Registration Dossier

Administrative data

Description of key information

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEL
90 mg/kg bw/day
Study duration:
chronic
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEC
406 mg/m³
Study duration:
subchronic
Species:
rat

Additional information

The potential for tertiary butyl alcohol to cause target organ toxicity following repeated exposure is well understood. All available studies were conducted according to NTP guidelines.

Repeated dose toxicity: oral

Ninety-day studies and information from carcinogenicity studies in rat and mice are available.

Rats

In a 90-day NTP study, groups of 10 male and 10 females F344/N rats were administered 0, 2.5, 5, 10, 20 and 40 mg/ml tertiary butyl alcohol (equivalent to 0, 230, 490, 840, 1520 or 3610 mg/kg bw/day in males and 290, 590, 850, 1560, 3620 mg/kg bw/day in females) via the drinking water. All males and six of the females in the top dose level died during the study. Body weight was significantly lower in top dose females (21 %), and in males receiving 20 mg/ml (17 %) and 10 mg/ml (12 %). Water consumption in both sexes dosed ≥ 10 mg/ml was less than control animals, correlating with the decrease in urine volume. A dose-related increase in clinical signs (ataxia, hypoactivity (males), hyperactivity (females and emaciation) were reported (specific details of the effects at each dose was not provided). The kidney, bladder and liver were identified as target organs. An increase in absolute and relative kidney weight was observed in both sexes at all doses (> 12 % absolute weight at 2.5 mg/ml). A dose related increase in the severity of chronic progressive nephropathy (CPN) was observed in males from 2.5 mg/ml (see table below – note at the top dose level all males died). CPN is a common, age-related renal disease that occurs in rats which can progress to end-stage kidney disease (Hard et al., 2013). The incidence and severity of this spontaneously occurring disease is a confounding factor in chronic toxicity and carcinogenicity bioassays, particularly if the kidney is a target organ. CPN occurs at higher incidence and with greater severity in males vs. female rats. The histological characteristics of CPN include basophilic tubules, thickened basement membranes, hyaline cast formation and glomerulosclerosis (Hard et al., 1999). Lesions of CPN are detectable in male rat kidney as early as 2 months of age. The development of CPN appears to be primarily under the control of physiological factors. These factors are mainly dietary (increasing protein exacerbates CPN and decreasing caloric intake protects), and hormonal, particularly involving androgens (Baylis, 1994; Keenan et al., 2000; Hard and Khan, 2004). CPN lesions are observed in 100% of the control male rats in a survey of 90-day studies, with increased severity of CPN in rats fed the NIH-07 diet (Travlos et al., 2011), as the animals in the tertiary butyl alcohol NTP studies were. CPN is a distinctive entity in rats to which there is no counterpart in human disease (Hard et al., 2009). A distinction in the features of nephropathy in rats compared to humans is the clinical course of the disease, the relationship to diet and immunological factors, and most distinctively, the presence of the thickened basement membrane around the basophilic, regenerative tubules is an early presentation in CPN. In humans, a thickened basement membrane is seen only with atrophic tubules and not associated with degeneration or regeneration as with rats (Hard et al., 2013). Although the NTP report stated that the increased severity of the CPN suggested a “treatment-related cytotoxicity” in the tertiary butyl alcohol -exposed rats, a Pathology Working Group reviewing the study slides could find no evidence of cytotoxicity in renal tubule cells. McGregor (2010) has reviewed the issue of CPN and concluded that given the dietary and physiological influences on CPN incidence and severity, exacerbation by tertiary butyl alcohol should not necessarily be considered a toxic response. A statistically significant increase in the incidence of mineralization was observed in males ≥ 10 mg/ml. In females, a dose related increase in the incidence of nephropathy but not of severity was observed from 10 mg/ml. Staining of kidneys (Mallory Heidenhaim and Lee’s methylene blue basic fuschin stains) revealed an increase in the presence of hyaline droplets and crystalline structures associated with the hyaline droplets within the renal tubule epithelium and tubule lumina of male kidneys (but not females) of all dose groups. The presence of the hyaline droplets and mineralisation suggests tertiary butyl alcohol induces α2u-globulin nephropathy in male kidneys; a rat-specific effect not considered relevant to humans. Both types of nephropathy are known to increase kidney weights.

