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Repeated dose toxicity: dermal

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Administrative data

Endpoint:
sub-chronic toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2003
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Cross-reference
Reason / purpose:
reference to same study
Reference
Endpoint:
sub-chronic toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Dec 2002 - Mar 2003
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Qualifier:
according to
Guideline:
other: According to the standard protocol posted on the NTP website 
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 411 (Subchronic Dermal Toxicity: 90-Day Study)
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Type of coverage:
open
Vehicle:
other: 95 % Ethanol in deionized water (1:1, v/v)
Details on exposure:
Treatment: After a 10- to 14-day quarantine period, animals are assigned at random  to treatment groups. The study includes five treatment groups each  administered a different concentrations of the test chemicals plus a  control group. Each group contains 10 animals per sex per species. The  animals receive the subject chemical by dermal route of exposure.  Controls receive vehicle alone. Animals are exposed five times per week,  weekdays only, for 90 days after which they are sacrificed with no  recovery period. All animals are housed individually. 
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
five times per week
Dose / conc.:
11.25 mg/kg bw/day (actual dose received)
Dose / conc.:
22.5 mg/kg bw/day (actual dose received)
Dose / conc.:
45 mg/kg bw/day (actual dose received)
Dose / conc.:
90 mg/kg bw/day (actual dose received)
Dose / conc.:
180 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Details on study design:
Post-exposure period: none
Positive control:
not appropriate
Observations and examinations performed and frequency:
BODY WEIGHT: Yes
Animals are weighed individually on day one on test, after seven days,  and at weekly periods thereafter. 

DETAILED CLINICAL OBSERVATIONS: Yes
Animals are observed twice daily, at  least six hours apart (before 10:00 AM and after 2:00 PM), including  holidays and weekends, for moribundity and death. Animals found moribund  or showing clinical signs of pain or distress are humanely euthanized.  Formal clinical observations are performed and recorded weekly. 

HAEMATOLOGY AND CLINICAL CHEMISTRY: Yes
Blood is collected from both sexes of "special study" rats, at days 4 and  22 and from the core study rats at the end of the study. These are  processed for haematology and clinical chemistry determinations. Blood is  collected from core study mice at the end of the study for haematology  determinations.

-Haematology:
Erythrocyte count,  Mean corpuscular volume,  Haemoglobin,  Packed cell volume,  Mean corpuscular haemoglobin,  Mean corpuscular haemoglobin concentration,  Erythrocyte morphologic assessment,  Leukocyte count,  Leukocyte differential,  Reticulocyte count,  Platelet count and morphologic assessment 
-Clinical chemistry:
Sorbitol dehydrogenase (SDH),  Alkaline Phosphatase (ALP),  Creatine Kinase (CK),  Creatinine,  Total Protein,  Albumin,  Urea Nitrogen (BUN),  Total Bile Acids,  Alanine Aminotransferase (ALT)

OTHER:
Sperm Morphology and Vaginal Cytology Evaluations (SMVCE) (see section  7.8.3): SMVCE are conducted on core study rats and mice. Mortality, body weight  changes and clinical signs of toxicity are used to determine the 3 dose  levels used for the SMVCE evaluations.
Sacrifice and pathology:
GROSS PATHOLOGY AND HISTOPATHOLOGY
Organ weights:  Liver, thymus, right kidney, right testis, heart, and lungs weights are  recorded from all animals surviving until the end of the study. 
A complete necropsy is performed on all treated and control animals that  either die or are sacrificed. All tissues required for complete  histopathology are trimmed, embedded, sectioned and stained with  hematoxylin and eosin for histopathologic evaluation.

HISTOPATHOLOGY:
A complete histopathologic evaluation inclusive of gross lesions is done  on all control animals, all animals in the highest dose group with at  least 60% survivors at the time of sacrifice, and all animals in higher  dose groups inclusive of early deaths and survivors. Chemical-related  lesions (target organs) are identified, and these organs plus gross  lesions are examined for all lower doses. Only those tissues designated  as target tissues and gross lesions are evaluated in lower doses to a  no-effect-level. A complete histopathologic evaluation is performed on  all natural death/moribund sacrifice animals in lower dose groups.

Tissues examined histopathologically:  Adrenal glands,  Brain (3 sections including frontal cortex and basal ganglia, parietal  cortex and thalamus, and cerebellum and pons), Clitoral glands,  Esophagus,  Eyes,  Femur, including diaphysis with marrow cavity and epiphysis (femoral  condyle with epiphyseal cartilage plate, articular cartilage and  articular surface),  Gallbladder (mouse),  Gross lesions,  Harderian glands,  Heart and aorta,  Intestine, large (cecum, colon, rectum),  Intestine, small (duodenum, jejunum, ileum), Kidneys,  Liver (2 sections including left lateral lobe and median lobe),  Lungs and mainstem bronchi,  Lymph nodes  - mandibular and mesenteric - inguinal, gluteal, internal iliac (chronic studies only, if lesion  observed, not merely discolouration),  Mammary gland with adjacent skin,  Muscle, thigh (only if neuromuscularsigns were present),  Nasal cavity and nasal turbinates (3 sections),  Ovaries,  Pancreas,  Parathyroid glands,  Pituitary gland,  Preputial glands,  Prostate,  Salivary glands,  Seminal vesicle,  Skin: site of application (topical studies),  Spinal cord and sciatic nerve (if neurologic signs were present),  Spleen, Stomach (forestomach and glandular),  Testes with epididymus,  Thymus,  Thyroid glands,  Tissue masses and regional lymph nodes,  Trachea,  Urinary bladder,  Uterus


Statistics:
yes
Clinical signs:
no effects observed
Dermal irritation:
effects observed, treatment-related
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
not examined
Details on results:
1.Survival
All Core Study male and female rats survived until terminal sacrifice.

2.Clinical observations
Significant observations noted in both sexes were limited to dermal  irritation at the site of application (SOA), thickened skin at the SOA  and ulcerations at the SOA.
In the males, the incidence of dermal irritation at the SOA was 10/10 for  all five test article treatment groups. Thickening of the skin at the SOA  was observed in 1/10 and 2/10 rats from the 90.0 and 180.0 mg/kg dose  groups, respectively. Ulceration at the SOA was observed in 1/10, 1/10,  5/10 and 8/10 rats from the 11.25, 22.5, 90.0 and 180.0 mg/kg dose  groups, respectively. All other observations noted during the study were  not considered to be biologically significant.
In the females, the incidence of dermal irritation at the SOA was also  10/10 for all five treatment groups. Thickening of the skin at the SOA  was observed in 3/10 rats from the 45.0 mg/kg dose group and in 10/10  rats each from the 90.0 and 180.0 mg/kg dose groups. Ulceration at the  SOA was observed in 10/10 rats from each of the 90.0 and 180.0 mg/kg dose  groups. All other observations noted during the study were not considered  to be biologically significant.

