64741-45-3
64741-57-7
64741-81-7
64742-90-1
64741-57-7
64741-62-4
64741-81-7
Dermal study: Doses of 2000, 4000, 8000, 20 000 or 40 000 mg/kg-bw per day were applied to the clipped dorsal interscapular skin of male and female B6C3F1 mice (5 animals per sex per dose) for 14 consecutive days. Skin lesions characterized by moderate acanthosis, perakeratosis and hyperkeratosis, accompanied by moderate mixed cellular inflammatory infiltrate within the upper dermis were observed at all doses. Mortality of all mice occurred between days 7 and 12 at the highest dose (NTP 1986).
Dermal study: Doses of 425, 818 or 1625 mg/kg-bw per day (11.9, 22.9 or 45.5 mg per day)Footnote Appendix G Table G-1[c],Footnote Appendix G Table G-1 [d]were applied to male and female C3Hf mice, 3 days per week for 40weeks. Decreased body weight (4–21%), increased spleen weight (male and female), increased relative kidney weight (females) and decreased relative kidney weight (males) were observed at 818 mg/kg-bw per day (Schultz et al. 1981).
Dermal study: Doses of 694 or 1111 mg/kg-bw per day (50 µL of 50% w/v diluted in cyclohexane or 50 µL neat)[c],Footnote Appendix G Table G-1 [e],Footnote Appendix G Table G-1 [f] were applied to the clipped interscapular skin of male and female C3Hf/Bd mice (15 animals per sex per dose), 3 times per week for 60 weeks. Hyperkeratosis, alopecia and ulceration at the application site, as well as increased daily water consumption (possibly due to increased water loss) and increased urine output, were observed at all doses. An increased incidence of macroscopic renal lesions (affected kidneys were shrunken, pale and nodular) were observed in females at the highest dose (Easley et al. 1982).
Dermal study: Doses of 250, 500, 1000 and 2000mg/kg-bw per day (diluted in 0.2 mL of acetone) or 4000 mg/kg-bw per day (neat) were applied to the shaved interscapular skin of male and female B6C3F1 mice (10 animals per sex per dose), 5 days per week for 13 weeks. Decreased body weight (8–13%) in males was observed at all doses. An increased incidence of dermatosis was observed, with mild dermatitis occurring at the highest dose. Extramedullary haematopoiesis in the spleen and karyomegaly in the liver were observed at an unspecified dose (NTP 1986).
Dermal study: A dose of 8000 mg/kg-bw per day (8mL/kg per day)Footnote Appendix G Table G-1 [g],Footnote Appendix G Table G-1 [h] was applied to male and female New Zealand white rabbits (4 animals per sex) for 5days, followed by 2 days of rest, followed by 5 more days of exposure. Severe dermal irritation and injury (acanthosis, chronic inflammation, crusting, dermal congestion, dermal oedema and hyperkeratosis) were observed at the application site. Mortality (25%) occurred after a single exposure. Reduced food consumption, slight epithelial hyperplasia of the urinary bladder mucosa (4/8 rabbits), slight centrilobular vacuolar degeneration in the liver (3/8rabbits) and severe multifocal liver necrosis (7/8rabbits) were observed (API 1980a, 1980b, 1980c).
Dermal study: Doses of 1070, 2140 or 2675 mg/kg-bw per day (1, 2 or 2.5 mL/kg per day)[g],[h]were applied to male and female Sprague-Dawley rabbits (4 animals per sex per dose) for 5 days, followed by 2 days of rest, followed by 5 more days of exposure. Significant skin irritation (acanthosis, acute and chronic inflammation, crusting, deep pyoderma, dermal congestion and oedema, hyperkeratosis and epidermal necrolysis) was observed at the treatment site at all doses. Multifocal necrosis and centrilobular vacuolar degeneration of the liver were also observed at all doses (API 1980d).
Dermal study: Doses of 496, 992 or 2480 mg/kg-bw per day (0.5, 1.0 or 2.5 mL/kg per day) were applied to male and female Sprague-Dawley rats (10 animals per sex per dose), 5 days per week for 28 days. Minimal reversible dermal irritation was observed at all dose levels. Hyperkeratosis (minimal severity) was observed at the application site at the highest dose. Significant increase in relative liver weight was observed for both sexes at all dose levels. No other substance-related systemic effects were observed (UBTL 1987).
