Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records

Referenceopen allclose all

Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
2003
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP study according to guideline. Although only summary available it has been peer internationally reviewed within OECD and assigned reliability 1.
Reason / purpose for cross-reference:
reference to same study
Qualifier:
according to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
no
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
- male/female
- Age of animals at study: 9 weeks old for males and females
- Weight at study repeated dose toxicity: 325.8 - 363.1 g for males and 198.5 - 229.3 g for females
- Number of test animals: 60 animals for each sex
Route of administration:
oral: gavage
Vehicle:
not specified
Details on mating procedure:
Each male and female rat was selected from the same test group in order to copulate. It spent 14 days in terms of mating. The day after the copulating, mating would be determined through the observation of sperm in a vaginal rinse.
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
Exposure period : 34, 36 - 45, and 51 days for male, copulated female and not copulated female animals, respectively.
Frequency of treatment:
Daily
Remarks:
Doses / Concentrations:
0, 150, 350 and 750 mg/kg/day
Basis:

No. of animals per sex per dose:
12 animals/sex/dose, plus 6 in 14-day recovery group/sex for control and high dose
Control animals:
yes, concurrent no treatment
Details on study design:
According to the preliminary test (Report No. P104), dose level was set to 0, 150, 350 and 750 mg/kg/day.
Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily; mortality: twice/day
- Cage side observations checked in table [No.?] were included.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Weekly

BODY WEIGHT: Yes
- Time schedule for examinations: once a week and just before the necropsy, but in case of pregnant females, it was measured on the day 0, 7, 14, 20 of the gestation period, date of delivery, and 4 days of the lactation day.

FOOD CONSUMPTION:
- Food consumption: Yes: once a week except mating period

WATER CONSUMPTION: No
Oestrous cyclicity (parental animals):
Not determined.
Sperm parameters (parental animals):
Not determined.
Litter observations:
PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
- The number of survivors and deaths during delivery
- Body weight and Survival rate: measured on the day of delivery and on the day 4 of lactation.
- Sex ratio: It is determined by anogenital distance, for more than 2 mm and less than 1 mm were male and female, respectively.
- Examination of the external surface of pups: It was observed on the day of delivery and on the day 4 of lactation to determine abnormalities.
Postmortem examinations (parental animals):
GROSS PATHOLOGY: Yes

ORGAN WEIGHT: testes, epididymider (all males) liver, kidney, adrenals, thymus, spleen, brain and heart (5 male and female rats from each test group).

HISTOPATHOLOGY: Yes
22 tissues were fixed to perform histopathological evaluations including: testes, epididymides, ovaries, accessory sex organs for all animals, brain (including cerebrum, cerebellum and pons), spinal cord, stomach, small and large intestines (including Peyer’s patches), liver, kidneys, adrenals, spleen, heart, thymus, thyroid, trachea, lungs, uterus, urinary bladder, lymph nodes (cervical mesenteric), peripheral nerve (sciatic or tibial), and bone marrow.
Postmortem examinations (offspring):
No infoirmation
Statistics:
Statistical decision tree, but in case of recovery group, either two-side Student’s t-test or two-side Aspin-Welch t-test was used. In case of categorical data, two-sided Fisher’s exact test was used.
Reproductive indices:
- Copulation index
- number of implantations
- number of corpus luteum
- Number of females pregnant
Offspring viability indices:
- Number of life pups
- post natal loss
- pre and post-implantation loss
Clinical signs:
effects observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed
CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
No mortality males; in females 350 mg/kg: 2/12 and at 750 mg/kg: 4/18
In the control groups, there were no specific clinical symptoms during test period.
150 mg: Intermittent (blood-like) salivation and staining around mouth (3/18 males, 6/18 females), and in females at delivery: difficult delivery, poor nursing, irregular respiration, uterus introsusception and piloerection.
350 mg: Intermittent (blood-like) salivation and staining around mouth were observed after day 15 and (blood-like) staining around nose (7/12 males, 4/12 females). Iintermittent soft stool and staining around anorectal region were observed for the most male animals and in 2 females. One female showed difficult delivery, lacrimation, and irregular respiration from day 4.
750 mg: soft stool and staining around anorectal region for most males and all females; and 5 cases of loss of hair around tail region were observed. Intermittent (blood-like) salivation and 9 cases of staining around mouth and 9 cases of (blood-like) staining around nose. Soft stool and staining around anorectal region for all animals; some cases of intermittent diarrhea were observed. Some animals with found dead and in dying condition had symptoms such as irregular respiration, crawing position, hypoactivity, and abdominal swelling.
In the 750 mg/kg/day recovery group, salivation, staining around mouth, soft stool and staining around anorectal region were not observed during the recovery period.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
From start of dosing BW gain at 750 mg/kg group a bit lower resulting to a lower BW of 8% in males and 5.5% in females compared to controls during first week of recovery which partly recovered during the second week of the recovery period.
Only during the first week food consumption some somewhat lower in the 705 mg group.

