Registration Dossier

Toxicological information

Repeated dose toxicity: dermal

Currently viewing:

Administrative data

Endpoint:
sub-chronic toxicity: dermal
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Justification for type of information:
HYPOTHESIS FOR THE CATEGORY APPROACH
The substances of this category have similar toxicological properties because:
- all substances are small organic molecules;
- they share structural similarities with common functional groups: one or more thiol and/or thioether group(s) and carboxylic acid (as free acid, salt or ester);
- the metabolism (i.e. ester hydrolysis) leads to comparable products (sulfur-containing core structure in its acid form and alcohols of differing chains lengths)

The substances were assigned to subgroups according to their main structural features (see Table 1); further justification for subgrouping based on toxicological properties is given below:
- TGA family: Thioglycolic acid, its salts and esters
- 3-MPA family: 3-Mercaptopropionic acid, its salts and esters
- TLA family: Thiolactic acid and its salts
- Intramolecular-S family: Thiodiglycolic acid or Dithiodiglycolic acid and its esters, Thiodipropionic acid or Dithiodipropionic acid and its esters, Methylene bis(butyl thioglycolate)
- Mercaptanes: Thioglycerol, Bis(2-mercaptoethyl) sulfide, 4-Mercaptomethyl-3,6-dithia-1,8-octanedithiol

The acids and salts will dissociate to the respective Thioglycolate or 3-Mercaptopropionate or Thiolactate and the corresponding cation. In case of the esters, the metabolism expected to occur is ester hydrolysis resulting in the corresponding acid and alcohol.

It was demonstrated, that PETMP and 3-MPA strongly bind to plasma proteins (e.g. via S-S bond to cysteine) in vitro, which is well known for substances containing free SH-groups (Bruno Bock, 2014). Strong protein binding is also expected to occur with the other substances assessed within this paper. The members of the intramolecular-S family are an exception, as they do not contain free SH-groups – protein binding may be less relevant for this family.

This read-across hypothesis corresponds to scenario 4 of the Read-Across Assessment Framework (RAAF), ECHA, March 2017 - different compounds have qualitatively similar properties - of the read-across assessment framework i.e. variations in the properties are observed among the source substances; the prediction is based on a worst-case approach.

Overall, based on close structural similarities, a read-across from the existing repeated dose and reproduction toxicity studies is considered as an appropriate adaptation to the standard information requirements of the REACH Regulation in accordance with the provisions of Annex XI, 1.5 of the REACH Regulation.

A detailed justification for this category approach is attached to Iuclid section 13.
Cross-referenceopen allclose all
Reason / purpose:
read-across: supporting information
Reason / purpose:
read-across source
Reference
Endpoint:
short-term repeated dose toxicity: dermal
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
For the time being, the draft report (TOX-80) is still undergoing a multi-tiered review that includes NTP staff review and external peer review. However, the data available on the NTP website - survival, body weight, organ weights and histopathology - are sufficiently detailed for a preliminary assessment.
Principles of method if other than guideline:
The goal of this is to provide a basis for identifying potential target  organs and toxicities and to assist in setting doses for the 13-week  exposure study.
GLP compliance:
not specified
Limit test:
no
Species:
mouse
Strain:
B6C3F1
Sex:
male/female
Type of coverage:
open
Vehicle:
other: 95 % Ethanol in deionized water (1:1, v/v)
Details on exposure:
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 concentration of test chemical per sex per  species plus a control. At each of five concentrations plus a control  group. Each group per sex per species contains five animals. The animals  receive the test chemical through a designated route of exposure and the  control animals receive vehicle alone. For topical studies animals are  exposured for 12 dose days, not including weekends or holidays with at  least two consecutive dose days before the terminal sacrifice day. Mice  are housed individually. 
Duration of treatment / exposure:
2 weeks
Frequency of treatment:
5 days/week
Remarks:
Doses / Concentrations:
22.5, 45, 90, 180 or 360 mg/kg
Basis:

Control animals:
yes, concurrent vehicle
Details on study design:
Post-exposure period: none
Observations and examinations performed and frequency:
Animals are weighed individually on day one on test, after seven days,  and at sacrifice. The 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. Observations  are made twice daily for clinical signs of pharmacologic and toxicologic  effects of the chemical. 
Sacrifice and pathology:
Liver, thymus, right kidney, right testicle, heart, and lungs weights are  recorded for 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. (necropsy list)  Histopathologic evaluation is done only on those organs/tissues showing  gross evidence of treatment-related lesions. The corresponding tissues  are evaluated in control animals (specific targets may also be required  if known).
Reason / purpose:
read-across source
Reference
Endpoint:
sub-chronic toxicity: dermal
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
2003
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
For the time being, the draft report (TOX-80) is still undergoing a multi-tiered review that includes NTP staff review and external peer review. However, the data available on the NTP website - survival, body weight, haematology, organ weights and histopathology are sufficiently detailed for a preliminary assessment.
Qualifier:
according to
Guideline:
other: guideline posted on the NTP website
GLP compliance:
not specified
Limit test:
no
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. 
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
Remarks:
Doses / Concentrations:
22.5, 45.0, 90.0, 180.0 and 360.0 mg/kg bw/d
Basis:

No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Details on study design:
Post-exposure period: none
Positive control:
no
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:
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).]




Dose descriptor:
NOAEL
Remarks:
systemic toxicity
Effect level:
>= 360 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no systemic effects sonserved
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:
histopathology: non-neoplastic
Critical effects observed:
no

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

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.

Data source

Materials and methods

Test material

Reference
Name:
Unnamed
Type:
Constituent

Results and discussion

Effect levels

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

Target system / organ toxicity

Key result
Critical effects observed:
no

Applicant's summary and conclusion