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Description of key information

NOAEL for systemic toxicity was determined to be 167 mg/kg/day based on an one-generation study in rats.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

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

Additional information

One-generation reproduction toxicity study (OECD TG 415)

One-generation study was conducted to evaluate the potential effects of oral administration of 1-(tert-dodecylthio) propan-2-ol on the integrity and performance of the reproductive system in male and female rats, including gonadal function, mating behavior, conception, gestation, parturition, lactation and weaning (Thorsrud, 2002). This study was also conducted to provide preliminary information concerning the effects of the test substance on neonatal moribundity, mortality and postnatal developmental toxicity. This standardized procedure was conducted according to OECD guidance 415.

The study consisted of a vehicle control and three treatment groups, with 28 males and 28 females in each group. 1-(tert-dodecylthio) propan-2-ol

was dissolved in corn oil and administered at dosage levels of 50, 167 and 500 mg/kg/day, by once daily oral gavage, to F0 parental animals. All doses were given at a constant volume of 2.5 mL/kg. Control animals were administered corn oil under the same experimental conditions at an equivalent dose volume. F0 males were treated for a minimum of 70 days prior to mating and until completion of parturition. F0 females were treated for a minimum of 14 days prior to mating through lactation day 20.

Both F0 parental animals and F1 offspring were closely examined for indications of toxicity. Experimental endpoints for F0 animals included clinical observations, body weights, food consumption, mating, parturition, lactation, hematology determinations and offspring growth and viability. All F0 and F1 animals were subjected to a gross necropsy examination at the time of death or terminal euthanasia.

Oral administration of the test substance to F0 male rats for a minimum of 70 days prior to mating and until completion of parturition produced clinical signs including salivation prior to dosing and a dose-related increase in post-dose salivation in the 167 and 500 mg/kg/day groups and lower mean body weights (reduced approximately 5-7 % compared to controls) in the 500 mg/kg/day group.

Mean food consumption of F0 males in the 50, 167 and 500 mg/kg/day groups was comparable to controls throughout the study. There were no toxicologically meaningful differences between the control, 50, 167 and 500 mg/kg/day groups with respect to the F0 male mating and fertility indices. The F0 male hematology parameters, F0 male gross necropsy observations, F0 male absolute or relative organ weights or the F0 male sperm parameters were evaluated and no statistically significant differences were observed. In addition, no toxicologically meaningful microscopic lesions were observed in any of the F0 male tissues/organs examined from this study.

Oral administration of the test substance to F0 female rats for a minimum of 14 days prior to mating and throughout lactation produced clinical signs for F0 females in the 50, 167 and 500 mg/kg/day groups. The clinical signs included a low incidence of reddish vaginal discharge, swelling (mammary glands), dark material around the eyes and dark material around the nose in the 50, 167 and 500 mg/kg/day groups; a low incidence of salivation prior to dosing, an increased incidence of urine stain and a dose-related increase in post-dose salivation in the 167 and 500 mg/kg/day groups; and a low incidence of ocular discharge in the 500 mg/kg/day group.

There were no toxicologically meaningful differences between the control, 50, 167 and 500 mg/kg/day groups with respect to F0 female mean body weights, body weight change, food consumption, mating and fertility indices, precoital intervals, gestation lengths or the hematology parameters evaluated. Gross necropsy findings for one F0 female in the 500 mg/kg/day group euthanized on post breeding day 25 included dark brownish-red fluid in the uterus and vagina and one small placenta and two nonviable pups in the vagina. No other remarkable findings were noted in the F0 females at necropsy and no toxicologically meaningful microscopic lesions were observed in any of the F0 female tissues/organs examined from this study.

No toxicologically meaningful differences were noted in F1 pup viability during lactation. Mean F1 pup weights were statistically lower than controls in the 167 mg/kg/day group on lactation day 14 and in the 500 mg/kg/day group on lactation days 14 and 21; however, mean F1 pup weights in these groups remained within the range of the test laboratory historical control data. With the possible exception of a slight increase in the incidence of pups cool to the touch, no remarkable F1 pup observations were noted during lactation. No remarkable findings were noted at necropsy for F1 pups stillborn, found dead, culled on day 4 or euthanized on lactation day 21.

Conclusion

According to the study director, a dosage level of 50 mg/kg/day was considered to be the no-observed-adverse-effect level (NOAEL) for parental (F0) toxicity. There were no indications of impaired fertility or other reproductive effects in the F0 males or females at dosage levels up to 500 mg/kg/day. A dosage level of 50 mg/kg/ay was considered the no-observed-adverse-effect level (NOAEL) for developmental effects, as a result of decreased pup weights noted for the 167 and 500 mg/kg/day group pups during the latter half of lactation.

The study results were re-examined and new NOAELs for for parental and developmental toxicity were determined. Comparing to 50 mg/kg/day, the additional clinical observations included salivation and urine stain in females treated with 167 mg/kg/day test substance. Because 1) salivation was considered to be a reflex to administration of the test substance, 2) urine staining did not correlate with urination pattern or kidney gross necropsy, and 3) the severity of the effects is limited.

Based on the decreased body weight gains in F0 animals treated with 500 mg/kg/day, a dosage level of 167 mg/kg/day was considered to be the NOAEL for parental (F0) toxicity.

