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Toxicological information

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:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
2016
Report Date:
2016
Reference Type:
other: WEB publication
Title:
Unnamed
Year:
2010
Reference Type:
other: draft study report
Title:
Unnamed
Year:
2003
Report Date:
2003

Materials and methods

Test guidelineopen allclose all
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

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Taconic Farms, Inc. (Germantown, NY)
- Age at study initiation: 5 to 6 weeks old
- Housing: 1/Solid-bottom polycarbonate cage
- Diet (ad libitum): NTP-2000 irradiated wafer diet (Zeigler Brothers, Inc., Gardners, PA)
- Water (ad libitum): Tap water (Washington Suburban Sanitary Commission Potomac Plant) via automatic watering system
- Acclimation period: 13-14 days

ENVIRONMENTAL CONDITIONS
- Temperature: 72° ± 3° F
- Humidity (%): 50 ± 15
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

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:
14 weeks
Frequency of treatment:
five days per week
Doses / concentrationsopen allclose all
Dose / conc.:
11.25 mg/kg bw/day (actual dose received)
Remarks:
9.1 mg/kg bw/d as mercaptoacetic acid
Dose / conc.:
22.5 mg/kg bw/day (actual dose received)
Remarks:
18.2 mg/kg bw/d as mercaptoacetic acid
Dose / conc.:
45 mg/kg bw/day (actual dose received)
Remarks:
36.3 mg/kg bw/d as mercaptoacetic acid
Dose / conc.:
90 mg/kg bw/day (actual dose received)
Remarks:
72.6 mg/kg bw/d as mercaptoacetic acid
Dose / conc.:
180 mg/kg bw/day (actual dose received)
Remarks:
145.3 mg/kg bw/d as mercaptoacetic acid
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

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.

-Haematology:
hematocrit; hemoglobin concentration; erythrocyte, reticulocyte, and platelet counts; mean cell volume; mean cell hemoglobin; mean cell hemoglobin concentration; and leukocyte count and differentials
-Clinical chemistry:
Sorbitol dehydrogenase (SDH),  Alkaline Phosphatase (ALP),  Creatine Kinase (CK),  Creatinine,  Total Protein,  Albumin,  Urea Nitrogen (BUN),  Total Bile Acids,  Alanine Aminotransferase (ALT), globulin, albumin-globulin ratio, total cholesterol, free fatty acids, and 3-hydroxybutyrate

Sacrifice and pathology:
GROSS PATHOLOGY AND HISTOPATHOLOGY
Organ weights: heart, right kidney, liver, lung, spleen, right testis, thymus, and thyroid gland 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


Other examinations:
Sperm Morphology and Vaginal Cytology Evaluations (SMVCE) (see section  7.8.3): At the end of the studies, sperm samples were collected from male animals exposed to 0, 45, 90 and 180 mg/kg for sperm count and motility evaluations. The following parameters were evaluated: spermatid heads per testis and per gram testis, sperm counts, and epididymal spermatozoal motility and concentration. The left cauda, left epididymis, and left testis were weighed.
Vaginal samples were collected for up to 12 consecutive days prior to the end of the studies from females exposed to 0, 45, 90 and 180 mg/kg for vaginal cytology evaluations.
Statistics:
Calculation and Analysis of Lesion Incidences
The Fisher exact test (Gart et al., 1979), a procedure based on the overall proportion of affected animals, was used to determine significance.
Analysis of Continuous Variables
Organ and body weight data were analyzed with the parametric multiple comparison procedures of Dunnett (1955) and Williams (1971, 1972). Hematology, clinical chemistry, spermatid, and epididymal spermatozoal data were analyzed using the nonparametric multiple comparison methods of Shirley (1977) (as modified by Williams, 1986) and Dunn (1964). Jonckheere’s test (Jonckheere, 1954) was used to assess the significance of the dose-related trends and to determine whether a trend-sensitive test (Williams’ or Shirley’s test) was more appropriate for pairwise comparisons than a test that does not assume a monotonic dose-related trend (Dunnett’s or Dunn’s test). Proportions of regular cycling females in each dosed group were compared to the control group using the Fisher exact test (Gart et al., 1979). Tests for extended periods of estrus, diestrus, metestrus, and proestrus, as well as skipped estrus and skipped diestrus, were constructed based on a Markov chain model proposed by Girard and Sager (1987). For each dose group, a transition probability matrix was estimated for transitions among the proestrus, estrus, metestrus, and diestrus stages, with provision for extended stays within each stage as well as for skipping estrus or diestrus within a cycle. Equality of transition matrices among dose groups and between the control group and each dosed group was tested using chi-square statistics.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Description (incidence and severity):
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.
Dermal irritation:
effects observed, treatment-related
Description (incidence and severity):
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.
Mortality:
no mortality observed
Description (incidence):
All Core Study male and female rats survived until terminal sacrifice.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
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.
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Description (incidence and severity):
There were limited statistically significant (p<0.05) differences in the haematology results when compared to the control group, but these were not dose responsive nor considered to be biologically significant.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
There were limited statistically significant (p<0.05) differences in the chemistry results when compared to the control group, but these were not dose responsive nor considered to be biologically significant.
Urinalysis findings:
not specified
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
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.
Gross pathological findings:
no effects observed
Description (incidence and severity):
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.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
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).]
Histopathological findings: neoplastic:
not examined
Description (incidence and severity):
There were no significant differences in sperm parameters of male rats or estrous cyclicity of female rats administered 45, 90, or 180 mg/kg sodium thioglycolate when compared to the vehicle controls.

