Document ID: EPA-HQ-OPP-2010-0905-0011
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2011-09-09T04:00Z

Amendment to DER for MRID 43293901 - Chronic Neurotoxicity Screening Battery [Rat] 
[2,4-DICHLOROPHENOXYACETIC ACID] 

This amendment provides an EXECUTIVE SUMMARY and data tables to upgrade the original DER [Document No. 011614].

EPA Reviewer: Linda L. Taylor, Ph.D.                                                                                                              
Reregistration Branch I, Health Effects Division (7509C)
EPA Secondary Reviewer: Whang Phang, Ph.D.                                                                                                
Reregistration Branch I, Health Effects Division (7509C)
TXR# 0051360

                        AMENDED DATA EVALUATION RECORD

STUDY TYPE: chronic neurotoxicity - rat 	§ 82-7/OPPTS 870.6200
P.C. CODE: 030001	REREGISTRATION CASE NO.: 818706
CASWELL NO.: 315	CAS NO.: 94-75-7
TEST MATERIAL (PURITY): 2,4-Dichlorophenoxyacetic acid [96.7%]
SYNONYMS: 2,4-D
SPONSOR: Industry Task Force II on 2,4-D Research Data

CITATION: Mattsson, J. L., Jeffries, T. K., Yano, B. L. (1994).  2,4-Dichlorophenoxyacetic acid: Subchronic Neurotoxicity Study in Fischer 344 Rats. The Toxicology Research Laboratory, Dow Chemical Co.; Study No. K-002372-064N, June 28, 1994. MRID 43293901. Document No. 011614. Unpublished. 

Jeffries, T. K., Yano, B. L., and Ormand, J. R. (1995). 2,4-Dichlorophenoxyacetic acid: Chronic Toxicity/Oncogenicity Study in Fischer 344 Rats. 1-Year Interim Report. The Toxicology Research Laboratory, Dow Chemical Co.; Study No. K-002372-064, June 23, 1993. MRID 43293901. Document No. 011614. Unpublished. 

EXECUTIVE SUMMARY: In this chronic toxicity/carcinogenicity study with a chronic neurotoxicity screening battery substudy [MRID 43293901], 50 Fischer 344 rats/sex/group [main study]; 15/sex/group [substudy] were administered 2,4-dichlorophenoxyacetic acid [96.4%] via the diet for up to 24 months at concentrations of 0 [basal diet], 5 mg/kg/day, 75 mg/kg/day, and 150 mg/kg/day [achieved doses were 4.6, 71.2, and 141.1 mg/kg/day [males] and 4.6, 68.0, and 138.9 mg/kg/day [females], respectively. Additionally, 10 rats/sex/group were sacrificed at 12 months [interim sacrifice]. NOTE: This DER presents the results of the interim [one-year] sacrifice and neurotoxicity substudy.

There were no treatment-related deaths or clinical signs of toxicity. Decreased body weight was observed throughout the first year of the study at the high-dose level in both sexes [males 91%/females 88% of control at the interim sacrifice] and at the mid-dose level in females [94% of control at the interim sacrifice]. At 90 days, the decrease in body weight was very slight in the high-dose males [96% of control] and somewhat greater in the mid- [95% of control] and high-dose [90% of control] females. Body-weight gains were decreased throughout the first year at the mid- and high-dose levels in both sexes, although statistical significance was not always attained in males at the mid-dose level [2-week interval (males: mid-dose 90%/high-dose 84%; females: mid-dose 81%/high-dose 63% of control); 3-month interval (males: mid-dose 98%/high-dose 88%; females: mid-dose 87%/high-dose 75% of control); and 1-year interval (males: mid-dose 95%/high-dose 82%; females: mid-dose 89%/high-dose 73% of control). Consistent with the decreased body-weight gains was a slight decrease in food consumption, which was observed in both sexes at the high-dose level.