3.Body Weights
Statistical analysis of the Core Study final (terminal) body weights  revealed statistically significant (p<0.05) decreased values in the male  group treated with 90.0 mg/kg when compared to the vehicle control. No  statistically significant differences in body weights were noted for the  female rats when the test article groups were compared to the vehicle  control group.

4.Organ Weights
a.Absolute Organ Weights
The absolute liver weights of the male rats treated with 45.0 mg/kg were significantly (+10%; p<=0.05) increased when compared to the vehicle  control group. There were no other statistically significant differences  in any other absolute organ weights in the male rats. There were no  statistically significant differences in any absolute organ weights in  the female rats.

b.Organ to Body Weight Ratios
The relative kidney and testes weights of the male rats treated with 90.0  (+7.6% and 6.7%, respectively) and 180.0 mg/kg (+8.2 and 7.6%,  respectively) were significantly (p<=0.05) increased when compared to the  vehicle control group. The relative liver weights for the male rats  treated with 45.0 mg/kg were significantly (+8.5%; p<=0.05) increased  when compared to the vehicle control group. The relative spleen weights  of the male rats treated with 90.0 mg/kg were significantly (+6.0%;  p<=0.05) increased when compared to the vehicle control group. The  relative kidney weights of the female rats treated with 180.0 mg/kg were  significantly (+6.6%; p<=0.05) increased when compared to the vehicle  control group. The relative thyroid/parathyroid weights of the female  rats treated with 22.5 mg/kg were significantly (-20%; p<=0.05) decreased  when compared to the vehicle control group. There were no other  statistically significant differences in any relative organ weight for  the male or female rats.

5.Clinical Pathology
There were limited statistically significant (p<0.05) differences in the  chemistry and haematology results when compared to the control group, but  these were not dose responsive nor considered to be biologically  significant.

6.Anatomic Pathology
a.Gross Lesions
For the males, abnormal gross necropsy findings were limited to skin  accumulation (no mass noted) at the SOA in 1/10 rats from the 11.25, 45.0  and 180.0 mg/kg dose groups, a nodule on the thoracic inlet of the  thoracic cavity in 1/10 rats from both the 11.25 and 22.5 mg/kg dose  groups, a mass on the median lobe of the liver in 1/10 rats from the  180.0 mg/kg dose group and a nodule on the liver in 1/10 rats from the  22.5 mg/kg dose group. In addition, one male from the 180.0 mg/kg dose  group had retained the right testis in its abdominal region. There were  no other significant abnormal gross lesions noted in any of the male  treatment groups. These findings were not considered to be test article  related or biologically significant.
For the females, abnormal gross necropsy findings were limited in number.  In the vehicle control group, one female rat was noted as having a focus  on the left kidney. In the 11.25 mg/kg test article treatment group, four  females were noted as having a nodule on the liver, one with a nodule on  the pancreas, one rat with a nodule on the thoracic cavity and one rat  with dilated uterine horns: One rat from the 22.5 mg/kg dose group had a  cyst on the left ovary. There were two and three rats from the 45.0 and  90.0 mg/kg treatment groups, respectively, noted as having a nodule on  the liver. In the high dose treatment group (180.0 mg/kg), there were two  animals with nodules on the liver, two animals with nodules in the  thoracic cavity, one rat with enlarged mediastinal lymph nodes and one  rat with dilated uterine horns. These findings were not considered to be  test article related or biologically significant. Findings which may be  contributed to the treatment of NaT were limited to the 180.0 mg/kg  treatment group where three rats were noted as having an irritation on  the SOA.

b.Microscopic Pathology Repeated dermal administration of Sodium Thioglycolate (NaT) for thirteen  weeks (excluding weekends) resulted in test article related microscopic  changes at the site of application (SOA) in both male and female rats at  all treatment doses. Changes in the skin SOA revealed minimal to mild  hyperplasia of the epidermis accompanied, in many animals, by sebaceous  gland hyperplasia and hyperkeratosis. The severity of the changes was  comparable between all treatment groups in both the male and female rats.  A NOEL was not reached in female or male rats.

Microscopic evaluation of the other tissues required by the protocol  revealed a few findings which were observed either in small numbers  and/or in both control and treated animals. And, all of these changes are  commonly observed in F344 rats. For these reasons, these changes were  considered incidental findings.
[NOTE: The pathologist used the following criteria for severity scoring  of the epidermal hyperplasia; minimal 2-3 cell layers thick, mild 4-6  cell layers thick, moderate 7-8 cell layers thick and marked >9 cell  layers thick (at the thickest point).]
Key result
Dose descriptor:
NOAEL
Remarks:
systemic toxicity
Effect level:
>= 180 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Remarks on result:
not determinable due to absence of adverse toxic effects
Key result
Dose descriptor:
LOAEL
Remarks:
Local effects
Effect level:
11.25 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
dermal irritation
Key result
Critical effects observed:
no

Female rats organ weight summary table

Dose Group (mg/kg)

Body Wt (Sac)(g)

Heart Wt (g)

%Heart/Body

Liver Wt (g)

%Liver/Body

Lung Wt (g)

%Lungs/Body

R Kidney Wt (g)

%R Kidney/Body

Spleen Wt (g)

%Spleen/Body

Thyroid Wt (g)

%Thyroid/Body

Day 93

 

 

 

 

 

 

 

 

 

 

 

 

 

0         

177.3 ± 2.98

0.65 ± 0.013

0.37 ± 0.004

5.60 ± 0.173

3.16 ± 0.068

1.053 ± 0.0289

0.59 ± 0.008

0.70 ± 0.014

0.392 ± 0.0041

0.44 ± 0.007

0.25 ± 0.002

0.026 ± 0.0009

0.014 ± 0.0006

11.25      

185.4 ± 2.56

0.65 ± 0.016

0.35 ± 0.005

5.59 ± 0.123

3.01 ± 0.048

1.001 ± 0.0427

0.54 ± 0.020

0.73 ± 0.009

0.391 ± 0.0025

0.45 ± 0.009

0.24 ± 0.004

0.026 ± 0.0010

0.014 ± 0.0006

22.5       

184.5 ± 2.74

0.66 ± 0.008

0.36 ± 0.007

6.04 ± 0.156

3.27 ± 0.057

0.978 ± 0.0219

0.53 ± 0.010

0.72 ± 0.010

0.389 ± 0.0044

0.44 ± 0.006

0.24 ± 0.004

0.023 ± 0.0007

0.012 ± 0.0004

45         

185.9 ± 2.75

0.65 ± 0.011

0.35 ± 0.004

5.90 ± 0.153

3.17 ± 0.048

1.101 ± 0.0468

0.59 ± 0.027

0.72 ± 0.020

0.389 ± 0.0086

0.45 ± 0.012

0.24 ± 0.005

0.024 ± 0.0013

0.013 ± 0.0007

90         

179.9 ± 3.54

0.67 ± 0.016

0.37 ± 0.008

5.94 ± 0.141

3.31 ± 0.066

1.059 ± 0.0414

0.59 ± 0.018

0.75 ± 0.021

0.415 ± 0.0090

0.44 ± 0.012

0.25 ± 0.007

0.026 ± 0.0009

Organ Weights Summary Table in male rats

(Mean ± SEM)