Effects in the kidney of male/female rats following 90-day administration of tertiary butyl alcohol

Sex

Concentration/effect

0 mg/ml

2.5 mg/ml

5 mg/ml

10 mg/ml

20mg/ml

40 mg/ml

Male

Mineralization

0

0

2 (1.5)

8** (1.4)

4* (1.0)

4* (1.0)

 

CPN

7 (1.0)

10 (1.6)*

10 (2.6) **

10 (2.7) **

10 (2.6) **

7 (1.1)

 

Hyaline Droplet Accumulation

0

+

++

++

++

0

Female

Mineralization

10 (1.7)

10 (2.0)

10 (2.0)

10 (2.0)

10 (2.0)

6 (1.2)

 

CPN

2 (1.0)

3 (1.0)

5 (1.0)

7 (1.0)*

8 (1.0)*

7 (1.0)*

* Statistically significant (P ≤ 0.05), **statistically significant (P≤ 0.01), ++ or + indicates increased accumulation compared to controls, (brackets) average severity of lesions in affected animals: 1 = minimal, 2 = mild, 3 = moderate – Note these values reflect effects in this study and are not comparable to the extent of the effects observed in the 2-year study.

Absolute and relative liver weights of females at all dose levels and relative liver weights of males at ≥ 5 mg/ml were increased. Apart from increased alanine transaminase activity in top dose females, these increases were not accompanied by any other effects. In the bladder, grossly visible calculi, microscopic inflammation of the lamina propria and hyperplasia of the transitional epithelium was observed in males in the 20 mg/ml group. Inflammation and hyperplasia were also observed in females dosed 40 mg/ml.

The LOAEL for the 90-day rat study was 2.5 mg/ml (equivalent to 230 mg/kg bw).

In a 2-year NTP carcinogenicity study, groups of 60 male and 60 females F344/N rats were administered 0, 1.25 (males only), 2.5, 5 or 10 (females only) mg/ml tertiary butyl alcohol (equivalent to 0, 90, 200 and 400 mg/kg bw/day in males and 0, 180, 330 and 650 mg/kg bw/day in females) via the drinking water. After 15 months, 10 animals/sex/group were sacrificed and urinalysis, hematological and organ weight (brain, kidney and liver) investigations conducted. At 15 months, females in the top two doses had reduced urine specific gravities and volume consistent with their decreased water intake.

Terminal survival rates were reduced in a dose dependent manner in males (12, 10, 4 and 2 animals from the control to high dose group), whereas survival in females was lower in top dose females only (29, 28, 26 and 17 animals from the control to the high dose group). In males, terminal body weight was adversely reduced from the lowest dose (15 %), whereas female body weight was only reduced at the top dose (20 %). There was a dose related increase in water consumption in males and a dose-related decrease in females.

In this study, the kidney was identified as the target organ.

At the 15 month interim, relative kidney weights of 2.5 and 5 mg/ml treated males and absolute and relative kidney weights of all treated females were statistically significantly increased compared to controls. CPN was present in all animals, with the severity slightly increased in all exposed groups of males (non-statistically significantly) (see table below). Increased incidence and severity of mineralization of the kidney was observed in 2.5 and 5 mg/ml treated males, although this increase was only statistically significant at 5 mg/ml.