Ophthalmology findings were comparable among the groups at the interim sacrifice. Decreased RBC [mid- and high-dose females (6 & 12 months) and high-dose males (12 months)], HCT [mid- and high-dose females and high-dose  males (6 & 12 months)], HGB  [high-dose females (6 months)], WBC 9high-dose females (6 months)], and platelet counts [mid- and high-dose females and high-dose males (6 & 12 months) were observed. A dose-related increase in aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase was observed in the mid- and high-dose males at 6 months but not at 12 months. The mid- and high-dose females displayed a dose-related increase in alkaline phosphatase values at both the 6 and 12-month intervals. Cholesterol levels were decreased in the mid- (males at 12 months only) and high-dose rats of both sexes at both time intervals. T4 values were decreased at both time points in both sexes at the mid- and high-dose levels, although the mid-dose males at 6 months did not attain statistical significance. The only urinalysis finding was a decrease in specific gravity , which was observed in both sexes and time points at the mid- and high-dose levels.

Thyroid weights [absolute and relative] were statistically-significantly  increased in the mid-dose females [20% greater than control] and in both sexes at the high-dose level [20% greater than control] at the 12-month interim sacrifice. Decreased testes weights [absolute and relative to brain] were observed at the high-dose level at 12 months [15% lower than control]. Kidney weights [absolute and relative] were increased at the 12-months sacrifice in males at the mid- [7%-12% greater than control] and high-dose [8%-16% greater than control] levels [dose-related].

Gross pathology findings included decreased fat in high-dose females [4/10] and multifocal pale foci in the lungs [1/10 mid-dose, 10/10 high-dose females]. Microscopically, there were increased incidences of lesions in the bone marrow [decreased hematopoiesis in high-dose females], eyes [bilateral retina degeneration in 1 male and 10 females at high dose], kidney [proximal tubule degeneration in mid- and high-dose males and females], liver [altered tinctorial properties in mid-dose females and both sexes at high dose], lungs [multifocal , subacute to chronic inflammation (mid-dose females, both sexes at high dose), alveolar histiocytosis in females at high dose], adipose tissue [atrophy in mid- and high-dose females], testes [atrophy at high dose], and thyroid [decreased secretory material, epithelial cells-high-dose females].

The NOAEL is 5 mg/kg/day. The LOAEL of 75 mg/kg/day is based on decreased body weight (females)/body-weight gain (both sexes), alterations in hematology [decreased RBC, HCT, and platelets (females)], clinical chemistry parameters [increased alanine and aspartate aminotransferases (males), alkaline phosphatase (both sexes), decreased cholesterol (both sexes), and decreased T4 (both sexes)], and urinalysis [decreased specific gravity (both sexes)], increased kidney weights (males), increased incidence of degeneration of the descending proximal tubules (both sexes), hepatocellular hypertrophy with altered tinctorial properties (females), lung inflammation (females), adipose tissue atrophy (females). At the high-dose level, there also were microscopic lesions in the eyes (both sexes), liver (males), testes (males), thyroid (females), and lungs (males).

NEUROTOXICITY STUDY

No treatment-related, hand-held, FOB observations were noted at any of the evaluation periods. Relative forelimb grip strength was significantly increased in both sexes at the high-dose level, but there was no treatment-related change in absolute grip strength. There was no treatment-related effect on motor activity. In agreement with the chronic toxicity portion of the study, an increased incidence of bilateral retinal degeneration was observed in the high-dose females. 

The NOAEL for neurotoxicity is 75 mg/kg/day, based on increased relative forelimb grip strength and increased incidence of bilateral retinal degeneration at the LOAEL of 150 mg/kg/day. 

This chronic toxicity/neurotoxicity study in the rat is classified ACCEPTABLE/Guideline, and it satisfies the guideline requirement [OPPTS 870. 6200; §82-7] for a subchronic neurotoxicity study in the rat.
      

                     Table 1. Body-Weight/Body-Weight Gain

                            Parameter/Day/Sex/Dose

                                  0 mg/kg/day

                                  5 mg/kg/day

                                 75 mg/kg/day

                                 150 mg/kg/day

                                BODY WEIGHT [g]
                                     MALES
                                      -2
                                       6
                                      27
                                      90
                                      365
                                       
                                    FEMALES
                                      -2
                                       6
                                      27
                                      90
                                      365

                                       
                                       
                                  197.6+-11.5
                                  217.5+-13.1
                                  246.0+-15.9
                                  308.3+-22.1
                                  409.8+-28.5
                                       
                                       
                                  129.2+-4.9
                                  139.2+-5.6
                                  160.5+-7.4
                                  187.0+-9.1
                                  217.5+-10.9