Dose Group (mg/kg)

Body Wt (Sac)(g)

Heart Wt (g)

%Heart/Body

Liver Wt (g)

%Liver/Body

Lung Wt (g)

%Lungs/Body

R Kidney Wt (g)

%R Kidney/Body

R Testis Wt (g)

%R Testis/Body

Spleen Wt (g)

%Spleen/Body

Thyroid Wt (g)

%Thyroid/Body

Day 93

0         

334.5 ± 3.86

0.97 ± 0.014

0.29 ± 0.003

11.22 ± 0.270

3.35 ± 0.048

1.532 ± 0.0627

0.46 ± 0.019

1.14 ± 0.021

0.340 ± 0.0044

1.442 ± 0.0248

0.432 ± 0.0089

0.72 ± 0.010

0.21 ± 0.002

0.026 ± 0.0015

0.008 ± 0.0004

11.25      

333.7 ± 4.16

0.98 ± 0.022

0.29 ± 0.005

11.90 ± 0.264

3.57 ± 0.062

1.502 ± 0.0512

0.45 ± 0.014

1.20 ± 0.026

0.359 ± 0.0065

1.468 ± 0.0227

0.440 ± 0.0042

0.72 ± 0.012

0.21 ± 0.003

0.026 ± 0.0010

0.008 ± 0.0004

22.5       

332.0 ± 7.07

0.95 ± 0.018

0.29 ± 0.004

11.71 ± 0.341

3.52 ± 0.062

1.541 ± 0.0849

0.46 ± 0.019

1.17 ± 0.024

0.352 ± 0.0054

1.386 ± 0.0247

0.418 ± 0.0075

0.72 ± 0.017

0.22 ± 0.004

0.027 ± 0.0011

0.008 ± 0.0004

45         

339.4 ± 4.77

0.97 ± 0.010

0.29 ± 0.003

12.36 ± 0.292

3.64 ± 0.046

1.518 ± 0.0535

0.45 ± 0.016

1.18 ± 0.019

0.348 ± 0.0053

1.419 ± 0.0286

0.418 ± 0.0067

0.72 ± 0.016

0.21 ± 0.003

0.030 ± 0.0049

0.009 ± 0.0014

90         

312.1 ± 8.54

0.95 ± 0.023

0.31 ± 0.005

10.46 ± 0.349

3.35 ± 0.074

1.451 ± 0.0448

0.47 ± 0.012

1.14 ± 0.023

0.366 ± 0.0041

1.435 ± 0.0300

0.461 ± 0.0082

0.71 ± 0.016

0.23 ± 0.004

0.028 ± 0.0018

0.009 ± 0.0007

180         

319.3 ± 5.89

0.93 ± 0.019

0.29 ± 0.004

11.26 ± 0.261

3.53 ± 0.066

1.497 ± 0.0268

0.47 ± 0.008

1.17 ± 0.024

0.368 ± 0.0048

1.482 ± 0.0282

0.465 ± 0.0081

0.72 ± 0.016

0.23 ± 0.003

0.027 ± 0.0011

0.008 ± 0.0004

Hematology Summary Table in male rats

(Mean ± SEM)

Dose Group (mg/kg)

Erythrcyt (10^6/uL)

Hgb (g/dL)

HCT (Automated) (%)

MCV (fL)

MCH (pg)

MCHC (g/dL)

Retics (10^6/uL)

Platelet (10^3/uL)

Leukocytes (10^3/uL)

Neut (10^3/uL)

Lymph (10^3/uL)

Mono (10^3/uL)

EOS (10^3/uL)

Basophils (10^3/uL)