Effects in the kidney of male/female rats following 15 month and 2-year administration of tertiary butyl alcohol

Sex

Sampling time and evaluation type

Effect/concentration

0 mg/ml

1.25 mg/ml

2.5 mg/ml

5 mg/ml

10 mg/ml

Male

15-month - standard

Mineralization

1 (1.0)

2 (1.0)

5 (1.8)

9**(2.3)

 

 

 

CPN

10 (2.4)

10 (2.7)

10 (2.8)

10 (2.6)

 

 

15-month – extended

Renal tubule hyperplasia

0

0

2

0

 

Females

15-month - standard

Mineralization

10 (2.8)

 

10 (2.9)

10 (2.9)

10 (2.8)

 

 

CPN

10 (1.5)

 

10 (1.4)

10 (2.0)

10 (1.8)

Males

Terminal – standard

CPN

49 (3.0)

49 (3.1)

50 (3.1)

50 (3.3)*

 

 

 

Transitional cell hyperplasia

25 (1.7)

32 (1.7)

36**(2.0)

40**(2.1)

 

 

 

Mineralization

26 (1.0)

28 (1.1)

35 (1.3)

48** (2.2)

 

 

 

Mineralization, linear

0

5* (1.0)

24**(1.2)

46** (1.7)

 

 

 

Renal tubule hyperplasia

3 (1.7)

7 (1.7)

6 (2.0)

6 (1.7)

 

 

Terminal – extended

Renal tubule hyperplasia

12 (2.3)

16 (2.3)

14 (2.2)

23* (2.8)

 

 

Combined

Renal tubule hyperplasia

14 (2.1)

20 (2.3)

17 (2.2)

25 ** (2.7)

 

Females

Terminal – standard

Inflammation, supparative

2 (1.0)

 

3 (1.3)

13**(1.0)

17**(1.1)

 

 

Mineralization

49 (2.6)

 

50 (2.6)

50 (2.7)

50 (2.9)

 

 

CPN

48 (1.6)

 

47 (1.9)*

48 (2.3)**

50 (2.9)**

 

 

Renal tubule hyperplasia

0

 

0

0

1 (1.0)

 

 

Transitional epithelium, hyperplasia

0

 

0

3 (1.0)

17** (1.4)

   * Statistically significant (P ≤ 0.05), **statistically significant (P≤ 0.01),, (brackets) average severity of lesions in affected animals: 1 = minimal, 2 = mild, 3 = moderate, 4= marked

At termination, a dose related increase in incidence and severity of foci of linear mineralization was observed in males. This type of mineralization has been specifically associated with accumulation of α2µ-globulin in male rats. The severity of the CPN was increased in all female dose groups and in 5 mg/ml treated males when compared to controls. Signs associated with CPN (inflammation, mineralization and transitional epithelial hyperplasia) were also increased from 2.5 mg/ml in males and 5 mg/ml in females. There was no progression of transitional cell hyperplasia to neoplasms.

The incidence of focal renal tubule hyperplasia was increased in all treated male groups (not dose dependently). Renal tubule hyperplasia was also observed in one 10 mg/mL female. Additional male rats with hyperplasia (11, 13, 11 and 19 animals in control through to high dose groups) were identified following examination of further sections of the kidney in male rats. The extent of the hyperplasia was statistically significant increased in males at 5 mg/ml.

A LOAEL for toxicity of 1.25 mg/L (equivalent to 90 mg/kg bw/day) tertiary butyl alcohol was derived due to effects on body weight in low dose male rats.

Mice

In a 13-week NTP study, groups of 10 male and 10 female B6C3F1 mice were administered tertiary butyl alcohol via the drinking water at doses of 0, 2.5, 5, 10, 20 and 40 mg/ml (equivalent to 0, 350, 640, 1590, 3940 or 8210 mg/kg bw/day in males and 500, 820, 1660, 6430, 11620 mg/kg bw/day in females). At 40 mg/ml, 2 males and 1 female died. At this dose, terminal body weight was lower in both males (25 %) and females (15%) and was also lower in males of the 20 mg/ml dose group (14 %). Clinical findings included emaciation, ataxia and hypoactivity in males and emaciation in females. The increased estrous cycle length observed in females of this dose was considered a consequence of the toxicity observed and not a specific effect of tertiary butyl alcohol.