Effect levels

open allclose all
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
Remarks:
145 mg/kg bw/d as mercaptoacetic acid
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

Target system / organ toxicity

Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
11.25 mg/kg bw/day (actual dose received)
System:
integumentary
Organ:
skin
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
yes

Any other information on results incl. tables

Survival and Body Weights of Rats in the 3-Month Dermal Study of Sodium Thioglycolatea

Dose (mg/kg)

Survivalb

Initial Body Weight (g)

Final Body Weight (g)

Change in Body Weight (g)

Final Weight Relative to Controls (%)

Male

0

10/10

93 ± 2

335 ± 4

242 ± 4

11.25

10/10

92 ± 2

334 ± 4

242 ± 4

100

22.5

10/10

91 ± 3

332 ± 7

241 ± 6

99

45

10/10

94 ± 3

339 ± 5

246 ± 3

101

90

10/10

90 ± 3

312 ± 9*

222 ± 7*

93

180

10/10

92 ± 3

319 ± 6*

227 ± 5*

95

Female

0

10/10

85 ± 2

177 ± 3

92 ± 2

11.25

10/10

84 ± 2

185 ± 3

101 ± 2*

105

22.5

10/10

85 ± 2

185 ± 3

100 ± 2

106

45

10/10

86 ± 2

186 ± 3

100 ± 2

105

90

10/10

83 ± 2

180 ± 4

97 ± 3

101

180

10/10

82 ± 3

173 ± 4

91 ± 2

98

* Significantly different (P=0.05) from the vehicle control group by Williams’ or Dunnett’s test

a Weights and weight changes are given as mean ± standard error.

b Number of animals surviving at 3 months/number initially in group

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

0.014 ± 0.0006

180         

173.3 ± 3.75

0.64 ± 0.017

0.37 ± 0.006

5.66 ± 0.127

3.27 ± 0.069

1.070 ± 0.0903

0.62 ± 0.049

0.72 ± 0.017

0.418 ± 0.0069

0.43 ± 0.013

0.25 ± 0.004

0.023 ± 0.0008

0.013 ± 0.0003

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 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

 

Incidences of Nonneoplastic Lesions of the Skin at the Site of Application in Rats in the 3-Month Dermal Study of Sodium Thioglycolate

 

Vehicle Control

11.25 mg/kg

22.5 mg/kg

45 mg/kg

90 mg/kg

180 mg/kg

Male

Number Examined Microscopically

10

10

10

10

10

10

Sebaceous Gland, Dermis, Hypertrophya

0

0

2 (1.0)b

4* (1.0)

5* (1.0)

6** (1.0)

Epidermis, Hyperkeratosis

0

6** (1.0)

9** (1.0)

4* (1.0)

4* (1.0)

4* (1.0)

Epidermis, Hyperplasia, Diffuse

0

1 (1.0)

2 (1.0)

3 (1.0)

5* (1.0)

6** (1.0)

Female

Number Examined Microscopically

10

10

10

10

10

10

Sebaceous Gland, Dermis, Hypertrophy

0

0

0

2 (1.0)

6** (1.0)

5* (1.0)

Epidermis, Hyperkeratosis

0

0

1 (1.0)

7** (1.0)

6** (1.0)

5* (1.0)

Epidermis, Hyperplasia, Diffuse

0

0

0

2 (1.0)

7** (1.3)

8** (1.5)

Epidermis, Ulcer, Focal

0

0

0

0

0

3 (1.0)

* Significantly different (P=0.05) from the vehicle control group by the Fisher exact test

** P=0.01

a Number of animals with lesion

b Average severity grade of lesions in affected animals: 1=minimal, 2=mild, 3=moderate, 4=marked

Applicant's summary and conclusion

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 (145 mg/kg bw/d as mercaptoacetic acid).
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 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. 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 significants 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 (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.

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 (145 mg/kg bw/d as mercaptoacetic acid).