Day 4

0         

6.79 ± 0.115

13.40 ± 0.228

40.3 ± 0.70

59.25 ± 0.250

19.71 ± 0.058

33.25 ± 0.033

6.790 ± 6.3157

594.38 ± 26.679

10.613 ± 0.6269

1.18 ± 0.065

8.550 ± 0.5125

0.645 ± 0.0619

0.034 ± 0.0032

0.228 ± 0.0272

11.25      

6.87 ± 0.099

13.53 ± 0.175

40.8 ± 0.53

59.44 ± 0.294

19.72 ± 0.101

33.18 ± 0.086

0.540 ± 0.0181

560.00 ± 39.746

9.267 ± 0.5191

1.03 ± 0.084

7.437 ± 0.3901

0.580 ± 0.0488

0.022 ± 0.0036

0.189 ± 0.0182

22.5       

6.70 ± 0.062

13.18 ± 0.122

39.7 ± 0.39

59.22 ± 0.324

19.64 ± 0.053

33.21 ± 0.090

0.526 ± 0.0253

530.56 ± 25.532

10.133 ± 0.4269

1.17 ± 0.075

8.011 ± 0.4151

0.614 ± 0.0411

0.047 ± 0.0231

0.289 ± 0.0648

45         

6.75 ± 0.088

13.21 ± 0.193

39.7 ± 0.55

58.78 ± 0.222

19.58 ± 0.092

33.23 ± 0.078

0.526 ± 0.0233

591.00 ± 15.200

9.467 ± 0.4304

1.05 ± 0.053

7.679 ± 0.3323

0.550 ± 0.0610

0.027 ± 0.0041

0.183 ± 0.0213

90         

6.62 ± 0.131

12.99 ± 0.231

39.1 ± 0.74

59.11 ± 0.200

19.64 ± 0.071

33.28 ± 0.072

0.454 ± 0.0250

561.78 ± 30.219

10.333 ± 0.6727

1.13 ± 0.068

8.326 ± 0.5376

0.620 ± 0.0624

0.032 ± 0.0066

0.224 ± 0.0306

180         

6.90 ± 0.127

13.55 ± 0.257

41.0 ± 0.76

59.38 ± 0.183

19.68 ± 0.067

33.15 ± 0.060

0.528 ± 0.0228

569.50 ± 29.019

10.788 ± 0.4951

1.33 ± 0.189

8.556 ± 0.4194

0.689 ± 0.0282

0.025 ± 0.0038

0.203 ± 0.0230

Day 22

0         

7.71 ± 0.209

15.18 ± 0.393

45.6 ± 1.20

59.11 ± 0.200

19.72 ± 0.060

33.32 ± 0.064

0.297 ± 0.0262

522.44 ± 36.472

15.089 ± 2.0608

1.27 ± 0.142

12.442 ± 1.7536

0.987 ± 0.1496

0.048 ± 0.0092

0.323 ± 0.0401

11.25      

7.42 ± 0.086

14.63 ± 0.169

43.9 ± 0.53

59.20 ± 0.200

19.73 ± 0.091

33.34 ± 0.079

0.307 ± 0.0153

563.70 ± 18.524

15.520 ± 3.0618

1.47 ± 0.262

12.694 ± 2.5321

0.905 ± 0.2006

0.059 ± 0.0109

0.390 ± 0.0828

22.5       

7.45 ± 0.151

14.68 ± 0.286

44.1 ± 0.91

58.90 ± 0.180

19.72 ± 0.053

33.36 ± 0.083

0.278 ± 0.0182

534.10 ± 31.043

18.050 ± 3.1819

1.60 ± 0.247

14.848 ± 2.6952

1.090 ± 0.1804

0.073 ± 0.0133

0.456 ± 0.0953

45         

7.45 ± 0.082

14.72 ± 0.113

44.2 ± 0.36

59.30 ± 0.213

19.78 ± 0.088

33.36 ± 0.072

0.318 ± 0.0104

512.30 ± 20.314

16.740 ± 4.6934

1.61 ± 0.472

13.853 ± 4.0386

0.785 ± 0.1583

0.059 ± 0.0135

0.443 ± 0.1542

90         

7.54 ± 0.108

14.87 ± 0.192

44.6 ± 0.56

59.30 ± 0.153

19.73 ± 0.075

33.37 ± 0.079

0.301 ± 0.0120

545.30 ± 14.062

14.410 ± 2.2688

1.42 ± 0.206

11.944 ± 1.9392

0.714 ± 0.0967

0.056 ± 0.0120

0.287 ± 0.0404

180         

7.38 ± 0.103

14.58 ± 0.208

43.8 ± 0.64

59.30 ± 0.213

19.78 ± 0.090

33.32 ± 0.076

0.301 ± 0.0197

519.00 ± 17.491

16.770 ± 3.2436

1.47 ± 0.265

14.046 ± 2.7995

0.885 ± 0.1514

0.039 ± 0.0071

0.346 ± 0.0533

Day 93

0         

9.13 ± 0.056

15.66 ± 0.130

45.3 ± 0.34

49.70 ± 0.213

17.17 ± 0.062

34.54 ± 0.078

0.200 ± 0.0114

511.60 ± 13.123

10.910 ± 0.3854

2.88 ± 0.178

7.087 ± 0.2720

0.591 ± 0.0522

0.122 ± 0.0087

0.228 ± 0.0256

11.25      

9.10 ± 0.105

15.62 ± 0.197

45.1 ± 0.55

49.40 ± 0.163

17.18 ± 0.057

34.64 ± 0.075

0.216 ± 0.0170

503.60 ± 12.751

11.080 ± 0.3797

3.03 ± 0.211

6.865 ± 0.3349

0.739 ± 0.0562

0.148 ± 0.0061

0.288 ± 0.0179

22.5       

9.19 ± 0.116

15.83 ± 0.205

45.8 ± 0.56

49.90 ± 0.180

17.26 ± 0.058

34.56 ± 0.109

0.221 ± 0.0067

518.30 ± 13.856

10.600 ± 0.4487

2.57 ± 0.221

7.083 ± 0.3183

0.602 ± 0.0525

0.117 ± 0.0118

0.222 ± 0.0224

45         

9.04 ± 0.107

15.45 ± 0.194

44.6 ± 0.55

49.30 ± 0.153

17.08 ± 0.049

34.60 ± 0.058

0.211 ± 0.0087

525.50 ± 12.172

10.990 ± 0.5098

2.76 ± 0.138

7.203 ± 0.3873

0.610 ± 0.0577

0.141 ± 0.0219

0.295 ± 0.0668

90         

9.26 ± 0.083

15.90 ± 0.146

46.1 ± 0.44

50.00 ± 0.149

17.16 ± 0.054

34.46 ± 0.076

0.232 ± 0.0125

524.80 ± 15.867

10.770 ± 0.3821

2.98 ± 0.139

6.784 ± 0.2742

0.606 ± 0.0611

0.132 ± 0.0178

0.259 ± 0.0316

180         

9.15 ± 0.081

15.79 ± 0.148

45.4 ± 0.44

49.70 ± 0.153

17.24 ± 0.062

34.73 ± 0.088

0.209 ± 0.0077

502.90 ± 13.825

9.750 ± 0.4143

2.19 ± 0.191

6.769 ± 0.3326

0.474 ± 0.0309

0.097 ± 0.0070

0.209 ± 0.0247

Abbreviations:

NA: Not Available,SEM: Standard Error of Means,V: Vehicle Control,Erythrcyt: Erythrocytes,Hgb: Hemoglobin,HCT: Hematocrit,MCV: Mean Corpuscular Volume,MCH: Mean Corpuscular Hemoglobin,MCHC: Mean Corpuscular Hemoglobin Concentration,Retics: Reticulocytes,Platelet: Platelets,Leukocytes: Leukocytes,Neut: Neutrophils,Lymph: Lymphocytes,Mono: Monocytes,EOS: Eosinophils,Basophils: Basophils, CL = Sample clotted

Conclusions:
The Lowest-Observed-Effect-Level (LOEL) at the application site was 11.25 mg/kg based on histopathologic examination. There was no No-Observed-Effect-Level (NOEL) at the application site.
The NOAEL for systemic toxicity can be estimated to be higher than 180 mg/kg bw/d.
Executive summary:

The potential subchronic dermal toxicity of sodium mercaptoacetate was evaluated according to a NTP protocol. Sodium mercaptoacetate was applied once daily in Sprague-Dawley rats (10 Males and 10 Females) skin, at the dose-levels of 11.25, 22.5, 45.0, 90.0, and 180.0  mg/kg bw/d during 90 days, 5 days a week. A control group was tested with vehicle (ethanol in water). No satellite group was tested for reversibility or persistence occurrence of toxic effects.