Water consumption was reduced in the top dose, although not throughout the study in males. Slight increases in hemoglobin and hematocrit values in the two top doses are consistent with slight dehydration. The kidney and bladder were identified as target organs. Absolute (12 %) and relative (35 %) kidney weights of 40 mg/L females were increased compared to controls. No nephropathy was noted. In the bladder, hyperplasia of the transitional epithelium was present in all males and three females dosed with 40 mg/ml and in six male mice dosed with 20 mg/ml. Chronic inflammation of the bladder (primarily macrophages, lymphocytes and plasma cells) was observed in six males and six females in the 40 mg/ml and six males in the 20 mg/ml group.

A NOAEL of 10 mg/ml (equivalent to 1590 mg/kg bw/day) can be derived from this study based on the effects on body weight and bladder at 20 mg/ml.

In a 2-year NTP carcinogenicity study, groups of 60 male and 60 females B6C3F mice were administered 0, 5, 10 or 20 mg/ml tertiary butyl alcohol (0, 540, 1040 and 2070 mg/kg bw/day in males and 0, 510, 1020 and 2110 mg/kg bw/day in females) via the drinking water. Survival was reduced in high dose males (27, 36, 34, 17 survivors from control to high dose) and as a consequence the interim sacrifice was not conducted in either sex. Survival was similar in females from all treated groups (36, 35, 41, 42 from control to high dose). In the 20 mg/ml group, female body weight was 10-15 % lower than control from week 13 and was 12 % lower than controls at the end of the study. Male body weight gain was 5 – 10 % lower at various stages during the treatment period. There was no difference at termination. Mean body weight of 10 mg/ml treated females was about 6 % lower than controls throughout the study and body weight was slightly lower than controls in 5 mg/ml females as well. Water consumption in both sexes was similar to the controls.

In this study the thyroid, urinary bladder and liver were identified as target organs.

In the thyroid a dose-related increase in the incidence of follicular cell hyperplasia was observed in both sexes. The extent of this increase reached statistical significance in all dose groups in males and in the top two dose groups in females.

In the urinary bladder, the incidence of chronic inflammation and transitional cell epithelium hyperplasia was increased at the top dose in both sexes. Similarly, an increase in the number of males with fatty liver was also observed at the top dose.

A LOAEL of 5 mg/ml (510 mg/kg bw/day) was derived for toxicity, based on a statistically significant increase in the incidence of thyroid follicular cell hyperplasia in both sexes at this dose level.

Repeated dose toxicity: inhalation

Information on the inhalation repeated dose toxicity of tertiary butyl alcohol is available from NTP studies conducted in both rats and mice and for durations of 18 and 90 days.

Rats

In an 18-day NTP study, groups of 5 male and 5 female F344/N rats were exposed to tertiary butyl alcohol by inhalation at concentrations of 0, 450, 900, 1750, 3500 and 7000 ppm (equivalent to 0, 1385, 2759, 5305, 10680, 21188 mg/m3) for 6 hours a day, 5 days per week. Investigations in this study were similar to the 90-day studies, apart from no hematology, clinical chemistry, urinalysis or sperm morphology/vaginal cytology evaluation was conducted. All animals in the top concentration group died on day 2. No deaths were observed in any other concentration group. Clinical signs including hypoactivity, hyperactivity and ataxia were observed at all concentration levels ≥ 900 ppm (no details on incidence, etc provided). At 3500 ppm, terminal body weights were significantly lower than controls in both sexes (> 10 %); concomitantly body weight gain was also lower than the controls at this concentration level. A NOAEC of 450 ppm (1385 mg/m3) was determined for this study based on clinical signs observed at 900 ppm.

