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Administrative data

Description of key information

Value used for CSA (route: oral):

NOAEL: 200 mg/kg bw/day (subchronic; rat)

Value used for CSA (route: dermal):

NOAEL: 250 mg/kg bw/day (subacute; rat)

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
200 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Klimisch code 1 (reliable without restriction)

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
250 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
Klimisch code 1 (reliable without restriction)

Additional information

Oral:

Key Study 1:

In the study for repeated dose toxicity, oral exposure, a study (Lamb, 1993) was conducted to the OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test) and GLP. A reliability rating of 1 was assigned according to the criteria of Klimisch, 1997. Based upon the results of this study, the apparent NOAEL (no observable adverse effect level) for parental toxicity was considered to be 200 mg/kg/day. Equivocal prenatal toxicity was observed at a dose level of 200 mg/kg/day.

Key Study 2:

A repeated dose toxicity, oral exposure study (Haas, 2010), was conducted to the OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents) and GLP. A reliability rating of 1 was assigned according to the criteria of Klimisch, 1997. Based upon the results this study, the no-observed-effect level (NOEL) was 125 mg/kg/day based on lower body weights and body weight gains at dose levels ≥ 250 mg/kg/day. Given that clinical observations, macroscopic and microscopic examinations, food consumption, hematology and serum chemistry parameters, and organ weights were unaffected by test substance administration and body weight effects were considered non-adverse, the NOAEL was considered to be 1000 mg/kg/day. The pituitary weight, a key effect noted in the Lamb study and the Nemec study (see Reproductive Toxicity Section for more details), was not measured in this study.

 

Although Key Study 1 (Lamb, 1993) was a screening study, its findings of parental systemic effects (increased pituitary weight, with a NOAEL of 200 mg/kg bw/day) were confirmed by a 2-generation reproductive study (Nemec, 1995), where an increase in pituatiry weight was also observed.

 Dermal:

In the key study for repeat dose toxicity, dermal exposure (Korenagaet al, 1986, report number: SOCAL 2319), the study was conducted to the OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study) and GLP. A reliability rating of 1 was assigned according to the criteria of Klimisch, 1997.

Supporting studies available:

- The Biodynamics study, 1981 was not considered the key study as it was conducted less recently than the above key study, there was no GLP data and no guideline was specified although it seems similar to OECD 410 with deviations. Deviations are as follows: Only 2 dose groups were used, dressing was only a paper towel, not gauze as specified in the OECD guideline and the test site was wiped with a paper towel, no solvent used to remove test material. A reliability rating of 2 was assigned according to the criteria of Klimisch, 1997.

Treatment-related effects were evident in the low- and high-dose males treated with the test material as indicated by marked, statistically significant, dose-related decreases in the absolute and relative (organ/body weight ratios) weights of the testes (absolute weight decreases of approximately 70% and 80%) and epididymides (absolute weight decreases of approximately 40% and 50%) at the end of the treatment period.

The results of the microscopic examinations indicated that the topical administration of 25% and 100% (w/v) of the test material, for the period used in this study, causes topical irritating skin lesions in both male and female rabbits. Male rabbits, receiving 25% and 100% (w/v) of the test material, had an increased incidence of aspermatogenesis, reduced numbers of spermatids and a diffuse tubular hypoplasia when compared to control males. These changes had not completely resolved themselves in the four week recovery rabbits receiving 25% and 100% (w/v) of the test material.

- The Biodynamics study, 1983 was not considered the key study as it was conducted less recently than the above key study and no guideline was specified although it seems similar to OECD 410 with deviations. Deviations are as follows: Only 2 dose groups were used there was no data on dressing or removal of test material at the test site and only males were used in this study, OECD specifies 5 males/females per dose. A reliability rating of 2 was assigned according to the criteria of Klimisch, 1997.

Increased incidence of desquamation, red raised pustules and red raised areas of eschar noted in the high dose group animals when compared to the control group animals. At necropsy, 2 animals in each of the treated groups were noted to have scabs, sores or necrotic areas on the dorsal cervical skin.

The Group 2 animals showed an increase in mean epididymal weights while the group 3 animals showed a decrease in mean epididymal weights when compared to control group animals. These findings are statistically significant.

Total bilirubin and total protein levels were decreased in group 2 animals when compared to the control group values. Total bilirubin and glucose levels and the albumin/globulin ratio were decreased in Group 3 animals when compared to the control group animals. These findings are statistically significant.

Inhalation:

In accordance with column 2 of REACH Annex XI, section 8.6, it is considered justifiable to omit the acute toxicity: inhalation study. The substance only exists in liquid form and it will not be aerosolized in its normal use pattern and does not exist as small particles or droplets. As such testing via the inhalation route is not considered appropriate for this substance.

 

The following information is taken into account for any hazard / risk assessment:

Oral:

Based upon the results of the Lamb study (1993), the apparent NOAEL (no observable adverse effect level) for parental toxicity was considered to be 200 mg/kg/day, based on systemic parental toxicity (increased pituitary weight) and neonatal toxicity.

Dermal:

The actual doses received were approximately 0, 20, 100 and 250 mg/kg b. wt. /day.

Repeated dermal applications of the test material caused no observable toxicity, with the exception of a slightly increased incidence and severity of skin irritation when compared to controls.

NOAEL is approximately >250 mg/kg b. wt. /day males and female rats, highest dose tested.

Justification for classification or non-classification

Oral:

The key parameter chosen for repeated dose toxicity for the oral route was greater than the criteria set out in Directive 67/548/EEC and also Regulation (EC) no 1272/2008, therefore classification for repeat dose toxicity was not considered to be necessary.

Dermal:

Classification according to Directive 67/548/EEC and Regulation (EC) 1272 /2008 could not be determined as the highest dose tested was less than the cut off criteria and was a greater than result.

However, it should be noted that there was no signs of toxicity seen at the highest dose tested (250 mg/kg) and it would be unlikely that classification would be necessary as the molecular weight is expected to be >500, and also the high log Kow (9.4) would suggest that entry via the dermal route is unlikely as maximum absorption is generally between log Kow 1 and 2 and therefore the substance is too lipophilic to be readily absorbed.