Body weights were recorded on day one on test, weekly and prior necropsy. Animals were observed twice daily for morbidity and mortality. Blood was collected from both sexes of "special study" rats, at days 4 and 22 and from the core study rats at the end of the study. These was processed for haematology and clinical chemistry determinations. Blood was collected from core study mice at the end of the study for haematology determinations. All animals were examined for gross pathology, and organs were weighted and submitted to histopathology.

No death were reported in any treated group. Significant observations noted in both sexes were limited to dermal irritation at the site of application (SOA), thickened skin at the SOA and ulcerations at the SOA. There were only limited statistically significant differences in the body weight, organ weight, chemistry and haematology results. No gross lesions finding were considered to be test article related or biologically significant. Repeated dermal administration of Sodium Thioglycolate (NaTG) for thirteen weeks (excluding weekends) resulted in test article related microscopic changes at the site of application (SOA) in both male and female rats at all treatment doses. Changes in the skin SOA revealed minimal to mild hyperplasia of the epidermis accompanied, in many animals, by sebaceous gland hyperplasia and hyperkeratosis. The severity of the changes was comparable between all treatment groups in both the male and female rats.

The Lowest-Observed-Effect-Level (LOEL) at the application site was 11.25 mg/kg based on histopathologic examination. There was no No-Observed-Effect-Level (NOEL) at the application site. The NOAEL for systemic toxicity can be estimated to be higher than 180 mg/kg bw/d.

Data source

Referenceopen allclose all

Reference Type:
other: draft study report
Title:
Unnamed
Year:
2003
Report Date:
2003
Reference Type:
other: WEB publication
Title:
Unnamed
Year:
2010

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: guideline posted on the NTP website
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
mouse
Strain:
B6C3F1
Sex:
male/female
Details on test animals and environmental conditions:
Treatment: After a 10- to 14-day quarantine period, animals are assigned at random  to treatment groups. The study includes five treatment groups each  administered a different concentrations of the test chemicals plus a  control group. Each group contains 10 animals per sex per species. The  animals receive the subject chemical by dermal route of exposure.  Controls receive vehicle alone. Animals are exposed five times per week,  weekdays only, for 90 days after which they are sacrificed with no  recovery period. All animals are housed individually. 

Administration / exposure

Type of coverage:
open
Vehicle:
other: 95 % Ethanol in deionized water (1:1, v/v)
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
five times per week
Doses / concentrationsopen allclose all
Dose / conc.:
22.5 mg/kg bw/day (actual dose received)
Dose / conc.:
45 mg/kg bw/day (actual dose received)
Dose / conc.:
180 mg/kg bw/day (actual dose received)
Dose / conc.:
360 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Details on study design:
Post-exposure period: none
Positive control:
no

Examinations

Observations and examinations performed and frequency:
BODY WEIGHT: Yes
Animals are weighed individually on day one on test, after seven days,  and at weekly periods thereafter. 

DETAILED CLINICAL OBSERVATIONS: Yes
Animals are observed twice daily, at  least six hours apart (before 10:00 AM and after 2:00 PM), including  holidays and weekends, for moribundity and death. Animals found moribund  or showing clinical signs of pain or distress are humanely euthanized.  Formal clinical observations are performed and recorded weekly. 

HAEMATOLOGY AND CLINICAL CHEMISTRY: Yes
Blood is collected from both sexes of "special study" rats, at days 4 and  22 and from the core study rats at the end of the study. These are  processed for haematology and clinical chemistry determinations. Blood is  collected from core study mice at the end of the study for haematology  determinations.

-Haematology:
Erythrocyte count,  Mean corpuscular volume,  Haemoglobin,  Packed cell volume,  Mean corpuscular haemoglobin,  Mean corpuscular haemoglobin concentration,  Erythrocyte morphologic assessment,  Leukocyte count,  Leukocyte differential,  Reticulocyte count,  Platelet count and morphologic assessment 
-Clinical chemistry:
Sorbitol dehydrogenase (SDH),  Alkaline Phosphatase (ALP),  Creatine Kinase (CK),  Creatinine,  Total Protein,  Albumin,  Urea Nitrogen (BUN),  Total Bile Acids,  Alanine Aminotransferase (ALT)

OTHER:
Sperm Morphology and Vaginal Cytology Evaluations (SMVCE) (see section  7.8.3): SMVCE are conducted on core study rats and mice. Mortality, body weight  changes and clinical signs of toxicity are used to determine the 3 dose  levels used for the SMVCE evaluations.
Sacrifice and pathology:
GROSS PATHOLOGY AND HISTOPATHOLOGY
Organ weights:  Liver, thymus, right kidney, right testis, heart, and lungs weights are  recorded from all animals surviving until the end of the study. 
A complete necropsy is performed on all treated and control animals that  either die or are sacrificed. All tissues required for complete  histopathology are trimmed, embedded, sectioned and stained with  hematoxylin and eosin for histopathologic evaluation.

HISTOPATHOLOGY:
A complete histopathologic evaluation inclusive of gross lesions is done  on all control animals, all animals in the highest dose group with at  least 60% survivors at the time of sacrifice, and all animals in higher  dose groups inclusive of early deaths and survivors. Chemical-related  lesions (target organs) are identified, and these organs plus gross  lesions are examined for all lower doses. Only those tissues designated  as target tissues and gross lesions are evaluated in lower doses to a  no-effect-level. A complete histopathologic evaluation is performed on  all natural death/moribund sacrifice animals in lower dose groups.

Tissues examined histopathologically:  Adrenal glands,  Brain (3 sections including frontal cortex and basal ganglia, parietal  cortex and thalamus, and cerebellum and pons), Clitoral glands,  Esophagus,  Eyes,  Femur, including diaphysis with marrow cavity and epiphysis (femoral  condyle with epiphyseal cartilage plate, articular cartilage and  articular surface),  Gallbladder (mouse),  Gross lesions,  Harderian glands,  Heart and aorta,  Intestine, large (cecum, colon, rectum),  Intestine, small (duodenum, jejunum, ileum), Kidneys,  Liver (2 sections including left lateral lobe and median lobe),  Lungs and mainstem bronchi,  Lymph nodes  - mandibular and mesenteric - inguinal, gluteal, internal iliac (chronic studies only, if lesion  observed, not merely discolouration),  Mammary gland with adjacent skin,  Muscle, thigh (only if neuromuscularsigns were present),  Nasal cavity and nasal turbinates (3 sections),  Ovaries,  Pancreas,  Parathyroid glands,  Pituitary gland,  Preputial glands,  Prostate,  Salivary glands,  Seminal vesicle,  Skin: site of application (topical studies),  Spinal cord and sciatic nerve (if neurologic signs were present),  Spleen, Stomach (forestomach and glandular),  Testes with epididymus,  Thymus,  Thyroid glands,  Tissue masses and regional lymph nodes,  Trachea,  Urinary bladder,  Uterus


Statistics:
yes

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Dermal irritation:
effects observed, treatment-related
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
not specified
Details on results:
1. Survival
All mice survived until terminal sacrifice.