                                       
                                       
                                  197.6+-9.9
                                  216.8+-12.0
                                  247.7+-13.9
                                  311.8+-20.0
                                  415.5+-23.5
                                       
                                       
                                  127.9+-5.6
                                  138.4+-5.6
                                  160.3+-7.6
                                  186.3+-8.6
                                  217.6+-12.4

                                       
                                       
                                  197.1+-9.2
                                  214.4+-11.1
                                  243.3+-14.6
                                  305.3+-20.4
                                  400.0+-30.2
                                       
                                       
                                126.6+-5.0*[98]
                                134.1+-5.7*[96]
                                151.1+-6.3*[94]
                                176.8+-8.0*[95]
                               205.6+-11.8*[95]

                                       
                                       
                                  197.8+-10.6
                                  213.5+-11.9
                               239.5+-14.6*[97]
                               295.2+-19.4*[96]
                               372.5+-26.6*[91]
                                       
                                       
                                126.2+-5.2*[98]
                                130.7+-5.1*[94]
                                145.8+-6.1*[91]
                                169.3+-7.3*[91]
                                190.7+-9.1*[88]

                             BODY-WEIGHT GAIN [g]
                                     MALES
                                     -2-6
                                     -2-13
                                     -2-90
                                    -2-365
                                       
                                    FEMALES
                                     -2-6
                                     -2-13
                                     -2-90
                                    -2-365

                                       
                                       
                                   19.9+-4.1
                                   33.0+-5.7
                                  110.7+-15.0
                                  212.2+-20.4
                                       
                                       
                                   10.0+-2.7
                                   17.5+-3.4
                                   57.8+-7.6
                                  88.3+-10.4

                                       
                                       
                                   19.2+-5.8
                                   33.3+-5.0
                                  114.3+-14.7
                                  217.9+-19.2
                                       
                                       
                                   10.5+-2.8
                                  19.1+-3.1*
                                   58.4+-6.5
                                  89.7+-10.7

                                       
                                       
                                17.3+-3.5*[87]
                                29.8+-6.4*[90]
                                  108.3+-14.6
                               202.4+-25.8*[95]
                                       
                                       
                                 7.5+-3.5*[75]
                                14.2+-3.3*[81]
                                50.2+-6.6*[87]
                                79.0+-10.6*[89]

                                       
                                       
                                15.7+-3.6*[79]
                                28.0+-5.6*[85]
                                97.4+-12.9*[88]
                               175.0+-20.5*[82]
                                       
                                       
                                 4.5+-3.7*[45]
                                11.0+-3.5*[63]
                                43.1+-5.9*[75]
                                64.5+-8.0*[73]
                         [% of control]; data from Tables 9-12 [pages 96-107] of the report

                   Table 2. Clinical Pathology Data - MALES

                             Dose/Month/Parameter

                                  0 mg/kg/day

                                  5 mg/kg/day

                                 75 mg/kg/day

                                 150 mg/kg/day

                            platelets [x10E3/cumm]
                                       6
                                      12

                                       
                                    615+-41
                                    586+-65

                                       
                                    613+-32
                                    598+-25

                                       
                                    604+-36
                                    572+-33

                                       
                                 529+-25*[86]
                                 474+-45*[81]

                               RBC[ x10E6/cumm]
                                       6
                                      12

                                       
                                  9.82+-0.35
                                  9.31+-0.28

                                       
                                  9.85+-0.30
                                  9.20+-0.22

                                       
                                  10.11+-0.26
                                  9.36+-0.19

                                       
                                  9.60+-0.34
                                8.55+-0.35*[92]

                                  HGB [g/dL]
                                       6
                                      12

                                       
                                   17.2+-0.5
                                   15.0+-0.5

                                       
                                   17.2+-0.6
                                   15.1+-0.3

                                       
                                   17.5+-0.5
                                   15.1+-0.3

                                       
                                   17.1+-0.4
                                   14.9+-0.7

                                    HCT {%}
                                       6
                                      12

                                       
                                   61.9+-2.2
                                   58.5+-1.8

                                       
                                   61.9+-2.1
                                   58.1+-1.5

                                       
                                   62.6+-1.7
                                   58.2+-1.2

                                       
                                59.3+-1.7*[86]
                                55.3+-2.7*[95]

