For female rats, the NOAEC was 300 ppm. 

 

Three inhalation studies have been documented as read-across arguments based on supporting substances (structural analogue or surrogate). In a repeat dose inhalation study (Carpenter 1975) both beagle dogs and rats were examined following exposure to atmospheres of Stoddard solvent (0, 84, 190, 330ppm). No statistically significant differences were reported in beagle dogs between control and test groups. However, rats exposed to 1.9 mg/liter (330 ppm) level for 65 days exhibited slight pathological changes in the kidney, which were related at least in part to the inherent murine nephrosis of the Harlan-Wistar rats employed. This observation is also likely due to a2u-globulin mediated nephropathy. Since humans do not have this protein, this finding is not toxicologically relevant. The NOAEC>330 ppm for male and female rats.

 

In a further inhalations study (Rector 1966) no mortality was reported in test groups of dogs, monkeys, or rabbits following repeated exposures. No outward signs of toxicity, significant alterations in weight or haematologic values, or noteworthy in gross pathologic or histopathologic findings were noted in dogs, monkeys, rabbits, or rats. The guinea pig was found to be the most susceptible, with significant mortality occurring at the 363 mg/m3continuous exposure level. The mortality rate generally increased as the concentrations of the mineral spirits were increased.

 

Finally Jenkins, 1971 reported on a repeats dose inhalation study of mineral spirits in the Guinea Pig. Test animals were exposed to an atmosphere of mineral spirits at a concentration of 900mg/m3continuously for 90 days. Test diets were fortified with ascorbic acid. The LOAEL for this study was 900 mg/m3.

 

A reliable (Klimisch 1) repeat dose inhalation toxicity study attributed to the C9-C14 aliphatics (2-25% aromatics) provides the key study result for constituents of Alchisor TAL 123. Consequently following the protective approach as detailed above, an inhalation NOAEC for Alchisor TAL 123 of 690ppm (3950mg/m3) is provided.

 

Dermal

The repeat dose dermal toxicity of C9-C14 aliphatics (2-25% Aromatics) was evaluated by read across from a13-Week subchronic dermal study with neurotoxicology evaluations of hydrodesulfurized kerosene in rats. Groups of 12 rats were dermally exposed to doses of the test material of 165, 330 and 495mg/kg. Dosing continued for five days per week for a total of 13 weeks. There were no systemic or neurological effects noted at any of the tested doses. The systemic NOAEL was >495 mg/kg/day.No repeat dose dermal studies were available for either undecan-1-ol or dodecan-1-ol. Consequently the study result from the C9-C14 aliphatics (2-25% aromatics) read across data will be used for the Alchisor TAL 123 repeat dose dermal endpoint. A systemic NOAEL in this instance is >495mg/kg/day.

Justification for classification or non-classification

On the basis of evidence presented, Alchisor TAL123 and its components have a low order of repeated dose toxicity. Kidney changes identified in male rats exposed to Alchisor TAL 123 and C9-C14 aliphatics (2-25% aromatics) are known to be species specific and of no known relevance to human hazard assessment. Consequently these findings do not warrant the classification of Alchisor TAL 123 as a repeated dose toxicant under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP) or under the Directive 67/518/EEC for dangerous substances and Directive 1999/45/EC for preparations.