In a 90-day NTP study, groups of 10 male and 10 female F344/N rats were exposed to tertiary butyl alcohol by inhalation at concentrations of 0, 135, 270, 540, 1080 and 2100 ppm (equivalent to 0, 406, 825, 1643, 3274 and 6369 mg/m3) for 6 hours a day, 5 days per week. At 2100 ppm, emaciation and hypoactivity was observed at one observation time point only. No effects on body weight were observed. The minor changes in clinical chemistry and hematology were not sufficiently severe to be considered adverse. At the top concentration, absolute kidney weight was increased in males (10%), and was accompanied by signs of mild CPN in all males (see table below). In top concentration females, relative liver weight was increased (9 %).

Effects in the kidney of male rats following 90-day administration of tertiary butyl alcohol

Sex

Concentration/effect

0 ppm

135 ppm

270 ppm

540 ppm

1080 ppm

2010 ppm

Male

CPN

9 (1.0)

8 (1.4)

9 (1.4)

10 (1.6)

10 (1.9)

10 (2.0)

(Brackets) average severity of lesions in affected animals: 1 = minimal, 2 = mild

At the next concentration (1080 ppm), similar effects were noted in the male kidney (11 % ↑ weight and CPN) and female liver (9 % ↑ relative weight). At the lower concentration levels, CPN was less severe than at the higher concentrations, but still more severe than in the control (CPN considered mild in controls). Sections of kidney from male rats in the 0, 1080 ppm and 2100 ppm concentration group were stained by Mallory-Heidernhain method for the presence of tubular hyaline droplets. There were no differences between the controls and treated groups in the number, shape or size of the droplets. In this study no NOAEC could be identified due to the increase in severity of the CPN observed in males of all concentration groups. The LOAEC is the lowest concentration tested 135 ppm (406 mg/m3). Mice In an 18-day NTP study, groups of 5 male and 5 female B6C3F1 mice were exposed to tertiary butyl alcohol by inhalation at concentrations of 450, 900, 1750, 3500 and 7000 ppm (equivalent to equivalent to 0, 1385, 2759, 5305, 10683, 21294 mg/m3) for 6 hours a day, 5 days per week. Investigations in this study were similar to the 90-day studies, apart from no hematology, clinical chemistry, urinalysis or sperm morphology/vaginal cytology evaluation was conducted. All animals in the top concentration group died on day 2. One male died on day 3 in the 3500 ppm concentration group. In this concentration group, animals were prostrate following the first three days of exposure. Clinical signs after this time include hypoactivity, ataxia and rapid respiration. At this concentration, female liver weight was increased as was relative liver weight in both sexes. Thymus weight was lower in females of this concentration (26 % ↓ absolute weight). At the next concentration level (1750 ppm), effects were limited to clinical signs (hypoactivity, hyperactivity, ataxia and urogenital wetness). No toxicologically adverse effects were observed at any other concentration level. The NOAEC for this study was 900 ppm (2759 mg/m3) based on clinical signs at 1750 ppm. In a 90-day NTP study, groups of 10 male and 10 female B6C3F1 mice were exposed to tertiary butyl alcohol by inhalation to 0, 135, 270, 540, 1080 and 2100 ppm (equivalent to 0, 406, 825, 1643, 3274 and 6369 mg/m3) for 6 hours a day, 5 days per week. In the top concentration group, 1 male died in week 7. Five males also died in the 1080 ppm concentration group; however, these deaths were attributed to problems with the water/food and not treatment with tertiary butyl alcohol. Body weight (↓19 %) and body weight gain (↓ 24%) were adversely affected in top concentration females, whereas only body weight gain (↓ 19%) was affected in the 1080 ppm concentration group. Relative female liver weights were also increased in these two groups (9 and 20 % in females of the 1080 and 2100 ppm groups, respectively); however, as there were no histopathological changes observed, these increases may be secondary to the reduced body weight, particularly at the top concentration. No adverse treatment related effects were noted at ≤ 540 ppm. The NOAEC for this study is 540 ppm (1643 mg/m3) based on effects on female body weight gain at the next concentration level (1080 ppm).