                        alanine aminotransferase [U/L]
                                       6
                                      12

                                       
                                     65+-8
                                    66+-18

                                       
                                    63+-14
                                    61+-15

                                       
                                 120+-61*[185]
                                 91+-21*[138]

                                       
                                 122+-26*[188]
                                    68+-15

                       aspartate aminotransferase [U/L]
                                       6
                                      12

                                       
                                    116+-16
                                    106+-21

                                       
                                    111+-21
                                    95+-20

                                       
                                 162+-64*[140]
                                 132+-39 [125]

                                       
                                 172+-27*[148]
                                    103+-15

                          blood urea nitrogen [mg/dL]
                                       6
                                      12

                                       
                                     17+-1
                                     15+-2

                                       
                                     17+-1
                                  13+-1 [87]

                                       
                                     18+-1
                                     14+-2

                                       
                                     18+-3
                                  13+-1 [87]

                              creatinine [mg/dL]
                                       6
                                      12

                                       
                                   0.7+-0.0
                                   0.6+-0.0

                                       
                                   0.8+-0.1
                                   0.6+-0.0

                                       
                                   0.8+-0.1
                                0.7+-0.1*[117]

                                       
                                0.9+-0.1*[129]
                                0.7+-0.1*[117]

                          alkaline phosphatase [U/L]
                                       6
                                      12

                                       
                                     73+-7
                                     57+-4

                                       
                                     75+-7
                                     57+-5

                                       
                                 85+-11*[116]
                                     58+-6

                                       
                                  92+-9*[126]
                                     55+-7

                                glucose [mg/dL]
                                       6
                                      12

                                       
                                    112+-16
                                    117+-9

                                       
                                    116+-17
                                    124+-4

                                       
                                    108+-15
                                    111+-7

                                       
                                 102+-15 [91]
                                 100+-10*[85]

                              cholesterol [mg/dL]
                                       6
                                      12

                                       
                                    86+-10
                                    87+-17

                                       
                                     80+-3
                                    83+-11

                                       
                                    84+-10
                                  69+-11*[79]

                                       
                                  71+-8*[83]
                                  53+-6*[61]

                             triglycerides [mg/dL]
                                       6
                                      12

                                       
                                    140+-27
                                    101+-29

                                       
                                    139+-36
                                    105+-29

                                       
                                    171+-38
                                  89+-21 [88]

                                       
                                    129+-12
                                  70+-9*[69]
                             [% of control]; n=10; * p<0.05; 
                              data from Tables 15-16 [pages 112-115] and Tables23-26 [pages 128-144] of the report  

                  Table 3. Clinical Pathology Data - FEMALES

                             Dose/Month/Parameter

                                  0 mg/kg/day

                                  5 mg/kg/day

                                 75 mg/kg/day

                                 150 mg/kg/day

                            platelets [x10E3/cumm]]
                                       6
                                      12
                                      18
                                      24

                                       
                                    599+-39
                                    583+-23
                                    591+-40
                                    562+-92

                                       
                                    609+-44
                                 548+-120 [94]
                                    613+-47
                                   549+-139

                                       
                                 461+-30*[77]
                                 471+-48*[81]
                                 496+-33*[84]
                                   551+-130

                                       
                                 403+-30*[67]
                                 486+-44*[84]
                                 491+-33*[83]
                                 523+-135 [93]

                               RBC[ x10E6/cumm]
                                       6
                                      12
                                      18
                                      24

                                       
                                  9.11+-0.21
                                  8.37+-0.29
                                  8.61+-0.18
                                  8.28+-1.60

                                       
                                  9.05+-0.22
                                  8.46+-0.50
                                  8.41+-0.21
                                7.91+-1.53 [96]

                                       
                                8.71+-0.16*[96]
                                7.78+-0.48*[93]
                                7.83+-0.93*[91]
                                7.44+-1.49*[90]

                                       
                                  8.22+-0.28
                                  7.59+-0.25
                                7.61+-0.25*[88]
                                7.01+-1.77*[85]

                                  HGB [g/dL]
                                       6
                                      12
                                      18
                                      24

                                       
                                   17.2+-0.3
                                   14.8+-0.4
                                   16.1+-0.3
                                   14.7+-2.6