Dermal study: Doses of 496, 992 or 1984 mg/kg-bw per day (0.5, 1.0 or 2.0 mL/kg per day)[h],Footnote Appendix G Table G-1 [i] were applied to male and female Sprague-Dawley rats (10 animals per sex per dose), 5 days per week for 4 weeks. Mild histopathologic dermal lesions (acanthosis and hyperkeratosis) were observed at 1984 mg/kg-bw in both sexes. Possible dose-related decrease in body weight gain was observed in males (decrease at 992mg/kg-bw and statistically significant decrease at 1984 mg/kg-bw). Test substance-related anemia was observed, as indicated by increased absolute and relative spleen weights in combination with the absence of abnormal pathological spleen appearances, as well as decreased red blood cell indices (erythrocyte count, hematocrit (%) and hemoglobin levels), at all three dose levels in both sexes (UBTL 1988).
Dermal LOAEL (short-term) = 1 mg/kg-bw per day for dose-related decreases in maternal body weight gain, body weight, food consumption and gravid uterine weight, as well as the occurrence of red vagin*l exudates. Doses of 0.05, 1.0, 10, 50 or 250mg/kg-bw per day were applied to the clipped skin of pregnant CD rats from gestational days 0 to 19 (Hoberman et al. 1995).
Other dermal study (short-term): Doses of 8, 30, 125 or 500 mg/kg-bw per day or 4, 30, 125 or 500mg/kg-bw per day were applied to the shaved backs of pregnant Sprague-Dawley rats (15 animals per dose) from gestational days 0 to 19 (4 mg/kg-bw per day dose given as 8 mg/kg-bw every other day). Aberrant serum chemistry, decreased body weight gain and food consumption, as well as vagin*l discharge, were observed at 8 mg/kg-bw per day (applied every other day) (Mobil 1990; Feuston et al. 1997).
Dermal LOAEL (subchronic) = 8 mg/kg-bw per day for increased relative liver weight (male and female rats) and increased absolute liver weight (female). Doses of 8, 30, 125, 500 or 2000 mg/kg-bw per day were applied to the shorn backs of Sprague-Dawley rats, 5 times per week for 13 weeks. Increased mortality, decreased body weights, decreased thymus weight and aberrant serum chemistry and haematology were also observed at unspecified doses (Feuston et al. 1994).
Dermal LOAEL (subchronic) = 8 mg/kg-bw per day for a significant reduction in platelet count. Doses of 8, 30, 125 or 500 mg/kg-bw per day were applied to the shaved backs of male and female Sprague-Dawley rats (10 animals per sex per dose), 5 times per week for 13 weeks. Increased liver weight was observed for males and females at 30 mg/kg-bw per day and 125mg/kg-bw per day, respectively. At 30 mg/kg-bw per day (male) and 125 mg/kg-bw per day (female), dose-related reductions in red blood cell, haemoglobin, haematocrit and platelet counts, a dose-related decrease in thymus weight, and increased mortality (20% males and 80% females) were also observed. At 125 mg/kg-bw per day, both sexes exhibited decreased body weight gain. All male and female rats died at 125 and 500 mg/kg-bw per day, respectively (Mobil 1988; Feuston et al. 1997).
(1) General observations (greater than or equal to 500 mg/kg): Red vagin*l discharge, perineal staining and decreased stool.
(2) Effects versus gestation day (2000 mg/kg): Decreased body weight gain and thymus weight (regardless of exposure day).
(3) Effects versus dose (GD 12): Dose-related decrease in body weight gain and thymus weight (Feuston and Mackerer 1996).