A dosage level of 167 mg/kg/day was considered the NOAEL for developmental effects, since the decreased pup weights noted for the 167 and 500 mg/kg/day group pups during the latter half of lactation were within the range of historical control data.

28 -day oral toxicity study (OECD TG 407)

This study was carried out according to OECD 407 guidelines (Auletta, 1991). The doses used were 1000 (10 rats/sex/group), 300 and 100 mg/kg/day (5 rats/sex/group) for a period of 28 days. Vehicle control animals (10 rats/sex/group) received corn oil at the same dose volume as administrated to the high-dose animals. The control and high-dose groups (5 rats/sex/group) were held for another 2-week treatment free recovery period to evaluate reversibility of any effects seen during the dosing period.

Physical observations were performed on all animals daily and on the remaining animals during the recovery period. Body weight and food consumption measurements were performed pretest and weekly thereafter. Hematology, clinical chemistry, and urinalyses parameters were evaluated for 5 animals/sex/group at the end of the treatment period and for all animals sacrificed at the end of the recovery period.

After 28 days of treatment, 5 animals/sex/group were sacrificed. The remaining animals were sacrificed after additional 14 days. Selected organs were weighed and organ/body weight ratio calculated for all animals. Complete gross postmortem examinations were conducted on all animals. Histopathological evaluation of the selected tissues was conducted on all animals in the control and high dose groups. In addition, histopathological evaluation of the kidney and liver were conducted on selected animals.

All animal survived throughout the study. Physical examinations were generally unremarkable. Other apparent effects of OS 81067 administration consisted of a transient decrease in food consumption and body weight gain in high-dose males during the first week of study and slight, reversible decreases, relative to control values, in hemoglobin and hematocrit values for high-dose females. This difference was seen at termination of dosing but was not clearly evident after a 2-week recovery period.

Alterations in the liver and kidneys of treated animals were observed during the organ weights and gross and microscopic pathology examinations. Dose-related elevation in mean liver and liver/body weight ratio were seen at study termination in males at all dose levels and in females at the mid-and high-dose groups. Recovery was apparent during the two-week post dose period. At termination of this interval, liver/body weight ratios for high-dose males were within 10% of the control value and although liver weights, liver/body weight ratios for females remained higher than control values, the difference (27 %) was less than that seen at termination of dosing (60 %).

Gross postmortem examination of the liver (5 per sex) revealed an accentuated lobular pattern in 2 of 5 mid-dose and 4 of 5 high-dose females at termination of the dosing period, but not termination of the recovery period. Microscopic examination of the liver revealed hepatocyte hypertrophy in 1 of 5 control males, 4 of 5 low-dose males, and in all mid- and high-dose animals (5 of 5 animals /sex/ group) at termination of dosing. This observation was present in 5 of 5 high-dose males and 2 of 5 high-dose females but was not present in any of the control animals at termination of the recovery period, these affects appears to be an adaptive change in response to test substance administration.

Kidney alterations were seen primarily in males. Kidney weights and kidney/body weight ratios for high-dose males were 45% higher than control values at termination of dosing but were comparable at termination of the recovery period. Similar effects were not apparent in low- or mid-dose males. Gross postmortem examination of the kidneys revealed pale or tan discoloration in 1 of 5 low-dose, 2 of 5 mid-dose and 5 of 5 high-dose males. Microscopic alterations consisted of increased incidences of globular casts and hyaline droplets in treated males, relative to the control incidence. Globular casts were seen primarily in the cortico-medullary junction and were present in 3 of 5 mid-dose and 5 of 5 high-dose males at termination of the dosing period, and in 3 of 5 high-dose males at termination of the recovery period. Similar casts were seen, unilaterally, in the renal cortex of 1 of 5 control males at termination of the dosing period. Hyaline droplets in the proximal tubules were seen at termination of dosing only, indicating this change was reversible after cessation of test substance administration. Although this finding was observed in one control male, its occurrence in 3 of 5 low-dose, 3 of 5 mid-dose and 5 of 5 high-dose males at termination of the treatment period was indicative of an effect of the test item administration.

These renal effects appeared to be similar to those previously reported in the literature of male-rat-specific hydrocarbon nephrotoxicity.

Although renal and hepatic changes were evident at all dose levels (100, 300 and 1000 mg/kg/day), evaluation of clinical chemistry and urinalysis studies revealed no evidence of renal or hepatic functional alterations, or any other signs of systemic effects of test substance administration, therefore, the renal changes seem to be species-specific and the hepatic changes are probably adaptive in nature.

Conclusion

Based on the decreased body weight gains in males treated with 1000 mg/kg/day, the NOEL for oral administration of test material to rats, for four weeks, under conditions of this study was 300 mg/kg/day.

In all test substance - treated animals, the observed renal changes were likely to be male-rat-specific, and the hepatic changes were probably adaptive in nature; in the high dose groups, the toxicological effects were reversible after cessation of treatment. Therefore, the NOAEL was proposed to be 1000 mg/kg/d.

Justification for classification or non-classification

In accordance with EU CLP (Regulation (EC) No. 1272/2008) classification of this substance is not required for systemic organ toxicity.