                                       
                                   17.1+-0.3
                                   15.0+-0.9
                                15.8+-0.3*[98]
                                   14.6+-1.9

                                       
                                   16.9+-0.4
                                   14.4+-0.9
                                14.8+-2.1*[92]
                                 13.9+-2.3[95]

                                       
                                16.6+-0.4*[97]
                                   14.5+-0.6
                                14.9+-0.3*[93]
                                13.3+-3.0 [90]

                                  HCT [&]
                                       6
                                      12
                                      18
                                      24

                                       
                                   60.6+-1.2
                                   57.3+-1.9
                                   46.8+-1.2
                                   43.6+-7.6

                                       
                                   60.3+-2.0
                                   57.7+-3.4
                                   xx.5+-0.9
                                   43.6+-4.3

                                       
                                58.4+-1.2*[96]
                                52.6+-3.1*[92]
                                   44.0+-4.4
                                41.6+-6.4 [95]

                                       
                                55.9+-2.3*[92]
                                51.8+-2.2*[90]
                                43.5+-1.4*[93]
                                40.9+-6.5 [94]

                        alanine aminotransferase [U/L]
                                       6
                                      12
                                      18
                                      24

                                       
                                     51+-8
                                    37+-10
                                     42+-8
                                    48+-28

                                       
                                    50+-19
                                    42+-20
                                     40+-5
                                    50+-28

                                       
                                    56+-16
                                     37+-8
                                    34+-12
                                    61+-78

                                       
                                    40+-6*
                                    33+-10
                                     36+-4
                                    55+-62

                       aspartate aminotransferase [U/L]
                                       6
                                      12
                                      18
                                      24

                                       
                                    96+-11
                                    71+-15
                                    80+-15
                                    92+-60

                                       
                                    101+-35
                                    80+-34
                                    70+-12
                                   105+-110

                                       
                                    103+-14
                                    63+-10
                                     72+-8
                                136+-291 [148]

                                       
                                    98+-13
                                    68+-16
                                     81+-9
                                134+-216 [146]

                          blood urea nitrogen [mg/dL]
                                       6
                                      12
                                      18
                                      24

                                       
                                     20+-3
                                     14+-1
                                     20+-1
                                    20+-10

                                       
                                     20+-3
                                     14+-1
                                     18+-2
                                     16+-2

                                       
                                     21+-3
                                     15+-2
                                     21+-3
                                     20+-6

                                       
                                     21+-2
                                     13+-2
                                     19+-2
                                    25+-28

                              creatinine [mg/dL]
                                       6
                                      12
                                      18
                                      24

                                       
                                   0.8+-0.1
                                   0.7+-0.1
                                   0.7+-0.0
                                   0.7+-0.1

                                       
                                   0.8+-0.1
                                   0.7+-0.1
                                   0.7+-0.0*
                                   0.7+-0.0

                                       
                                0.9+-0.1*[113]
                                0.8+-0.1*[114]
                                0.9+-0.0*[129]
                                0.8+-0.1*[114]

                                       
                                0.9+-0.1*[113]
                                   0.7+-0.0*
                                0.9+-0.1*[129]
                                0.8+-0.1*[114]

                          alkaline phosphatase [U/L]
                                       6
                                      12
                                      18
                                      24

                                       
                                     47+-9
                                     32+-3
                                     37+-5
                                    47+-28

                                       
                                     46+-4
                                     32+-6
                                    40+-10
                                    63+-50

                                       
                                  59+-7*[126]
                                  47+-8*[147]
                                 69+-48*[186]
                                 84+-77*[179]

                                       
                                 73+-16*[155]
                                 54+-10*[169]
                                 76+-18*[205]
                                 99+-52*[211]

                                glucose [mg/dL]
                                       6
                                      12
                                      18
                                      24

                                       
                                    96+-12
                                    109+-8
                                     97+-6
                                    94+-18

                                       
                                    96+-10
                                    114+-10
                                    103+-10
                                    94+-11

                                       
                                  88+-9 [92]
                                    112+-9
                                  86+-11*[89]
                                  82+-18*[87]

                                       
                                   72+-8[75]
                                    113+-11
                                  79+-6*[81]
                                  77+-11*[82]

