Octane-1-thiol

Endpoint summary

Description of key information

There is a 28-day repeat oral dosing study with octane-1-thiol. There are also repeat dose toxicity studies by the inhalation route with dodecane-1-thiol, which is a structural analogue of octane-1-thiol.  Oral gavage treatment of rats with octane-1-thiol resulted in effects consistent with forestomach irritation and corrosion (thickening of forestomach wall, ulcers, inflammatory cell infiltration).  The effects on the forestomach reflect effects from direct contact with octane-1-thiol and not to systemic effects. Other treatment-related effects appear to be secondary to the irritation/corrosive effects on the forestomach, with the possible exception of the centrilobular hepatocyte hypertrophy. The NOAEL for the 28-day study is 50 mg/kg bw/day.
Exposure of rats, dogs and mice to structural analog dodecane-1-thiol resulted in skin irritation and secondary effects in the regional lymph nodes.  There were treatment-related effects on the respiratory system.  The effects of the skin reflect direct contact with dodecane-1-thiol and not to systemic effects. The NOAEC from these studies is 1.9 ppm (20 mg/m3). 

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Dose descriptor:

NOAEL

50 mg/kg bw/day

Study duration:

subacute

Species:

rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Dose descriptor:

NOAEC

20 mg/m³

Study duration:

subacute

Species:

mouse

Additional information

Oral Repeat Dose Toxicity

One key study was identified to evaluate the oral repeat dose toxicity potential of octane-1-thiol. 

 

In a key guideline (OECD 422) repeat dose oral toxicity study (MHLW, 2004; Klimisch score = 1), male and female rats (Crj:CD(SD)IGS, SPF; 12/sex/dose) were administered 0, 10, 50 or 250 mg/kg bw of octane-1-thiol (CAS Number 111 -88 -6) by gavage in corn oil daily for 35 days in the males and from 14 days before mating to day 4 of lactation for the females.  

There was no treatment related mortality, clinical signs, or changes in urinalysis measurements in any dose level for either sex. Males exhibited no treatment related changes in food and water consumption while females showed a lower food consumption rate than the control at the highest dose level. Decreased body weight was observed in both sexes at 250 mg/kg bw in the later period of administration. For males, decreased red blood cell count, hemoglobin concentration, MCHC, and concentration of chloride, and increased MCV, reticulocyte ratio, concentration of albumin and calcium and A/C ratio were observed at 250 mg/kg bw.  No toxicological significances were noted at the lower dose levels. For females, decreased red blood cell count, MCHC, ALAT (GPT) and total billirubin, and increased MCV, MCH, reticulocyte ratio, and concentration of triglyceride were observed at 250 mg/kg bw. No toxicological significances were noted at the lower dose levels.  A relative weight increase of the liver, kidney, heart, and relative and absolute weight increase in spleen as well as a decrease in relative and absolute weight of the thymus was observed in males at 250 mg/kg bw. A relative increase in liver weight was observed for males at 50 mg/kg bw. Females showed an absolute and relative increase in weight of the spleen, liver, adrenal, a relative weight increase in the kidney, and a decrease in absolute and relative weight in the thymus in 250 mg/kg bw. Necropsy revealed the spleen to be dark reddish and thickening of the forestomach wall in males at the highest dose level. Females exhibited a spleen that was dark reddish and enlarged and thickening of the wall of the forestomach at the highest dose level. No other observations were noted in the three lowest dose levels of either sex.

 

Histopathological changes were observed in the stomach, spleen, liver and thymus of both sexes and in the bone marrow (femur) of males including: edema of the forestomach, hyperkeratosis,  forestomach hyperkeratosis squamous, forestomach inflammatory cell infiltration in males and females at 50 and 250 mg/kg bw/day; erosion of the forestomach in males at 50 and 250 mg/kg bw/day and females at 250 mg/kg bw/day; forestomach ulcers in males at 250 mg/kg bw/day and females at 50 mg/kg bw/day; congestion of the spleen in males and females at 250 mg/kg bw/day; erythrocytic extramedullary hematopoiesis in males and females at all dose levels; hemosiderin deposition in males at 250 mg/kg bw/day and females in all dose levels; atrophy of the thymus in males at 250 mg/kg bw/day and females at 0, 50, and 250 mg/kg bw/day; liver hypertrophy, hepatocyte, centrilobular in males at 250 mg/kg bw/day and females at 50 and 250 mg/kg bw/day; and bone marrow increase in hematopoietic cell, erythrocytic in males at 250 mg/kg bw/day.     

 

The toxicological changes in the forestomach in the 50 and 250 mg/kg bw/day groups were attributed to localized inflammation and did not appear to be systemic in nature. Based on the toxicological effects observed in the spleen and liver in both male and female rats dosed at the 250 mg/kg bw/day, the NOAEL was considered to be 50 mg/kg/day.