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
- Pregnancy and delivery: No effects were seen between the groups in duration of pregnancy, number of corpus luteum, number of implantation, pre-implantation loss, post-implantation loss
- Index of copulation, fertility and gestation: There was no significant difference between the control and treatment group in terms of copulation, fertility and gestation index. The sex mis-confirmation for new born pups in this test did not have relationship with test substance since its frequency was low and no dose-correlation. (See Table)

ORGAN WEIGHTS (PARENTAL ANIMALS)
No effects were seen in sex-organ weights. Weight of the spleen was increased in treatment groups compared to controls for both males and females, although in females not relative weight. No differences in spleen weights were seen in recovery groups. In males the absolute, but not the relative, weight of the heart was decreased in the 750 mg/kg group. In the female recovery group the weights for adrenal and the brain were increased. (See table)

GROSS PATHOLOGY (PARENTAL ANIMALS)
No information provided

HISTOPATHOLOGY (PARENTAL ANIMALS)
See table.
Key result
Dose descriptor:
NOAEL
Effect level:
750 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: NOAEL parental: Above the highest tested dose (750 mg/kg/day)
Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Description (incidence and severity):
Examination of the external surface of pups
Histopathological findings:
not specified
Number of pups born, viability and sex ratio: No significant difference was observed between the treatment groups and the control group at the time of the delivery and on the day 4 of the lactation.
Reproductive effects observed:
not specified

Mating, fertility, gestation and viability data:

DOSE: (mg/kg) 

0

150

350

750

 No. of mated males 

12

12

12

11

 Copulation index (%) 

100

100

100

90.9

 Fertility index (%) 

91.7

100

100

100

 No. of mated females 

12

12

12

11

 Copulation index (%) 

100

100

100

90.9

 Fertility index (%) 

91.7

100

100

100

 Gestation index (%) 

100

91.7

83.3

90

 No. of corpora lutea 

14.9

14.5

15.1

14.1

 Mean±S.D

1.1

2.5

1.7

0.9

 No. of implantations

14.4

12.7

12.7

13.3

 Mean±S.D

1

4.2

2.8

1

 Mean % preimplantation loss

3.5

15.5

14.3

5.4

 No. of embryo/fetal death 

2

1.7

2

2.3

 No. of live pups born 

12.4

12

10.7

11

 Mean±S.D

0.9

2.5

3.3

3.2

 Mean pregnancy period (day) 

21.7

21.8

21.8

21.9

 Viability at birth pp 

95.4

92.1

93.9

92.3

 Viability at LD 4 

99.2

97.8

88.3

99

 Body weights of pups (g) 

 

 

 

 

 Male (at birth)

6.25

5.99

6.37

5.98

 Day 4 

8.57

8.56

9.71

8.7

 Female (at birth)

5.75

5.62

5.73

5.59

 Day 4 

8.03

7.98

8.59

8.21

 

 

Organ weights:

Dose (mg/kg) 

0

150

350

750

 satellite 

0

750

Absolute (sex) organ weight of males

Testes(g) 

3.04

3.285

3.332

3.203

3.337

3.208

Epididymis(g) 

1.258

1.29

1.37

1.3

1.388

1.335

Liver (g) 

10.698

11.142

10.698

10.01

11.139

10.736

Thymus(g) 

0.355

0.307

0.356

0.32

0.31

0.297

Kidneys(g) 

2.364

2.272

2.502

2.385

2.397

2.474

Adrenals(g) 

0.061

0.064

0.062

0.068

0.053

0.055

Spleen(g) 

0.632

0.725

0.783

0.794

0.844

0.716

Brain(g) 

1.985

1.947

2.022

1.91

2.064

2.018

Heart(g) 

1.325

1.244

1.282

1.182

1.411

1.382

Absolute organ weight of females

Liver (g) 

6.947

6.886

7.298

7.431

6.855

6.621

Kidneys(g) 

1.46

1.451

1.433

1.5

1.523

1.509

Adrenals(g) 

0.071

0.073

0.073

0.072

0.057

0.066

Thymus(g) 

0.106

0.14

0.161

0.096

0.298

0.291

Brain(g) 

1.884

1.885

1.883

1.855

1.742

1.87

Spleen(g) 

0.397

0.419

0.494

0.476

0.477

0.472

Heart(g) 

0.818

0.809

0.853

0.767

0.876

0.829

 

Histopathology:

Histopathological findings of males (Group)

 Dose level (mg/kg/day) 

0

150

350

700

 No. of animals examined 

5

5

5

5

 Observation(s) 

 No. of animals observed 

No significant findings 

2

4

4

3

Liver: focal necrosis

 

 

 

 

Minimal 

0

0

0

1

Nongrandular stomach: epithelial proliferation and vacuolation

 

 

 

 

Minimal

0

2

0

0

Moderate

0

3

0

0

Marked 

0

0

5

5

Nongrandular stomach: hyperkeratosis

 

 

 

 

Minimal 

0

3

0

0

Slight 

0

2

5

5

Nongrandular stomach: submucosal edema

 

 

 

 

Minimal 

0

0

0

1

Slight 

0

0

4

4

Moderate

0

3

1

0

Nongrandular stomach: inflammation

 

 

 

 

Slight 

0

3

5

5

No. of animals examined (reproductive organs)

12

12

12

12

Observation(s) 

 No. of animals observed 

No significant findings

10

12

12

10

Testes: atrophy and degeneration of seminiferous tubules

 

 

 

 

Minimal

0

0

0

1

Moderate

2

0

0

0

Marked 

0

0

0

1

Epididymides: oligospermia

 

 

 

 

Minimal

1

0

0

0

Marked 

1

0

0

1

 

Histopathological findings of females (Group)

 Dose level (mg/kg/day) 

0

150

350

700

 No. of animals examined 

5

0

0

0

 Observation(s) 

 No. of animals observed 

No significant findings 

5

1

0

0

Liver: focal necrosis

 

 

 

 

Minimal 

0

0

0

0

Heart: inflammatorycell foci

 

 

 

 

Minimal 

1

0

0

0

Nongrandular stomach: epithelial proliferation and vacuolation

 

 

 

 

Minimal

0

1

1

1

Slight 

0

2

3

3

Marked 

0

0

1

1

Nongrandular stomach: hyperkeratosis

 

 

 

 

Minimal 

0

1

3

1

Slight 

0

0

2

3

Moderate

0

0

0

1

Nongrandular stomach: submucosal edema

 

 

 

 

Slight 

0

1

1

1

Nongrandular stomach: inflammation

 

 

 

 

Minimal 

0

1

2

3

No. of animals examined (reproductive organs)

12

12

10

9

Observation(s) 

 No. of animals observed 

No significant findings

12

12

10

9

 

Conclusions:
There were no reproductive effects seen at 750 mg/kg, the highest dose tested
Executive summary:

Tosyl chloride has been evaluated in a Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test according to OECD 422 and in compliance to GLP.