                              cholesterol [mg/dL]
                                       6
                                      12
                                      18
                                      24

                                       
                                    116+-11
                                    105+-13
                                    155+-9
                                    169+-38

                                       
                                    123+-5
                                    110+-16
                                    148+-14
                                    166+-29

                                       
                                  81+-6*[70]
                                  54+-7*[51]
                                  76+-11*[49]
                                 104+-57*[62]

                                       
                                  76+-8*[66]
                                  57+-7*[54]
                                  81+-4*[52]
                                 109+-36*[64]

                             triglycerides [mg/dL]
                                       6
                                      12
                                      18
                                      24

                                       
                                    77+-14
                                     52+-8
                                    136+-46
                                    183+-85

                                       
                                    88+-22
                                    56+-18
                                    129+-34
                                    180+-98

                                       
                                    88+-16
                                     54+-6
                                  93+-14*[68]
                                 126+-52*[69]

                                       
                                     83+-6
                                     56+-4
                                  88+-14*[65]
                                 105+-21*[57]
                             [% of control]; n=10 [6, 12, 18 months]/n=20 [24 months]; * p<0.05; 
                               data from Tables 15-16 [pages 112-115] and Tables23-26 [pages 128-144] of the report  

                         Table 4.  T4 Results [ug/dL]

                                Dose/Sex/Month

                                  0 mg/kg/day

                                  5 mg/kg/day

                                 75 mg/kg/day

                                 150 mg/kg/day

                                     MALES
                                       6
                                      12

                                       
                                   3.2+-0.5
                                   3.0+-0.4

                                       
                                   3.4+-0.6
                                   3.1+-0.3

                                       
                                 2.7+-0.2 [84]
                                 2.6+-0.3*[87]

                                       
                                 2.1+-0.9*[66]
                                 0.9+-0.2*[30]

                                   FE MALES
                                       6
                                      12

                                       
                                   2.6+-0.5
                                   2.3+-0.4

                                       
                                   2.7+-0.4
                                   2.2+-0.4

                                       
                                 1.1+-0.3*[42]
                                 0.8+-0.2*[35]

                                       
                                 0.9+-0.2*[35]
                                 0.7+-0.2*[30]
                       [% of control]; n=10 [6, 12, 18 months]/n=20 [24 months]; * p<0.05; data from  Tables 27-28 [pages 136-139] of the report     

                Table 5. Organ Weight Data - MALES [12 months]

                                  Dose/Organ

                                  0 mg/kg/day

                                  5 mg/kg/day

                                 75 mg/kg/day

                                 150 mg/kg/day

                                     brain
                                 absolute [g]
                           relative-to-body [g/100]

                                       
                                 2.039+-0.105
                                 0.536+-0.016

                                       
                                 2.000+-0.066
                                 0.515+-0.017

                                       
                                 2.025+-0.062
                                 0.557+-0.040

                                       
                               1.988+-0.095 [97]
                                 0.056+-0.031

                                     liver
                                 absolute [g]
                           relative-to-body [g/100]
                           relative-to-brain [g/100]

                                       
                                 9.508+-0.662
                                 2.496+-0.062
                                 466.26+-19.50

                                       
                                 9.630+-0.661
                                 2.476+-0.111
                                 481.45+-30.38

                                       
                               8.543+-0.677*[90]
                               2.338+-0.080*[94]
                              421.69+-28.47*[90]

                                       
                                 8.942+-0.370
                                 2.520+-0.125
                                 450.74+-30.15

                                    kidney
                                 absolute [g]
                           relative-to-body [g/100]
                           relative-to-brain [g/100]

                                       
                                 2.231+-0.105
                                 0.586+-0.019
                                 109.47+-3.49

                                       
                                 2.255+-0.111
                                 0.580+-0.017
                                 112.75+-4.24

                                       
                              2.391+-0.150*[107]
                              0.655+-0.026*[112]
                              118.09+-6.45*[108]

                                       
                              2.409+-0.125*[108]
                              0.678+-0.013*[116]
                              121.32+-6.73*[111]

                                    testes
                                 absolute [g]
                           relative-to-body [g/100]
                           relative-to-brain [g/100]

                                       
                                 3.158+-0.293
                                 0.832+-0.092
                                 155.10+-14.49