Chronic dermal studies
Doses of 0, 250 or 500 mg/kg-bw (100 µL applied; test substance diluted in acetone) were applied to the clipped dorsal interscapular skin of B6C3F1 mice (49-50 animals per sex per dose) 5 times per week for 103 weeks. High-dose mice were sacrificed early due to severe irritation at the application site. Skin tumour incidence in male mice (squamous cell papillomas or carcinomas combined) occurred at the application site at the high dose (0/49, 0/49 and 3/49 of mice developed tumours, respectively). Incidence in female mice (squamous cell carcinomas only) at the application site was (0/50, 1/45 and 2/48, respectively). Liver tumour incidence in male mice (hepatocellular adenomas or carcinomas combined) was 9/50, 17/48 and 14/49, respectively. Liver tumour incidence in female mice (hepatocellular adenomas and carcinomas combined) were 4/50, 4/45 and 5/50 (NTP 1986).
Doses of 0, 694 or 1111 mg/kg-bw (50 µL at 50% w/v[c],[e]or 100%[c],[f], respectively) were applied to the clipped interscapular skin of C3Hf/Bd mice (15animals per sex per dose) 3 times per week for 60weeks. Of a larger combined group (groups of mice that received 1 of 5 other test substances), 34/360 developed skin tumours. A breakdown of the number of mice that received 68476-31-3 and developed tumours was not provided. Exposure to the negative control resulted in 1/60 mice developing skin tumours (Easley et al. 1982).
Doses of 8.4, 16.8, 42, 83.8 or 167.6 mg/kg-bw (25 μL of catalytically cracked clarified oil at 1, 2, 5, 10 or 20% in mineral oil)[c],[f],Footnote Appendix G Table G-1 [k],Footnote Appendix G Table G-1 [l] were applied to male C3H mice (50 animals per dose) 3 times per week for life. At 1%, 9/50 exposed mice developed tumours (4 carcinomas, 5 papillomas). At 2%, 34/50 exposed mice developed tumours (30 carcinomas, 4 papillomas with a latency period of 92 weeks). At 5%, 46/50 exposed mice developed tumours (46 carcinomas with a latency period of 61 weeks). At 10%, 48/50 exposed mice developed tumours (47 carcinomas, 1 papilloma with a latency period of 45 weeks). At 20%, all (50/50) exposed mice developed tumours (50 carcinomas with a latency period of 36 weeks). Of the 610 mice tested with the negative control (highly refined mineral oil) from this study and two other similar studies conducted by the same authors, only 2 mice developed benign papillomas and none developed carcinomas (McKee et al. 1990).
Initiation/promotion dermal study
Initiation: A dose of 16.8 mg/kg-bw (50 μL of catalytically cracked clarified oil at 1% in toluene)[c],[f],[l]was applied to groups of male CD mice (30 per group) for 5 consecutive days. After a 2-week rest period, the promoter phorbol-12-myristate-13-acetate (PMA) was applied 2 times per week for 25 weeks. A significant increase in skin tumour incidence was observed (26/30 exposed mice developed tumours after 16weeks).
Promotion: Details of study design not provided. No increase in histologically confirmed tumour incidence. However, a statistically significant increase in the number of mice with gross masses and shortened latency periods were observed, suggesting a possible weak promoting activity (API 1989).
Dermal reproductive LOAEL (female) = 1 mg/kg-bw per day for decreased number of live fetuses, increased incidence of resorptions, early resorptions and the percentage of dead or resorbed conceptuses per litter (these effects were dose-related and were observed at doses that were maternally toxic). Doses of 0.05, 1.0, 10, 50 or 250 mg/kg-bw per day were applied to the clipped skin of pregnant CD rats from gestational days 0 to 19. At 1 mg/kg-bw per day, an increased incidence in fetal variations associated with a decrease in fetal body weight was observed, including slight dilation of the lateral ventricles of the brain, moderate dilation of the renal pelvis, bifid thoracic vertebral centrum and decreased average number of ossified caudal vertebrae, metacarpals and hindpaw phalanges (these effects were noted to be reversible delays in development). (Hoberman et al. 1995).
Dermal developmental LOAEL = 8 mg/kg-bw for fetal external abnormalities. Doses of 4, 8, 30, 125 or 250mg/kg-bw per day were applied to the shaved backs of pregnant Sprague-Dawley rats (10 per dose) for gestational days 0–19 (the 4 mg/kg-bw dose was given as 8 mg/kg-bw every other day). At 8 mg/kg-bw per day, external abnormalities in living and dead fetuses, including cleft palate, micrognathia (shortened lower jaw) and kinked tail, were observed. An increased incidence of resorptions, decreased number of viable offspring, reduced fetal size, visceral anomalies and skeletal variations were observed at 30mg/kg-bw per day. There were no viable fetuses at 250 mg/ kg-bw per day (Feuston et al. 1989; Mobil 1987e).