Tosyl chloride was dose by gavage to groups of 12 Sprague-Dawley rats/sex/dose level at levels of 0, 150, 350 and 750 mg/kg/day for 35 days and 36 - 51 days for male and female rats, respectively. A separate group of 6 animals/sex were added for a 14-day recovery group to the control and the high dose groups.

Results:

Parental toxicity: No mortality males; in females 350 mg/kg: 2/12 and at 750 mg/kg: 4/18.

Some clinical signs were observed at the dose level of 150 mg/kg/day in both male and females such as intermittent (blood-like) salivation and staining around mouth. Effects were more severe at 350 mg/kg and at 750 mg/kg reported clinical signs were soft stool and staining around anorectal region for most males and all females; and 5 cases of loss of hair around tail region were observed. Intermittent (blood-like) salivation and 9 cases of staining around mouth and 9 cases of (blood-like) staining around nose. Soft stool and staining around anorectal region for all animals; some cases of intermittent diarrhea were observed. A decreased BW gain was observed in the 750 mg group resulting to a lower BW that was maximal 8% lower in males and 5.5% in females compared to controls. Food consumption was a bit lower during the first week in the 750 mg group. Histopathology showed dose related effects of epithelial proliferation and inflammation of the forestomach already visible in animals treated at 150 mg.

There were no further major changes observed in other parameters (haematology, biochemistry, neurobehavioral functions, organ weights)

In the 750 mg/kg/day recovery group, salivation, staining around mouth, soft stool and staining around anorectal region were not observed during the recovery period.

 

Reproductive parameters were not affected.No effects were seen between the groups in duration of pregnancy, number of corpus luteum, number of implantation, pre-implantation loss, post-implantation loss. There was no significant difference between the control and treatment group in terms of copulation, fertility and gestation index.

Among the clinical signs was remarked for the 150 mg/kg treated group only that thefemale animals additionally showed difficulty in delivery, poor nursing, and irregular respiration. However, as this is not remarked for the higher dose groups, and no effects are seen in any of the reproductive parameters, these likely represents an accidental observation.

 

Consequently the NOAEL for fertility was established at 750 mg/kg bw/day, the highest dose tested.

Endpoint:
extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
the extended one-generation reproductive toxicity study does not need to be conducted because there are no results from available repeated dose toxicity studies that indicate adverse effects on reproductive organs or tissues, or reveal other concerns in relation with reproductive toxicity
other:
Justification for type of information:
Further testing of Tosyl chloride for reproductive toxicity is not indicated on the basis of low exposures, no effects seen on reproductive parameters seen in an OECD 422 screening at highest dose levels tested leading to mortality.
Reproductive effects observed:
not specified
Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
750 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
Study of high validity
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Tosyl chloride has been evaluated in a Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test according to OECD 422 and in compliance to GLP.

 

Tosyl chloride was dose by gavage to groups of 12 Sprague-Dawley rats/sex/dose level at levels of 0, 150, 350 and 750 mg/kg/day for 35 days and 36 - 51 days for male and female rats, respectively. A separate group of 6 animals/sex were added for a 14-day recovery group to the control and the high dose groups.

Results: Parental toxicity: No mortality males; in females 350 mg/kg: 2/12 and at 750 mg/kg: 4/18.

Some clinical signs were observed at the dose level of 150 mg/kg/day in both male and females such as intermittent (blood-like) salivation and staining around mouth. Effects were more severe at 350 mg/kg and at 750 mg/kg reported clinical signs were soft stool and staining around anorectal region for most males and all females; and 5 cases of loss of hair around tail region were observed. Intermittent (blood-like) salivation and 9 cases of staining around mouth and 9 cases of (blood-like) staining around nose. Soft stool and staining around anorectal region for all animals; some cases of intermittent diarrhea were observed. A decreased BW gain was observed in the 750 mg group resulting to a lower BW that was maximal 8% lower in males and 5.5% in females compared to controls. Food consumption was a bit lower during the first week in the 750 mg group. Histopathology showed dose related effects of epithelial proliferation and inflammation of the forestomach already visible in animals treated at 150 mg.

There were no further major changes observed in other parameters (haematology, biochemistry, neurobehavioral functions, organ weights)

In the 750 mg/kg/day recovery group, salivation, staining around mouth, soft stool and staining around anorectal region were not observed during the recovery period.

 

Reproductive parameters were not affected. No effects were seen between the groups in duration of pregnancy, number of corpus luteum, number of implantation, pre-implantation loss, post-implantation loss. There was no significant difference between the control and treatment group in terms of copulation, fertility and gestation index.

Also the BW of the pups and external examination of pups (group) on post-natal day 1 and 4 show no effects.