2.Clinical Observations
Significant clinical observations noted in the male mice included irritation at the site of application in 6/10 animals treated at the 360 mg/kg dose leveOther clinical signs (a thin appearance) did not occur in a test article related manner. In the female mice, no clinical signs of toxicity were noted which were considered to be test article related.

3.Body Weights
Body weights were not affected by the treatment in either sex during the course of the study.

4.Organ Weights
a.Absolute Organ Weights
The absolute heart and liver weights of male and female mice treated with 180.0 and 360.0 mg/kg of NaT were significantly (p <= 0.05) increased when compared to the vehicle control group. The absolute heart weights of female mice treated with 45.0 mg/kg were also increased, as well as the absolute liver weights of female mice treated with 45.0 and 90.0 mg/kg of NaT. Absolute kidney weights of female mice treated with 180.0 and 360.0 mg/kg were also significantly (p <= 0.05) increased.
The absolute spleen weights of male mice treated with 22.5 mg/kg of NaT were significantly (p <= 0.05) decreased, while the absolute spleen weights of female mice treated with 45.0 mg/kg and 360.0 mg/kg were significantly (p <= 0.05) increased.

b. Organ to Body Weight Ratios
Relative heart weights of male mice treated with 22.5, 45.0, 180.0, and 360.0 mg/kg NaT were significantly (p <= 0.05) increased (when compared to the vehicle control), as well as the relative heart weights of female mice treated with 360.0 mg/kg NaT. Relative kidney weights of male mice treated with360.0 mg/kg NaT were significantly (p <= 0.05) increased. Relative liver weights of male mice treated with 180.0 and 360.0 mg/kg NaT were significantly (p <= 0.05) increased, as well as the relative liver weights of female mice treated with 45.0, 90.0, 180.0, and 360.0 mg/kg NaT.

Relative spleen weights of male mice treated with 22.5 mg/kg of NaT were significantly (p <= 0.05) decreased.

5.Clinical Pathology
For the male mice, statistically significant (p<0.05) increases were limited to the high dose (360 mg/kg) treatment group when compared to the vehicle control animals in the mean corpuscular volume (MCV) and the mean corpuscular haemoglobin (MCH) values. These findings were not considered to be either dose responsive or biologically significant. For the female mice, there were numerous statistically significant findings when compared with the vehicle control animals. Those findings which elicited a dose and/or or test article related response were limited to decreased red blood cells (RBC) in the 22.5, 45.0, 180.0 and 360.0 mg/kg treatment groups and decreased haemoglobin (HGB) and haematocrit (HCT) in the 22.5, 45.0, and 360.0 mg/kg treatment groups. All other statistically significant findings were sporadic and did not appear to be biologically significant.

6.Anatomic Pathology
a.Gross Lesions
There was one abnormal gross necropsy finding in a male mouse at the 180.0 mg/kg treatment level, which was two foci in the glandular stomach. All other male and female mice at all dose levels revealed no abnormalities at the time of terminal necropsy.

b.Microscopic Pathology
Repeated dermal administration of Sodium Thioglycolate (NaT) for thirteen weeks (excluding weekends) resulted in test article related microscopic changes at the site of application (SOA) in both male and female mice at all treatment doses, with the exception of the 22.5 mg/kg dose group males. Changes in the skin, SOA revealed minimal to moderate hyperplasia of the epidermis accompanied, in some animals, by sebaceous gland hyperplasia, hyperkeratosis, dermal inflammation and/or parakeratosis. The severity of the changes was comparable between all treatment groups in both the male and female mice. A NOEL was not reached in female or male mice.
Microscopic evaluation of the other tissues required by the protocol revealed a few findings which were observed either in small numbers and/or in both control and treated animals. And, all of these changes are commonly observed in B6C3F1 mice. For these reasons, these changes were considered incidental findings.

[NOTE: The pathologist used the following criteria for severity scoring of the epidermal hyperplasia; minimal 2-3 cell layers thick, mild 4-6 cell layers thick, moderate 7-8 cell layers thick and marked >9 cell layers thick (at the thickest point).]




Effect levels

open allclose all
Key result
Dose descriptor:
NOAEL
Remarks:
systemic toxicity
Effect level:
>= 360 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Remarks on result:
not determinable due to absence of adverse toxic effects
Key result
Dose descriptor:
NOEL
Remarks:
local effects
Effect level:
22.5 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
dermal irritation

Target system / organ toxicity

Key result
Critical effects observed:
no

Any other information on results incl. tables

Hematology Summary Table in male mice

(Mean ± SEM)

Dose Group (mg/kg)

Erythrcyt (10^6/uL)

Hgb (g/dL)

HCT (Automated) (%)

MCV (fL)

MCH (pg)

MCHC (g/dL)

Retics (10^6/uL)

Platelet (10^3/uL)

Leukocytes (10^3/uL)

Neut (10^3/uL)

Lymph (10^3/uL)

Mono (10^3/uL)

EOS (10^3/uL)

Basophils (10^3/uL)