Other dermal study: Doses of 4, 8, 30, 125 or 500mg/kg-bw per day were applied to the shaved backs of pregnant Sprague-Dawley rats (15 per dose) from gestational days 0 to 19 (4 mg/kg-bw per day dose was administered as 8 mg/kg-bw every other day). At 8mg/kg-bw per day, an increased incidence of resorptions and a decreased number of viable fetuses was observed (biologically significant). At 30mg/kg-bw per day, a statistically significant increased incidence of resorptions was observed, as well as decreased fetal body weight. An increased incidence of fetal external, skeletal and visceral anomalies (primarily rib malformations and cleft palate) was observed at 500 mg/kg-bw per day (Mobil 1990; Feuston et al. 1997).
Other dermal study: Doses of 8, 30, 125 or 500mg/kg-bw per day were applied to the shaved backs of male Sprague-Dawley rats (10 per dose), 5times per week for 13 weeks. Decreased sperm count after 9 weeks of exposure was observed at 500mg/kg-bw per day (Mobil 1988; Feuston et al. 1997).
Oral reproductive and developmental LOAEL = greater than or equal to125mg/kg for increased resorptions, decreased fetal body weight and increased incidence of skeletal malformations. Pregnant Sprague-Dawley rats were administered 2000 mg/kg on one of gestational days (GD) 11–14 (to generate a profile of teratogenic effects as a function of gestation day). Additionally, 125, 500 or 2000 mg/kg was administered on gestational day 12 (to generate a profile of teratogenic effects as a function of dose). Test samples were clarified slurry oilandsyntower bottoms.
(1) Teratogenic effects per gestation day (2000mg/kg): The greatest incidence of resorptions/decreased litter size occurred on GDs11–12. Fetal body weights were reduced on all GDs. The greatest incidence of fetal external anomalies and visceral malformations occurred on GDs 12–14 and 12–13, respectively. Various fetal skeletal malformations occurred on all GDs.
(2) Teratogenic effects per dose (GD 12): There was a dose-related response for increased resorptions, decreased litter size, decreased fetal body weight and increased incidence of fetal skeletal malformations. A variety of fetal external anomalies were also observed at 2000 mg/kg (Feuston and Mackerer 1996).
Unscheduled DNA Synthesis
Groups of male Fischer 344 rats (3 animals per dose) were administered by oral gavage a single dose of 50, 200 or 1000 mg/kg-bw of test substance, 2 or 12hours before sacrifice. A significant increase in UDS in primary hepatocyte cultures was observed at 200mg/kg-bw (after 12 hours only) and 1000mg/kg-bw (after 2 and 12 hours) (API 1985a).
Sister Chromatid Exchange
Groups of male and female B6C3F1 mice (5 animals per sex per dose) were administered 400, 2000 or 4000 mg/kg-bw test substance via intraperitoneal injection. A significant increase in sister chromatid exchange (SCE)/metaphase in bone marrow cells was observed at greater than or equal to2000 mg/kg-bw (male; P less than 0.05) and at 4000 mg/kg-bw (female; Pless than0.01). The effect exhibited a positive dose-dependent trend at all doses (API 1985b).
Groups of CD Swiss mice (10 animals per sex per dose) were administered 1250, 2500 or 5000mg/kg-bw test substance by oral gavage over 2days. Another group (15 animals per sex) was administered a single dose of 5000 mg/kg-bw. A significant increase in micronucleated polychromatic erythrocytes was observed at greater than or equal to 1250 mg/kg-bw (males) and at 5000 mg/kg-bw (females) (Khan and Goode 1984).
Mutagenicity
Test substance was negative in S. typhimurium TA1535, TA1537, TA98 and TA100 with and without S9 metabolic activation (NTP 1986).
Test substance was negative inS. typhimurium TA98 with and without S9 metabolic activation (Schultz et al. 1981).