Consequently the NOAEL for developmental effects was stated to be above the highest tested dose (750 mg/kg/day)

 

 

Tosyl chloride rapidly hydrolyses intoToluene-4-sulphonic acid and HCl, both strong acids. Systemic exposures will therefore actually be on Toluene-4-sulphonic acid. Consequently, cross-reading from Toluene-4-sulphonic acid for longer term repeated dose studies such as fertility and developmental toxicity can be applied. For Toluene-4-sulphonic acid, studies from the chemically related hydrotropes category are being recommended as read across for this endpoint. The following information is available for these substances:

No fertility studies are reported for the aromatic sulphonic acids. These substances are very corrosive as was demonstrated in skin and eye irritation studies, in the acute oral studies, and in the single repeated dose oral study. For animal welfare, long-term exposures to corrosive substances are not recommended. There are however studies for the chemically related hydrotrope substances that looked at reproductive organs and development of offspring. Hydrotropes are the salt form of the sulphonic acids and therefore are used as read-across for this endpoint. The 90-day oral rat and oral mouse studies and the 2-year chronic dermal rat and mouse studies with the closely related compound sodium xylene sulfonate (CAS No. 1300-72-7) included examination of sex organs of both sexes. No treatment related effects on reproductive organs were reported at doses roughly equivalent to those in the developmental toxicity study. The 1994 study with calcium xylene sulphonate (CAS No. 28088-63-3) did not follow a specific guideline but was fully documented and conducted in accordance with GLP requirements. No adverse effects were reported. The NOAEL for both maternal and foetal toxicity was the highest dose tested - 3000 mg/kg bw /day which is equivalent to 936 mg active ingredient per kilogram body weight per day. The conclusion of the study was no indications of developmental toxicity including teratogenesis.

 

The available data indicate a low concern for reproduction toxicity for Tosyl chloride. An OECD 422 screening study indicated no effects on any reproductive parameter up to 750 mg/kg, the highest dose tested. It should be remarked that this levels is 5 times the LOAEL level of 150 mg/kg based on local gastro-intestinal irritation with specific marked effects in the nonglandular stomach seen at this dose level. Also cross-reading from comparable structures do not indicate a concern for reproductive toxicity. When further considering the low likelihood of exposures followingthe use as a chemical intermediate in industrial or professional settings and as result of its physical-chemical properties, there is no need for further testing.

Short description of key information:

There were no reproductive effects seen in a Reproduction/Developmental Toxicity Screening Test according to OECD 422 at 750 mg/kg, the highest dose tested.

Justification for selection of Effect on fertility via oral route:

Only available data for reproduction on Tosyl chloride.

Justification for selection of Effect on fertility via inhalation route:

Exposures by inhalation are unlikely in view of the low vp of 0.13 Pa at 20°C, its low dustiness (the respirable fraction (≤ 4 µm) of the hygroscopic, crystalline solid is below 0,04%) and low likelihood of exposures by aerosols with uses limited to chemical intermediate in industrial settings. Furthermore Tosyl chloride readily hydrolyses to toluene sulfonic acid and HCL which are both corrosive acids. Inhalation of dust particles will therefore lead to respiratory irritation/corrosion rather than expected to result in systemic toxicity. Additionally it would technically be difficult to perform inhalation studies with Tosyl chloride dust in view of its hygroscopic properties.

Justification for selection of Effect on fertility via dermal route:

In view of irritation properties to skin and no effects observed via oral route which is considered a more efficient route of administration, there is no need to perform an additional study via dermal route to evaluate reproduction toxicity.

Effects on developmental toxicity

Description of key information

There were no developmental effects seen in a Reproduction/Developmental Toxicity Screening Test according to OECD 422 at 750 mg/kg, the highest dose tested. A developmental toxicity study on a structurally related substance also showed no developmental toxicity at the highest dose tested of 936 mg/kg.

Link to relevant study records

Referenceopen allclose all

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
February 7-24, 1994
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Not a guideline study per se. GLP compliance. Full documentation
Qualifier:
no guideline followed
Principles of method if other than guideline:
Females were mated with males of the same strain and source. A block design was used to assign 30 mated females to controls and each of three dosing levels. Doses were selected based on a range finding study where the highest dose was 3000 mg/kg/day and no maternal or developmental toxicity was observed. The test material was prepared weekly. Analysis of dosing preparations stored for 10 days at room temperature verified the stability of the dosing preparation for at least a week. Dosing was done by intragastric intubation through needles at a volume of 10 m?/kg. Dosing was done on gestation days 6 through 15. A vehicle control was included in the study design. The concentration of the dosing preparation was confirmed analytically. Animals were observed twice daily for mortality and signs of overt toxicity. Clinical observations were made from gestation days - 20. Individual body weights were recorded on gestation days 0, 6, 9, 12, 16 and 20. Individual food consumption was recorded concurrent with the body weighing days. Food consumption was calculated. On gestation day 20 all surviving animals were euthanized and immediately examined by cesarean section. The uterus and overies were exposed and examined. The uterus was weighed. The location of viable and nonviable fetuses, early and late resorptions, and the number of total implantations and corpora lutea were recorded. The abdominal and thoracic cavities and organs were examined for grossly evident morphological changes. Uteri from nongravid females were placed in 10% ammonium sulfide solution for detection of implantations. Individual fetuses were weighed, sexed, and examined for external malformations and variations. Approximately one-half of the fetuses were placed in Bouin's solution for subsequent soft-tissue examination using hte Wilson razor-blade sectioning technique. The remainder of the fetuses were prepared for skeletal examination. All gross, visceral and skeletal alterations observed were classified as malformations or developmental variations. Treatment and control groups were subjected to appropriate statistical comparison.
GLP compliance:
yes (incl. QA statement)
Limit test:
no
Species:
rat
Strain:
other: Charles River Crl:CD VAF/Plus
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Michigan
- Age at study initiation: 12.5 weeks
- Weight at study initiation: 243-312g
- Fasting period before study: no data
- Housing: individually in suspended stainless steel wire mesh cages
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 10 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 71-71 degrees F
- Humidity (%): 48-59%
- Air changes (per hr): controlled
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: From: February 7 To: February 24
Route of administration:
oral: gavage
Vehicle:
not specified
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:

DIET PREPARATION
- Rate of preparation of diet (frequency): weekly
- Mixing appropriate amounts with (Type of food): Purina Certified Rodent Chow #5002
- Storage temperature of food: room temperature


VEHICLE
- Justification for use and choice of vehicle (if other than water): vehicle used but no data
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
no data
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1/1
- Length of cohabitation: until evidence of copulatory plug (7 days maximum)
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: vaginal plug
- Any other deviations from standard protocol: no data
Duration of treatment / exposure:
On gestation days 6-15
Frequency of treatment:
Daily
Duration of test:
Until gestation day 20
Remarks:
Doses / Concentrations:
150, 1500 and 3000 mg/kg/day
Basis:
analytical conc.
No. of animals per sex per dose:
30 females
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale: prior range finding study (study 715-001)
- Rationale for animal assignment (if not random): random block
- Other:
Maternal examinations:
Animals were observed twice daily for mortality and signs of overt toxicity. Clinical observations were made from gestation days - 20. Individual body weights were recorded on gestation days 0, 6, 9, 12, 16 and 20. Individual food consumption was recorded concurrent with the body weighing days. Food consumption was calculated. On gestation day 20 all surviving animals were euthanized and immediately examined by cesarean section.
Ovaries and uterine content:
The uterus and overies were exposed and examined. The uterus was weighed. The location of viable and nonviable fetuses, early and late resorptions, and the number of total implantations and corpora lutea were recorded. The abdominal and thoracic cavities and organs were examined for grossly evident morphological changes. Uteri from nongravid females were placed in 10% ammonium sulfide solution for detection of implantations.
Fetal examinations:
Individual fetuses were weighed, sexed, and examined for external malformations and variations. Approximately one-half of the fetuses were placed in Bouin's solution for subsequent soft-tissue examination using hte Wilson razor-blade sectioning technique. The remainder of the fetuses were prepared for skeletal examination. All gross, visceral and skeletal alterations observed were classified as malformations or developmental variations.
Statistics:
Treatment and control groups were subjected to appropriate statistical comparison. Dunnett t-test for body wight, food consumption, numbers of corpora lutea, total implantations, live fetuses and mean fetal body weights. Chi-square or Fishers test for male to female sex ratios and proportion of litters with malformations and developmental variations. Kruskal-Wallis test for the proportion of resorbed and dead fetuses and postimplantation losses
Indices:
see "Statistics" above
Details on maternal toxic effects:
Maternal toxic effects:no effects

Details on maternal toxic effects:
One death occurred at the 1500 mg/kg/day dose but it was considered a gavage injury. No clinical observations or necropsy findings. No effects on body weight or body weight gain. There was a significant increase in food consumption for the 3000 mg/kg/day during gestation interval 12-16 but this was considered normal biological variation and not a direct effect of the test substance.
Key result
Dose descriptor:
NOAEL
Effect level:
> 3 000 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: other:
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
No indications of developmental toxicity including teratogenesis. All indices were comaparable to the corresponding controls.
Key result
Dose descriptor:
NOAEL
Effect level:
> 3 000 mg/kg bw/day
Based on:
test mat.
Sex:
not specified
Basis for effect level:
other:
Remarks on result:
other: No indications of developmental toxicity including teratogenesis
Abnormalities:
not specified
Developmental effects observed:
not specified
Conclusions:
The test substance did not induce developmental or teratogenic effects at doses up to 3000 mg/kg/day.
Executive summary:

Thirty (30) female rats received 0, 150, 1500 or 3000 mg test substance per kilogram body weight by oral gavage on days 6 to 15 of gestation. Clinical symptoms were noted daily through day 20. Body weight and food consumption were recorded every three days through day 20. All females were macroscopically examined on day 20. The uteri were removed, weighed and examined for number of corpora lutea, implant sites, and number and location of fetuses and resorptions. Fetuses were inspected on total number, sex, weight and external, visceral (one-half) and skeletal (one-half) defects. One death occurred at the 1500 mg/kg/day dose but it was considered a gavage injury. There were no abnormal clinical observations or necropsy findings. There were no effects on body weight or body weight gain. There was a significant increase in food consumption for the 3000 mg/kg/day dose during gestation interval (day) 12-16 but this was considered normal biological variation and not a direct effect of the test substance. All indices were comparable to the corresponding controls. The NOAEL based on active ingredient of the test substance is 936 mg/kg bw/day.

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
2003
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP study according to guideline. Although only summary available it has been peer internationally reviewed within OECD and assigned reliability 1.
Reason / purpose for cross-reference:
reference to same study
Qualifier:
according to guideline
Guideline:
other: OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
no
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
- male/female
- Age of animals at study: 9 weeks old for males and females
- Weight at study repeated dose toxicity: 325.8 - 363.1 g for males and 198.5 - 229.3 g for females
- Number of test animals: 60 animals for each sex
Route of administration:
oral: gavage
Vehicle:
not specified
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
Each male and female rat was selected from the same test group in order to copulate. It spent 14 days in terms of mating. The day after the copulating, mating would be determined through the observation of sperm in a vaginal rinse.
Duration of treatment / exposure:
Exposure period : 34, 36 - 45, and 51 days for male, copulated female and not copulated female animals, respectively.
Frequency of treatment:
Daily
Duration of test:
34-51, covering the full duration of pregnancy
Remarks:
Doses / Concentrations:
0, 150, 350 and 750 mg/kg/day
Basis:

No. of animals per sex per dose:
12 animals/sex/dose, plus 6 in 14-day recovery group/sex for control and high dose
Control animals:
yes, concurrent no treatment
Details on study design:
According to the preliminary test (Report No. P104), dose level was set to 0, 150, 350 and 750 mg/kg/day.
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily; mortality: twice/day
- Cage side observations checked in table [No.?] were included.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Weekly

BODY WEIGHT: Yes
- Time schedule for examinations: once a week and just before the necropsy, but in case of pregnant females, it was measured on the day 0, 7, 14, 20 of the gestation period, date of delivery, and 4 days of the lactation day.