                                       
                                 3.247+-0.128
                                 0.836+-0.032
                                 162.35+-5.67

                                       
                                 3.198+-0.193
                                 0.877+-0.052
                                 157.96+-8.63

                                       
                               2.669+-0.540*[85]
                               0.748+-0.139 [90]
                              134.09+-26.32*[86]

                                    thyroid
                                 absolute [g]
                           relative-to-body [g/100]
                           relative-to-brain [g/100]

                                       
                                 0.027+-0.002
                                0.0071+-0.0006
                                1.3178+-0.1091

                                       
                                 0.025+-0.002
                                0.0064+-0.0006
                                1.2517+-0.1068

                                       
                                 0.026+-0.003
                                0.0070+-0.0006
                                1.2582+-0.1198

                                       
                              0.032+-0.003*[119]
                             0.0091+-0.0009*[128]
                             1.6308+-0.1805*[124]

                           terminal body weight [g]

                                  380.8+-21.9

                                  388.6+-14.8

                                  365.5+-28.3

                               355.4+-18.8*[93]
                               [% of control]; n=10; * p<0.05; data from Tables 27-28 [pages 136-139] of the report 
      

               Table 6. Organ Weight Data - FEMALES [12 months]

                                  Dose/Organ

                                  0 mg/kg/day

                                  5 mg/kg/day

                                 75 mg/kg/day

                                 150 mg/kg/day

                                     brain
                                 absolute [g]
                           relative-to-body [g/100]

                                       
                                 1.833+-0.058
                                 0.926+-0.037

                                       
                                 1.852+-0.051
                                 0.887+-0.045

                                       
                                 1.837+-0.049
                                 0.942+-0.060

                                       
                                 1.796+-0.056
                            1.013+-0.056*[109]    

                                     liver
                                 absolute [g]
                           relative-to-body [g/100]
                           relative-to-brain [g/100]

                                       
                                 5.294+-0.350
                                 2.673+-0.154
                                 288.80+-15.35

                                       
                                 5.560+-0.418
                                 2.655+-0.125
                                 300.34+-23.66

                                       
                                 5.354+-0.445
                                 2.735+-0.118
                                 291.59+-24.39

                                       
                                 5.499+-0.422
                              3.094+-0.171*[116]
                              305.97+-19.45 [106]

                                    kidney
                                 absolute [g]
                           relative-to-body [g/100]
                           relative-to-brain [g/100]

                                       
                                 1.440+-0.069
                                 0.727+-0.029
                                  78.55+-2.53

                                       
                                 1.481+-0.112
                                 0.708+-0.041
                                  80.05+-6.75

                                       
                                 1.558+-0.092
                              0.797+-0.036*[110]
                               84.89+-5.60 [108]

                                       
                              1.544+-0.148 [107]
                              0.868+-0.061*[119]
                               85.94+-7.63*[109]

                                    ovaries
                                 absolute [g]
                           relative-to-body [g/100]
                           relative-to-brain [g/100]

                                       
                                 0.057+-0.013
                                 0.029+-0.006
                                  3.11+-0.70

                                       
                                 0.056+-0.012
                                 0.027+-0.005
                                  3.03+-0.64

                                       
                                 0.058+-0.005
                                 0.029+-0.003
                                  3.13+-0.24

                                       
                               0.052+-0.009 [91]
                                 0.029+-0.005
                                2.87+-0.44 [92]

                                    thyroid
                                 absolute [g]
                           relative-to-body [g/100]
                           relative-to-brain [g/100]

                                       
                                 0.018+-0.001
                                0.0093+-0.0008
                                1.0052+-0.0872

                                       
                                 0.019+-0.002
                                0.0091+-0.0010
                                1.0276+-0.1280

                                       
                              0.022+-0.001*[122]
                             0.0111+-0.0006*[119]
                             1.1816+-0.0659*[118]

                                       
                              0.022+-0.003*[122]
                             0.0126+-0.0012*[135]
                             1.2463+-0.1265*[124]

                           terminal body weight [g]

                                  198.2+-10.5

                                  209.3+-10.5

                                  195.7+-13.1

                                177.7+-9.8*[90]
                               [% of control];* p<0.05; n=10; data from  Tables 27-28 [pages 136-139] of the report