Inhibition of Morphological Transformation
Test substance was negative in ST-FeSV-infected human foreskin fibroblasts without metabolic activation (Blakeslee et al. 1983).
Mutagenicity
S. typhimurium TA1535, TA1538, TA98 and TA100 were exposed with and without S9 metabolic activation (Aroclor 1254-induced rat liver). Mutagenicity was not observed (Vandermeulen et al. 1985).
Test substance was also negative in a forward mutation assay using Chlamydomonas reinhardtii (Vandermeulen and Lee 1986).
Sister Chromatid Exchange
Chinese hamster ovary cells were exposed with and without S9 metabolic activation (Aroclor 1254-induced rat liver). No increase in SCE was observed (Farrow et al. 1983).
Mouse Lymphoma Assay
L5178Y TK+/- cells were exposed to test substance with and without S9 metabolic activation (Aroclor 1254-induced rat liver). Mutant frequency did not increase (Farrow et al. 1983).
L5178Y cells were exposed to sample API 81-15 at concentrations ranging from 0.061–31.3 nL/mL for 4hours, with and without S9 rat liver metabolic activation. Toxicity was noted at all levels and survival was less than 10% at concentrations above 3.9 nL/mL. Without activation, the test substance was weakly positive at the highest concentration only. With activation, the test substance induced a concentration-related increase in mutant frequency at concentrations greater than 0.977 nL/mL (API 1985c).
S. typhimurium TA98 was exposed to DMSO extracts of combined test substances at concentrations of 0.5, 1, 2.5, 5 or 10 µL/plate with S9 metabolic activation (Aroclor 1254-induced rat liver). A concentration-related increase in mutagenic potency was observed, with a mutagenicity index of 130 (Blackburn et al. 1984). Additionally, S. typhimurium TA98 was exposed to DMSO extracts (dissolved in cyclohexane) at concentrations of 0.5, 1, 1.5, 2 or 5µL/plate with S9 metabolic activation (Aroclor 1254-induced Syrian golden hamster liver). A concentration-related increase in mutagenic potency was observed, with a mutagenic index of approximately 58 (Blackburn et al. 1986).
Unscheduled DNA Synthesis
Primary rat hepatocyte cultures derived from F-344 male rat liver were exposed to ethanol dilutions of aromatic pyrolysis oilat concentrations of 0.5, 2, 10 or 60 μg/mL for 18–20 hours (without S9 metabolic activation). A concentration-response was observed for UDS at greater than or equal to 2 μg/mL (Brecher and Goode 1984).
Mutagenicity
Chinese hamster ovary cells were exposed to ethanol dilutions of aromatic pyrolysis oil at concentrations of 32, 64, 96, 128, 175 or 256 μg/mL without S9 metabolic activation (Aroclor-1254 induced rat liver) and 128, 175, 256, 375, 512 or 750 μg/mL with S9 metabolic activation. A repeat experiment was conducted at concentrations of 500, 600 or 750 μg/mL with S9 metabolic activation. Reduced cell count was observed at all concentrations (with and without S9) and significant toxicity was observed at all concentrations with S9. An increase in mutant frequency was definitive at 750 μg/mL with an observed linear concentration-related trend for mutagenicity at lower concentrations. In the repeat experiment, an increase in mutant frequency was observed at 500 μg/mL (and the higher concentrations were toxic). No mutagenic effects were observed without S9 metabolic activation (Papciak and Goode 1984).
Sister Chromatid Exchange
Chinese hamster ovary cells were exposed to the test substance at concentrations of 5–100 μg/mL without S9 metabolic activation and 100–5000 μg/mL with S9 metabolic activation. An increase in SCE was observed with activation. No increase in SCE observed without activation (API 1985e).
Cell Transformation
BALB/3T3 mouse embryo cells were exposed to the test substance at concentrations of 1, 3, 6 or 9 μg/mL without S9 metabolic activation (for 3 days) or 10, 30, 100 or 300 μg/mL with S9 metabolic activation (for 4days). S9 was prepared from Aroclor-induced male rat liver. An increase in the frequency of transformation was observed at 100 μg/mL after 4hours. Low survival rates were observed at 300μg/mL. No increase in morphological transformation without activation (API 1986b).