FOOD CONSUMPTION:
- Food consumption: Yes: once a week except mating period

WATER CONSUMPTION: No
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Fetal examinations:
Body weight of pups
Examination of the external surface of pups: It was observed on the day of delivery and on the day 4 of lactation to determine abnormalities.
Statistics:
Statistical decision tree, but in case of recovery group, either two-side Student’s t-test or two-side Aspin-Welch t-test was used. In case of categorical data, two-sided Fisher’s exact test was used.
Indices:
Reproductive indices:
- Copulation index
- number of implantations
- number of corpus luteum
- Number of females pregnant
Offspring viability indices:
- Number of life pups
- post natal loss
- pre and post-implantation loss
Details on maternal toxic effects:
Maternal toxic effects:yes. Remark: at 150 mg/kg (lowest dose)

Details on maternal toxic effects:
CLINICAL SIGNS AND MORTALITY
No mortality males; in females 350 mg/kg: 2/12 and at 750 mg/kg: 4/18
In the control groups, there were no specific clinical symptoms during test period.
150 mg: Intermittent (blood-like) salivation and staining around mouth (3/18 males, 6/18 females), and in females at delivery: difficult delivery, poor nursing, irregular respiration, uterus introsusception and piloerection.
350 mg: Intermittent (blood-like) salivation and staining around mouth were observed after day 15 and (blood-like) staining around nose (7/12 males, 4/12 females). Iintermittent soft stool and staining around anorectal region were observed for the most male animals and in 2 females. One female showed difficult delivery, lacrimation, and irregular respiration from day 4.
750 mg: soft stool and staining around anorectal region for most males and all females; and 5 cases of loss of hair around tail region were observed. Intermittent (blood-like) salivation and 9 cases of staining around mouth and 9 cases of (blood-like) staining around nose. Soft stool and staining around anorectal region for all animals; some cases of intermittent diarrhea were observed. Some animals with found dead and in dying condition had symptoms such as irregular respiration, crawing position, hypoactivity, and abdominal swelling.
In the 750 mg/kg/day recovery group, salivation, staining around mouth, soft stool and staining around anorectal region were not observed during the recovery period.

BODY WEIGHT AND WEIGHT GAIN
From start of dosing BW gain at 750 mg/kg group a bit lower resulting to a lower BW of 8% in males and 5.5% in females compared to controls during first week of recovery which partly recovered during the second week of the recovery period.

FOOD CONSUMPTION:
Only during the first week food consumption some somewhat lower in the 750 mg group.

HAEMATOLOGY
No major changes were seen compared to control, although the reported that dose related decrease in RBC and HCT and an increase in platelet counts were observed in males.

CLINICAL CHEMISTRY
In males and females BUN is decreased compared to control at 750 mg/kg but not in the recovery groups. Total cholesterol was decreased in the recovery groups. In females chloride is decreased at 750 mg/kg.

NEUROBEHAVIOUR
No significant effects were found.

ORGAN WEIGHTS
No effects were seen in sex-organ weights. Weight of the spleen was increased in treatment groups compared to controls for both males and females, although in females not relative weight. No differences in spleen weights were seen in recovery groups. In males the absolute, but not the relative, weight of the heart was decreased in the 750 mg/kg group. In the female recovery group the weights for adrenal and the brain were increased.

GROSS PATHOLOGY
No information provided.

HISTOPATHOLOGY:
dose related effects of epithelial proliferation and inflammation of the forestomach already visible in animals treated at 150 mg.
Dose descriptor:
NOAEL
Effect level:
750 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: developmental toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
Number of pups born, viability and sex ratio: No significant difference was observed between the treatment groups and the control group at the time of the delivery and on the day 4 of the lactation.
External examination of pups (group) showed no developmental abnormalities.
Abnormalities:
not specified
Developmental effects observed:
not specified

Body weights of pups (group)

Group 

Sex 

Pup BW at birth

At lactation day 4

Male

Female

Male

Female

0

 Mean 

6.25

5.75

8.57

8.03

 SD 

0.6

0.66

1.26

1.18

 N 

67

69

66

69

150

 Mean 

5.99

5.62

8.56

7.98

 SD 

0.56

0.46

1.34

1.27

 N 

62

70

63

66

350

 Mean 

6.37

5.73

9.71

8.59

 SD 

0.9

0.8

2.17

1.57

 N 

59

48

55

44

750

 Mean 

5.98

5.59

8.7

8.21

 SD 

0.6

0.51

0.87

0.74

 N 

48

51

46

49

 

External examination of pups (group)

Group

No.
of
animals

 At birth

No.
of
animals

Lactation day 4

No.of pups examined

No.of pups

Obser-vations 

No.of pups examined

No.of pups

Obser-vations 

0

11

143

140

 NGF 

11

136

134

 NGF 

 

 

 

2

 BT 

 

 

2

 BT 

 

 

 

1

 Runt 

 

 

 

 

150

11

143

144

 NGF 

11

129

129

 NGF 

350

10

116

116

 NGF 

9

100

100

 NGF 

750

9

105

105

 NGF 

8

95

95

 NGF 

NGF: No Gross findings

BT: Blunt-tipped Tail

Conclusions:
There were no reproductive or developmental effects seen at 750 mg/kg, the highest dose tested
Executive summary:

Tosyl chloride has been evaluated in a Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test according to OECD 422 and in compliance to GLP.