Inhalation Repeat Dose Toxicity

 

No key oral repeat dose toxicity data is available for octane-1-thiol. Several criteria justify the use of the read across approach to fill data gaps for octane-1 -thiol using dodecane-1-thiol as an analog. Octane-1-thiol, like dodecane-1-thiol, is a heavy mercaptan and has similar physiochemical properties. Hence, the toxicological properties of both these substances are also expected to be similar. Key read across data from dodecane-1-thiol was therefore used to evaluate the short-term repeat dose toxicity potential.

 

Three key read-across studies were identified to evaluate the short-term repeat dose inhalation toxicity potential of octane-1-thiol.

 

In a key short-term repeat dose inhalation toxicity study (Ulrich, 1985; Klimisch score = 1), dodecane-1-thiol was administered to 10 Sprague-Dawley rats/sex/concentration by whole body exposure at measured concentrations of 0, 0.43, 1.6 and 7 ppm (4, 10 and 60 mg/m³) for 6 hours per day, 5 days/week for 4 weeks. No deaths occurred in rats during the exposure period. During the first week of exposure clinical signs in the high-exposure group included ungroomed appearance, squinting of the eyes, swollen ears, and discharge from the nose and mouth. At week 2, the 7 ppm group showed signs of gasping, dyspnea, erythema of the ears, alopecia of the head area and high carriage. By weeks 3 and 4 the areas of alopecia became more generalized and dry, cracked peeling of the skin was evident in a number of anatomical locations including the head, feet, legs, and anogenital areas. In all 7 ppm exposed animals, skin effects were related to the following microscopic findings: acanthosis, hyperkeratosis and a generalized chronic active inflammation present in the dermis and epidermis. A secondary regional lymphoid hyperplasia was present in a few rats of both sexes at different dosage levels. No test article related microscopic changes were observed in the respiratory tract system. Mean body weights of the 7 ppm male rats were significantly reduced below that of the controls throughout the study. Food consumption in the 7ppm group (both sexes) was significantly decreased below the control levels at weeks 1 and 2, in both sexes. The LOAEC for this study is 7 ppm (60 mg/m³), with the NOAEC being 1.6 ppm (10 mg/m³).

 

In another key short-term repeat dose inhalation toxicity study (Ulrich, 1985; Klimisch score = 1), dodecane-1-thiol was administered to 3 Beagle dogs/sex/concentration by whole body exposure at concentrations of 0, 0.43, 1.9 or 8 ppm (0, 4, 20 or 70 mg/m³) for 6 hours per day, 5 days/week (Ulrich, 1985). Clinical signs in the 7ppm animals were limited for the most part to the skin although decreased activity and ptosis were observed in most dogs (male and female). Skin-related signs included dryness, cracking, peeling, a generally thickened appearance, and red inflamed-appearing areas. These signs were noted on the head, particularly around the eyes, nose, and edges of the pinna of the ears and inside the ears, as well as on the legs and male genital areas. Microscopic changes in the skin consisted of dermatitis, acanthosis and/or hyperkeratosis/ parakeratosis around the head. In addition, there was oedema or hemorrhage of superficial lymph nodes, which were considered to be secondary reaction to the irritation and inflammation of skin. There were no test article related microscopic changes evident in the respiratory system of exposed dogs. The NOAEC is 1.9 ppm (20 mg/m³).

 

In an additional key short-term repeat dose inhalation toxicity study (Ulrich, 1985; Klimisch score = 1), dodecane-1-thiol was administered to Swiss derived mice (10/sex/concentration) by whole body exposure at concentrations of 0, 0.43, 1.9 or 8 ppm, (4, 20 or 70 mg/m³) for 6 hours per day, 5 days/week.All mice exposed to 8.0 ppm died or were sacrificed in extremis (no mice were alive at week 3).There were no visible abnormalities in the 7 ppm mice during week 1. By week 2, hypoactivity, tremors, ptosis, and wet yellow stains of the genital and/or abdominal areas were seen in the 8 ppm animals. A low incidence of centrilobular hepatocellular hypertrophy was observed in males and females found dead after exposure to 8.0 ppm, and in 2 ppm females at study termination. There was no evidence of respiratory system damage even in the 8 ppm mice that died during the study. The LOAEC is 8.0 ppm (70 mg/m³) and the NOAEC is 1.9 ppm (20 mg/m³).

Justification for classification or non-classification

Repeat dose toxicity studies on octane-1-thiol and its structural analogue indicate that oral and inhalation exposure results in gastric and skin irritation, respectively. Although systemic toxicity was noted by the oral route, the effects were considered secondary to the gastic irritation/corrosive effects. Therefore, classification of octane-1-thiol for repeat dose toxicity under DSD or CLP is unwarranted.