Day 93

0         

10.88 ± 0.109

16.85 ± 0.175

50.9 ± 0.56

46.20 ± 0.249

15.31 ± 0.057

33.13 ± 0.060

0.256 ± 0.0154

629.30 ± 24.759

7.350 ± 0.4888

0.51 ± 0.059

6.462 ± 0.4469

0.199 ± 0.0432

0.059 ± 0.0087

0.117 ± 0.0198

22.5       

10.85 ± 0.081

16.80 ± 0.157

50.8 ± 0.49

46.70 ± 0.260

15.43 ± 0.060

33.11 ± 0.075

0.271 ± 0.0128

605.30 ± 30.739

7.220 ± 0.6918

0.47 ± 0.079

6.386 ± 0.5714

0.146 ± 0.0167

0.080 ± 0.0228

0.156 ± 0.0388

45         

10.85 ± 0.130

16.89 ± 0.166

50.9 ± 0.53

46.89 ± 0.200

15.57 ± 0.076

33.19 ± 0.079

0.281 ± 0.0170

636.44 ± 15.876

8.644 ± 0.7385

0.59 ± 0.118

7.681 ± 0.6175

0.180 ± 0.0216

0.060 ± 0.0120

0.133 ± 0.0257

90         

10.93 ± 0.083

16.88 ± 0.116

51.0 ± 0.37

46.70 ± 0.147

15.43 ± 0.037

33.12 ± 0.061

0.255 ± 0.0124

579.30 ± 16.986

7.490 ± 0.5115

0.48 ± 0.038

6.698 ± 0.4670

0.147 ± 0.0116

0.050 ± 0.0067

0.111 ± 0.0144

180         

10.90 ± 0.089

16.92 ± 0.120

51.3 ± 0.45

47.10 ± 0.180

15.52 ± 0.053

33.01 ± 0.090

0.272 ± 0.0142

634.70 ± 15.556

6.880 ± 0.5291

0.42 ± 0.046

6.126 ± 0.4633

0.151 ± 0.0153

0.050 ± 0.0113

0.118 ± 0.0248

360         

10.51 ± 0.104

16.42 ± 0.206

49.8 ± 0.65

47.50 ± 0.269

15.63 ± 0.080

32.96 ± 0.083

0.259 ± 0.0135

582.80 ± 30.057

7.510 ± 0.6239

0.53 ± 0.092

6.574 ± 0.5335

0.173 ± 0.0185

0.073 ± 0.0268

0.161 ± 0.0492

Abbreviations:

NA: Not Available,SEM: Standard Error of Means,V: Vehicle Control,Erythrcyt: Erythrocytes,Hgb: Hemoglobin,HCT: Hematocrit,MCV: Mean Corpuscular Volume,MCH: Mean Corpuscular Hemoglobin,MCHC: Mean Corpuscular Hemoglobin Concentration,Retics: Reticulocytes,Platelet: Platelets,Leukocytes: Leukocytes,Neut: Neutrophils,Lymph: Lymphocytes,Mono: Monocytes,EOS: Eosinophils,Basophils: Basophils, CL = Sample clotted


Hematology Summary Table in female mice

 

(Mean ± SEM)

 

Dose Group (mg/kg)

Erythrcyt (10^6/uL)

Hgb (g/dL)

HCT (Automated) (%)

MCV (fL)

MCH (pg)

MCHC (g/dL)

Retics (10^6/uL)

Platelet (10^3/uL)

Leukocytes (10^3/uL)

Neut (10^3/uL)

Lymph (10^3/uL)

Mono (10^3/uL)

EOS (10^3/uL)

Basophils (10^3/uL)

Day 93

 

0         

11.21 ± 0.145

17.84 ± 0.163

54.6 ± 0.48

48.90 ± 0.180

15.94 ± 0.052

32.67 ± 0.105

0.276 ± 0.0144

495.70 ± 25.768

6.950 ± 0.3478

0.33 ± 0.020

6.365 ± 0.3221

0.164 ± 0.0109

0.021 ± 0.0038

0.052 ± 0.0096

22.5       

10.59 ± 0.141

16.92 ± 0.185

51.1 ± 0.62

48.30 ± 0.260

16.00 ± 0.054

33.08 ± 0.107

0.253 ± 0.0149

495.80 ± 32.790

6.500 ± 0.7060

0.36 ± 0.045

5.827 ± 0.6444

0.188 ± 0.0222

0.045 ± 0.0110

0.092 ± 0.0206

45         

10.66 ± 0.076

16.99 ± 0.116

51.7 ± 0.45

48.40 ± 0.163

15.90 ± 0.065

32.89 ± 0.114

0.261 ± 0.0166

514.90 ± 22.081

6.370 ± 0.5596

0.46 ± 0.065

5.527 ± 0.4889

0.174 ± 0.0216

0.064 ± 0.0185

0.128 ± 0.0345

90         

10.88 ± 0.088

17.39 ± 0.127

53.3 ± 0.48

49.00 ± 0.178

16.00 ± 0.047

32.64 ± 0.110

0.282 ± 0.0105

489.10 ± 19.833

7.840 ± 0.4494

0.55 ± 0.063

6.800 ± 0.3772

0.214 ± 0.0135

0.086 ± 0.0196

0.180 ± 0.0377

180         

10.78 ± 0.107

17.33 ± 0.189

52.6 ± 0.56

49.10 ± 0.180

16.13 ± 0.047

32.97 ± 0.062

0.280 ± 0.0095

465.60 ± 30.150

6.650 ± 0.3423

0.40 ± 0.059

5.960 ± 0.3143

0.154 ± 0.0161

0.040 ± 0.0126

0.103 ± 0.0318

360         

10.37 ± 0.109

16.79 ± 0.175

51.1 ± 0.59

49.30 ± 0.213

16.17 ± 0.052

32.89 ± 0.067

0.261 ± 0.0234

511.30 ± 36.516

5.880 ± 0.4846

0.30 ± 0.024

5.338 ± 0.4537

0.157 ± 0.0192

0.025 ± 0.0040

0.055 ± 0.0078


Organ Weights Summary Table in female mice

(Mean ± SEM)

Dose Group (mg/kg)

Body Wt (Sac)(g)

Heart Wt (g)

%Heart/Body

Liver Wt (g)

%Liver/Body

Lung Wt (g)

%Lungs/Body

R Kidney Wt (g)

%R Kidney/Body

Spleen Wt (g)

%Spleen/Body

Thyroid Wt (g)

%Thyroid/Body

Day 93

0         

24.4 ± 0.47

0.12 ± 0.003

0.51 ± 0.010

1.12 ± 0.030

4.59 ± 0.084

0.225 ± 0.0146

0.92 ± 0.050

0.18 ± 0.006

0.735 ± 0.0166

0.07 ± 0.003

0.30 ± 0.009

0.006 ± 0.0002

0.024 ± 0.0011

22.5       

24.8 ± 0.37

0.13 ± 0.003

0.53 ± 0.009

1.20 ± 0.029

4.83 ± 0.087

0.225 ± 0.0169

0.91 ± 0.072

0.19 ± 0.005

0.761 ± 0.0180

0.08 ± 0.003

0.33 ± 0.014

0.005 ± 0.0003

0.022 ± 0.0014

45         

25.4 ± 0.67

0.13 ± 0.002

0.53 ± 0.012

1.26 ± 0.025

4.95 ± 0.113

0.193 ± 0.0092

0.76 ± 0.042

0.19 ± 0.004

0.753 ± 0.0201

0.08 ± 0.003

0.33 ± 0.008

0.005 ± 0.0004

0.020 ± 0.0018

90         

24.6 ± 0.31

0.13 ± 0.002

0.53 ± 0.007

1.23 ± 0.022

5.01 ± 0.064

0.230 ± 0.0088

0.93 ± 0.036

0.18 ± 0.003

0.748 ± 0.0092

0.08 ± 0.002

0.32 ± 0.006

0.006 ± 0.0003

0.023 ± 0.0013

180         

25.3 ± 0.37

0.13 ± 0.003

0.53 ± 0.014

1.29 ± 0.019

5.09 ± 0.068

0.238 ± 0.0166

0.95 ± 0.073

0.20 ± 0.003

0.774 ± 0.0089

0.08 ± 0.003

0.32 ± 0.013

0.006 ± 0.0002

0.023 ± 0.0010

360         

25.5 ± 0.37

0.14 ± 0.003

0.55 ± 0.011

1.34 ± 0.027

5.24 ± 0.082

0.211 ± 0.0084

0.83 ± 0.032

0.20 ± 0.002

0.776 ± 0.0111

0.08 ± 0.004

0.33 ± 0.014

0.006 ± 0.0003

0.025 ± 0.0012

Abbreviations:

NA: Not Available,SEM: Standard Error of Means,V: Vehicle Control,Thyroid: Thyroid WT: Weight, * Thyroid weights were taken post-fixation.