Tosyl chloride was dose by gavage to groups of 12 Sprague-Dawley rats/sex/dose level at levels of 0, 150, 350 and 750 mg/kg/day for 35 days and 36 - 51 days for male and female rats, respectively. A separate group of 6 animals/sex were added for a 14-day recovery group to the control and the high dose groups.

Results:

Parental toxicity: No mortality males; in females 350 mg/kg: 2/12 and at 750 mg/kg: 4/18.

Some clinical signs were observed at the dose level of 150 mg/kg/day in both male and females such as intermittent (blood-like) salivation and staining around mouth. Effects were more severe at 350 mg/kg and at 750 mg/kg reported clinical signs were soft stool and staining around anorectal region for most males and all females; and 5 cases of loss of hair around tail region were observed. Intermittent (blood-like) salivation and 9 cases of staining around mouth and 9 cases of (blood-like) staining around nose. Soft stool and staining around anorectal region for all animals; some cases of intermittent diarrhea were observed. A decreased BW gain was observed in the 750 mg group resulting to a lower BW that was maximal 8% lower in males and 5.5% in females compared to controls. Food consumption was a bit lower during the first week in the 750 mg group. Histopathology showed dose related effects of epithelial proliferation and inflammation of the forestomach already visible in animals treated at 150 mg.

There were no further major changes observed in other parameters (haematology, biochemistry, neurobehavioral functions, organ weights)

In the 750 mg/kg/day recovery group, salivation, staining around mouth, soft stool and staining around anorectal region were not observed during the recovery period.

 

Reproductive parameters were not affected.No effects were seen between the groups in duration of pregnancy, number of corpus luteum, number of implantation, pre-implantation loss, post-implantation loss. There was no significant difference between the control and treatment group in terms of copulation, fertility and gestation index.

Also the BW of the pups and external examination of pups (group) on post-natal day 1 and 4 show no effects.

Consequently the NOAEL for developmental effects was stated to be above the highest tested dose (750 mg/kg/day)

Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
Also attached :

Category of Aromatic Sulphonic Acids (ASA)

The aromatic sulphonic acids category consists of the following five (5) substances:

• Benzene sulphonic acid (CAS No. 98-11-3)
• 4-hydroxybenzene sulphonic acid (CAS No. 98-67-9)
• Toluene-4-sulphonic acid (CAS No. 104-15-4)
• Xylene sulphonic acid (CAS No. 25321-41-9)
• p-cumene sulphonic acid (CAS No. 16066-35-6)


Sulphonic acids are a class of organic acids with the general formula R-S(=O)2-OH, where R is usually a hydrocarbon (aromatic) side chain. The sulphonic acids are strong acids and in watery environments they are almost completely ionized even at low pH.

The five aromatic sulphonic acids in this category are chemically related and quite similar. Benzenesulphonic acid is an organic compound with the formula C6H5SO3H. It is the simplest aromatic sulphonic acid. Benzene with a hydroxyl group is hydroxybenzene (or phenol). Benzene with a methyl group is toluene. Benzene with two methyl groups is xylene. And benzene with an isopropyl group is cumene.
Acidity of the sulphonic acid group is influenced by two factors:

1. The substitution group exerts an electron donating effect and so makes the negative charge on the resulting sulphonate ion, after deprotonation, more or less stable.
2. The resonance effect stabilizes the negative charge on the sulphonate ion by dividing the charge on the oxygen atoms.

As a result, the acidity of the sulphonic acid group is not expected to change significantly among the five aromatic sulphonic acids. The measured pKa values confirm this expectation: 2.68 for benzene sulphonic acid, 2.50 for hydroxybenzene sulphonic acid, 2.96 for toluene-4-sulphonic acid, 2.88 for xylene sulphonic acid and 3.17 for cumene sulphonic acid. Thus the reactivity of the sulphonic acids are very similar and they can each be used as a surrogate for the others.
A full set of 2010 guideline physical-chemical studies demonstrates the similar chemical and physical properties and behavior of the 5 sulphonic acids in the category.
The sulphonic acid moiety is the primary driver for mammalian toxicity and any difference between the benzene, xylene, cumene, and toluene moieties would be insignificant given the relatively high level of corrosivity of all five substances in the category.
As noted, the aromatic sulphonic acids are almost completely ionized in watery environments.
These acids are precursors to hydrotropes (or “sulphonates”) which include ammonium, calcium, potassium and sodium salts. Because of the chemical similarities and because much of the production of the aromatic sulphonic acids goes to manufacturing the salts, the extensive database for the hydrotropes is also used as a source of read-across for some of the endpoints in this aromatic sulphonic acid dossier.

Read across from Hydrotropes to Aromatic Sulphonic Acids
The studies with the salts (hydrotropes) provide valid read-across for the acids. The specific cation is not expected to have an appreciable effect on fate, ecotoxicity or mammalian toxicity and therefore the dataset for the entire hydrotropes category can be applied broadly.
The aromatic sulphonic acids are almost completely ionized in watery environments even at low pH. The salts of these acids are the hydrotropes (or “sulphonates”) which include ammonium, calcium, potassium and sodium cations. In principle the salts get dissociated when in contact with water, so forming back to the acids. Because of their close chemical similarities and because much of the production of the aromatic sulphonic acids goes to manufacturing the salts, the extensive dataset for the hydrotropes can also be used as a source of read-across for endpoints in an aromatic sulphonic acid dossier. This is particularly relevant for studies that are conducted in water (e.g., ecotoxicity and biodegradation) as well as for mammalian toxicity studies where the relatively high acidity of the acid form has an immediate and harsh local effect, whereas the salt form provides an indication of potential systemic toxicity beyond the site of application or initial contact