Summary

The effects of repeated exposure to tertiary butyl alcohol have been extensively investigated in standard subchronic and carcinogenicity studies via the oral route and subacute and subchronic studies via the inhalation route.

The study NOAELs and LOAELS are summarized in the following table:

Route

Duration

Species

LOAEL/C

NOAEL/C

Reference

Oral, drinking water

90-day

Rat

230 mg/kg bw/day

 Not derived

 NTP (1995)

Oral, Drinking water

2-year

Rat

90 mg/kg/bw/day

Not derived

NTP (1995)

Oral, Drinking water

90-day

Mice

3940 mg/kg bw/day

1590 mg/kg bw/day

 NTP (1995)

Oral, Drinking water

2-year

Mice

510 mg/kg/bw/day

Not derived

NTP (1995)

Inhalation

18-day

Rat

2759 mg/m3

1385 mg/m3

NTP (1997)

Inhalation

90-day

Rat

406 mg/m3

Not derived

NTP (1997)

Inhalation

18-day

Mice

5305 mg/m3

2759 mg/m3

NTP (1997)

Inhalation

90-day

Mice

3274 mg/m3

1643 mg/m3

NTP (1997)

In rats, for the oral route, sub-chronic and carcinogenicity studies consistently showed the kidney to be the principal target organ for tertiary butyl alcohol toxicity. The effects in the kidney ranged from increased weight, increased incidence/severity of CPN and the presence of hyaline droplet (males only) indicative of α2u-nephropathy. Other effects, seen at higher exposures (40 mg/ml) in the sub-chronic studies included death and body weight effects. In the carcinogenicity studies, bodyweight effects occurred in males of all dose levels (≥ 90 mg/kg bw/day) and may be a result of the increased kidney toxicity in these animals. A dose related increase in clinical signs (ataxia, hypoactivity, hyperactivity and emaciation) was observed in the oral sub-chronic study and similar effects observed in the top dose of the chronic study (10 mg/ml). LOAELs (but not NOAELS) of 230 mg/kg bw/day for sub-chronic and 90 mg/kg bw/day for chronic exposure were derived via the oral route. In the sub-chronic inhalation study similar effects were observed as via the oral route, with the kidney as the target organ. In the sub-acute study, the driving effect was clinical signs (hypo/hyperactivity and ataxia) observed at all doses ≥ 2759 mg/m3. At higher doses (≥ 10680 mg/m3) other effects included deaths and body weight effects. A NOAEC of 1385 mg/m3 was derived for sub-acute exposure and a LOAEC of 406 mg/m3 was derived for sub-chronic exposure.

Repeated oral exposure of mice showed them to be less sensitive to tertiary butyl alcohol than rats. In the sub-chronic study effects were only observed at doses ≥ 20 mg/ml. At this dose level, effects on body weight and in the bladder (transitional cell hyperplasia and chronic inflammation) were observed. Deaths, clinical signs, kidney and liver effects were observed at the highest dose (40 mg/ml). A NOAEL was derived for sub-chronic exposure of 10 mg/ml (3940 mg/kg bw/day). In the carcinogenicity study, effects on the bladder and body weight were again observed at 20 mg/ml (highest dose tested). The target organ in this study was the thyroid with a dose-related increase in the incidence of thyroid follicular cell hyperplasia observed from the lowest dose. A LOAEL of 510 mg/kg bw/day was derived from this study.