Organ Weights Summary Table in male mice

(Mean ± SEM)

Dose Group (mg/kg)

Body Wt (Sac)(g)

Heart Wt (g)

%Heart/Body

Liver Wt (g)

%Liver/Body

Lung Wt (g)

%Lungs/Body

R Kidney Wt (g)

%R Kidney/Body

R Testis Wt (g)

%R Testis/Body

Spleen Wt (g)

%Spleen/Body

Thyroid Wt (g)

%Thyroid/Body

Day 93

0         

29.0 ± 0.48

0.14 ± 0.002

0.47 ± 0.004

1.30 ± 0.022

4.49 ± 0.051

0.205 ± 0.0069

0.71 ± 0.030

0.28 ± 0.009

0.971 ± 0.0178

0.118 ± 0.0016

0.408 ± 0.0073

0.06 ± 0.002

0.20 ± 0.006

0.005 ± 0.0005

0.018 ± 0.0021

22.5       

28.2 ± 0.32

0.15 ± 0.002

0.52 ± 0.009

1.28 ± 0.028

4.54 ± 0.080

0.212 ± 0.0107

0.75 ± 0.034

0.28 ± 0.007

0.992 ± 0.0173

0.120 ± 0.0022

0.424 ± 0.0085

0.05 ± 0.001

0.18 ± 0.004

0.005 ± 0.0004

0.017 ± 0.0015

45         

28.1 ± 0.71

0.15 ± 0.004

0.52 ± 0.009

1.25 ± 0.023

4.46 ± 0.062

0.202 ± 0.0057

0.72 ± 0.029

0.27 ± 0.007

0.945 ± 0.0120

0.124 ± 0.0019

0.442 ± 0.0148

0.05 ± 0.001

0.19 ± 0.006

0.005 ± 0.0006

0.018 ± 0.0023

90         

28.2 ± 0.44

0.14 ± 0.002

0.50 ± 0.008

1.33 ± 0.024

4.72 ± 0.059

0.220 ± 0.0081

0.78 ± 0.029

0.28 ± 0.007

1.004 ± 0.0156

0.117 ± 0.0010

0.415 ± 0.0051

0.06 ± 0.001

0.21 ± 0.004

0.006 ± 0.0003

0.020 ± 0.0010

180         

28.8 ± 0.36

0.15 ± 0.002

0.51 ± 0.007

1.40 ± 0.025

4.88 ± 0.069

0.214 ± 0.0107

0.74 ± 0.031

0.29 ± 0.007

0.994 ± 0.0143

0.119 ± 0.0018

0.415 ± 0.0086

0.06 ± 0.001

0.21 ± 0.003

0.005 ± 0.0003

0.019 ± 0.0009

360         

28.3 ± 0.31

0.15 ± 0.002

0.52 ± 0.008

1.41 ± 0.025

4.98 ± 0.070

0.224 ± 0.0166

0.79 ± 0.059

0.30 ± 0.008

1.045 ± 0.0216

0.115 ± 0.0033

0.407 ± 0.0091

0.06 ± 0.002

0.22 ± 0.007

0.006 ± 0.0005

0.020 ± 0.0018

Applicant's summary and conclusion

Conclusions:
The Lowest-Observed-Effect-Level (LOEL) at the application site was 45 mg/kg based on histopathologic examination. The No-Observed-Effect-Level (NOEL) at the application site was 22.5 mg/kg.
At the exception of the microscopic changes observed at the site of application, the other statistically significant changes, organ weights and clinical pathology, were very small and in the range of the historical control data. Accordingly, the NOAEL for systemic toxicity can be estimated to be higher than 360 mg/kg bw/d.
Executive summary:

The potential subchronic dermal toxicity of sodium mercaptoacetate was evaluated according to a NTP protocol. Sodium mercaptoacetate was applied once daily in B6C3F1 mices (10 Males and 10 Females) skin, at the dose-levels of 22.0, 45.0, 90.0, 180.0 and 360. 0 mg/kg bw/d during 90 days, 5 days a week. A control group was tested with vehicle (ethanol in water). No satellit group was tested for reversibility or persistence occurence of toxic effetcs.

Body weights were recorded on day one on test, weekly and prior necropsy. Animals were observed twice daily for morbidity and mortality. Blood was collected from both sexes of "special study" rats, at days 4 and 22 and from the core study rats at the end of the study. These was processed for haematology and clinical chemistry determinations. Blood was collected from core study mice at the end of the study for haematology determinations. All animals were examined for gross pathology, and organs were weighted and submitted to histopathology.

No death were reported in any treated group. At 360 mg/kg , significant dermal irritation at the site of application (SOA) were noted in both sexe.There were only limited statistically significants differences in the body weight, organ weight, chemistry and haematology results. Few gross lesions finding were considered to be test article related or biologically significant : only increased absolute and relative heart and spleen weights in female mice at 360 mg/kg, increased absolute kidney weights in female mice at 180 and 360 mg/kg, increased relative kidney weights in male mice at 360 mg/kg, and increased absolute and relative liver weights in male and female mice at 180 and 360 mg/kg were considered to be treatment-related even though the observed response was slight .

Moreover, repeated dermal administration of Sodium Thioglycolate (NaT) for thirteen weeks (excluding weekends) resulted in test article related microscopic changes at the site of application (SOA) in both male and female mices at almost all treatment doses. Changes in the skin SOA revealed minimal to mild hyperplasia of the epidermis. The other changes in other tissues were considered incidental findings. According to this experience, the Lowest-Observed-Effect-Level (LOEL) at the application site was 45 mg/kg based on histopathologic examination; the No-Observed-Effect-Level (NOEL) at the application site was 22.5 mg/kg. The NOAEL for systemic toxicity can be estimated to be higher than 360 mg/kg bw/d.