Reason / purpose for cross-reference:
read-across source
Details on maternal toxic effects:
Maternal toxic effects:no effects

Details on maternal toxic effects:
One death occurred at the 1500 mg/kg/day dose but it was considered a gavage injury. No clinical observations or necropsy findings. No effects on body weight or body weight gain. There was a significant increase in food consumption for the 3000 mg/kg/day during gestation interval 12-16 but this was considered normal biological variation and not a direct effect of the test substance.
Key result
Dose descriptor:
NOAEL
Effect level:
> 3 000 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: other:
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
No indications of developmental toxicity including teratogenesis. All indices were comaparable to the corresponding controls.
Dose descriptor:
NOAEL
Effect level:
> 3 000 mg/kg bw/day
Based on:
test mat.
Sex:
not specified
Basis for effect level:
other:
Remarks on result:
other: No indications of developmental toxicity including teratogenesis
Abnormalities:
not specified
Developmental effects observed:
not specified
Conclusions:
The test substance Calcium xylene sulponate did not induce developmental or teratogenic effects at doses up to 3000 mg/kg/day. This conclusion is read acrossed to p-Toluene sulfonyl chloride.
Executive summary:

Thirty (30) female rats received 0, 150, 1500 or 3000 mg test substance per kilogram body weight by oral gavage on days 6 to 15 of gestation. Clinical symptoms were noted daily through day 20. Body weight and food consumption were recorded every three days through day 20. All females were macroscopically examined on day 20. The uteri were removed, weighed and examined for number of corpora lutea, implant sites, and number and location of fetuses and resorptions. Fetuses were inspected on total number, sex, weight and external, visceral (one-half) and skeletal (one-half) defects. One death occurred at the 1500 mg/kg/day dose but it was considered a gavage injury. There were no abnormal clinical observations or necropsy findings. There were no effects on body weight or body weight gain. There was a significant increase in food consumption for the 3000 mg/kg/day dose during gestation interval (day) 12-16 but this was considered normal biological variation and not a direct effect of the test substance. All indices were comparable to the corresponding controls. The NOAEL based on active ingredient of the test substance is 936 mg/kg bw/day.

Based on the results of this study, the following NOAEL of Calcium xylene sulphonate was established, and read acrossed to p-Toluene Sulfonyl Chloride:

Developmental NOAEL 936 mg/kg bw/day.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
936 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
Most relevant GLP compliant study available, evaluating developmental toxicity, based on cross-reading.
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

Tosyl chloride has been evaluated in a Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test according to OECD 422 and in compliance to GLP. (See under reproduction toxicity)

Reproductive parameters were not affected. No effects were seen between the groups in duration of pregnancy, number of corpus luteum, number of implantation, pre-implantation loss, post-implantation loss. There was no significant difference between the control and treatment group in terms of copulation, fertility and gestation index.Also the BW of the pups and external examination of pups (group) on post-natal day 1 and 4 show no effects.

Consequently the NOAEL for developmental effects was stated to be above the highest tested dose (750 mg/kg/day)

 

Tosyl chloride rapidly hydrolyses intoToluene-4-sulphonic acid and HCl, both strong acids. Systemic exposures will therefore actually be on Toluene-4-sulphonic acid. Consequently, cross-reading from Toluene-4-sulphonic acid for longer term repeated dose studies such as fertility and developmental toxicity can be applied. For Toluene-4-sulphonic acid, studies from the chemically related hydrotropes category are being recommended as read across for this endpoint. The following information is available for these substances:

 

A developmental toxicity study comparable to OECD 414 was performed with on the structurally related substance Calcium xylenesulphonate.

In the developmental toxicity study, thirty (30) female rats received 0, 150, 1500 or 3000 mg test substance per kilogram body weight by oral gavage on days 6 to 15 of gestation. Clinical symptoms were noted daily through day 20. Body weight and food consumption were recorded every three days through day 20. All females were macroscopically examined on day 20. The uteri were removed, weighed and examined for number of corpora lutea, implant sites, and number and location of foetuses and resorptions. Foetuses were inspected on total number, sex, weight and external, visceral (one-half) and skeletal (one-half) defects. One death occurred at the 1500 mg/kg/day dose but it was considered a gavage injury. There were no abnormal clinical observations or necropsy findings. There were no effects on body weight or body weight gain. There was a significant increase in food consumption for the 3000 mg/kg/day dose during gestation interval (day) 12-16 but this was considered normal biological variation and not a direct effect of the test substance. All indices were comparable to the corresponding controls. The NOAEL based on active ingredient of the test substance is 936 mg/kg bw/day.(On molar basis equivalent to 870 mg Tosyl chloride/kg bw.

 

The available data indicate a low concern for developmental toxicity for Tosyl chloride. An OECD 422 screening study indicated no effects on any reproductive parameter up to 750 mg/kg, the highest dose tested. It should be remarked that this levels is 5 times the LOAEL level of 150 mg/kg based on local gastro-intestinal irritation with specific marked effects in the nonglandular stomach seen at this dose level. Also cross-reading to developmental toxicity study comparable to OECD 414 on a comparable structure does not indicate a concern for developmental toxicity. When further considering the low likelihood of exposures followingthe use as a chemical intermediate in industrial or professional settings and as result of its physical-chemical properties, there is no need for further testing.

Justification for selection of Effect on developmental toxicity: via oral route:

Most relevant available study evaluating developmental toxicity, based on cross-reading.

Justification for selection of Effect on developmental toxicity: via inhalation route:

Not preferred route for testing (See fertility)

Justification for selection of Effect on developmental toxicity: via dermal route:

Not preferred route for testing (See fertility)

Justification for classification or non-classification

Available data do not indicate a concern for reproduction or developmental toxicity.

Additional information