Via the inhalation route in mice, effects were more varied. In the subacute study, clinical signs (hypoactivity, hyperactivity and urogenital wetness) were observed at concentrations of ≥ 1750 ppm (5305 mg/m3). Other effects were observed at the highest dose only (7000 ppm or 21194 mg/m3) and included death, liver weight increase and decreased thymus weight. In the sub-chronic study, no clinical signs were observed, although it is noted that the top concentration in this study (2100 ppm) is relatively close to the LOAEC for these effects in the 18-day study and may reflect experimental variation. In the sub-chronic study, reduced body weight was the lead effect and was reduced from 1050 ppm (3274 mg/m3). A NOAEC of 900 ppm (2759 mg/m3) was derived for sub-acute exposure and 540 ppm (1643 mg/m3) for sub chronic exposure.

Additional references:

Baylis, C. (1994). Age-dependent glomerular damage in the rat. Dissociation betweenglomerular injury and both glomerular hypertension and hypertrophy. Male gender as a primary rsk factor. J. Clin. Invest. 94:1823–1829.

Hard, G.C., Alden, C.L., Bruner, R.H., Frith, C.H., Lewis, R.M., Owen, R.A., Krieg, K. and Durchfeld-Meyer, B., (1999). Non-proliferative lesions of the kidney and lower urinary tract in rats. In: Guides for Toxicologic Pathology, STP/ARP/AFIP, Washington, DC; pp. 1–32.

Hard, G.C. & Khan, K.N. (2004) A contemporary overview of chronic progressive nephropathy in the laboratory rat, and its significance for human risk assessment. Toxicol. Pathol. 32:171-180

Hard GC, Bruner RH, Cohen SM, Pletcher JM, Regan KS. (2011). Renal histopathology in toxicity and carcinogenicity studies with tert-butyl alcohol administered in drinking water to F344 rats: a pathology working group review and re-evaluation. Regul Toxicol Pharmacol. 59(3):430-6.

Hard, G.C., Banton, M.I., Bretzlaff, R.S., Dekant, W., Fowes, J.R., Mallett, A.K., McGregor, D.B., Roberts, K.M., Sielkin, R.L., Jr., Valdez-Flores, C., and Cohen, S.M. (2013). Consideration of rat chronic progressive nephropathy in regulatory evaluations for carcinogenicity. Toxicol. Sci. 132: 268-275

Keenan, K. P., Coleman, J. B., McCoy, C. L., Hoe, C-M., Soper, K. A., and Laroque, P. (2000). Chronic nephropathy in ad libitum overfed Sprague-Dawley rats and its early attenuation by increasing degrees of dietary (caloric) restriction to control growth. Toxicol Pathol 28: 788–98

McGregor, D. (2010) Tertiary-Butyl alcohol: A toxicological review. Crit Rev Toxicol., 40:697-727.

Travlos, G. S., Hard, G. C., Betz, L. J., and Kissling, G. E. (2011). Chronic progressive nephropathy in male F344 rats in 90-day studies: Its occurrence and association with renal tubule tumors in subsequent 2-year bioassays. Toxicol Pathol 39, 381–89.

Repeated dose toxicity: inhalation - systemic effects (target organ) urogenital: kidneys

Justification for classification or non-classification

Chronic progressive nephropathy (CPN) is present as a spontaneous lesion in F344/N rats and is usually less prominent in females than males. CPN has not been reported in humans and was not reported in male or female mice exposed to dose levels of approximately 2000 mg/kg bw/day for a lifetime. A number of chemicals, when tested for prolonged periods at high concentrations, have caused thyroid follicular cell hyperplasia in rodents with no corresponding effect reported in humans exposed to lower concentrations. Thyroid effects were not observed in rats following lifetime exposure or in mice following 13-week exposure by the oral or inhalation routes. By comparison to rodents, the human thyroid appears to be much less sensitive to adverse effects on thyroid hormone production/secretion and the proposed mechanism leading to thyroid hyperplasia in rodents. Based on a weight-of–the-evidence assessment, tertiary butyl alcohol is not classified for Specific Target Organ Toxicity – Repeated Exposure according to Dangerous Substances Directive 67/548/EEC and EU Classification, Labeling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.